Fixed-duration ibrutinib-venetoclax induces deep responses in treatment-naive CLL
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Fixed-duration first-line treatment with ibrutinib plus venetoclax induced deep, durable responses among patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, according to results of the phase 2 CAPTIVATE study.
The results — presented during the virtual ASCO Annual Meeting — showed efficacy among patients with high-risk features, and researchers characterized response, PFS and OS outcomes as favorable.
The findings support using ibrutinib (Imbruvica; Janssen, Pharmacyclics) plus venetoclax (Venclexta; AbbVie, Genentech) as an all-oral, once-daily, chemotherapy-free, fixed-duration regimen in this setting, researcher Paolo Ghia, MD, PhD, of the division of experimental oncology at Università Vita-Salute San Raffaele in Italy, told Healio.
“One can always ask for a [randomized phase 3 study] ... to compare [this combination] with standard therapy, but the results from this phase 2 study are already so compelling and ... support the possibility of adopting this strategy in the real world,” Ghia told Healio.
The option of fixed-duration treatment with ibrutinib and venetoclax “will have a major impact” on this patient population, Ghia added.
“We would like to reduce the period of treatment to reduce the risk of resistance to the drug, reduce the risk [for] adverse events, and also reduce the economic burden,” Ghia said. “On the other side, we have a very potent combination that is all oral, so we don't need to add infusion or to have the patient coming to the hospital frequently during follow-up.”
Ibrutinib — a Bruton tyrosine kinase inhibitor — is the only targeted therapy shown in randomized phase 3 studies to demonstrate significant OS benefit as first-line treatment for CLL. However, nearly all patients receive treatment indefinitely.
Venetoclax is a BCL-2 inhibitor approved as monotherapy or in combination with anti-CD20 monoclonal antibodies for treatment of CLL.
Ghia and colleagues conducted the international, multicenter CAPTIVATE study to assess whether combining these two agents — which have complementary mechanisms of action — as first-line treatment may improve outcomes.
In one cohort of CAPTIVATE, patients received three cycles of ibrutinib as lead-in therapy, followed by 12 cycles of ibrutinib plus venetoclax.
Researchers than randomly assigned patients to minimal residual disease-guided treatment. Those with confirmed undetectable minimal residual disease received either placebo or ibrutinib, whereas those who did not have confirmed undetectable minimal residual disease received either ibrutinib alone or ibrutinib plus venetoclax.
Previously released results from that cohort showed more than two-thirds of patients who received all 12 cycles of ibrutinib-venetoclax achieved undetectable minimal residual disease (peripheral blood, 75%; bone marrow, 68%). More than 95% of patients in that cohort achieved 30-month PFS regardless of subsequent minimal residual disease-guided treatment.
During ASCO, Ghia presented results of a second cohort designed to assess fixed-duration treatment.
Patients received three lead-in cycles with ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib-venetoclax (ibrutinib, 420 mg once daily; venetoclax, 5-week ramp-up to 400 mg once daily). Upon progression, patients could be retreated with single-agent ibrutinib, or fixed-duration ibrutinib-venetoclax if they had durable response.
The cohort included 159 patients (median age, 60 years; range, 33-71; 67% men) with previously untreated CLL or small lymphocytic lymphoma. Slightly more than one-quarter (28%) had Rai stage III or stage IV disease.
High-risk features included 17p deletion/TP53 mutation (17%), 11q deletion (18%), complex karyotype (19%) and unmutated immunoglobulin heavy-chain variable (IGHV) region gene (56%).
Complete response rate — including complete response with incomplete bone marrow recovery — per investigator assessment among patients who did not have 17p deletion served as the primary endpoint. Secondary endpoints included overall response rate, undetected minimal residual disease rate (defined as less than 10-4 by eight-color flow cytometry), PFS, OS, tumor lysis syndrome risk reduction and adverse events.
Six patients discontinued treatment during the lead-in (adverse events, n = 3; consent withdrawal, n = 2; death, n = 1). Six others discontinued treatment during the combination therapy stage (adverse events, n = 4; progressive disease/Richter’s transformation, n = 1; investigator decision/adverse event, n = 1).
Overall, 147 patients (92.4%) completed all 12 planned cycles of ibrutinib-venetoclax. Median treatment duration was 13.8 months (range, 0.5-24.9), equivalent to 15 28-day cycles.
Median follow-up was 14 months after therapy completion.
The study met its primary endpoint. Researchers reported complete response rates of 55% (95% CI, 48-63) in the overall population and 56% (95% CI, 48-64) among 136 patients without 17p deletion. These rates appeared consistent across most high-risk subgroups.
The majority of complete responses lasted at least 1 year (overall population, 89%; no 17p deletion, 87%).
Nine patients who achieved complete response had less than 1 year of follow-up and, therefore, were not evaluable, Ghia said. Another patient died 7 months after achieving complete response.
