Frontline Ibrutinib/Venetoclax Combo Shows High MRD-Negative Responses for CLL

William G. Wierda, MD, PhD

The frontline combination of ibrutinib (Imbruvica) and venetoclax (Venclexa) demonstrated a 100% objective response rate (ORR) for patients with chronic lymphocytic leukemia (CLL), with 77% of patients testing negative for minimal residual disease in the peripheral blood after 6 cycles, according to early findings from the phase II CAPTIVATE trial presented at the 2018 ASCO Annual Meeting.¹

In 11 patients treated with 12 cycles of ibrutinib and venetoclax with available bone marrow data, the complete remission (CR) rate was 36% and the rate of CR with incomplete hematologic recovery was 18%. Remaining responses consisted of nodular partial remissions (nPR; 9%) and PR (36%). All patients with a CR/CRi had confirmed undetectable MRD in the bone marrow. Sixty percent of those with a PR/nPR were MRD-negative.

After 12 cycles of therapy, all patients with a CR/CRi had undetectable MRD in the bone marrow (6 of 6). For those with a PR/nPR, the MRD rate was 60%.

"This is an early report of an ongoing study that combined ibrutinib plus venetoclax for patients with CLL younger than 70 years old," said lead investigator William G. Weirda, MD, executive medical director of the Leukemia Center at, The University of Texas MD Anderson Cancer Center. "Early MRD data showed very encouraging results, with 77% of the first patients have undetectable disease after just 6 cycles of treatment. These results show a highly active, safe treatment with a fixed duration of venetoclax and ibrutinib."

The study enrolled 164 patients with treatment-naive CLL. The median age of patients was 58 years, and 32% had Rai stage III/IV disease. Fifteen percent of patients had 17p deletions (del17p) and 18% had 11q deletions. IGHV was unmutated for 60% of patients. The median creatinine clearance (CrCl) was 95 mL/min and 30% of patients had clearance below 80 mL/min.

Undetectable MRD was seen early in the study. In MRD evaluable patients (n = 30), the MRD-negative rate was 77% after cycle 9. In 14 patients receiving 12 cycles, the MRD rate was 86% and the rate was 93% after cycle 15. After cycle 12, 79% of patients were MRD-negative in the peripheral blood and bone marrow. After cycle 15, MRD was undetectable in the bone marrow for 86% of patients.

The lead-in period with ibrutinib effectively shifted patients toward less bulky disease. Before to treatment with ibrutinib, 29% of patients had a longest lymph node diameter (LDi) of ≥5 cm and 3% had a LDi of ≥10 cm. After treatment with the BTK inhibitor, no patients had LDi of ≥10 cm and just 6% had an LDi of ≥5 cm.

Lymphadenopathy resolved to <1.5 cm in 47%. Additionally, all patients with baseline splenomegaly had a reduction in spleen size with treatment, with a return to normal for 63%.

At the time of the analysis, 100% of efficacy-evaluable patients remained on treatment (N = 30). The median duration of treatment was 10.4 months for ibrutinib and 7.6 months for venetoclax. There were 2 cases of tumor lysis syndrome (TLS) according to laboratory values; however, these patients did not demonstrate any clinical characteristics associated with TLS.

Of the full population of patients in the trial, 40 were at high risk for TLS at the beginning of the trial (24%). After the ibrutinib lead in period, just 4 patients were at high risk (3%), representing a decline to low (29%) or medium (65%) risk for 90% of high-risk patients. In those at medium risk for TLS and CrCl <80 mL/min (n = 37), 19% were downgraded to low risk following ibrutinib, and 29 no longer required hospitalization.

"Three cycles of lead-in ibrutinib monotherapy resulted in reduced tumor bulk, particularly in patients at highest risk for TLS," Weirda noted.

Safety findings were available for 164 patients who received the full 3 cycle lead-in plus at least 1 dose of venetoclax. The most common adverse events (AEs) with the combination were diarrhea (63%), fatigue (27%), nausea (35%), headache (24%), upper respiratory tract infection (24%), and arthralgia (29%). The most common grade ≥3 AEs were neutropenia (27%), hypertension (6%), diarrhea (4%), and thrombocytopenia (6%).

AEs led to treatment discontinuation for 5% of patients, and a dose reduction was required for 16% of patients. During the ibrutinib lead in, atrial fibrillation (AF) occurred in 3% of patients, 1.2% of which was grade 3 in severity. With the combination treatment, AF occurred for 4.3% of patients (0.6% was grade 3). There were no grade 4 events. Rates of infection were low both in the lead-in (2.4) and the combination phase (2.4). There were no grade 4 infections.

"Spectrum and frequency of observed adverse events was consistent with monotherapy, and there were no new safety signals or concerns with the combination," Weirda said.

Findings from CAPTIVATE trial join those from the phase II TAP CLARITY study, which was presented at the 2017 ASH Annual Meeting.² In this trial, the CR/CRi rate with ibrutinib and venetoclax in patients with relapsed/refractory CLL was 47% for 38 efficacy-evaluable patients. The ORR was 100% and the MRD-negative rate was 37% in the peripheral blood and 32% in the bone marrow.

A phase III study known as GLOW/CLL3011 is currently recruiting patients to explore the combination of ibrutinib and venetoclax compared with chlorambucil and obinutuzumab as a frontline treatment for patients with CLL (NCT03462719). Additionally, another study (GAIA) is looking at various combinations for fit patients with untreated CLL. One arm of this trial is looking at ibrutinib and venetoclax combined with obinutuzumab (NCT02950051).

References

1. Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). J Clin Oncol. 2018;36 (suppl; abstr 7502).
2. Hillmen P, Munir T, Rawstron A, et al. Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 428.

<<< 2018 ASCO Annual Meeting

Ibrutinib was initially administered alone in a lead-in stage at 420 mg daily for the first 3 cycles. After this stage, venetoclax was added and eventually escalated to a 400-mg-per-day dose. MRD was defined as fewer than 0.01% CLL cells by flow cytometry in the peripheral blood after 6 cycles of combination therapy and measured again by bone marrow after 12 cycles of ibrutinib plus venetoclax.