CHICAGO — The combination of cobimetinib and atezolizumab was well tolerated and demonstrated encouraging clinical activity in patients with microsatellite stable colorectal cancer (CRC), according to a study presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting.1
“Microsatellite instability CRC, which is associated with deficiency in DNA mismatch repair and high mutation load, demonstrated response to single-agent therapy targeting PD-L1/PD-1 axis,” said lead investigator Johanna Bendell, MD, director of the GI Cancer Research Program at the Sarah Cannon Research Institute/Tennessee Oncology in Nashville. “However, high microsatellite instability comprises only about 4% of mCRC.”
Atezolizumab monotherapy has shown activity in numerous tumor types, but response rates in microsatellite stable CRCs have been lower than in other cancer types. Because MEK inhibition leads to upregulation of major histocompatibility complex class I (MHC I) on tumor cells, induces intratumoral T-cell infiltration, and enhances anti-PD-L1 activity, researchers sought to evaluate the activity and tolerability of cobimetinib with atezolizumab in patients with advanced solid tumors.
For the phase 1 study, researchers enrolled 23 patients with CRC, of which 20 had KRAS-mutant tumors. Patients had received a median of 5 prior therapies. Patients received cobimetinib at varying doses, ranging from 20 mg to 60 mg, orally daily for 21 days of each 28-day cycle plus atezolizumab 800 mg IV every 2 weeks.
Results showed that the objective response rate was 17%. Four patients achieved partial responses and 5 had stable disease. Among patients with KRAS-mutant tumors, the objective response rate was 20%.
“Responses are ongoing in 2 of 4 responding patients,” Dr Bendell added.
Researchers also found that response was not associated with baseline PD-L1 expression, but they observed enhanced PD-L1 upregulation, CD8 T-cell infiltration, and MHC I expression on treatment in serial biopsies.
“Tumor volume reduction was not associated with PD-L1 status,” Dr Bendell noted.
In terms of safety, the most frequently reported treatment-related adverse events were diarrhea (70%), fatigue (52%), dermatitis acneiform (44%), rash (35%), maculopapular rash (26%), pruritus (26%), and nausea (26%). Approximately one-third of patients experienced grade 3 treatment-related adverse events, the most common of which was diarrhea. Importantly, no grade 5 or treatment-related grade 4 toxicities were reported and no dose-limiting toxicities were observed.
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“Cobimetinib plus atezolizumab was well tolerated at the maximum administered doses in patients with chemotherapy-refractory KRAS-mutant mCRC, and the combination resulted in a higher clinical response rate in microsatellite stable patients than is expected from either cobimetinib or atezolizumab alone,” Dr Bendell explained.
Based on these encouraging preliminary findings, the expansion of this phase 1b trial is ongoing in patients with mCRC.
- Bendell JC, Kim TW, Goh BC, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol. 2016; 34 (suppl; abstr 3502).