Results showed 96% of patients responded to therapy; 77% of patients achieved undetected minimal residual disease response in peripheral blood and 60% achieved that status in bone marrow.
“This really tells us that this is a potent combination that can reach deeper responses,” Ghia said. “More interestingly, these responses are durable.”
Researchers performed a survival analysis based on median follow-up of 27.9 months (range, 0.8-33.2).
They reported estimated 24-month PFS rates of 95% (95% CI, 90-97) in the overall population and 96% (95% CI, 91-98) for those without 17p deletion. They reported the same 24-month OS rate among all treated patients (98%; 95% CI, 94-99) and those without 17p deletion (98%; 95% CI, 93-99).
“What surprised us is that — despite the fact that the treatment has been given for a fixed time ... and despite the fact that not everyone reached undetectable minimal residual disease — 95% of the patients maintained the response in the follow-up,” Ghia said. “[This suggests] the combination of these two drugs is somehow modifying perhaps the natural history of the disease. So, even in the absence of the treatment, when we stop it, efficacy is maintained.”
The most frequent adverse events included diarrhea (any grade, 62%; grade 1/grade 2, 59%), nausea (any grade, 43%; grade 1/grade 2, 42%), neutropenia (any grade, 42%; grade 1/grade 2, 9%) and arthralgia (any grade, 33%; grade 1/grade 2, 32%).
More than half (62%) of patients experienced grade 3/grade 4 adverse events, the most common of which were neutropenia (33%), infections (8%), hypertension (6%) and decreased neutrophil count (5%).
Any-grade adverse events of clinical interest included atrial fibrillation (4%) and major hemorrhage (2%).
Thirty-six patients (23%) experienced serious adverse events and one patient experienced a fatal adverse event, described as sudden death during ibrutinib lead-in.
Five patients (3%) discontinued ibrutinib due to adverse events, and three patients (2%) discontinued both ibrutinib and venetoclax for the same reason.
Thirty-three patients (21%) required dose reductions of at least one agent due to adverse events, and 88% of patients who experienced adverse events that prompted dose reduction had resolution of those events at the time of analysis, Ghia said.
The ibrutinib-venetoclax combination appeared well-tolerated with common concomitant medications such as antihypertensives, acid-reducing agents, anticoagulants and antiplatelet agents, Ghia said.
Eight patients who experienced disease progression after fixed-duration treatment underwent retreatment with single-agent ibrutinib. Six achieved a partial response; response evaluation is pending for the other two.
The regimen is deliverable in the outpatient setting for most young, fit patients with CLL or small lymphocytic lymphoma, Ghia said.
“I think ibrutinib plus venetoclax — in particular, because of the high efficacy and the fixed-duration scheme — will become a viable option in the treatment of patients with CLL,” Ghia told Healio. “Some patients will still prefer monotherapy — continuous therapy — which is showing a high level of efficacy ... with follow-up up to 7 years. ... [The fixed-duration regimen] will really help us to personalize the treatment based on the patient's expectations.”
The randomized phase 3 GLOW study evaluated fixed-duration ibrutinib-venetoclax vs. chlorambucil plus obinutuzumab (Gazyva, Genentech) for first-line treatment of older (median age, 71 years) or unfit patients with CLL or small lymphocytic lymphoma.
Results, presented at European Hematology Association Congress, showed superior PFS, improved duration of remission and improved depth of remission with ibrutinib-venetoclax.
“We are talking about elderly patients with comorbidities,” Ghia said. “The results of this study show that ... the elderly patients are responding well to the combination, reaching at any time of treatment [a] similar level of undetectable minimal residual disease as we have seen in the younger population.”
References:
- Ghia P, et al. Abstract 7501. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
- Kater A, et al. Abstract LB1902. Presented at: European Hematology Association Virtual Congress; June 9-17, 2021.
Perspective
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The results are great, but the only result in this population that really matters in my mind is the duration of minimal residual disease negativity. These are young patients with early disease so, if they weren’t achieving meaningful survival, it would be a major problem. They should have 10-year survival with any therapy we have. The real issue is whether you can use a completely oral, fixed-duration-regimen and get durable response.
I love the idea of the fixed duration, because it means patients may not have to take a lifetime of expensive therapy. It looks like this regimen was equally good in terms of maintaining response for the time these patients have been followed. To me, however, this all comes down to longer follow-up.
There is always the assumption that you can retreat when needed. Ghia and colleagues only showed a little bit of the retreatment data but that is because so many patients stayed in remission. The question I have won’t be answered for many years. That is: When these patients are no longer minimal residual disease negative and their disease slowly starts to come back, does having them off therapy for a long period of time — hopefully years — allow them to maintain sensitivity to the same treatment they received before? If so, then CLL becomes like chronic myeloid leukemia, and that would be very exciting.
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Ghia P, et al. Abstract 7501. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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