Various Combinations With Venetoclax Show Positive Signs in CLL

Catherine Coombs, MD

The core combination therapy for chronic lymphocytic leukemia (CLL) is venetoclax (Venclexta) plus obinutuzumab (Gazyva), which demonstrated progression-free survival (PFS) superiority over chemoimmunotherapy combinations through the open-label, phase 3 CLL14 trial (NCT02242942) (88.2% vs 64.1%, respectively, at 28.1 months) and the open-label, phase 3 GAIA-CLL13 trial (NCT02950051) (90.5% vs 75.5% at 15 months). Combination therapies outside of this are investigational; however, they are generating excitement with ongoing trials that could expand standard practice for the future.^1,2

“We always worry about the concept of using all our most effective agents up front, and then think, ‘What happens now?’ but very few patients are progressing on these regimens because they’re so effective,” Catherine Coombs, MD, said in an interview.

Coombs, an associate professor in the Division of Hematology/Oncology at the University of California, Irvine School of Medicine, in Orange, California, explored the topic during the Meet-the-Professor session at the Twelfth Annual Meeting of the Society of Hematologic Oncology (SOHO 2024).

For instance, group D of the open-label, multicenter, phase 3 SEQUOIA trial (NCT03336333) evaluated the efficacy of the combination of zanubrutinib (Brukinsa) plus venetoclax. Preliminary data from November 2019 to June 2022 of the additional nonrandomized group D (n = 66) were presented at the European Hematology Association (EHA) 2024 Congress.³

As of October 31, 2023, with a median follow-up of 28.6 months, data showed that the median PFS was not reached and the estimated 36-month PFS was 92% (95% CI, 81%-97%) for 65 response-evaluable patients with treatment-naive CLL/small lymphocytic lymphoma with del(17p) and/or TP53 mutation. The overall response rate was 100%, the complete response rate was 45%, and undetectable minimal residual disease (uMRD) was achieved in at least 1 peripheral blood (PB) sample from 48% of patients in the study.

There were 55 patients who remained on treatment, with 16 patients receiving zanubrutinib plus venetoclax and 39 receiving zanubrutinib monotherapy after venetoclax. Most patients were male (52%), and the median age was 66 years (range, 26-87). There were 4 deaths, 1 withdrawal, and 1 patient who was lost to follow-up among the 66 patients who were treated with the combination, and 3 patients discontinued treatment during the zanubrutinib lead-in period.

Those participating in the trial received a 160-mg dose of lead-in zanubrutinib twice daily for 3 cycles and then an escalation dose to 400 mg once daily of zanubrutinib plus venetoclax for 24 cycles. This was followed by monotherapy zanubrutinib until disease progression, unacceptable toxicity, or achieving the early dose-stopping rules for either agent. Regarding safety, 97% of patients experienced grade 1 or greater treatment-emergent adverse events (TEAEs) with the most common all-grade TEAEs being COVID-19 (55%), diarrhea (41%), contusion (29%), and nausea (29%). The most common grade 3 or greater TEAEs were diarrhea (8%) and hypertension (8%), and overall grade 3 or greater nonhematologic TEAEs occurred in 44% of patients. The most common hematologic toxicity, all grade (21%) and grade 3 or greater (17%), was neutropenia. The percentage of patients at high risk for tumor lysis syndrome (TLS) dropped from 35% during screening to 3% after 3 cycles of lead-in zanubrutinib, with no instances of TLS reported. Investigators reported that the safety profile of the combination was consistent with results of prior studies administering zanubrutinib, and no new safety signals were identified.

Microscopic image of CLL cells - Generated with Google Gemini AI

“The SEQUOIA trial was a little bit of a complicated study design due to the length of time in which patients were on therapy and to the subsequent stopping rules. Nonetheless, that combination [in cohort D] looks promising,” Coombs said.

Nitin Jain, MD, a professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, Texas, presented data at the EHA 2024 Congress from a phase 2 trial (NCT05536349). In the trial, investigators evaluated the triplet combination of pirtobrutinib (Jaypirca), venetoclax, and obinutuzumab in treatment-naive CLL or Richter transformation.⁴ Although the trial included Richter transformation, the EHA presentation focused mainly on CLL, Coombs added.

