Acalabrutinib Plus Venetoclax/Obinutuzumab Demonstrates Efficacy, Safety in Mantle Cell Lymphoma

Acalabrutinib (Calquence) in combination with venetoclax (Venclexta) and obinutuzumab (Gazyva) demonstrated preliminary antitumor activity and a manageable safety profile in patients with relapsed/refractory or treatment-naive, transplant-ineligible or TP53-aberrant mantle cell lymphoma (MCL), according to findings from a phase 1/2 study (NCT04855695) presented at the 2024 ASH Annual Meeting.

Safety data for all treated patients (n = 39) indicated that the most common any-grade treatment-emergent adverse effects (AEs) occurring in at least 25% of patients included headache (49%), neutropenia (44%), bruising (41%), anemia (31%), diarrhea (26%), fatigue (26%), nausea (26%), and thrombocytopenia (26%).

Grade 3 or higher AEs most frequently reported included neutropenia (31%), thrombocytopenia (11%), anemia (5%), and diarrhea (3%). Any-grade AEs of special interest included infections (18%), infusion-related reactions (13%), secondary malignancies (5%), bleeding events (5%), and hypertension (5%); grade 3 or higher AEs of special interest comprised infection (8%), infusion-related reactions (3%), and secondary malignancies (3%).

Preliminary efficacy results from the relapsed/refractory MCL cohort (n = 18; cohort A) showed that patients who received the triplet regimen achieved a complete response (CR) rate of 78% and an objective response rate (ORR) of 83%. The treatment-naive cohort (n = 21; cohort B) experienced a CR rate of 81% and an ORR of 86%, Among patients with TP53-aberrant disease (n = 8), the CR and ORR rates were 75% and 88%, respectively. The treatment-naïve cohort (n = 21) demonstrated a CR rate of 81% and an ORR of 86%, with patients achieving a primary end point CR rate of 80% at cycle 8.

"[The combination regimen of acalabrutinib, venetoclax, and obinutuzumab] is safe and active in patients with relapsed/refractory and treatment-naive, TP53-aberrant and transplant-ineligible MCL," lead study investigator Austin I. Kim, MD, of the Department of Medical Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues, wrote in a poster presentation of the data. "Preliminary efficacy and feasibility of a time-limited, minimal residual disease [MRD]–guided treatment approach is encouraging in this high-risk transplant-naive cohort.”

Study Design and Patient Demographics

The phase 1 portion of the study utilized a 3+3 dose-finding schema and enrolled patients with relapsed/refractory MCL who had received at least 1 prior anti-CD20 monoclonal antibody–based therapy. Patients were required to have an ECOG performance status of 0 to 2, adequate renal and hepatic function, and meet select hematologic criteria. Those with prior exposure to a BTK or BCL-2 inhibitor were excluded, as were patients with confirmed central nervous system involvement or other significant comorbidities.

The phase 2 portion of the study included patients with treatment-naive MCL who were deemed transplant ineligible due to physician assessment or harbored a TP53 mutation confirmed by next-generation sequencing, or had more than 50% p53 expression on immunohistochemistry.

Cohort A included patients with relapsed/refractory disease; cohort B consisted of patients who were treatment-naive with TP53-aberrant disease or transplant ineligibility; and cohort C included treatment-naive patients with TP53 wild-type disease who were transplant eligible.

In all cohorts, patients received 7 cycles of the triplet combination, followed by maintenance therapy based on MRD status. In Cohort B, treatment discontinuation was permitted when peripheral blood MRD negativity was achieved and sustained for at least 3 months, with the earliest discontinuation allowed after 10 cycles.

The primary end points included establishing the recommended phase 2 dose, evaluating safety and tolerability, and assessing the CR rate following 7 cycles of treatment. Secondary end points included MRD-negativity rates and long-term clinical outcomes.

Patients in cohort A (n = 18) had a median age of 66 years (range, 55-79), and the majority were male (89%). The median number of prior therapies was 1 (range, 1-2), and 22% had relapsed disease after prior autologous stem cell transplant. One patient (6%) had relapsed following anti-CD19 CAR T-cell therapy, and 28% were considered primary refractory. High-risk disease features included TP53 aberrations in 44% of patients, Ki67 levels of at least 30% in 50% of patients, and complex karyotype in 22% of patients.

Patients in cohort B (n = 21) had a median age of 65 years (range, 44-81), and 90% were male. Notably, 81% had TP53-aberrant disease, 71% had TP53 mutations, and 57% had complex karyotypes. Additionally, 52% had a Ki67 level of at least 30%, and 67% had high-risk MCL International Prognostic Index scores.

Additional Efficacy Insights

In cohort A, the 18-month progression-free survival (PFS) rate was 77%; cohort B achieved a 12-month PFS rate of 86%. Among patients with TP53-mutated disease, the 12-month PFS rate was 87%. Cohort A experienced an 18-month overall survival (OS) rate of 90%, and cohort B achieved a 12-month OS rate of 95%. The TP53-mutated subset in cohort B achieved a 12-month OS rate of 93%.

MRD data indicated that among the 17 patients in cohort B with baseline peripheral blood MRD markers, 12 achieved MRD negativity at a threshold of 1 × 10⁻⁶. The MRD-negative CR rate was 86%, with patients with TP53-mutations demonstrating a higher MRD-negative CR rate of 91% (n = 11).

Treatment discontinuation and relapse patterns were also evaluated. Seven patients discontinued acalabrutinib and venetoclax, with 6 stopping after 10 cycles and 1 after 12 cycles. The median follow-up after treatment discontinuation was 5 months. One patient experienced clinical relapse at cycle 15, occurring 4 months after stopping therapy, and was subsequently retreated.

Based on these findings, a phase 2 expansion cohort (cohort C) is currently enrolling patients with treatment-naive, transplant-eligible, TP53 wild-type MCL based on the efficacy and safety outcomes observed in Cohort B.

Reference

Kim AI, Armand P, Ryan CE, et al. Preliminary efficacy and safety of a phase 1/2 study of acalabrutinib, venetoclax, and obinutuzumab in patients with relapsed/refractory and previously untreated mantle cell lymphoma (MAVO). Blood. 2024;144(supp 1):4408. doi:10.1182/blood-2024-198056