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Targeted therapy shrank tumors, shows promise in improving survival

Medical oncologist and senior author of a new lung cancer study, Ramaswamy Govindan, MD, of Washington University School of Medicine in St. Louis, talks about the newly FDA-approved drug sotorasib. The new study shows that sotorasib benefits some patients who have non-small-cell lung cancer that has a specific mutation in the KRAS gene. Ongoing clinical trials for lung cancer patients are investigating combinations of sotorasib plus other experimental drugs.

The new drug sotorasib reduces tumor size and shows promise in improving survival among patients with lung tumors caused by a specific DNA mutation, according to results of a global phase 2 clinical trial. The drug is designed to shut down the effects of the mutation, which is found in about 13% of patients with lung adenocarcinoma, a common type of non-small-cell lung cancer.

The Food and Drug Administration approved sotorasib May 28 as a targeted therapy for patients with non-small-cell lung cancer whose tumors express a specific mutation called G12C in the KRAS gene and who have undergone at least one previous therapy for their cancer.

Non-small-cell lung cancer makes up over 80% of all lung cancers. More than 200,000 new cases of non-small-cell lung cancer are diagnosed annually in the United States.

The study, led by researchers at Washington University School of Medicine in St. Louis, Perlmutter Cancer Center at NYU Langone Health in New York, MD Anderson Cancer Center in Houston, and Memorial Sloan Kettering Cancer Center in New York, will be presented June 4 at the annual meeting of the American Society of Clinical Oncology and published the same day in The New England Journal of Medicine.

Sotorasib, also known by the brand name Lumakras, is made by Amgen, which funded the trial.

This is a group of patients whose tumors have been difficult to treat and for whom we did not have targeted therapies, said co-senior author and medical oncologist Ramaswamy Govindan, MD, the Anheuser Busch Endowed Chair in Medical Oncology at Washington University. The new drug is addressing an unmet need for these patients, targeting the most common mutation that we can go after. Were also continuing to investigate this drug in combination with other experimental drugs to see if we can further improve responses and survival.

The study involved 126 patients with non-small-cell lung cancer that had a specific mutation in the KRAS gene. A single DNA error swaps out an important protein building block, placing a cysteine where a glycine should be. Tumors with the mutation manufacture a version of the KRAS protein that is almost constantly active, driving tumor growth. Sotorasib, taken daily by mouth, blocks tumor growth by trapping the KRAS protein in its inactive form.

Most patients in the trial previously had been treated with standard chemotherapy along with an immunotherapy drug that targets a protein called PD-1. To evaluate this new therapy, all patients enrolled in the study were treated with sotorasib; phase 2 trials evaluating safety and effectiveness often do not include a placebo group.

The drug caused at least some tumor shrinkage in 102 out of 126 patients (82%). About 37% of the patients tumors reduced in size at least 30%. In contrast, response rates to standard therapy in these patients range from 6% to 20%.

Forty-two patients tumors (34%) showed a partial response to the therapy, meaning the tumor shrank substantially and its growth was controlled for a period of time; and four patients (3%) showed a complete response that left no evidence of disease. For tumors that shrank, the tumor size was reduced by about 60%, on average.

A new study led by Washington University School of Medicine in St. Louis shows that the new drug sotorasib benefits many patients with non-small-cell lung cancer with a specific mutation in the KRAS gene. In a small subset of patients, the drug eliminated all evidence of the tumors. Pictured on the left is a scan showing a lung tumor (yellow circle) that has spread to the muscle. The image on the right shows the same patient after two months of sotorasib therapy. No tumor is visible in the yellow circle on the right.

The effects of sotorasib lasted an average of 11 months, and the drug also showed progression-free survival meaning the tumor did not continue growing during this time of almost seven months. In contrast, patients with this lung cancer who receive standard therapy have an average progression-free survival of two to four months. The average overall survival for all patients in the trial was 12 months.

We are hopeful that this approach will be a new option for patients with lung cancer driven by this specific type of KRAS gene alteration, said Govindan, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. KRAS gene alterations have long been considered not amenable for targeted therapies. A number of combination regimens are being tested here at the Siteman Cancer Center and at other leading cancer centers around the world. This highlights work that Washington University has excelled at over the past few decades studying the genomic alterations in tumors with the goal of identifying treatment targets. This early cancer genome research is now coming full circle to help our patients.

Govindan and his team have led pioneering studies to define genomic alterations in lung cancer, including making key contributions to The Cancer Genome Atlas, a national effort supported by the National Institutes of Health (NIH).

The excitement surrounding this trial result is that sotorasib is now the first targeted therapy for lung cancer patients with KRAS mutations, said co-corresponding author Vamsidhar Velcheti, MD, of NYU Langone Health. KRAS-targeted treatments, decades in the making, are urgently needed for these patients with limited treatment options.

About 7% of patients stopped sotorasib treatment because of severe side effects, but no side effects were life-threatening, and no patient died as a result of the treatment. The drug caused adverse events severe enough to require a reduced dose of the drug in about 22% of patients. Almost 70% of patients experienced side effects of some kind related to the drug; the most common were diarrhea, fatigue, nausea and increased liver enzyme levels, the latter an indicator of liver damage.

Sotorasib showed clinically significant benefit without any new safety concerns in patients with this specific form of KRAS mutant lung cancer, Govindan said. Moving forward, our team will seek to inform the development of combination therapies featuring sotorasib and other emerging drugs, and to determine which best fit the mix of mutations in each patients cancer cells.

The researchers currently are conducting a phase 3 clinical trial comparing the effectiveness of sotorasib with a chemotherapy drug called docetaxel in 345 patients who have non-small-cell lung cancer and this specific KRAS mutation.

This work was supported by Amgen, which makes sotorasib. This work also was supported in part by the National Institutes of Health (NIH) Cancer Center Core at Memorial Sloan Kettering Cancer Center, grant number P30 CA008748.

Velcheti, of New York University, is a paid consultant for Amgen.

Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, Italiano A, Schuler M, Borghaei H, Barlesi F, Kato T, Curioni-Fontecedro A, Sacher A, Spira A, Ramalingam SS, Takahashi T, Besse B, Anderson A, Ang A, Tran Q, Mather O, Henary H, Ngarmchamnanrith G, Friberg G, Velcheti V, Govindan R. Sotorasib for lung cancers with KRAS p.G12C mutations (CodeBreak 100). The New England Journal of Medicine. June 4, 2021.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, consistently ranking among the top medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Newly approved drug effective against lung cancer caused by genetic mutation Washington University School of Medicine in St. Louis - Washington...

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Nanofiber device allows insulin to be released while defending against immune cells

Researchers at Washington University School of Medicine in St. Louis and Cornell University have collaborated to implant insulin-secreting beta cells grown from human stem cells into mice with diabetes, to normalize their blood sugar. The cells pictured (in purple) are inside a tiny implant that is porous enough to allow these cells to secrete insulin yet small enough to prevent immune cells from accessing and destroying them.

A team of researchers led by diabetes specialists and biomedical engineers at Washington University School of Medicine in St. Louis and Cornell University has demonstrated that, using a miniscule device, they can implant insulin-secreting cells into diabetic mice. Once implanted, the cells secrete insulin in response to blood sugar, reversing diabetes without requiring drugs to suppress the immune system.

The findings are published June 2 in the journal Science Translational Medicine.

We can take a persons skin or fat cells, make them into stem cells and then grow those stem cells into insulin-secreting cells, said Jeffrey R. Millman, PhD, an associate professor of medicine at Washington University and one of the studys co-senior investigators. The problem is that in people with Type 1 diabetes, the immune system attacks those insulin-secreting cells and destroys them. To deliver those cells as a therapy, we need devices to house cells that secrete insulin in response to blood sugar, while also protecting those cells from the immune response.

In previous research, Millman, also an associate professor of biomedical engineering, developed and honed a method to make induced pluripotent stem cells, and to then grow those stem cells into insulin-secreting beta cells. Millman previously used those beta cells to reverse diabetes in mice, but it was not clear how the insulin-secreting cells might safely be implanted into people with diabetes.

The device, which is about the width of a few strands of hair, is micro-porous with openings too small for other cells to squeeze into so the insulin-secreting cells consequently cant be destroyed by immune cells, which are larger than the openings, said Millman. One of challenges in this scenario is to protect the cells inside of the implant without starving them. They still need nutrients and oxygen from the blood to stay alive. With this device, we seem to have made something in what you might call a Goldilocks zone, where the cells could feel just right inside the device and remain healthy and functional, releasing insulin in response to blood sugar levels.

Millmans laboratory worked with researchers in the lab of Minglin Ma, PhD, an associate professor of biomedical engineering at Cornell. Ma has been working to develop biomaterials that can help implant beta cells safely into animals and, eventually, people with Type 1 diabetes.

Several implants have been tried in recent years, with varying levels of success. For this study, Ma, the studys other co-senior investigator, and his colleagues developed what they call a nanofiber-integrated cell encapsulation (NICE) device. They filled the implants with insulin-secreting beta cells that had been manufactured from stem cells and then implanted the devices into the abdomens of mice with diabetes.

The combined structural, mechanical and chemical properties of the device we used kept other cells in the mice from completely isolating the implant and, essentially, choking it off and making it ineffective, Ma said. The implants floated freely inside the animals, and when we removed them after about six months, the insulin-secreting cells inside the implants still were functioning. And importantly, it is a very robust and safe device.

