End-of-Year Wrap Up: Examining Past, Present, and Future Developments in CLL – Cancer Network

The year 2021 played host to several developments in the treatment of chronic lymphocytic leukemia (CLL), including promising data related to novel Burton Tyrosine kinase (BTK) inhibitors such as zanubrutinib (Brukinsa) and the examination of the benefit of continuous vs time limited regimens, according to Matthew S. Davids, MD, MMSc.

Looking forward into the new year, Davids spotlighted some potential events that the clinicians in the space witness in the new year.

There are a lot of exciting things going on right now in CLL, he explained. I do expect [that] we are likely to see a label for ibrutinib [Imbruvica] plus venetoclax [Venclexta] in the frontline setting in 2022. This is the first time well have the option to have an all-oral novel agent time-limited regimen for frontline CLL. We also have emerging data for noncovalent BTK inhibitors, for example, pirtobrutinib [LOXO-305]; we saw some great data at the [2021 American Society of Hematology Annual Meeting & Exposition (ASH)] suggesting this drug can work even for patients who have progressed on first-generation covalent BTK inhibitors, even if theyve already had venetoclax. Its hard to always knows what the timeframe is for these types of approvals, but I do think well see at least evolving datasets for pirtobrutinib in 2022.

In an interview with CancerNetwork, Davids, a physician and director of clinical research in the Division of Lymphoma at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, highlighted potential FDA decisions that may take place in 2022, such as the potential approval of frontline ibrutinib/venetoclax and the decision to either approve or extend the label for ublituximab (TG-1101) and umbralisib (Ukoniq) in the treatment of CLL and small lymphocytic leukemia (SLL).

Please be sure to read part 1 of our 3-part End-of-Year Wrap Up series in which Yael Cohen, MD, discusses updates in the multiple myeloma space that took place in 2021.

Davids: There were several impactful abstracts at this years ASH meeting in CLL. For me, one of the more exciting ones that I saw was the [phase 3] CLL13 trial [NCT02950051].1 This is an almost 1000-patient study going on in Europe that is largely comparing various venetoclax-based combinations with chemoimmunotherapy. At this ASH meeting, we saw for the first time the minimal residual disease (MRD) data from the study. Some of the takeaways for me were that the venetoclax plus obinutuzumab [Gazyva] combination performed well [with] high rates of undetectable MRD. [It was] certainly much higher than with chemoimmunotherapy, which wasnt a huge surprise, but also much higher than venetoclax with rituximab [Rituxan], which is a little bit surprising that the CD20 antibody made such a big difference. The study also had a triplet regimen of ibrutinib, venetoclax, and obinutuzumab. Although it looked a little bit more potent than venetoclax/obinutuzumab on its own, I do think that the doublet performed quite well. [Thus], its an open question whether the third drug is actually needed in the up-front setting.

We also saw [cohort 1] data from phase 3 SEQUOIA study [NCT03336333] for the first time.2 This is a registrational study looking at zanubrutinib, a newer, more specific BTK inhibitor compared with bendamustine and rituximab. This was a positive study favoring the PFS with zanubrutinib and is likely to lead to a label for [the regimen], hopefully in the future, in CLL. Several other impactful studies were presented, [including] various combinations of Ibrutinib plus venetoclax, both in older patients, for example, in an update to the phase 3 GLOW study [NCT03462719],3 as well as in younger fit patients in an update to the phase 2 CAPTIVATE study [NCT02910583] which really showed very nice durable responses.4 We presented some of our data on the combination of ibrutinib plus fludarabine, cyclophosphamide, and rituximab for young patients with CLL. This also has proven to be quite durable in terms of deep responses, [including] a 97% PFS rate with about 40 months of follow up. [It is] not something that would be broadly applied to a large population of patients with CLL, but [it could be] for those very young, fit patients who might want the potential for a functional cure of their disease. We think that this is the type of regimen that should be explored in larger comparative studies.

There are 3 main areas that I would focus on here from 2021. One of them is the idea of longer-term follow-up with venetoclax plus obinutuzumab. We saw the publication of the [phase 3 CLL14 trial (NCT02242942)] earlier this year with 4-year follow-up [that showed] a 74% rate of progression-free survival (PFS) at 4-years in patients treated with 1 year of venetoclax plus obinutuzumab.5 To me, that was impactful [and] gave me the confidence that my patients can enjoy a long remission after 1 year of time limited therapy largely across the board with the possible exception of high-risk patients with TP53 aberrant disease. Those patients did have a shorter PFS, although it was still close to 4 years which is quite impressive.

We also saw longer-term data presented at the 2021 American Society of Clinical Oncology Annual Meeting on the phase 3 Elevate-TN study [NCT02475681].6 This is the registrational trial for the more specific BTK inhibitor acalabrutinib [Calquence] in the frontline setting; this also looks quite good. About 87% of the patients are progression free [at 48 months] when treated with acalabrutinib/obinutuzumab and a little bit lower with acalabrutinib alone but still very good results. Again, [this] gives a lot of confidence that we can use acalabrutinib as a continuous treatment.

