Cobimetinib Plus Atezolizumab Active in Microsatellite Stable mCRC

Johanna C. Bendell, MD

Combined inhibition of the PD-L1/PD-1 axis with atezolizumab (Tecentriq) and the MEK pathway with cobimetinib (Cotellic) showed promising clinical activity and a good safety profile in heavily pretreated patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), according to findings from a phase 1b study presented at the 2016 World Congress on Gastrointestinal Cancer.

The cobimetinib/atezolizumab combination showed an investigator-assessed observed response rate (ORR) of 17% in 23 patients overall. An ORR of 20% was observed in 22 patients with KRAS-mutant tumors.

The 6-month overall survival rate (OS) rate was 72%. Partial response (PR) confirmed per RECIST v1.1 was achieved by 4 patients, and 5 patients showed stable disease.

"So far, immunotherapy has only shown activity in patients with microsatellite instability—high colorectal cancer, which is only about 4% of the population,” said principal investigator Johanna C. Bendell, MD, director of the GI Cancer Research Program at the Sarah Cannon Research Institute and an associate with Tennessee Oncology in Nashville.

“Microsatellite instability—high colorectal cancers are associated with a deficiency in DNA mismatch repair and a high mutation burden which demonstrates response to single-agent therapy targeting the PD-L1/PD-1 axis; however, the majority of mCRC patients are MSS and have lower response rates to PD-L1/PD-1 blockade,” she continued. “So what do we do with the remaining 96% of patients?”

Reasoning that MEK inhibition leads to an upregulation of major histocompatibility complex class I (MHC I) expression on tumor cells and increased intratumoral T-cell infiltration, Bendell and colleagues tested whether cobimetinib could enhance the anti-PD-L1 activity of atezolizumab in patients with MSS mCRC and advanced solid tumors.

The study treated 23 patients with cobimetinib at 20, 40, or 60 mg orally daily for 21 days of a 28-day cycle plus fixed-dose atezolizumab 800 mg IV every 2 weeks.

Patients had received a median of 3 (Range: 1 to 5) prior therapies; 22 patients had tumors with KRAS mutations and one patient had a KRAS wild-type tumor.

Among responding patients, the duration of response ranged from 4.0 to 7.7 months. No patients with microsatellite instability (MSI)—high disease were identified among the responders; 3 patients with PR were MSS or MSI-low by local testing, and the status of 1 patient with PR was unknown. "Responses are ongoing in 3 of 4 responding patients," Bendell said.

Additionally, "tumor volume reduction was not associated with PD-L1 status," Bendell noted. Among patients having reduced tumor volume, 18 had low baseline PD-L1 expression on tumor cells (TC0), and PD-L1 status was not available for 4 patients. One patient with high levels of PD-L1 expression (TC3) showed progressive disease following treatment.

The median safety follow-up was 3.78 months (range, 1.1-15.1). No dose-limiting toxicities, all-cause grade 5, or treatment-related grade 4 adverse events (AEs) were reported.

Treatment-related serious AEs included nausea, vomiting, and cerebrovascular accident in one patient each, which all were resolved.

“The majority of treatment-related adverse events were associated with MEK inhibition rather than PD-L1 blockade,” Bendell said.

Diarrhea, fatigue, dermatitis acneiform, and rash were reported by 70%, 52%, 44%, and 35% of patients, respectively. Maculopapular rash, pruritus, and nausea were each reported in 26% of patients.

"Cobimetinib plus atezolizumab was relatively 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," Bendell said.

Co-chair of the session, Eric Van Cutsem. MD, PhD, professor of internal medicine at the University of Leuven in Belgium, asked why this combination is particularly effective. Bendell replied: “These results suggest that cobimetinib can sensitize tumors to atezolizumab; serial biopsies taken during treatment showed increased MHC 1 expression on tumor cells and CD8 T-cell accumulation.”

She also noted that, “we don’t know yet whether cobimetinib will have a different effect depending on inhibition by PD-LI or PD1 agents; it is hard to say if you would see a difference, but this needs to be addressed in a large, randomized trial.

“These encouraging preliminary results have led to a phase III trial evaluating this combination in patients with chemorefractory mCRC that is now actively recruiting,” Bendell reported, adding that this trial would include both baseline and serial biopsies, and MHC expression would be done for biomarker analysis.

Bendell J, Tae Won K, Cheng Ean C, et al. Safety and efficacy of cobimetinib (cobi) and atezolizumab (atezo) in a Phase 1b study of metastatic colorectal cancer (mCRC). Presented at: 2016 World Congress on GI Cancer; June 28 - July 2, 2016; Barcelona, Spain. Abstract LBA-01.

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