The cells in the implants continued to secrete insulin and control blood sugar in the mice for up to 200 days. And those cells continued to function despite the fact that the mice were not treated with anything to suppress their immune systems.

Wed rather not have to suppress someones immune system with drugs, because that would make the patient vulnerable to infections, Millman said. The device we used in these experiments protected the implanted cells from the mices immune systems, and we believe similar devices could work the same way in people with insulin-dependent diabetes.

Millman and Ma are reluctant to predict how long it might be before such a strategy could be employed clinically, but they plan to continue working toward that goal.

Wang X, et al. A nanofibrous encapsulation device for safe delivery of insulin-producing cells to treat type 1 diabetes. Science Translational Medicine, published online June 2, 2021.

This work was supported by the Novo Nordisk Co., the Hartwell Foundation and by the Juvenile Diabetes Research Foundation. Additional funding from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH), grant numbers R01 DK105967, 5R01 DK114233 and T32 DK108742.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, consistently ranking among the top medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Tiny implant cures diabetes in mice without triggering immune response Washington University School of Medicine in St. Louis - Washington University...

Pediatric and young adult patients with refractory cancers did not experience clinical activity with selumetinib, according to findings from the phase 2 National Cancer Institute (NCI)-Childrens Oncology Group (COG) Pediatric MATCH Trial (NCT03155620). Cohort findings from the trial were recently presented at the 2021 ASCO Annual Meeting.1

Although the agent was well tolerated, no objective responses were observed with selumetinib. Three patients achieved stable disease with the agent, while 15 patients had progressive disease. One patient was not RECIST classifiable, and 1 patient was not evaluable. Additionally, the 6-month progression-free survival (PFS) rate was 15% (95% CI, 4%-34%).

Selumetinib was generally well tolerated in this cohort of children, who had diverse treatment-refractory cancers. Unfortunately, no objective responses were observed, Olive S. Eckstein, MD, of Texas Childrens Hospital/Baylor College of Medicine and an investigator on the trial, said in a presentation during the meeting. The big point to discuss and to think about in the future, when we design these trials, is histology and mutation status. We learned here that MAPK pathway mutation status alone is insufficient to predict response to selumetinib monotherapy.

Although pediatric cancers harbor targetable molecular alterations that cross multiple disease histologies, similar to adult malignancies, the low frequency of individual gene alterations makes evaluating targeted agents in pediatric tumors challenging, Eckstein explained.

Several malignancies have been known to have a high frequency of MAPK pathway mutations, such as RAS (hairy cell leukemia, melanoma, and papillary thyroid cancer), BRAF (hairy cell leukemia, melanoma, Langerhans Cell Histiocytosis, and papillary thyroid cancer), and MEK1/2 (colorectal cancer, glioma, Langerhans Cell Histiocytosis, and ovarian cancer). Of these pathway mutations, RAS is the most frequently observed, at 22%, followed by BRAF (7%), MEK1/2 (<1%), and ERK (rare).

Selumetinib is a potent, orally bioavailable selective inhibitor of MEK1/MEK2 that blunts the RAS-RAF-MEK1/2-ERK cascade, reduces cell proliferation, and promotes pro-apoptotic signal transduction. The TKI has previously shown efficacy in the phase 1 Pediatric Brain Tumor Consortium trial in low-grade gliomas; 2 because of these data, investigators chose to not include this patient subgroup in this screening protocol.

Selumetinib is also approved by the FDA for the treatment of patients with plexiform neurofibroma who are aged 2 years or younger.

The data presented at during 2021 ASCO Annual Meeting were part of the NCI-COG Pediatric MATCH trial (APEC1621SC), which facilitates molecular profiling of treatment-refractory cancers in US pediatric and young adult patients. Patients between the ages of 1 year and 21 years with refractory solid tumors, lymphomas, and histiocytosis had to have measurable disease and adequate performance status.

Patients had their tumors biopsied before moving onto the screening protocol for tumor sequencing. If actionable mutations in the RAS/RAF/MAPK1/2-ERK pathway were detectedNF1, NRAS, KRAS, HRAS, ARAF, MAP2K1, GNA11, GNAQ mutations or BRAF mutations or fusionpatients were enrolled on the selumetinib subprotocol of pediatric MATCH (APEC1621E), arm E of the trial, which is designed to test the tolerability and efficacy of selumetinib in children with relapsed tumors, which contain molecular MAPK pathway alterations.

Also, on this subprotocol, patients needed to meet standard phase 2 protocol criteria, consisting of organ function and washout periods. FFPE tumor samples were centrally processed, and Targeted Oncomine was harmonized and performed in 3 laboratories.

Selumetinib monotherapy was administered orally at 25 mg/m2 twice daily, with a maximum dose of 75 mg/m2 for up to 2 years in 28-day cycles. Responses were evaluated every other cycle for 3 occurrences, and then every 3 cycles.

Eckstein noted that the trial would have potential for histology-specific expansion cohorts if objective responses were observed in at least 3 patients with the same histology.

The primary end point of the study was ORR; secondary end points included PFS and tolerability.

Twenty-one patients were enrolled on the trial, and 20 were eligible for selumetinib treatment. One patient was deemed ineligible because they had low-grade glioma. The median age was 14 years (range, 5-21 years), and 50% of patients were male. Most patients (n = 15) were Caucasian, and 1 patient each was African American, Asian, and Native American. Two patients ethnicities were not reported.

Eleven hotspot mutations were found in RAS genes: KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1); 7 patients had inactivating NF1 mutations, and 2 patients had activating missense mutations in BRAF V600E.

The most common tumor histology subtypes were central nervous system astrocytoma (n = 7), of which there were BRAF mutations (n = 2), NF1 (n = 2), KRAS (n = 1), NF1 plus PTEN (n = 1), and KRAS plus NF1 (n = 1); and rhabdomyosarcoma, of which were had NRAS mutations (n = 2), KRAS (n = 4), and HRAS mutations (n = 1).

Additional tumor histologies were carcinoma (n = 2), neuroblastoma, plexiform neurofibroma, Yolk sac tumor, and other sarcoma (n = 1 each). Carcinoma harbored 1 mutation each of KRAS and NF1, neuroblastoma of 1 NRAS mutation, plexiform neurofibroma of NF1 plus BRCA2, Yolk sac tumor of 1 KRAS, and other sarcoma of 1 NF1 mutation.

The median number of completed cycles was 2 (range, 1-13), and the data cutoff date was December 31, 2020.

Of the 3 patients with SD, 1 had high-grade NF1-PTENmutant glioma and had received 6 cycles of treatment until disease progression, the second had high-grade KRAS-mutant glioma and received 12 cycles until experiencing disease progression, and the third had NF1-BRCA2mutant plexiform neurofibroma and was treated for 13 cycles until experiencing grade 4 elevated creatine kinase (CPK) elevation.

Adverse effects that were potentially linked with selumetinib therapy included lymphopenia, uveitis, and thromboembolic event (n = 1 each; all grade 3), elevated CPK (n = 1; grade 4), and thromboembolic event through pulmonary embolism that led to death (n = 1; grade 5). The patient who died had adenocarcinoma and was on treatment for 11 days.

Future directions should focus on identifying histologic, molecular, and clinical features of responder and non-responders with gliomas, as well to determine biological features for predictive response to MEK inhibitors as single agents and exploring the synergy with selumetinib or other MEK inhibitors in combination with targeted or cytotoxic agents, Eckstein concluded.

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MAPK Expression Does Not Drive Selumetinib Response in Refractory Pediatric and AYA Cancers - Cancer Network

SAN FRANCISCO and SUZHOU, China, June 3, 2021 /PRNewswire/ --Innovent Biologics, Inc. (Innovent) (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of cancer, metabolic, autoimmune and other major diseases, and Eli Lilly and Company (NYSE: LLY) today jointly announced that the National Medical Products Administration (NMPA) of China has approved the supplemental New Drug Application (sNDA) for TYVYT (sintilimab injection) in combination with gemcitabine and platinum chemotherapy as first-line therapy for people with unresectable locally advanced or metastatic squamous non-small cell lung cancer (sqNSCLC).

This is the third NMPA-approved indication of TYVYT (sintilimab injection), following the approval in December 2018 for the treatment of relapsed or refractory classical Hodgkin's lymphoma, and the approval in February 2021 for the first-line treatment of nonsquamous non-small cell lung cancer (nsqNSCLC). This is also the first regulatory approval of a PD-1/PD-L1 immunotherapy in combination with gemcitabine and platinum chemotherapy for the first-line treatment for people with sqNSCLC.

This new approval was based on a randomized, double-blind, Phase 3 clinical trial (ORIENT-12) which evaluated TYVYT (sintilimab injection) or placebo in combination with GEMZAR (gemcitabine) and platinum chemotherapy as first-line therapy for people with unresectable locally advanced or metastatic sqNSCLC.