After 6 months of treatment, uMRD rates in bone marrow (BM) were 64% and in PB were 79%. After 12 months, these rates improved to 85% in BM and 90% in PB. These uMRD rates exceed those observed in a previous trial using ibrutinib (Imbruvica) plus venetoclax as first-line therapy, where the uMRD rates after 6 months were 33% and after 12 months were 52%.⁵ “The study showed astounding rates of uMRD. But the follow-up was short, and we’ll need to see a bit more on the longevity of that triplet regimen,” Coombs said.

The AE profile resembled that of previous studies that combined treatments for first-line CLL, according to investigators. As of a median follow-up of 11.7 months, there have been no instances of disease progression or mortality among the patients. Out of the 40 patients who started the study treatment, 39 completed cycle 7, which was the primary end point. There were 19 patients in cycles 10 to 13 at the time of the presentation, and 20 patients have completed cycle 13, according to study investigators. The trial is actively enrolling participants for an additional cohort of 40 patients.

The 4-year follow-up data from the phase 2 CAPTIVATE trial (NCT02910583), which investigated a fixed duration of ibrutinib plus venetoclax, examined whether any patients developed resistance mutations, “and it doesn’t look like that is a problem,” Coombs said.⁶ The fixed-duration treatment regimen resulted in a 70% PFS rate (95% CI, 62%-77%) among the 159 patients studied. The median duration until the need for subsequent treatment has not been reached, with an estimated 82% (95% CI, 76%-87%) freedom from requiring further treatment at 4.5 years.

New data are eagerly awaited in ongoing trials for lymphocytic leukemia: the phase 3 AMPLIFY trial (NCT03836261) evaluating acalabrutinib (ACP-196; Calquence) in combination with venetoclax, with and without obinutuzumab vs chemoimmunotherapy, and the phase 3 MAJIC trial (NCT05057494) evaluating acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab. MAJIC does not follow a conventional trial design where patients cease treatment after a specified duration; instead, it uses MRD-guided discontinuation, Coombs added. Lastly, the phase 3 CELESTIAL-TNCLL trial (NCT06073821) evaluating sonrotoclax (BGB-11417) plus zanubrutinib compared with venetoclax plus obinutuzumab is anticipated.

“There are a lot of options, and they continue to evolve,” Coombs said. “We now can continue to refine and perfect the way that we treat this disease. It will be exciting to see how well these regimens perform when repeated, but I do think we need longer follow-up to see how efficacious that would be.”

REFERENCES:

1. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/nejmoa1815281

2. Eichhorst B, Niemann CU, Kater AP, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754. doi:10.1056/nejmoa2213093

3. Ma S, Munir T, Lasica M, et al. Combination of zanubrutinib + venetoclax for treatment-naive (TN) CLL/SLL with del (17p) and/or TP53: preliminary results from sequoia arm D. Presented at: European Hematology Association 2024 Congress; June 13-16, 2024; Virtual and Madrid, Spain. Abstract S160.

4. Jain N, Atluri H, Ferrajoli A, et al. Combined pirtobrutinib, venetoclax, and obinutuzumab in first-line treatment of patients with chronic lymphocytic leukemia (CLL): a phase 2 trial. Presented at: European Hematology Association 2024 Congress; June 13-16, 2024; Virtual and Madrid, Spain. Abstract S164.

5. Jain N. Combined ibrutinib and venetoclax for first-line treatment of patients with chronic lymphocytic leukemia (CLL): 5-year follow-up data. Presented at: American Society of Hematology Annual Meeting and Exposition; December 11, 2023; San Diego, CA. Abstract 4635.

6. Barr PM, Allan JN, Siddiqi T, et al. Fixed-duration ibrutinib + venetoclax for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 4-y follow-up from the FD cohort of the phase 2 CAPTIVATE study. J Clin Oncol. 2023;41(16 suppl):7535. doi:10.1200/jco.2023.41.16_suppl.7535