A phase III study determined that the combination of atezolizumab and cobimetinib wasn't more effective than standard therapy in patients with inoperable, locally advanced or metastatic colorectal cancer. The overall survival for patients treated with the combination was 8.9 months, versus 8.5 months for standard-of-care regorafenib. Further, only 2.7% of patients responded to the drug duo, versus 2.2% for regorafenib.

The combination of Genentech's atezolizumab (Tecentriq) and cobimetinib (Cotellic) is no more effective than standard of care for patients with previously treated metastatic colorectal cancer, according to results presented recently at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer in Barcelona, Spain (Ann Oncol 2018;29 [suppl_5; abstr LBA-004]).

PD-L1 inhibitors such as atezolizumab have worked poorly as a monotherapy in patients with microsatellite-stable colorectal cancer, which accounts for 95% of cases. However, a 2016 study of mice with colorectal tumors found that adding a MEK inhibitor, such as cobimetinib, spurs T cells to enter the tumors and boosts the effectiveness of anti–PD-L1 immunotherapy (Immunity 2016;44:609–21). Those results led to a phase Ib trial of atezolizumab plus cobimetinib in patients with metastatic colorectal cancer.

Building on that study, the phase III IMblaze370 trial assessed the drugs in patients with inoperable, locally advanced or metastatic colorectal cancer, 91.7% of whom had cancers that were microsatellite-stable or showed a low degree of instability. Patients received atezolizumab alone, atezolizumab with cobimetinib, or the multikinase inhibitor regorafenib (Stivarga; Bayer), the standard of care.

At the Congress, researchers presented data for 363 patients, and the results revealed no statistically significant difference in effectiveness between the combination and regorafenib. The median overall survival was 8.9 months for patients treated with the two drugs, 8.5 months for those who received regorafenib, and 7.1 months for those who received atezolizumab. The overall response rates were 2.7% in the combination therapy group and 2.2% in the atezolizumab and regorafenib monotherapy groups. Progression-free survival was also similar across the three groups.

The atezolizumab/cobimetinib combination was also comparable to regorafenib in severity and frequency of side effects. The rate of grade 3 or higher adverse effects in patients who received the two drugs was 45%, versus 49% for the regorafenib group. Among the patients who received the drug duo, 56% developed diarrhea, 42% developed a rash, and 32% suffered nausea. In the regorafenib group, the most common side effect was hand–foot syndrome, a condition that affected 51% of the patients. Forty-three percent of the patients in this group reported fatigue, and 35% suffered diarrhea.

“These results are very discouraging,” says Patrick Boland, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, NY, who wasn't connected to the study. Given that “there is virtually no response here,” he says, “it seems doubtful that we will identify a group of patients that's going to benefit from this combination.”

However, the two drugs may still prove useful, says Adam Snook, PhD, of Thomas Jefferson University in Philadelphia, PA, who also wasn't connected to the study. The work “seems to suggest that PD-1/PD-L1 signaling is not the primary cause of immune suppression in colorectal cancer,” Snook says. Therefore, treatments that target other checkpoint proteins, such as OX40, might stimulate tumors to activate PD-1/PD-L1 signaling and become vulnerable to atezolizumab/cobimetinib therapy. “I'm excited to see what these other checkpoint pathways are going to do,” he says. –Mitch Leslie

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