Professor Caicun Zhou, head of the Oncology Department at Shanghai Pulmonary Hospital, stated: "Lung cancer is the leading cause (nearly 25%) of all cancer deaths, of which non-small cell lung cancer accounts for about 80 to 85 percent. Approximately 70 percent of patients with non-small cell lung cancer have unresectable tumors at the time of diagnosis, and 30 to 60 percent of patients with Stage I-III non-small cell lung cancer who undergo radical surgery subsequently have recurrence or distant metastasis. Over the past two decades, drug development for non-small cell lung cancer has been mainly focused on nonsquamous non-small cell lung cancer, while drug development for squamous non-small cell lung cancer has been relatively slow due to its unique epidemiology, histopathology and molecular biology. The ORIENT-12 study showed that, in the first-line treatment of patients with squamous non-small cell lung cancer, TYVYT (sintilimab injection) in combination with gemcitabine and platinum chemotherapy demonstrated a statistically significant improvement in progression-free survival compared to placebo and gemcitabine and platinum chemotherapy. Meanwhile, although the median overall survival data was not yet mature, the TYVYT (sintilimab injection) combination arm showed a potential overall survival benefit over chemotherapy alone. The approval of TYVYT (sintilimab injection) provides a new clinical approach in China for the first-line treatment of advanced or metastatic squamous non-small cell lung cancer. We look forward to offering this new indication of TYVYT (sintilimab injection) and helping to treat people with squamous non-small cell lung cancer in China."

Dr. Yongjun Liu, President of Innovent, stated: "As one of the most life-threatening diseases, cancer has always been a key focus for the pharmaceutical companies, researchers and clinicians that help develop oncology treatments. Innovent is committed to discovering and developing innovative medicines for diseases with unmet medical needs. This approval of TVYYT (sintilimab injection) in a third indication represents another remarkable achievement for our novel, high quality PD-1 inhibitor in cancer treatment. We are very excited about this approval, and we look forward to now offering this as a first-line treatment option for people with squamous non-small cell lung cancer."

Dr. Hui ZHOU, Senior Vice President of Clinical Development of Innovent, stated: "In China, lung cancer has the highest incidence and mortality rate among all tumor types. Although treatment development has been advancing in recent years, there is still a large number of people with lung cancer that lack effective treatment options particularly those with the squamous type. This new indication of TYVYT (sintilimab injection) provides an additional first-line treatment option for people with squamous non-small cell lung cancer. We are hopeful that TYVYT (sintilimab injection) will help many people with this type of cancer."

Julio Gay-ger, Lilly China President and General Manager, stated: "Oncology is one of the most important strategic therapeutic areas for Lilly. In particular, we have been deeply rooted in lung cancer treatment for many years. We're excited to see two new indications for TYVYT (sintilimab injection) in combination with two Lilly classic anti-tumor drugs pemetrexed and gemcitabine, respectively and platinum chemotherapy as first-line therapy for people with non-small cell lung cancer, both approved this year by the NMPA within a few months of each other. We are committed to the development and commercialization of effective cancer therapies and devote ourselves to helping patients with more innovative products through independent R&D and strategic collaborations."

Dr. Li WANG, Senior Vice President of Lilly China and Head of Lilly China Drug Development and Medical Affairs Center, stated: "Results of multiple clinical studies show that immuno-oncology therapy has become one of the standard global treatment options for lung cancer due to its proven clinical efficacy and safety. The approval of this new indication has further demonstrated its potential to treat people with lung cancer. Lilly will continue to work closely with Innovent to further explore TYVYT's clinical potential in other tumor types with the hopes of helping more cancer patients."

About Squamous Non-Small Cell Lung Cancer

Lung cancer is a malignancy with the highest morbidity and mortality in China.Non-small cell lung cancer (NSCLC) accounts for about 80 to 85 percent of lung cancer. Approximately 70 percent of people with NSCLC have locally advanced or metastatic disease at initial diagnosis, rendering many of those patients with no chance of radical resection.Meanwhile, even after radical surgery, patients still have a high chance of recurrence and eventually die from disease progression.About 30 percent of people in China with NSCLC have tumors of the squamous subtype and there are limited approved second-line therapies for these patients. Therefore, this remains a huge unmet medical need in China.

About ORIENT-12

ORIENT-12 ClinicalTrials.gov, NCT03629925is a randomized, double-blind, Phase 3 clinical trial evaluating TYVYT (sintilimab injection) or placebo in combination with GEMZAR (gemcitabine) and platinum chemotherapy (carboplatin or cisplatin) as a first-line treatment for advanced or metastatic squamous non-small cell lung cancer (sqNSCLC).A total of 357 participants were enrolled and randomized in a 1:1 ratio (179 participants in the TYVYT (sintilimab injection) combination arm, 178 participants in the placebo combination arm).

ORIENT-12 demonstrated a statistically significant improvement in progression-free survival (PFS), the study's primary endpoint, of TYVYT (sintilimab injection) in combination with GEMZAR and platinum chemotherapy compared with placebo in combination with GEMZAR and platinum chemotherapy. The median PFS of the TYVYT (sintilimab injection) combination arm was 5.5 months compared to 4.9 months on the placebo combination arm (HR=0.536, 95% CI: 0.422-0.681, P< 0.00001)as assessed by Independent Radiographic Review Committee (IRRC), and 6.7 months compared to 4.9 months respectively (HR=0.532, 95% CI: 0.419-0.674, P< 0.00001), as assessed by the study's investigators. Overall survival (OS), a secondary endpoint, of the TYVYT (sintilimab injection) combination arm showed a positive trend when compared to the placebo combination arm (HR=0.567, 95%CI: 0.353-0.909, P=0.01701), though the data were not yet mature at an interim analysis. The safety profile is consistent with previously reported TYVYT (sintilimab injection) studies, and no new safety signals were identified.

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is an innovative PD-1 inhibitor with global quality standards jointly developed by Innovent and Lilly. Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved for three indications, including:

Additionally, Innovent currently has regulatory submissions under review in China for sintilimab:

In May 2021, the U.S. FDA accepted for review the Biologics License Application (BLA) for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of nonsquamous non-small cell lung cancer.

Sintilimab was included in China's National Reimbursement Drug List (NRDL) in 2019 as the first PD-1 inhibitor and the only PD-1 included in the list in that year.

About Innovent

Inspired by the spirit of "Start with Integrity, Succeed through Action," Innovent's mission is to develop, manufacture and commercialize high-quality biopharmaceutical products that are affordable to ordinary people. Established in 2011, Innovent is committed to developing, manufacturing and commercializing high-quality innovative medicines for the treatment of cancer, autoimmune, metabolic and other major diseases. On October 31, 2018, Innovent was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 01801.HK.

Since its inception, Innovent has developed a fully integrated multi-functional platform which includes R&D, CMC (Chemistry, Manufacturing, and Controls), clinical development and commercialization capabilities. Leveraging the platform, the company has built a robust pipeline of 24 valuable assets in the fields of cancer, metabolic, autoimmune disease and other major therapeutic areas, with 4 products TYVYT (sintilimab injection), BYVASDA (bevacizumab biosimilar injection), SULINNO (adalimumab biosimilar injection) and HALPRYZA (rituximab biosimilar injection) officially approved for marketing in China, sintilimab's Biologics License Application (BLA)acceptance in the U.S. , 6 assets in Phase 3 or pivotal clinical trials, and an additional 14 molecules in clinical trials. In 2019, TYVYT was the first PD-1 inhibitor included in the National Reimbursement Drug List (NRDL) and the only PD-1 inhibitor included in the NRDL in that year.

Innovent has built an international team with advanced talent in high-end biological drug development and commercialization, including many global experts. The company has also entered into strategic collaborations with Eli Lilly and Company, Adimab, Incyte, MD Anderson Cancer Center, Hanmi and other international partners. Innovent strives to work with many collaborators to help advance China's biopharmaceutical industry, improve drug availability and enhance the quality of the patients' lives. For more information, please visit: http://www.innoventbio.com.

About Eli Lilly and Company

Lilly is a global healthcare leader that unites caring with discovery to create medicines to make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit lilly.com

and lilly.com/newsroom.

About Innovent Biologics' strategic collaboration with Eli Lilly and Company

Innovent entered into a strategic collaboration with Lilly focused on biological medicine in March 2015 a groundbreaking partnership between a Chinese pharmaceutical company and a multinational pharmaceutical company. Under the agreement, Innovent and Lilly are co-developing and commercializing oncology medicines, including TYVYT (sintilimab injection), in China. In October 2015, the two companies announced the extension of their existing collaboration to include co-development of three additional oncology antibodies targeting oncology indications. In August 2019, Innovent further entered into a licensing agreement with Lilly to develop and commercialize a potentially global best-in-class diabetes medicine in China. Its collaboration with Lilly is an example of how Innovent has established a comprehensive level of cooperation between China's innovative pharmaceuticals sector and the international pharmaceuticals sector in fields such as R&D, CMC, clinical development and commercialization. In August 2020Lilly and Innovent announced a global expansion of their strategic alliance for sintilimab, whereby Lilly obtained an exclusive license for sintilimab for geographies outside of China and plans to pursue registration of sintilimab in the U.S. and other geographies outside of China.

Note:

[1]The PFS and OS data in China approved indication label for TYVYT (sintilimab injection).

TYVYT (sintilimab injection;Innovent), BYVASDA (bevacizumab biosimilar injection;Innovent), SULINNO (adalimumab biosimilar injection;Innovent), and HALPRYZA (rituximab biosimilar injection;Innovent) are not approved products in the United States.

