Combo Immunotherapy Failed to Improve Outcomes in MSS Colorectal Cancer

A phase III trial examining immunotherapy in patients with microsatellite-stable (MSS) metastatic colorectal cancer failed to meet its primary endpoint of improved overall survival.

The IMblaze370 trial was a phase III open-label trial that randomly assigned 363 patients 2:1:1 to atezolizumab with or without cobimetinib, or regorafenib. The trial was designed to test the combination treatment in patients with predominantly MSS metastatic colorectal cancer, which is historically unresponsive to immunotherapy.

With a median follow-up of 7.3 months, there was no difference in median overall survival between the 3 groups, and patients assigned to the combination of atezolizumab plus cobimetinib had double the frequency of grade 3 or worse adverse events and serious adverse events compared with atezolizumab alone.

“These results highlight the strong biological differences between microsatellite-stable tumors and those with high microsatellite instability, underscoring the divergent treatment needs between these two disease types,” wrote researcher Cathy Eng, MD, of the University of Texas MD Anderson Cancer Center, and colleagues, in Lancet Oncology. “Other immunotherapy combinations are worth exploring in patients with metastatic colorectal cancer, despite the negative results of the IMblaze370 study, because a high unmet need remains for patients with chemo-refractory metastatic colorectal cancer and the potential of immunotherapy has not been demonstrated with single drugs.”

Leonard Saltz, MD, chief of the gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center told Cancer Network that on the basis of a small phase II study with a small number of patients showing benefit from the combination of atezolizumab plus cobimetinib, the investigators and the sponsor did the right thing: a definitive randomized trial to answer the question.

“The answer was not the one any of us had hoped for, but it is a clear answer that we cannot ignore,” Saltz said. “This is a very important study in that it is cautionary about the importance of exploring preliminary observations in a rigorous manner before drawing conclusions.”

Included patients had unresectable locally advanced or metastatic disease and had progressed or were intolerant to at least two previous systemic chemotherapy regimens. Ninety-five percent of patients had MSS disease.

According to the study, “preclinical results, supported by early-phase studies, provided an impetus to assess the combination of atezolizumab plus cobimetinib in a phase III trial (IMblaze370) in patients with predominantly microsatellite-stable metastatic colorectal cancer who had progressed or were intolerant of 5-fluoropyrimidine, oxaliplatin, and irinotecan.”

The median overall survival for combination atezolizumab plus cobimetinib was 8.87 months compared with 7.10 months for atezolizumab alone and 8.51 months for regorafenib. Median progression-free survival was 1.91 months for combination treatment compared with 1.94 months for atezolizumab alone and 2.00 months for regorafenib.

Of the patients assigned to combination treatment, 61% reported grade 3/4 adverse events compared with 31% assigned to atezolizumab alone, and 58% assigned to regorafenib. The most common all-cause grade 3/4 adverse events were diarrhea (11%), anemia (6%), increased blood creatinine phosphokinase levels (7%), and fatigue (4%). Serious adverse events occurred in 40% of patients assigned to the combination compared with 17% of patients assigned single-agent atezolizumab and 23% of patients assigned regorafenib.

Commenting on the results of the IMblaze370 trial in an accompanying editorial, Francesco Sclafani, MD, of Université Libre de Bruxelles in Brussels, wrote that the negative results are a “great disappointment” and require “dwelling on potential reasons for such an unexpected failure.”

Among those reasons could be moving too quickly from a phase Ib trial, which had only a modest percentage of patients achieve an objective response, to a large phase III trial.

“The IMblaze370 trial appears to put an end to the suggestion that MEK inhibition might be a valid approach to unlock the inherent immune resistance of mismatch repair–proficient microsatellite-stable metastatic colorectal cancer,” he wrote. “Unleashing the full potential of immunotherapy in mismatch repair–proficient microsatellite-stable metastatic colorectal cancer should remain a priority of cancer research.”