Fixed-Duration Ibrutinib Plus Venetoclax Shows ‘Deep, Durable’ Remissions in CLL, SLL

Fixed-duration ibrutinib plus venetoclax “continues to provide deep, durable remissions” as first-line treatment for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to four-year follow-up data from the phase II CAPTIVATE study.

Paul Barr, MD, of the Wilmot Cancer Institute at the University of Rochester Medical Center, and colleagues conducted the study and presented their findings during the 2023 American Society of Clinical Oncology Annual Meeting.

The multicenter, phase II study enrolled 159 patients who were at least 70 years old who had previously untreated CLL/SLL. Around half (56%) of the patients had unmutated IGHV, while 17% had del(17p) or a TP53 mutation. They received three cycles of ibrutinib followed by 12 cycles of ibrutinib plus venetoclax. Patients received oral ibrutinib 420 mg daily, with a ramp-up to oral venetoclax 400 mg daily. The median time on study was 50 months.

With four years of follow-up data, the best complete response (CR) rate was 58%, and the overall response rate was unchanged at 96%. The four-year progression-free survival (PFS) rate was 79%, and the four-year overall survival (OS) rate was 98%. The four-year PFS rate was 73% in patients with unmutated IGHV, while it was 63% in those with del(17p) or a TP53 mutation. However, OS rates “remained consistently high” in those patients, according to Dr. Barr and colleagues.

The four-year PFS rates were significantly higher in patients who had undetectable measurable residual disease (MRD) three months after stopping therapy than those who had detectable MRD at that time point (90% vs 66%). However, “this difference was minimal” at 24 months (100% vs 91%), according to the study’s authors.

The median time to next treatment was not reached overall. The four-year rate of freedom from next treatment was 84%.

“Second malignancies continue to be collected off treatment,” Dr. Barr and colleagues noted, with one adverse event (AE) of prostate cancer occurring during this year of follow-up.

To date, 19 patients who had progressive disease after completing fixed-duration ibrutinib plus venetoclax in either cohort initiated retreatment with ibrutinib. Of those patients, 17 had available data, including 13 who had a partial response (PR), one with a CR, one with a PR with lymphocytosis, one with a PR with stable disease, and one with a PR with progressive disease. The median time on retreatment was 11 months.

The most common AEs with retreatment, occurring in at least 10% of patients, were diarrhea, COVID-19, and anemia.

“New safety findings off-treatment were expectedly negligible, highlighting the benefits of a fixed-duration regimen,” according to Dr. Barr and colleagues. “Promising responses were observed upon retreatment with [ibrutinib] in progressing [patients].”

Furthermore, four patients have started retreatment with ibrutinib plus venetoclax to date.

“Results of the CAPTIVATE study support [ibrutinib plus venetoclax] as an all-oral, once-daily fixed-duration regimen for previously untreated [patients] with CLL/SLL,” Dr. Barr and colleagues concluded. “With [four years of] follow-up, fixed-duration [ibrutinib plus venetoclax] continues to provide deep, durable remissions with clinically meaningful PFS and time off treatment, including in [patients] with high-risk disease features.”

Reference

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. Abstract 7535. Presented at the 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, Illinois.