Innovent Biologics, Inc. Forward-Looking Statements

This news release may contain certain forward-looking statements that are, by their nature, subject to significant risks and uncertainties. The words "anticipate", "believe", "estimate", "expect", "intend" and similar expressions, as they relate to Innovent, are intended to identify certain of such forward-looking statements. Innovent does not intend to update these forward-looking statements regularly.

These forward-looking statements are based on the existing beliefs, assumptions, expectations, estimates, projections and understandings of the management of Innovent with respect to future events at the time these statements are made. These statements are not a guarantee of future developments and are subject to risks, uncertainties and other factors, some of which are beyond Innovent's control and are difficult to predict. Consequently, actual results may differ materially from information contained in the forward-looking statements as a result of future changes or developments in our business, Innovent's competitive environment and political, economic, legal and social conditions.

Innovent, the Directors and the employees of Innovent assume (a) no obligation to correct or update the forward-looking statements contained in this site; and (b) no liability in the event that any of the forward-looking statements does not materialise or turn out to be incorrect.

Eli Lilly and Company Forward-Looking Statement

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about sintilimab and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there can be no guarantee that future study results will be consistent with study results to date, or that sintilimab will receive additional regulatory approvals or be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

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Innovent and Lilly Jointly Announce the China NMPA Approval of TYVYT (sintilimab injection) in Combination with Gemcitabine and Platinum Chemotherapy...

WILMINGTON, Del.--(BUSINESS WIRE)--Updated results from the positive PACIFIC Phase III trial showed AstraZenecas IMFINZI (durvalumab) demonstrated a sustained, clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit at five years in patients with unresectable Stage III non-small cell lung cancer (NSCLC) who had not progressed following concurrent chemoradiation therapy (CRT).

Lung cancer is the leading cause of cancer death in the US, accounting for about a quarter of all cancer deaths, and 80-85% of patients with lung cancer have NSCLC.1 One in four patients with NSCLC are diagnosed at Stage III, where the majority of tumors are unresectable (cannot be removed with surgery).2-3 The approval of IMFINZI in this setting, based on the results of this trial, was the first new treatment to be available to these patients in decades.4-6

Results from the updated post-hoc analyses showed an estimated five-year OS rate of 42.9% for patients treated with IMFINZI versus 33.4% for those on placebo after CRT. Median OS was 47.5 months for IMFINZI versus 29.1 for placebo. Following a maximum treatment course of one year, an estimated 33.1% of patients treated with IMFINZI had not progressed five years after enrollment versus 19% for placebo. These results build on the primary PFS and OS analyses published in The New England Journal of Medicine in 2017 and 2018, which demonstrated a sustained, significant benefit with IMFINZI for these primary endpoints.7,8

David Spigel, MD, Chief Scientific Officer at the Sarah Cannon Research Institute, and investigator in the PACIFIC trial, said: This trial has once again set a new precedent in the treatment of patients with unresectable Stage III non-small cell lung cancer. Historically, only 15-30% of these patients survived five years but these results show that with up to one year of treatment with IMFINZI, an estimated 43% of patients are still alive at five years. Moreover, three quarters of these patients had also not progressed in that time. This is a momentous achievement at the five-year landmark in this curative-intent setting.

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: Five-year survival is a clinically significant and emotionally meaningful milestone for people with cancer and their families, and it's incredible to see the majority of patients surviving that long have not progressed four years after completing treatment. These results the first of their kind in Stage III unresectable lung cancer reinforce the long-term benefit of IMFINZI as the established standard of care in this curative-intent setting. With trials like PACIFIC and our comprehensive development program in early-stage disease across cancer settings, our strategy is to improve cancer outcomes by treating patients as early as possible, aiming to deliver life-changing treatments that increase the potential for cure.

In the primary OS analysis of the PACIFIC Phase III trial, the most common adverse events (AEs) (greater than or equal to 20%) among patients treated with IMFINZI versus placebo were cough (35.2% versus 25.2%), fatigue (24.0% versus 20.5%), dyspnea (22.3% versus 23.9%) and radiation pneumonitis (20.2% versus 15.8%). A grade 3 or 4 AE was experienced by 30.5% of patients treated with IMFINZI versus 26.1% for placebo, and 15.4% of patients discontinued treatment due to AEs with IMFINZI versus 9.8% for placebo.8

These results were presented on June 4 during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Important Safety InformationThere are no contraindications for IMFINZI (durvalumab).

Immune-Mediated Adverse ReactionsImportant immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity. See Dosing and Administration for specific details. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated PneumonitisIMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.0% (28/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions. In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 16.6% (79/475) in patients receiving IMFINZI and 13.2% (31/234) in patients receiving placebo. Of the 79 patients who received IMFINZI, 1.1% were fatal and 2.5% were Grade 3-4 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC when in combination with chemotherapy.

Immune-Mediated ColitisIMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.6% (31/1889) of patients receiving IMFINZI, including Grade 4 (0.1%) and Grade 3 (0.3%) adverse reactions.

Immune-Mediated HepatitisIMFINZI can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.0% (19/1889) of patients receiving IMFINZI, including fatal (<0.1%) and Grade 3 (0.6%) adverse reactions.

Immune-Mediated Endocrinopathies

Immune-Mediated Nephritis with Renal DysfunctionIMFINZI can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (5/1889) of patients receiving IMFINZI, including Grade 3 (0.1%) adverse reactions.

Immune-Mediated Dermatology ReactionsIMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), have occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 1.6% (30/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions.

Other Immune-Mediated Adverse ReactionsThe following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or were reported with the use of other PD-1/PD-L1 blocking antibodies.

Infusion-Related ReactionsIMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity. See Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.

Complications of Allogeneic HSCT after IMFINZIFatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal ToxicityBased on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for at least 3 months after the last dose of IMFINZI.

LactationThere is no information regarding the presence of IMFINZI in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI, advise women not to breastfeed during treatment and for at least 3 months after the last dose.

Adverse Reactions

The safety and effectiveness of IMFINZI have not been established in pediatric patients.

Indications:

IMFINZI is indicated for the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).

Please see complete Prescribing Information, including Patient Information.

NOTES TO EDITORS

About Stage III NSCLCIn 2021, an estimated 235,760 new cases of lung cancer will be diagnosed in the United States.1 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.1 Approximately one in four patients with NSCLC in the United States present with Stage III disease, which is estimated to affect over 43,000 patients.2 The majority of Stage III NSCLC patients are diagnosed with unresectable tumors.3

Stage III (locally advanced) NSCLC is divided into three sub-categories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally and the possibility of surgery.7 In contrast to Stage IV, when cancer has spread (metastasised) to distant organs, Stage III is currently treated with curative intent.9,10

About PACIFICThe PACIFIC trial was a Phase III, randomized, double-blinded, placebo-controlled, multi-center trial of IMFINZI as treatment in all-comer patients (regardless of PD-L1 status) with unresectable Stage III NSCLC whose disease had not progressed following concurrent platinum-based CRT.

The trial was conducted at 235 centers across 26 countries involving 713 patients. The primary endpoints of the trial were PFS and OS, and secondary endpoints included landmark PFS and OS, objective response rate (ORR) and duration of response (DoR).

About IMFINZI (durvalumab)IMFINZI is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumors immune-evading tactics and releasing the inhibition of immune responses.

In addition to approvals in the unresectable Stage III NSCLC setting, IMFINZI is approved for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial in the EU, US, Japan and many other countries around the world. IMFINZI is also approved for previously treated patients with advanced bladder cancer in several countries.

As part of a broad development program, IMFINZI is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with NSCLC, SCLC, bladder cancer, hepatocellular carcinoma, biliary tract cancer (a form of liver cancer), esophageal cancer, gastric and gastroesophageal cancer, cervical cancer, ovarian cancer, endometrial cancer and other solid tumors.

About tremelimumabTremelimumab is a human monoclonal antibody and potential new medicine that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T cell activation, priming the immune response to cancer and fostering cancer cell death. Tremelimumab is being tested in a clinical trial program in combination with IMFINZI in NSCLC, SCLC, bladder cancer and liver cancer.

About AstraZeneca Support ProgramsAstraZeneca strives to ensure that appropriate patients and their oncologists have access to IMFINZI and relevant support resources. These include educational resources, an Oncology Nurse Educator program and affordability and reimbursement programs, such as Access 360.

Additionally, AstraZeneca has launched Lighthouse, a program that provides support to patients during any immune-mediated adverse events they may encounter during treatment, through medically trained Lighthouse Advocates. The program aims to make patients treatment experience as comfortable as possible. Find out more about Lighthouse at LighthouseProgram.com or call 1-855-LHOUSE1 (1-855-546-8731).

About AstraZeneca in lung cancerAstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Companys comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations including osimertinib; durvalumab and tremelimumab; trastuzumab deruxtecan and datopotamab deruxtecan in collaboration with Daiichi Sankyo; and savolitinib in collaboration with HUTCHMED; as well as a pipeline of new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer including and beyond treatment.

About AstraZeneca in ImmunotherapyImmunotherapy (IO) is a therapeutic approach designed to stimulate the bodys immune system to attack tumors. The Companys IO portfolio is anchored in immunotherapies that have been designed to overcome anti-tumor immune suppression. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumor types.

