August 2021: Targeted Therapy & Immuno-Oncology – AJMC.com Managed Markets Network

The addition of zanubrutinib to the guidelines was based on the findings from the ASPEN studypublished in Blood. The study compared the safety and efficacy of zanubrutinib, a novel highly selective Bruton tyrosine kinase (BTK) inhibitor, with ibrutinib, a first-generation BTK inhibitor.2

In ASPEN, 28% of patients on zanubrutinib and 19% on ibrutinib achieved a very good partialresponse (VGPR); no patient achieved a complete response (CR). The study did not meet the primary end point, which was proportion of patients achieving CR or VGPR, but the investigators noted that there was a trend toward better disease control for zanubrutinib vs ibrutinib.

Major response rate was similar (77% for zanubrutinib vs 78% for ibrutinib), as was progression-freesurvival (85% for zanubrutinib vs 84% for ibrutinib). Patients on zanubrutinib had fewer instancesof atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, andpneumonia, as well as adverse events that led to treatment discontinuation.

This study established that zanubrutinib is highly effective in the treatment of WM; zanubrutinibis associated with important safety advantages, especially with respect to cardiovascular toxicity,the authors wrote.

The data from ASPEN was used in a supplemental new drug application (sNDA) with the FDA forzanubrutinib in the treatment of WM, which was submitted in February 2021. Health Canada approved zanubrutinib in WM in March based on the findings of ASPEN.

We are pleased that the FDA has accepted the sNDA for Brukinsa in WM, a rare disease with significant morbidity, Jane Huang, MD, chief medical officer, Hematology, BeiGene, said in a statement. BTK inhibitors have transformed the treatment of WM in recent years, but discrepancies in response exist in patients with different subtypes, and toxicity can remain an issue.3

References1. NCCN. Clinical Practice Guidelines in Oncology. Version 1.2022. Waldenstrm macroglobulinemia/lymphoplasmacytic lymphoma. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=14752. 2. Tam CS, OPat S, DSa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenstrm macroglobulinemia: the ASPEN study.Blood. 2020;136:2038-2050. doi:10.1182/blood.20200068443. BeiGene announces US FDA acceptance of supplemental New Drug Application for Brukinsa (zanubrutinib) in Waldenstrms Macroglobulinemia. News release. BeiGene. Published February 17,2021. Accessed July 20, 2021. https://ir.beigene.com/news-releases/news-release-details/beigene-announces-us-fda-acceptancesupplemental-new-drug

With more treatment options needed in glioblastoma multiforme (GBM) to successfully attack disease, attention has been paid to chimeric antigen receptor (CAR) T-cell therapy, which hasshown great promise in hematologic malignancies and is being studied in other settings, includingcentral nervous system solid tumors, like GBM. In a recent paper, investigators provide a look atclinical trials currently assessing the potential of treatment for the disease.

Although theres hope that CAR T-cell therapy can revolutionize the way GBM is treated, there isstill more research to be done, investigators write inCancer Medicine, noting that research on CART-cell therapy in this setting is still in early stages.1

Despite the promising results of CAR T technology in hematological malignancies, CAR T cellsfor GBM are still in their earlier stage, wrote the investigators. Several GBM-associated antigenshave served as the targets of ongoing clinical trials (EGFRvIII, NKG2D, B7-H3, CD147, IL13Ralpha2,and HER2). Most of the current clinical trials are still in phase 1, testing the safety and efficacy ofmostly second-generation CAR T cells constructed with CD28 and 4-1BB costimulatory intracellulardomains.

The investigators write that, to date, evidence suggests combined therapy is more effective thanmonotherapy in GBM, which not only gives insight into how to enhance the efficacy of CAR T-celltherapy but also to potentially curtail adverse effects. The investigators outlined various ongoingtrials of CAR T-cell therapy that combine the therapy with other agents in patients with GBM.

With 70% of patients with GBM expressing B7-H3, which is not expressed on normal tissues, 1 ongoing trial is currently assessing the safety and tolerability of B7-H3 CAR T-cell therapy withtemozolomide, with B7-H3 CAR T being injected between temozolomide cycles. Data from the study are expected in 2022.2

EGFRvIII CAR T-cell therapy is being studied in several trials, with an ongoing phase 1 studyassessing the therapy in combination with temozolomide and another assessing EGFRvIIICAR T following radiosurgery in patients with recurrent GBM.

CAR T-cell therapy in combination with immune checkpoint inhibitors is also being assessed for both recurrent and resistant disease, say the investigators. A phase 1 trial is currently looking at the safety and efficacy of IL13Ralpha2-CRT T cells used alone or in combination with nivolumab and ipilimumab.

Although still in the preclinical stage, Fc-CRs T cells may prove to be a leader in the treatment ofGBM and other solid tumors, say the investigators. As research on CAR T-cell therapy in GBMprogresses, the investigators are also calling attention to the challenges facing the therapy inthe disease, including the highly unstable tumor microenvironment and the variable genetic natureof the disease.

The mechanism by which the apparent tumor responses or growth delay in CAR-T cell-treatedGBM are multifactorial. This cannot be attributed to the therapy but could instead result from differences in the natural history of disease between patients, commented the investigators. Although there are no direct ways to demonstrate the actual killing of tumor cells by CAR T in situ, previous clinical and preclinical data suggest that CAR-T-EGFRvIII cells induce their action by antigen-directed cytolysis after crossing the bloodbrain barrier.

References

1. Marei HE, Althani A, Afifi N, et al. Current progress in chimeric antigen receptor T cell therapy for glioblastoma multiforme.Cancer Med. Published online June 19, 2021. doi:10.1002/cam4.4064

2. Pilot Study of B7-H3 CAR-T in Treating Patients With Recurrent and Refractory Glioblastoma. Updated May 12, 2020. Accessed July 15, 2021. https://clinicaltrials.gov/ct2/show/NCT04385173.

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August 2021: Targeted Therapy & Immuno-Oncology - AJMC.com Managed Markets Network