In patients with relapsed/refractory multiple myeloma (RRMM), preliminary results from this phase 1b/2 study of cobimetinib alone or plus venetoclax, with or without atezolizumab show manageable toxicity, moderate efficacy overall, and higher efficacy for those with t(11;14).
Mitogen-activated protein kinase (MAPK) pathway mutations are exhibited in >50% of patients with RRMM. MAPK kinase (MEK) inhibitors alone have shown modest activity in RRMM. However, combining these agents with a B-cell lymphoma 2 (BCL2) inhibitor with or without a programmed death-ligand 1 (PD-L1) inhibitor could increase efficacy by augmenting both apoptosis and the antitumor immune response. In patients with RRMM, a phase 1b/2 study of single-agent cobimetinib (C; a MEK inhibitor), C plus venetoclax (V; a BCL2 inhibitor), with or without atezolizumab (A; a PD-L1 inhibitor), was conducted.
Enrollment criteria for these patients included RRMM and 3 to 5 prior therapies, including a proteasome inhibitor and an immunomodulatory drug. The safety of C+V and C+V+A, respectively, was evaluated in safety run-in cohorts 1 and 2. Then, randomization was performed 1:2:2 to cobimetinib 60 mg orally daily on days 1 to 21 (arm A); cobimetinib 40 mg orally daily on days 1 to 21 and venetoclax 800 mg orally daily on days 1 to 28 (safety run-in cohort 1, arm B); and atezolizumab 840 mg intravenously on days 1 and 15 (safety run-in cohort 2, arm C) on 28-day cycles. Pharmacokinetic analyses and exploratory biomarker assessments were performed.
A total of 49 patients were enrolled (safety run-in cohort 1, N = 6; safety run-in cohort 2, N = 6; arm A, N = 6; arm B, N = 16; arm C, N = 15). Median patient age was 65 years, 63% of patients were male, 94% had Eastern Cooperative Oncology Group performance status 0/1, and 47% had International Staging System II/III disease. Patients received a median of 4 prior lines of therapy (prior autologous stem-cell transplantation: 43%; prior daratumumab: 41%). Present in 24% of patients were high-risk cytogenetics, defined as del(17p), t(4;14), t(14;16); 20% were t(11;14) positive; 51% had RAS mutations (KRAS, NRAS, BRAF, NF-1); and 31% had high PD-L1 expression.
The most common adverse events (AEs; any grade) were diarrhea (C: 33%; C+V: 82%; C+V+A; 91%), nausea (C: 17%; C+V: 50%; C+V+A: 67%), anemia (C: 17%; C+V: 46%; C+V+A: 57%), neutropenia (C: 0%; C+V: 32%; C+V+A: 57%), thrombocytopenia (C: 0; C+V: 27%; C+V+A: 33%), blood creatine phosphokinase increase (C: 17% C+V: 32%; C+V+A: 24%), and rash (C: 50% C+V: 14%; C+V+A: 33%). The most common grade 3/4 AEs were neutropenia (C: 0%; C+V: 14%; C+V+A: 38%), anemia (C: 0%; C+V: 23%; C+V+A: 24%), thrombocytopenia (C: 0%; C+V: 18%; C+V+A: 24%), and pneumonia (C: 0%; C+V: 14%; C+V+A: 14%). The most common serious AE was pneumonia (C: 0%; C+V: 23%; C+V+A: 14%). In 2 patients, tumor lysis syndrome was reported. AEs leading to treatment discontinuation occurred in 17%, 18%, and 14% of patients receiving C, C+V, and C+V+A, respectively. At a median follow-up of 13.4 months, 27 deaths (55%) occurred (C: 4 [67%]; C+V: 14 [64%]; C+V+A: 9 [43%]), with the leading cause being progressive disease (C: 2 [50%]; C+V: 11 [79%]; C+V+A: 7 [78%]). Deaths due to pneumonia in 1 patient (C+V) and general physical health deterioration in 1 patient (C+V+A) were considered treatment-related.
Median overall survival rates were 12.9 months, 12.4 months, and 23.3 months with C, C+V, and C+V+A, respectively. Overall response rates were 0% (0/6) for C, 27% (6/22) for C+V, and 29% (6/21) for C+V+A. Higher response rates were observed with C+V and C+V+A among patients with t(11;14) versus those with non-t(11;14) (100% [5/5] and 50% [2/4], respectively). Median duration of response rates were 11.5 months and 5.1 months for C+V and C+V+A, respectively. Four patients remain on treatment: 3 are t(11;14) positive and 1 is t(11;14) negative and RAS wild-type but BCL2/BCL2L1 (BCL-X) high (log2 fold change ≥2.3). There were no clinically relevant drug–drug interactions observed.
Phase 1b/2 preliminary study results indicate that C, C+V, and C+V+A are tolerable in heavily pretreated patients with RRMM. Moderate efficacy overall and higher efficacy for t(11;14) patients were shown, suggesting that biomarkers should be considered for future development of C+V in multiple myeloma.
Reference
Abstract 295. ASH 2020. December 5, 2020. Safety and preliminary efficacy results from a phase Ib/II study of cobimetinib as a single agent and in combination with venetoclax with or without atezolizumab in patients with relapsed/refractory multiple myeloma.