75% of Patients on Ibrutinib-Venetoclax Combo in CLL Achieve Undetectable MRD in CAPTIVATE

Most patients with previously untreated chronic lymphocytic leukemia (CLL) who received a combination of ibrutinib and venetoclax achieved undetectable minimal residual disease (MRD), according to partial results from the phase 2 CAPTIVATE trial¹ presented this weekend at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida.

Patients in the study, who were under age 70, received a daily oral dose of 420 mg of ibrutinib (Imbruvica) for 3 cycles (28 days each), followed by 12 cycles of ibrutinib with an escalating dose of venetoclax (Venclexta/Venclyxto) up to 400 mg. Of the evaluable patients, 75% achieved undetectable MRD in their peripheral blood at some point after baseline, while 72% achieved undetectable MRD in their bone marrow.

Lead investigator Constantine Tam, MD, of the Peter MacCallum Cancer Centre, Victoria, Australia, presented results from the MRD cohort prior to randomization based on their MRD status. Results presented at ASH involved 164 patients who began the trial and 151 who were able to complete all 12 cycles. In the next phase, which will be reported later, patients with undetectable MRD were randomized 1:1 to receive ibrutinib or placebo, while those with detectable MRD will randomized to receive ibrutinib or ibrutinib with venetoclax.

And, Tam said, based on the successful results to date, “We have now accrued a third 159 patients in a separate, fixed duration cohort,” and these patients will receive the combination therapy “without any further treatment.”

Ibrutinib has transformed CLL care as the only daily inhibitor of Bruton tyrosine kinase (BTK). Its benefits have been seen in first-line CLL in both RESONATE-2 and ECOG-1912; investigators for these studies reported additional data during this weekend's meeting. Venetoclax is an oral inhibitor of BCL2, proteins that regulate cell death, or apoptosis. As CAPTIVATE investigators discuss in their abstract, the 2 therapies are believed to have synergistic properties given the ability of ibrutinib to draw CLL cells from lymphoid tissue into the blood, where they would rely on BCL2. Tam is also leading studies of the 2-drug combination in mantle cell lymphoma.

MRD is an increasingly important measure of the small number of cancer cells remaining in the body after treatment. These cells can be hard to detect, but they are important because they can be indicators of which patients will relapse. The use of MRD as a guide for treatment will be the focus of CAPTIVATE when the next wave of results are reported, and this will help answer one of the important questions the trial is designed to address, Mark Wildgust, PhD, vice president, Global Medical Affairs, Oncology, Janssen, said in an interview with The American Journal of Managed Care.®

Before ibrutinib, he said, the reason patients with CLL would only be treated with 6 cycles of the regimen known as FCR—fludarabine, cyclophosphamide, and rituximab—was because they could not tolerate any more therapy. Ibrutinib “changed the paradigm,” Wildgust said; he noted that new data from ECOG-1912 presented at ASH show that the continuously treating patients with ibrutinib is better than the old “gold standard” of 6 cycles of FCR.²

With CAPTIVATE, the question of stopping therapy is raised not because patients can no longer tolerate treatment, but because once they are MRD negative, it might be possible to stop therapy without CLL progressing. “Really,” said Wildgust, “the question of stopping is, ‘Can we do it safely?’”

Thus, the study seeks to answer (1) Can patients who have 15 cycles of therapy reach a point where MRD cannot be measured, and (2) If therapy is stopped, is it safe?

Clinicians got an early glimpse at CAPTIVATE data in June 2018 during the annual meeting of the American Society of Clinical Oncology, where 77% of the first 30 patients had undetectable MRD after 6 cycles of the combination. Presenters explained at that time that the lead-in with ibrutinib alone helps prevent tumor-lysis syndrome (TLS); this protocol is also seen in the CLARITY trial for patients with relapsed for refractory CLL.

In the results presented at ASH 2019, the median treatment duration was 14.7 months (range 0.5 to 19.9 months) with ibrutinib and 12 months (range 0.8-12.7 months) with venetoclax. The most common adverse events (AEs) of any grade were diarrhea (31%) with single agent ibrutinib, and diarrhea (60%), neutropenia (40%), and nausea (34%) with the combination. AEs leading to dose reductions occurred in 20% of patients, and AEs that caused patients to stop therapy occurred in 7% of patients (ibrutinib 5%, venetoclax, 4%).

“This study was not intended to enroll high-risk patients,” Tam said during his presentation, but many in the original 164 enrollees (median age 58 years) had genetic risk factors:

• 16% had deletion 17p
• 20% had deletion 17p or TP53 mutation
• 16% had deletion 11q without deletion 17p
• 19% had complex karyotype
• 59% had unmutated immunoglobin heavy (IGHV) chain gene mutation

Tam noted the high rate of undetectable MRD was seen across subgroups, including these high-risk patients: deletion 17p, 75%; deletion 17p or TP53 mutation, 70%: deletion 11q, 84%; complex karyotype, 83%, and unmutated IGHV, 81%.

Of the patients who reached the combination therapy cycles:

• Undetectable MRD in peripheral blood (PB) rose over time, from 57% after 6 cycles to 68% after 9 cycles and 73% after 12 cycles.
• Undetectable MRD was achieved in 75% of patients (122 of 163) in PB when measured; and 72% (111 of 155 patients) in bone marrow.

“We are encouraged by these data and the potentially potent combination of ibrutinib plus venetoclax treatment for CLL and potentially other blood cancers in the future,” Tam said in a statement.

New Analysis From Earlier Studies. An integrated analysis³ of the RESONATE and RESONATE-2 studies, which incudes up to 6 years of follow-up, covered a total of 271 patients, including 136 patients who received ibrutinib as first-line therapy and 135 who received it for relapsed or refractory CLL. The analysis shows that using ibrutinib earlier in treatment of CLL results in better progression-free survival (PFS), overall survival, and overall risk reduction. Results include:

• A higher share of patients treated with ibrutinib in earlier lines remained progression-free or alive at 60 months (first-line, 70%; 1-2 lines prior, 60%; 3 or more, 33%).
• First-line treatment brought a 34% reduction in risk of disease progression or death compared with 1-2 prior lines, with a hazard ratio (HR) of 0.66 (95% CI, 0.40-1.09).
• PFS was prolonged for first-line vs 3 or more lines, HR 0.32 (95% CI, 0.21-0.49), and 1-2 lines vs 3 or more lines, HR 0.48 (95% CI, 0.30-0.77).

Wildgust said Janssen will continue to support research to explore questions of whether patients can safely stop therapy for CLL, and if so, what is the best way.

“We’re at a point where ibrutinib has 5 front-line studies that show a survival benefit,” he said, including the new RESONATE analyses that show earlier treatment is better. “Now the question is whether we can look at potential ways of stopping—and as a company we’re looking at all those different ways of stopping.”

References

1. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Presented at the 61^st American Society of Hematology Annual Meeting and Exposition, Orlando, Florida; December 7-10, 2019; Abstract 35. ash.confex.com/ash/2019/webprogram/Paper121424.html.
2. Shanafelt TD, Wang V, Kay NE, et al. Ibrutinib an rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 trial. outcomes for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at the 61^st American Society of Hematology Annual Meeting and Exposition, Orlando, Florida; December 7-10, 2019; Abstract 33. ash.confex.com/ash/2019/webprogram/Paper126824.html.
3. Barr PM, Tedeschi A, Munir T, et al. Using ibrutinib in earlier lines of treatment results in better outcomes for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at the 61^st American Society of Hematology Annual Meeting and Exposition, Orlando, Florida; December 7-10, 2019; Abstract 3054. ash.confex.com/ash/2019/webprogram/Paper123327.html