AstraZeneca is pursuing a comprehensive clinical-trial program that includes IMFINZI as a single treatment and in combination with tremelimumab and other novel antibodies in multiple tumor types, stages of disease and lines of therapy, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine the IO portfolio with radiation, chemotherapy, and small, targeted molecules from across AstraZenecas Oncology pipeline and from research partners, may provide new treatment options across a broad range of tumors.

About AstraZeneca in oncologyAstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Companys focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

About AstraZenecaAstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism and Respiratory & Immunology. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS.

REFERENCES

1. American Cancer Society. Key Statistics for Lung Cancer. Available at https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html. Accessed June 2021.

2. EpiCast Report: NSCLC Epidemiology Forecast to 2025. GlobalData. 2016. Available at https://store.globaldata.com/report/gdhcer132-16--epicast-report-non-small-cell-lung-cancer-nsclc-epidemiology-forecast-to-2025/. Accessed June 2021

3. Provencio M, et al. Inoperable Stage III Non-Small Cell Lung Cancer: Current Treatment and Role Of Vinorelbine. J Thorac Dis. 2011;3:197-204

4. Curran WJ, et al. Sequential vs Concurrent Chemoradiation for Stage III NonSmall Cell Lung Cancer: Randomized Phase III Trial RTOG 9410. J Natl Cancer Inst. 2011;103(19):14521460

5. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 4.2021. March 3.

6. Hanna N, et al. Current Standards and Clinical Trials in Systemic Therapy for Stage III Lung Cancer: What is New? Am Soc Clin Oncol Educ Book. 2015;e442-447.

7. Anthonia SJ et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377:1919-1929.

8. Antonia SJ, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018;379:2342-2350.

9. ASCO. Cancer.net. Lung Cancer Non-Small Cell. Available at https://www.cancer.net/cancer-types/lung-cancer-non-small-cell. Accessed June 2021.

10. Cheema PK, et al. Perspectives on Treatment Advances For Stage III Locally Advanced Unresectable Non-Small-Cell Lung Cancer. Curr Oncol. 2019;26(1):37-42.

US-52747 Last Updated 6/21

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IMFINZI Demonstrated Unprecedented Survival in Unresectable Stage III Lung Cancer With 43% Of Patients Surviving Five Years - Business Wire

Basel, June 4, 2021 Novartis today announced the first published mature overall survival (OS) and updated overall response rate (ORR) data following treatment with Tabrecta (capmatinib) in adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to MET exon 14 skipping (METex14)1-3. Data from the ongoing, pivotal, multi-cohort Phase II GEOMETRY mono-1 study will be presented today during the 2021 Annual American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting (Poster Discussion Session, Lung CancerNon-Small Cell Metastatic; June 4, 2021, 9:00 AM-10:00 AM CT; abstract 9020).

This new analysis further supports Tabrecta as a cornerstone targeted treatment for METex14 NSCLC patients and highlights the importance of biomarker testing, said Juergen Wolf, MD, from the Center for Integrated Oncology, University Hospital Cologne, and lead investigator of the GEOMETRY study. The impressive overall survival outcome and confirmed outstanding response in the first-line setting will help oncologists decide upon a therapeutic option for patients.

The analysis includes new data from the treatment-nave (1L) expansion cohort 7 and previously-treated (2L+) cohort 6, and mature data from previously-reported cohorts, for a total of 160 patients1,2.

The introduction of Tabrecta a year ago dramatically changed the treatment landscape for patients with METex14 NSCLC. Now we have further evidence that Tabrecta, the market-leading treatment specifically for METex14 NSCLC patients4, has the potential to help people live longer, said Jeff Legos, Senior Vice President, Head of Oncology Drug Development, Novartis Oncology.

The results presented today provide additional data on the efficacy of Tabrecta in both treatment-nave and previously-treated patients with METex14 metastatic NSCLC 2:

No new safety signals or unexpected safety findings were observed. Ninety-eight percent of subjects had at least one adverse event (AE) of any grade and 50.9% of subjects had at least one serious adverse event (SAE). Thirteen percent were suspected to be treatment-related. The most common adverse events (>20%, all grades) across all cohorts were peripheral edema, nausea, vomiting, increased blood creatinine, dyspnea, fatigue and decreased appetite. The majority of AEs were grade 3 or 42.

Currently, the five-year survival rate for lung cancer is less than 20%5, decreasing further when the disease is diagnosed at later stages6. Nearly one in three patients with metastatic NSCLC may have an actionable mutation7,8. METex14 has been reported to occur in 3%-4% of metastatic NSCLC cases9. Many patients with mutations that lead to METex14 are not diagnosed with NSCLC until their disease has progressed to later stages and often have poor prognosis10,11.

A separate analysis of patient-reported outcomes (PROs) evaluated cough, delayed time to lung symptom deterioration, and quality of life (QoL) in NSCLC patients with METex14 (abstract 9056)3.

Additionally, a retrospective analysis of GEOMETRY mono-1 validates the clinical utility of liquid biopsy testing to identify METex14 positivepatientsfor treatment withTabrecta (Poster Session: Lung CancerNon-Small Cell Metastatic; abstract 9111)12.

Visithttps://www.hcp.novartis.com/virtual-congress/a-2021/ for the latest information from Novartis, including our commitment to the Oncology community, and access to our ASCO21 Virtual Scientific Program data presentations (for registered participants).

About GEOMETRY mono-1GEOMETRY mono-1 is a Phase II a multi-center, non-randomized, open-label, multi-cohort study in adult patients with EGFR wild-type, ALK-negative rearrangement, metastatic NSCLC harboring mutations that lead to MET exon-14 skipping who received capmatinib tablets 400 mg orally twice daily.

Patients were assigned to cohorts on the basis of MET status and previous lines of therapy13. The primary endpoint was overall response rate (ORR) based on the Blinded Independent Review Committee (BIRC) assessment per RECIST v1.1. The key secondary endpoint was duration of response (DOR) evaluated by BIRC.

About Tabrecta (capmatinib)Tabrecta (capmatinib) is a kinase inhibitor that targets MET. Tabrecta was discovered by Incyte and licensed to Novartis in 2009. Under the Agreement, Incyte granted Novartis worldwide exclusive development and commercialization rights to capmatinib and certain back-up compounds in all indications. In May 2020, Tabrecta was approved by the US Food and Drug Administration (FDA) for adult patients with metastatic NSCLC whose tumors have a mutation that leads to METex14 as detected by an FDA-approved test. This indication was approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

In June 2020, Tabrecta was approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) for adult patients with metastatic NSCLC whose tumors have a mutation that leads to METex14 as detected by an FDA-approved test.Tabrecta was also approved in Hong Kong in February 2021 and Switzerland in April 2021.

Novartis and Lung CancerLung cancer is the most common cancer worldwide, accounting for more than 2 million new cases diagnosed each year14. There are two main types of lung cancer small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)15,16. NSCLC accounts for approximately 85% of lung cancer diagnoses, resulting in nearly 2 million new cases each year14,16.More people die of lung cancer every year than any other cancer type14. Treatment options are limited for people with lung cancer who experience cancer growth or progression while on current standard of care treatments17-19.

Novartis is committed to developing best-in-class treatments for lung cancer patients around the world. With a focus on both targeted, personalized medicine and the role of newer core immuno-oncology therapies, the lung cancer drug development program at Novartis is among the most robust in the industry. Novartis research activities are informed by our long-term relationships with leading lung cancer thought leaders and patient advocates. With them, Novartis is committed to reimagining the treatment of lung cancer.

IndicationTABRECTA (capmatinib) tablets is a prescription medicine used to treat adults with a kind of lung cancer called non-small cell lung cancer (NSCLC) that has spread to other parts of the body or cannot be removed by surgery (metastatic), and whose tumors have an abnormal mesenchymal-epithelial transition (MET) gene.

The effectiveness of TABRECTA in these patients is based on a study that measured 2 types of response to treatment (response rate and duration of response). There is no clinical information available to show if patients treated with TABRECTA live longer or if their symptoms improve. There are ongoing studies to find out how TABRECTA works over a longer period of time.

It is not known if TABRECTA is safe and effective in children.

Important Safety InformationTABRECTA may cause serious side effects, such as lung or breathing problems. TABRECTA may cause inflammation of the lungs during treatment that may lead to death. Patients should be advised to contact their health care provider right away if they develop any new or worsening symptoms, including cough, fever, trouble breathing, or shortness of breath.

TABRECTA may cause abnormal blood test results, which may be a sign of liver problems. Patients should be advised that their health care provider will do blood tests to check their liver before starting and during treatment with TABRECTA. Patients should be advised to contact their health care provider right away if they develop any signs and symptoms of liver problems including the skin or the white part of their eyes turning yellow (jaundice), dark or tea-colored urine, light-colored stools (bowel movements), confusion, loss of appetite for several days or longer, nausea and vomiting, pain, aching, or tenderness on the right side of the stomach area (abdomen), or weakness or swelling in the stomach area.

The skin may be sensitive to the sun (photosensitivity) during treatment with TABRECTA. Patients should be advised to use sunscreen or wear clothes that cover their skin during treatment with TABRECTA to limit direct sunlight exposure.

