An immunotherapy and targeted therapy combination failed to improve survival over standard third-line therapy for patients with chemorefractory metastatic colorectal cancer (CRC) and microsatellite-stable disease, a phase III trial found.
Median overall survival with the PD-L1 inhibitor atezolizumab (Tecentriq) plus MEK inhibitor cobimetinib (Cotellic) was no better than treatment with regorafenib (Stivarga) for these patients (8.9 vs 8.5 months; HR 1.00, 95% Cl 0.73-1.38, P=0.99), reported Fortunato Ciardiello, MD, PhD, of Università degli Studi della Campania Luigi Vanvitelli in Naples, Italy, and colleagues.
And with a median overall survival of 7.1 months, atezolizumab alone was numerically worse than regorafenib (HR 1.19, 95% Cl 0.83-1.71, P=0.34), the researchers wrote in Lancet Oncology.
Median progression-free survival was 1.9 months in each of the atezolizumab arms versus 2.0 months in the regorafenib arm, and objective responses occurred in 3% of patients treated with atezolizumab-cobimetinib and in 2% of patients treated with each of the single agents.
“Although many patients with metastatic colorectal cancer who have tumors with high microsatellite instability benefit from clinical improvement after immune checkpoint inhibitor therapy, patients with microsatellite-stable tumors do not,” Ciardiello’s group wrote.
Only about 3% to 5% of CRC patients have microsatellite instability, a genetic marker for immunotherapy response that led to the FDA approval of the anti-PD-1 agents pembrolizumab (Keytruda) and nivolumab (Opdivo) and the anti–CTLA-4/PD-1 combination of ipilimumab (Yervoy) plus nivolumab for all solid tumor patients who harbor this genetic abnormality and have previously been treated with chemotherapy.
Mouse models of cobimetinib showed anti-tumor activity “while promoting the effector phenotype and longevity of tumor-infiltrating CD8+ T cells,” and an anti-MEK/PD-L1 combination had a synergistic effect that led to durable treatment responses and complete regression in some cases. A phase Ib trial that reported objective responses in 8% of CRC patients with microsatellite stable disease led to development of the phase III IMblaze370 trial.
“Despite the rationale supported by preclinical data, our results suggest that dual inhibition of the PD-L1 immune checkpoint and MAPK-mediated immune suppression is insufficient to generate anti-tumor immune responses in immune-excluded tumors, such as microsatellite-stable metastatic colorectal cancer,” the authors wrote. “This failure to generate a response could be because of alternative mechanisms to bypass the inhibition of the MAPK pathway by a MEK inhibitor.”
In an editorial that accompanied the study, Francesco Sclafani, MD, of the Institut Jules in Brussels, said the findings appear to put an end to the suggestion that MEK inhibition can overcome immune resistance in CRC patients with microsatellite-stable disease.
“There is great disappointment for the negative results of the IMblaze370 trial because of the scientific interest and general enthusiasm for the underlying biological rationale and supportive preliminary clinical findings,” he wrote. “Dwelling on potential reasons for such an unexpected failure is therefore imperative.”
Sclafani noted that the immunomodulatory effects of MEK inhibition are not actually a settled matter, with some data reporting “suppression of T lymphocyte proliferative response and antigen-specific expansion and impairment of antigen processing by dendritic cells,” which could account for the trial’s negative findings.
He also questioned the trial’s lack of a biomarker strategy and said that heterogeneous tumor characteristics in microsatellite-stable CRC may require “distinct immunomodulatory strategies” to restore immunogenicity and generate anti-tumor immune responses.
The investigators noted that a limitation of the study was that it was not designed to examine patient subgroups that may have been more likely to respond to the combination therapy.
From 2016 to 2017, the IMblaze370 study randomized 363 adult CRC patients 2:1:1 to the combination of 840-mg atezolizumab (IV every 2 weeks) plus 60-mg oral cobimetinib daily (days 1-21 of 28-day cycles), 1200-mg atezolizumab monotherapy (IV every 3 weeks), or 160-mg regorafenib monotherapy (days 1-21 of 28-day cycles). Patients were eligible if they had an Eastern Cooperative Oncology Group performance status of 0-1 and had progressed or were intolerant of ≥2 prior lines of systemic therapy. Enrollment of patients with microsatellite instability–high CRC was allowed, but capped at 5%.
Grade 3/4 adverse events (AEs) in the combination arm were twice as frequent as in the atezolizumab monotherapy arm (61% vs 31%, respectively), but similar to the regorafenib arm (58%). Common grade 3/4 AEs (>5%) in the combination arm included diarrhea (11%), increased blood creatine phosphokinase (7%), and anemia (6%).
Serious AEs occurred in 40% of patients in the combination arm versus 23% with regorafenib and 17% with atezolizumab alone. There were two therapy-related deaths with the combination arm due to sepsis and one in the regorafenib arm due to intestinal perforation.
The study was funded by Roche/Genentech.
Ciardiello disclosed financial relationships with Roche/Genentech, Merck Serono, Pfizer, Amgen, Servier, Lilly, Bayer, Bristol-Myers Squibb, and Celgene. Co-authors reported relationships with Roche/Genentech and various other industry entities.
Sclafani declared no competing interests.