Related Experiment Video
Updated: Jan 27, 2026
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors
M D Hellmann1, T-W Kim2, C B Lee3
1Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, USA.
Background:
Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors.
Patients And Methods:
This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival.
Results:
Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases.
Conclusions:
Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study.
Clinicaltrials.Gov Identifier:
NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix, available at Annals of Oncology online).
Insights
Combining cobimetinib (a MEK inhibitor) and atezolizumab (a PD-L1 inhibitor) showed manageable safety and clinical activity in patients with solid tumors. While synergistic activity was observed in metastatic colorectal cancer, it was not confirmed in later studies.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Preclinical studies indicate MEK inhibition enhances anti-tumor T cell responses and synergizes with immune checkpoint inhibitors.
- This study investigates the combination of cobimetinib (MEK inhibitor) and atezolizumab (PD-L1 inhibitor) in solid tumors.
Purpose of the Study:
- To evaluate the safety and clinical activity of combining cobimetinib and atezolizumab in patients with solid tumors.
- To assess response rates, progression-free survival, and overall survival as secondary endpoints.
Main Methods:
- A Phase I/Ib study involving dose-escalation and expansion cohorts in PD-L1/PD-1-naive patients with solid tumors.
- Cobimetinib administered orally (21 days on, 7 days off); atezolizumab administered intravenously every 2 weeks.
- Primary objectives: safety and tolerability; Secondary objectives: objective response rate, progression-free survival, overall survival.
Main Results:
- 152 patients enrolled; 150 received atezolizumab. Most common adverse events: diarrhea (67%), rash (48%), fatigue (40%).
- Confirmed responses observed in metastatic colorectal cancer (8%), melanoma (41%), and non-small-cell lung cancer (18%).
- Clinical activity was consistent across KRAS/BRAF statuses.
Conclusions:
- The combination of atezolizumab and cobimetinib demonstrated manageable safety and clinical activity in solid tumors, regardless of KRAS/BRAF status.
- Potential synergistic activity in metastatic colorectal cancer was noted but not confirmed in a subsequent Phase III trial.
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