For women of reproductive potential, TABRECTA can harm their unborn baby. They should use an effective method of birth control during treatment with TABRECTA and for 1 week after the last dose. Men who have partners who can become pregnant should use effective birth control during treatment with TABRECTA and for 1 week after the last dose.

Before taking TABRECTA, patients should tell their health care provider about all their medical conditions, including if they have or have had lung or breathing problems other than lung cancer, have or have had liver problems, or if they are pregnant or plan to become pregnant, as TABRECTA can harm their unborn babies. Females who are able to become pregnant should have a pregnancy test before they start treatment with TABRECTA and should use effective birth control during treatment and for 1 week after the last dose of TABRECTA. Patients should be advised to talk to their health care provider about birth control choices that might be right for them during this time and to tell their health care provider right away if they become pregnant or think they may be pregnant during treatment with TABRECTA. Males who have female partners who can become pregnant should use effective birth control during treatment and for 1 week after their last dose of TABRECTA.

Patients should tell their health care provider about all the medicines they take or start taking, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of TABRECTA include swollen hands, ankles, or feet (peripheral edema); nausea and/or vomiting; tiredness and/or weakness (fatigue, asthenia); shortness of breath (dyspnea); loss of appetite; changes in bowel movements (diarrhea or constipation); cough; pain in the chest; fever (pyrexia); back pain; and decreased weight.

Please see full Prescribing Information for Tabrecta available athttps://www.novartis.us/sites/www.novartis.us/files/tabrecta.pdf

DisclaimerThis press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as potential, can, will, plan, may, could, would, expect, anticipate, seek, look forward, believe, committed, investigational, pipeline, launch, or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AGs current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About NovartisNovartis is reimagining medicine to improve and extend peoples lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the worlds top companies investing in research and development. Novartis products reach nearly 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 110,000 people of more than 140 nationalities work at Novartis around the world. Find out more at https://www.novartis.com/.

Novartis is on Twitter. Sign up to follow @Novartis at https://twitter.com/novartisnewsFor Novartis multimedia content, please visit https://www.novartis.com/news/media-libraryFor questions about the site or required registration, please contact media.relations@novartis.com

References

*FoundationOneCDx is a registered trademark of Foundation Medicine, Inc.

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Novartis announces Tabrecta first published overall survival and updated overall response data in patients with METex14 - GlobeNewswire

ALAMEDA, Calif.--(BUSINESS WIRE)--Exelixis, Inc. (NASDAQ: EXEL) today announced results from a post-hoc analysis of the phase 3 CheckMate -9ER trial demonstrating that CABOMETYX (cabozantinib) in combination with Bristol Myers Squibbs OPDIVO (nivolumab) resulted in a statistically significant and clinically meaningful increase in quality-adjusted survival compared with sunitinib for patients with previously untreated advanced renal cell carcinoma (RCC). The quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) data will be presented as part of the Poster Session: Health Services Research and Quality Improvement at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, which is being held virtually, June 4-8, 2021. All posters will be available on demand beginning at 6:00 a.m. PT on Friday, June 4.

Physicians must balance efficacy, safety and quality-of-life considerations when recommending treatment for patients with advanced kidney cancer; longer survival alone is not enough if the quality of life during that time is poor, said David Cella, Ph.D., the Ralph Seal Paffenbarger Professor and chair of the Department of Medical Social Sciences at the Northwestern University Feinberg School of Medicine and presenting author. This analysis shows that the overall survival benefit demonstrated in the phase 3 CheckMate -9ER trial results in clinically important gains in quality-adjusted survival. For this community, time with relatively good health can be an important factor in treatment decisions, and these results offer both patients and physicians a fuller picture of the clinical benefits of the combination of cabozantinib and nivolumab.

The Q-TWiST metric combines the quantity and quality of time patients spend in each of the following three states: time without symptoms of disease or toxicity before progression (TWiST), time with any grade 3 or 4 adverse events after randomization and before progression or censoring and time after disease progression until death. In the intent-to-treat population (n = 651) in this post-hoc analysis, patients treated with CABOMETYX in combination with OPDIVO had a Q-TWiST gain of 4.0 months (95% confidence interval [CI]: 2.4-5.7) compared with patients treated with sunitinib. The resulting relative gain of 16.9% is considered clearly clinically important (defined as a gain of at least 15% based on published minimally important difference norms).

Most gains were driven by added time in relatively good health (TWiST) (4.7 months; 95% CI: 2.9-6.7) for CABOMETYX in combination with OPDIVO compared with sunitinib. Time with any grade 3/4 adverse events was 0.5 months longer (95% CI: 0.1-0.9) with CABOMETYX in combination with OPDIVO than with sunitinib. Time after disease progression until death was 2.0 months longer (95% CI: 0.1-4.1) with sunitinib than with CABOMETYX in combination with OPDIVO.

There is a need for additional first-line advanced kidney cancer treatments that demonstrate quality-of-life improvements as well as efficacy benefits, and this analysis along with the patient-reported outcomes from CheckMate -9ER presented earlier this year add to the clinical evidence supporting the use of CABOMETYX in combination with OPDIVO, said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. These are important findings that reinforce our efforts to bring treatment options to patients that may offer an improved quality of life while on therapy.

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized (1:1), multi-national phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma with a clear cell component. A total of 651 patients (22% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1 1%) were randomized to CABOMETYX at a dose of 40 mg QD and OPDIVO (n = 323) versus sunitinib (n = 328). The primary endpoint is PFS. Secondary endpoints include OS and ORR. The primary efficacy analysis compares the doublet combination regimen of CABOMETYX and OPDIVO versus sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co. and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About RCC

The American Cancer Societys 2021 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common form of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 13%.1 Approximately 32,000 patients in the U.S. and 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2021.3

About 70% of RCC cases are known as clear cell carcinomas, based on histology.4 The majority of clear cell RCC tumors have below-normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.5,6 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.7,8,9,10 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.6,7

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with OPDIVO. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade 2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade 2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade 2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. Johns wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.FDA.gov/medwatch or call 1-800-FDA-1088.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX (cabozantinib), COMETRIQ (cabozantinib), COTELLIC (cobimetinib) and MINNEBRO (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of the Standard & Poors (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. In November 2020, the company was named to Fortunes 100 Fastest-Growing Companies list for the first time, ranking 17th overall and the third-highest biopharmaceutical company. For more information about Exelixis, please visit http://www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

Forward-Looking Statements

This press release contains forward-looking statements, including, without limitation, statements related to: the presentation of data from the phase 3 CheckMate -9ER trial at ASCO 2021; the potential for the combination of CABOMETYX and OPDIVO to offer RCC patients an improved quality of life while on therapy; and Exelixis plans to reinvest in its business to maximize the potential of the companys pipeline, including through targeted business development activities and internal drug discovery. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the availability of data at the referenced times; complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere; Exelixis and BMS continuing compliance with applicable legal and regulatory requirements; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating the combination of CABOMETYX and OPDIVO; Exelixis dependence on its relationships with its collaboration partners, including their pursuit of regulatory approvals for partnered compounds in new indications and their adherence to their obligations under relevant collaboration agreements; Exelixis dependence on third-party vendors for the development, manufacture and supply of cabozantinib; Exelixis ability to protect its intellectual property rights; market competition, including the potential for competitors to obtain approval for generic versions of CABOMETYX; changes in economic and business conditions, including as a result of the COVID-19 pandemic; and other factors affecting Exelixis and its development programs discussed under the caption Risk Factors in Exelixis Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 6, 2021, and in Exelixis future filings with the SEC. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law.

Exelixis, the Exelixis logo, CABOMETYX, COMETRIQ and COTELLIC are registered U.S. trademarks. MINNEBRO is a Japanese trademark.

OPDIVO is a registered trademark of Bristol-Myers Squibb Company.

1

American Cancer Society: Cancer Facts & Figures 2021. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf. Accessed June 2021.

2

Jonasch, E., Gao, J., Rathmell, W., Renal cell carcinoma. BMJ. 2014; 349:g4797.

3

Decision Resources Report: Renal Cell Carcinoma. October 2014 (internal data on file).

4

American Cancer Society: What is Kidney Cancer? Available at: https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.html. Accessed June 2021.

5

Harshman, L., and Choueiri, T. Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J. 2013; 19:316-323.

6

Rankin, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci USA. 2014; 111:13373-13378.

7

Zhou, L., Liu, X-D., Sun, M., et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016; 35:2687-2697.

8

Koochekpour, et al. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999; 19:59025912.

9

Takahashi, A., Sasaki, H., Kim, S., et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994; 54:4233-4237.

10

Nakagawa, M., Emoto, A., Hanada, T., Nasu, N., Nomura, Y. Tubulogenesis by microvascular endothelial cells is mediated by vascular endothelial growth factor (VEGF) in renal cell carcinoma. Br J Urol. 1997; 79:681-687.

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Exelixis Announces Quality-Adjusted Survival Benefit Demonstrated in Analysis of Phase 3 CheckMate -9ER Trial of CABOMETYX (cabozantinib) in...

Joshua K. Sabari, MD, discusses the need for EGFR inhibitors designed specifically to treat patients withEGFR-mutant nonsmall cell lung cancer and an exon 20 insertion.