The third area that was very impactful for clinical practice was the readout of the phase 3 Elevate-RR study [NCT02477696].7 This was a trial weve been waiting on for several years. Its a head-to-head study of the original BTK inhibitor ibrutinib compared with acalabrutinib in relapsed/refractory higher-risk patients with CLL. The study showed complete equivalence in terms of the efficacy; the median PFS was 38.4 months in both arms. But there were significant advantages from a safety perspective with acalabrutiniblower rates of cardiovascular disorders overall, less atrial fibrillation, less hypertension, less bleeding overall, and lower rates of other factors such as interstitial lung disease. For me, this was influential that for patients who are newly starting on a BTK inhibitor, Im now leaning more toward acalabrutinib even though we do have a long-standing experience with ibrutinib. Its still a great drug, but acalabrutinib is also now an appealing option for many patients with CLL.

With ublituximab and umbralisib [U2], we have some early-phase data with both of these drugs on their own and in combination that looked promising. That inspired the development of the phase 3 UNITY-CLL trial [NCT02612311]. Thats now the largest dataset that we have looking at the U2 regimen. The study randomized both frontline and relapsed/refractory patients in a stratified manner to U2 vs chlorambucil with obinutuzumab. Weve seen the data presented from that study suggesting a significantly longer PFS both in frontline and relapsed patients for U2 as compared with chlorambucil plus obinutuzumab. Also, the tolerability of umbralisib does look somewhat more favorable than what we expect from other PI3K inhibitor drugs that are already approved like idelalisib [Zydelig] and duvelisib [Copiktra], particularly in the frontline setting where it has not been possible to safely use those other drugs. They did show feasibility in the UNITY-CLL study in the frontline setting using U2. Thats the main dataset that the FDA will be reviewing as they decide on whether to extend the label of umbralisib to CLL and whether to approve, for the first time, ublituximab in this disease.

The ASH meeting in 2021 was a huge [event] for CAR T-cell therapy in diffuse large B-cell lymphoma. But for CLL, things were a little bit more quiet. We had seen data presented earlier in the year at the summer congresses on lisocabtagene maraleucel [Liso-cel; Breyanzi], a CD19-directed CAR T-cell [therapy for] relapsed CLL, [in the phase 1 TRANSCEND-CLL-004 study (NCT03331198)].8 Those data were published this year in 2021, which is very helpful to see and do look promising. The single-agent data for liso-cel show about a 45% complete response rate, and upwards of 80% or more patients achieving undetectable MRD. There were also some data presented earlier this year [regarding] a combination CAR T-cell therapy with ibrutinib. This is also with liso-cel, which is a promising combination. The numbers of patients treated are still pretty small; were awaiting larger datasets. I dont think its going to be too soon that were going to see an approval yet for a CAR T-cell therapy in CLL. [However], I do think this is a promising therapeutic modality for our patients, [and] it will eventually have a role in this disease. Im hopeful that well start to see larger datasets emerge soon.

There are a lot of exciting things going on right now in CLL. I do expect in 2022, we are likely to see a label for ibrutinib plus venetoclax in the frontline setting. This is the first time well have the option to have an all-oral novel agent, time-limited regimen for frontline CLL. I think thats exciting. We also have data emerging for noncovalent BTK inhibitors, for example, pirtobrutinib. We saw some great data at ASH suggesting this drug can work even for patients who have progressed on the first generation of covalent BTK inhibitors, even if theyve already had Venetoclax. Its hard to always knows what the timeframe is for these types of approvals but I do think well see at least evolving datasets for pirtobrutinib in 2022.

We also have the U2 regimen in development that the FDA will be reviewing in 2022, [in which theyll] decide on whether that will get a label. We have a number of important ongoing studies around the world looking to answer some of the key questions in the field. [There are] couple of them that Im most excited about, one [being] the phase 3 CLL17 study [NCT04608318], which has already launched in Europe led by the German CLL study group, helping to answer this key question of continuous vs time-limited frontline therapy. Which is better? That study [features] ibrutinib continuously vs 1 of 2 time-limited combinations: ibrutinib plus venetoclax or obinutuzumab plus venetoclax. We also are launching the phase 3 MAGIC study [NCT03836261] in 2022 here in the US and around the world. This is looking at whats the optimal combination partner for Venetoclax in the frontline setting; is it the BTK inhibitor acalabrutinib, or is it obinutuzumab? Its a phase 3 randomized trial comparing those 2 regimens, both given in an MRD-driven fashion. Were hoping that eventually will answer an important question about time-limited therapy in the field.

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End-of-Year Wrap Up: Examining Past, Present, and Future Developments in CLL - Cancer Network