More than 50% of patients with relapsed/refractory multiple myeloma (RRMM) exhibit mitogen-activated protein kinase (MAPK) pathway mutations. Whereas MAPK kinase (MEK) inhibitors alone have shown modest activity in RRMM, 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. A phase 1b/2 study of single-agent cobimetinib (C; a MEK inhibitor) or C + venetoclax (V; a BCL2 inhibitor), with or without atezolizumab (A; a PD-L1 inhibitor), was conducted in patients with RRMM.
Enrollment criteria 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, were evaluated in safety run-in (SRI) cohorts 1 and 2. Randomization was then performed 1:2:2 to cobimetinib 60 mg orally daily on days 1 through 21 (Arm A); cobimetinib 40 mg orally daily on days 1 through 21 and venetoclax 800 mg orally daily on days 1 through 28 (SRI 1, Arm B); and atezolizumab 840 mg intravenously on days 1 and 15 (SRI 2, Arm C) in 28-day cycles. Pharmacokinetic analyses and exploratory biomarker assessments were performed.
A total of 49 patients were enrolled (Arm A, n = 6; Arm B, n = 22; Arm C, n = 21). The median age was 65 years; 63% of patients were male, 94% had Eastern Cooperative Oncology Group performance status 0 to 1, and 47% had International Staging System stage II/III disease. Patients received a median of 4 prior lines of therapy (prior autologous stem-cell transplant, 43%; prior daratumumab, 41%). High-risk cytogenetics, defined as del(17p), t(4;14), t(14;16), were present in 24% of patients; 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 as follows: diarrhea (cobimetinib, 33%; C+V, 82%; C+V+A, 91%), nausea (cobimetinib, 17%; C+V, 50%; C+V+A, 67%), anemia (cobimetinib, 17%; C+V, 46%; C+V+A, 57%), neutropenia (cobimetinib, 0%; C+V, 32%; C+V+A, 57%), thrombocytopenia (cobimetinib, 0; C+V, 27%; C+V+A, 33%), blood creatine phosphokinase increase (cobimetinib, 17%; C+V, 32%; C+V+A, 24%), and rash (cobimetinib, 50%; C+V, 14%; C+V+A, 33%). The most common grade 3/4 AEs were neutropenia (cobimetinib, 0%; C+V, 14%; C+V+A, 38%), anemia (cobimetinib, 0%; C+V, 23%; C+V+A, 24%), thrombocytopenia (cobimetinib, 0%; C+V, 18%; C+V+A, 24%), and pneumonia (cobimetinib, 0%; C+V, 18%; C+V+A, 14%). Pneumonia was the most common serious AE (cobimetinib, 0%; C+V, 23%; C+V+A, 14%). Tumor lysis syndrome was reported in 2 patients. AEs leading to treatment discontinuation occurred in 17%, 18%, and 14% of patients receiving cobimetinib, C+V, and C+V+A, respectively. Twenty-seven deaths (55%) occurred at a median follow-up of 13.4 months (cobimetinib, 4 [67%]; C+V, 14 [64%]; C+V+A, 9 [43%]), with the leading cause being progressive disease (cobimetinib, 2 [50%]; C+V, 11 [79%]; C+V+A, 7 [78%]). Deaths, resulting from pneumonia in 1 patient (C+V) and general physical health deterioration in 1 patient (C+V+A), were considered treatment related.
Median overall survival was 12.9 months, 12.4 months, and 22.0 months with cobimetinib, C+V, and C+V+A, respectively. The overall response rate was 0% (0/6) for cobimetinib, 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 t(11;14) versus non-t(11;14) patients (100% [5/5] and 50% [2/4], respectively). Median duration of response was 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). No clinically relevant drug–drug interactions were observed.
Preliminary results from this phase 1b/2 study indicate that cobimetinib, 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 was demonstrated, thereby suggesting that biomarkers should be considered for future development of C+V in multiple myeloma.
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.