Joshua K. Sabari, MD, assistant professor, Department of Medicine, NYU Grossman School of Medicine, discusses the need for EGFR inhibitors designed specifically to treat patients withEGFR-mutant nonsmall cell lung cancer (NSCLC) and an exon 20 insertion.

The standard of care for patients with EGFR-mutant disease is chemotherapy combination therapy which has been shown to achieve a median survival of about 7 months. According to Sabari, the survival rate reveals a need for more effective treatment overall.

The landscape for those with an exon 20 insertion is less populated with effective agents, says Sabari. These patients do not respond to treatment with traditional tyrosine kinase inhibitors like those with exon 19 and 21 insertions tend to respond. More exon 20-specific inhibitor are needed in the space. Further, there is a need for therapies with better safety profiles for patients with EGFR-mutant and exon 20 insertion-positive NSCLC.

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Addressing Unmet Needs to Precision Medicine in EGFR Exon 20-Positive NSCLC - Targeted Oncology

FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD) today announced new data from the Phase 3 ASCENT study evaluating Trodelvy (sacituzumab govitecan-hziy) in relapsed or refractory metastatic triple-negative breast cancer (TNBC). In this subgroup analysis of brain metastases-negative patients who received only one line of prior systemic therapy in the metastatic setting in addition to having disease recurrence or progression within 12 months of (neo)adjuvant chemotherapy, Trodelvy improved progression-free survival (PFS), with a 59% reduction in the risk of disease worsening or death (HR: 0.41; 95% CI: 0.22-0.76) and a median PFS of 5.7 months (n=33) versus 1.5 months with chemotherapy (n=32). Trodelvy also extended median overall survival to 10.9 months versus 4.9 months with chemotherapy (HR: 0.51; 95% CI: 0.28-0.91). The results were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #1080).

In patients with relapsed or refractory metastatic triple-negative breast cancer, outcomes are typically poor especially among patients who progress within 12 months of (neo)adjuvant chemotherapy, said Lisa Carey, MD, Medical Director of the UNC Breast Center, the Physician-in-Chief of the North Carolina Cancer Hospital and Associate Director of Clinical Research at UNC Lineberger Comprehensive Cancer Center. In the Phase 3 ASCENT study, Trodelvy was the first treatment to demonstrate a proven survival advantage in pre-treated patients with locally advanced or metastatic TNBC, and the analysis presented at ASCO reaffirms this benefit over standard of care with important new data in the second-line setting.

Additional results showed Trodelvy demonstrated a higher overall response rate compared with chemotherapy (30% versus 3%). Efficacy results from this subgroup were consistent with those observed in the overall ASCENT study population.

The safety profile of Trodelvy in this subgroup was consistent with prior reports. The most frequent Grade 3 treatment-related adverse reactions for Trodelvy compared to chemotherapy were neutropenia (61% versus 21%), leukopenia (9% versus 0%), diarrhea (6% versus 0%), anemia (3% versus 6%), and fatigue (3% versus 0%). One patient in this subgroup who received Trodelvy experienced febrile neutropenia. Adverse reactions leading to treatment discontinuation were low across both groups (6% in each). There were no treatment-related deaths with Trodelvy in this subgroup. The Trodelvy U.S. Prescribing Information has a BOXED WARNING for severe or life-threatening neutropenia and severe diarrhea; see below for Important Safety Information.

With Trodelvy, we continue to challenge the standard of care in locally advanced and metastatic TNBC. The efficacy observed in the second-line metastatic setting with Trodelvy is highly meaningful, since many patients will progress quickly following chemotherapy. Among these patients, we see median overall survival more than doubled where need is particularly great, said Daejin Abidoye, MD, Senior Vice President, Head of Oncology Clinical Development, Gilead Sciences. We are committed to improving the prognosis for people with this aggressive cancer, and as we continue to study Trodelvy, we are encouraged by this proven efficacy in TNBC.

Two additional ASCENT subgroup analyses that support the efficacy benefit of Trodelvy were also presented at the meeting one evaluating Trodelvy efficacy by patients age (Abstract #1011) and the other comparing Trodelvy with specific single-agent chemotherapy chosen by the patients treating physicians (Abstract #1077).

About Triple-Negative Breast Cancer (TNBC)

TNBC is an aggressive type of breast cancer, accounting for approximately 15% of all breast cancers. The disease is diagnosed more frequently in younger and premenopausal women and is more prevalent in African American and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER2. Medicines targeting these receptors therefore are not typically effective in treating TNBC.

About the ASCENT Study

The Phase 3 ASCENT study, an open-label, active-controlled, randomized confirmatory trial, enrolled more than 500 patients with relapsed/refractory metastatic triple-negative breast cancer who had received two or more prior systemic therapies, including a taxane, at least one of them for metastatic disease. Patients were randomized to receive either Trodelvy or a chemotherapy chosen by the patients treating physicians. The primary efficacy outcome was PFS in patients without brain metastases at baseline, as measured by a blinded, independent, centralized review using RECIST v1.1 criteria. Additional efficacy measures included PFS for the full population, including all patients with and without brain metastases, and overall survival. More information about ASCENT is available at http://clinicaltrials.gov/show/NCT02574455.

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer and metastatic urothelial cancer, where high expression is associated with poor survival and relapse.

In the U.S., Trodelvy is indicated for the treatment of:

Beyond the regulatory approvals of Trodelvy in the U.S., regulatory reviews for Trodelvy in metastatic triple-negative breast cancer are currently underway in the EU, U.K., Canada, Switzerland and Australia, as well as in Singapore through our partner Everest Medicines. Trodelvy is also being investigated as potential treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer and metastatic non-small cell lung cancer. Additional evaluation across multiple solid tumors is also underway.

U.S. Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 61% of patients treated with Trodelvy. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 7%. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever.

Diarrhea: Diarrhea occurred in 65% of all patients treated with Trodelvy. Grade 3-4 diarrhea occurred in 12% of patients. One patient had intestinal perforation following diarrhea. Neutropenic colitis occurred in 0.5% of patients. Withhold Trodelvy for Grade 3-4 diarrhea and resume when resolved to Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of Trodelvy was 0.3%. The incidence of anaphylactic reactions was 0.3%. Pre-infusion medication is recommended. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use. Permanently discontinue Trodelvy for Grade 4 infusion-related reactions.

Nausea and Vomiting: Nausea occurred in 66% of all patients treated with Trodelvy and Grade 3 nausea occurred in 4% of these patients. Vomiting occurred in 39% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold Trodelvy doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade 1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with Trodelvy. The incidence of Grade 3-4 neutropenia was 67% in patients homozygous for the UGT1A1*28, 46% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 25% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 11% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue Trodelvy based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, Trodelvy can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. Trodelvy contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Trodelvy and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Trodelvy and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence 25%) were fatigue, neutropenia, diarrhea, nausea, alopecia, anemia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence 25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes.

In the TROPHY study (IMMU-132-06), the most common adverse reactions (incidence 25%) were diarrhea, fatigue, neutropenia, nausea, any infection, alopecia, anemia, decreased appetite, constipation, vomiting, abdominal pain, and rash. The most frequent serious adverse reactions (SAR) (5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence 25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of Trodelvy with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with Trodelvy.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with Trodelvy.

Please see full Prescribing Information, including BOXED WARNING.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gileads ability to initiate, progress or complete clinical trials within currently anticipated timelines or at all, including those involving Trodelvy; the possibility of unfavorable results from ongoing or additional trials, including those involving Trodelvy; Gileads ability to receive regulatory approvals in a timely manner or at all, including additional regulatory approvals of Trodelvy for the treatment of metastatic TNBC, metastatic breast cancer, metastatic UC, metastatic non-small cell lung cancer and other solid tumors, and the risk that any such approvals may be subject to significant limitations on use; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gileads Quarterly Report on Form 10-Q for the quarter ended March 31, 2021, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Investors are cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and are cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements.

U.S. Prescribing Information for Trodelvy including BOXED WARNING, is available at http://www.gilead.com.

Trodelvy, Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc., or its related companies.

For more information about Gilead, please visit the companys website at http://www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

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Trodelvy Demonstrates Superior Outcomes to Standard of Care in Second-Line Treatment of Metastatic Triple-Negative Breast Cancer in Phase 3 ASCENT...

EAST HANOVER, N.J., June 3, 2021 /PRNewswire/ -- Novartis today reported the final analysis from the NETTER-1 phase III study comparing treatment using Lutathera (INN: lutetium (177Lu) oxodotreotide / USAN: lutetium Lu 177 dotatate) plus 30 mg octreotide LAR to 60 mg of octreotide LAR in patients with midgut neuroendocrine tumors. The previously reported primary analysis of the trial demonstrated a statistically significant improvement in progression free survival (PFS) (HR: 0.18*, p < 0.0001)3. In the final analysis of overall survival, a secondary objective of the trial, treatment with Lutathera resulted in a clinically relevant prolongation in median overall survival of 11.7 months [48.0 months (95%CI: 37.4-55.2) compared to the control arm (36.3 months (95%CI: 25.9-51.7)]1.While this analysis did not reach statistical significance (Hazard ratio for OS (HR): 0.84 with 95% CI: (0.60, 1.17) (p=0.30, two-sided))1, the analyses of overall survival may have been impacted by multiple factors, including the crossover of patients from the control arm receiving subsequent radioligand therapy (36% of patients) as well as heterogenous subsequent anti-cancer treatments in both study arms1.No new safety signals emerged in the final analysis1. These results will be presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on June 4.

