In one of the first clinical trials combining immunotherapy and targeted therapy for patients with BRAF V600E–mutated colorectal cancer, researchers discovered that a combination regimen of dabrafenib, trametinib, and spartalizumab resulted in long-lasting responses. The study findings published by Tian et al in Nature Medicine suggested how targeted therapies in combination with immunotherapies may improve patient outcomes.
Background
BRAF mutations occur most commonly in melanoma but are also found in 10% of colorectal cancers. BRAF is a known component of the MAPK signaling pathway.
Several drugs have been developed to target components of this pathway. BRAF inhibitors have been highly effective for patients with melanoma, with a majority of them showing strong initial responses to these agents. But responses to BRAF inhibitors occur in less than 5% of patients with BRAF V600E–mutated colorectal cancer. Further, immunotherapy generally has been ineffective at treating colorectal cancers, excluding the 4% of tumors with microsatellite instability.
Study Methods and Results
“Immunotherapy and targeted therapy represent two of the biggest breakthroughs in cancer treatment in the last decade,” explained co-corresponding study author Ryan Corcoran, MD, PhD, Associate Professor of Medicine at Harvard Medical School and Director of the Massachusetts General Hospital Gastrointestinal Cancer Center program. “By combining these two approaches, we saw a dramatic increase in patients who responded to treatment and unprecedented durability, with 18% of patients staying in the trial for a year or more,” he emphasized.
Dr. Corcoran and his colleagues drew inspiration for the clinical trial from observations seen in preclinical models—the findings of which demonstrated that inhibitors targeting the MAPK pathway might enhance the immune system’s response. Based on these observations, the team investigated whether combining a therapy targeting BRAF could enhance the effectiveness of the immunotherapy.
In a proof-of-concept, single-arm phase II clinical trial, the researchers analyzed samples collected from 71 patients before and during an earlier clinical study in which patients received only BRAF-targeted therapy. Using single-cell RNA sequencing, the researchers looked for molecular changes that occurred as a result of the treatment. They then administered the BRAF inhibitor dabrafenib, the MEK inhibitor trametinib, and the PD-1 inhibitor spartalizumab to 37 patients with BRAF V600E–mutated colorectal cancer.
The study successfully met its primary endpoint and achieved a confirmed response rate of 24.3%, compared with a response rate of 7% in a prior trial where patients were treated with each of the same targeted therapies individually.
The researchers also reported improved outcomes in one of the trial’s secondary endpoints: durability. Previously, patients with BRAF V600E–mutated colorectal cancer have seen only a short-lived clinical benefit after treatment with BRAF or MEK inhibitors. But the combination therapy resulted in an increased durability of response, with a median progression-free survival of 5 months compared with 3.5 months with BRAF or MEK inhibitors alone. The researchers noted that 57% of the patients continued with the treatment for more than 6 months and 18% continued for more than 1 year.
Additionally, the researchers performed single-cell RNA sequencing on samples collected before and on day 15 of the combined treatment. For patients who had better clinical outcomes, they saw an increase in tumor cell–intrinsic immune programs and more complete MAPK inhibition.
Conclusions and Next Steps
The findings suggested that improving MAPK inhibition, possibly by focusing on other treatment targets in the pathway, may drive a greater immune response and improve treatment overall.
“Our findings suggest that there is tremendous potential for these two therapies to cooperate when given together,” underscored co-corresponding study author Nir Hacohen, PhD, Professor of Medicine at Harvard Medical School and Director of the Massachusetts General Hospital Center for Cancer Immunotherapy. “This merits further clinical investigation and preclinical experiments to determine the best targeted approach to increase immune reactivity against [BRAF-mutated] colorectal cancer.”
The researchers acknowledged that the implications of their research may go well beyond colorectal cancer.
“For almost every type of cancer, a large percentage of tumors will harbor mutations in the MAPK pathway,” stressed Dr. Corcoran. “Our work suggests that combining other treatments that target this pathway with an immunotherapy could lead to a cooperative, enhanced immune response that may improve outcomes for patients,” he concluded.
Additional clinical trials are underway to more fully understand the benefits of MAPK inhibition. The researchers hope to further evaluate optimized targeted and immune combinations in treating patients with colorectal cancer in future clinical trials.
Disclosure: The research in this study was supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) Gastrointestinal Cancer SPORE, the NIH/NCI Moonshot Drug Resistance and Sensitivity Network, and Stand Up to Cancer Colorectal Dream Team Translational Research; and made possible by research grants from the American Association for Cancer Research. Partial clinical trial funding was provided by Novartis. For full disclosures of the study authors, visit nature.com.