Jonathan Strosberg, MD, Principal Investigator and Associate Professor, Section Head, Neuroendocrine Tumor Program at Moffitt Cancer Center, said, "Lutathera plus long-acting octreotide was associated with a nearly 12-month difference in median overall survival compared to high-dose long-acting octreotide in these difficult to treat patients with inoperable midgut NETs progressing under standard dose octreotide LAR treatment.While not statistically significant, I consider this difference to be clinically relevant for these patients. It is also important to emphasize that PFS was the primary endpoint of this study.Moreover, 36% of patients in the control arm crossed over to receive subsequent radioligand treatment, which may have impacted the comparison of survival between both study arms."

"We are proud of our 30-year legacy as an innovator for patients in the neuroendocrine tumor community," said John Tsai, Head of Global Drug Development and Chief Medical Officer for Novartis. "Since its approval by the European Commission in 2017 and the FDA in 2018, Lutathera has been administered to more than 9,000 gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients in Europe and the United States1. We believe in the potential of targeted radioligand therapy and are investing in new discovery and expansion of this important platform, including exploration of new radioisotopes and combinations with complementary mechanisms of action, such as immunotherapy and inhibitors of DNA damage response."

At this final analysis, no new safety signals emerged in the long-term safety follow-up with a median of 6.3 years. In terms of secondary hematological malignancies, no new cases of MDS or acute leukemia were reported in the long term follow up4.

Radioligand therapy combines a targeting compound that binds to receptors expressed by tumors and a radioactive isotope, causing DNA damage that inhibits tumor growth and replication and may lead to cell death5-7. In the case of Lutathera, it binds to somatostatin receptor type 2, which is over-expressed on certain types of cells, such as gastroenteropancreatic neuroendocrine tumor cells8,9.

Novartis has established global expertise and specialized supply chain and manufacturing capabilities across its network of four radioligand therapy production sites, and is further increasing capacity to ensure delivery of future targeted radioligand therapies to patients in need. Novartis is the only pharmaceutical company which is pursuing four different cancer treatment platforms. These include targeted radioligand therapy, cell and gene therapy, targeted therapy and immunotherapy, with an opportunity to combine these platforms for the best outcomes for each cancer patient.

Visithttps://www.hcp.novartis.com/virtual-congress/a-2021/for the latest information from Novartis, including our commitment to the Oncology community, and access to our ASCO21 Virtual Scientific Program data presentations (for registered participants).

* HR: 0.21 (0.13, 0.32) in the US Package Insert

About NETTER-1NETTER-1 is a Phase III international, multicenter, controlled, randomized study that compared treatment using Lutathera every eight weeks plus best standard of care (octreotide LAR 30 mg) to 60 mg of octreotide LAR (dosed every four weeks) in patients with inoperable midgut NETs progressing under standard dose octreotide LAR treatment and overexpressing somatostatin receptors3.

The primary endpoint was to compare the progression-free survival (PFS) after treatment with Lutathera plus octreotide LAR 30 mg versus octreotide LAR 60 mg using RECIST 1.1 criteria3. Secondary trial endpoints included comparing objective response rate, overall survival, time to tumor progression, duration of response and safety between the two study arms3.

About GEP-NETs Neuroendocrine tumors (NETs) are a type of cancer that originate in neuroendocrine cells throughout the body. NETs are commonly considered slow-growing malignancies. However, some NETs are associated with rapid progression and poor prognosis10-11. In many cases, NET diagnosis is delayed until patients have advanced disease12. Symptoms such as fatigue, diarrhea, and abdominal pain can occur on a daily basis13. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are subdivided into two categories: tumors of the gastrointestinal (GI) tract and pancreas14. There is a need for additional treatment options for inoperable or advanced GEP-NET, including those who have progressed while taking first-line somatostatin analogs.

The estimated age-adjusted incidence, or rate of new cases of NETs in the United States is approximately 6.98/100,000 per year (as of 2012), while the estimated 20-year limited-duration prevalence for 2014, based on the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, was 171,32111. Even though NETs have historically been considered to be rare (orphan disease), their incidence has grown over 500% over the last 3 decades 10,11,12,15.

About LutatheraLutathera (lutetium Lu 177 dotatate) is an Advanced Accelerator Applications product approved in the United States for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut and hindgut neuroendocrine tumors in adults16.

Lutathera (lutetium (177Lu) oxodotreotide) is also approved in Europe for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults3.

Important Safety InformationLUTATHERA(lutetium Lu 177 dotatate) is a prescription medicine used to treat adults with a type of cancer known as gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that are positive for the hormone receptor somatostatin, including GEP-NETs in the foregut, midgut, and hindgut.

LUTATHERA is associated with some serious safety considerations, and in some cases these may require a healthcare provider to adjust or stop treatment. Treatment with LUTATHERA will expose patients to radiation which can contribute to long-term radiation exposure. Overall radiation exposure is associated with an increased risk for cancer. The radiation will be detectable in urine for up to 30 days following administration of the drug. It is important to minimize radiation exposure to household contacts consistent with good radiation safety practices as advised by your healthcare provider. Treatment with LUTATHERA increases the risk of myelosuppression, a condition in which bone marrow activity is decreased, resulting in a drop in blood cell counts. You may experience blood-related side effects such as low red blood cells (anemia), low numbers of cells that are responsible for blood clotting (thrombocytopenia), and low numbers of white blood cells (neutropenia). Speak with your healthcare provider if you experience any signs or symptoms of infection, fever, chills, dizziness, shortness of breath or increased bleeding or bruising. Other serious conditions that you may develop as a direct result of treatment with LUTATHERA include blood and bone marrow disorders known as secondary myelodysplastic syndrome and cancer known as acute leukemia. Your healthcare provider will routinely check your blood cell counts and tell you if they are too low or too high. Treatment with LUTATHERA will expose kidneys to radiation and may impair their ability to work as normal. You may be at an increased risk for kidney problems after LUTATHERA treatment if you already have kidney impairment before treatment. In some cases, patients have experienced kidney failure after treatment with LUTATHERA. Your healthcare provider will provide you with an amino acid solution before, during, and after LUTATHERA to help protect your kidneys. You should stay well hydrated before, during, and after your treatment. You should urinate frequently during and after administration of LUTATHERA. Your doctor will monitor your kidney function and may withhold, reduce, or stop your LUTATHERA treatment accordingly. In clinical studies of LUTATHERA, less than 1% of patients were reported to have tumor bleeding (hemorrhage), swelling (edema) or tissue damage (necrosis) to the liver. If you have tumors in your liver, you may be more likely to experience these side effects. Signs that you may be experiencing liver damage include increases in blood markers called ALT, AST and GGT. Your healthcare provider will monitor your liver using blood tests and may need to withhold, reduce, or stop your LUTATHERA treatment accordingly. During your treatment you may experience certain symptoms that are related to hormones released from your cancer. These symptoms may include flushing, diarrhea, difficulty breathing (bronchospasm), and low blood pressure (hypotension), and may occur during or within the 24 hours after your first LUTATHERA treatment. Your healthcare provider will monitor you closely. Speak with your healthcare provider if you experience any of these signs or symptoms. Tell your healthcare provider if you are pregnant. LUTATHERA can harm your unborn baby. Females should use an effective method of birth control during treatment and for 7 months after the final dose of LUTATHERA. Males with female partners should use an effective method of birth control during treatment and for 4 months after the final dose of LUTATHERA. You should not breastfeed during treatment with LUTATHERA and for 2.5 months after your final dose of LUTATHERA. Treatment with LUTATHERA may cause infertility. This is because radiation absorbed by your testes or ovaries over the treatment period falls in the range of exposure where temporary or permanent infertility may occur.

The most common and most serious side effects of LUTATHERA include: vomiting, nausea, decreased blood cell counts, increased liver enzymes, decreased blood potassium levels, and increased blood glucose. Talk to your doctor if you experience any of these, or any other side effects.

Tell your healthcare provider if you are taking any other medications. Somatostatin analogs and corticosteroids may affect how your LUTATHERA treatment works. You should stop taking your long-acting somatostatin analog at least 4 weeks before LUTATHERA treatment. You may continue taking short-acting somatostatin analogs up to 24 hours before your LUTATHERA treatment. Avoid repeated high doses of glucocorticosteroids during treatment with LUTATHERA.

Please see fullPrescribing Informationfor LUTATHERA.

Disclaimer

This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "may," "could," "would," "expect," "anticipate," "seek," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Advanced Accelerator Applications S.A. Advanced Accelerator Applications, S.A. (AAA), a Novartis company, is developing targeted radioligand therapies and precision imaging radioligands for oncology indications. We are committed to transforming patients' lives by leading innovation in nuclear medicine. AAA has a legacy as a leader in radiopharmaceutical drugs for Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) diagnostic imaging. For more information, please visit: https://www.adacap.com

About NovartisNovartis is reimagining medicine to improve and extend people's lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world's top companies investing in research and development. Novartis products reach nearly 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 110,000 people of more than 140 nationalities work at Novartis around the world. Find out more at https://www.novartis.com

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