Abstract
Dual inhibition of the MAPK pathway helps boost immune responses to checkpoint inhibitors in patients with previously treated BRAFV600E-mutated metastatic colorectal cancer.
Dual inhibition of the MAPK pathway helps boost immune responses to checkpoint-blocking drugs in patients with BRAF-mutant colorectal cancer, according to a recently published study (Nat Med 2023;29:458–66).
In the first published report of a trial combining molecularly targeted agents with immunotherapy in patients with BRAFV600E-altered metastatic colorectal cancer, clinicians discovered that giving a BRAF inhibitor plus a MEK inhibitor—namely, Novartis's dabrafenib (Tafinlar) and trametinib (Mekinist)—promotes T-cell infiltration into tumors and activates genes that enhance immune responses to the anti–PD-1 agent spartalizumab (Novartis).
In the single-arm study, Ryan Corcoran, MD, PhD, and his colleagues from Massachusetts General Hospital (MGH) in Boston, observed responses in nine of 37 patients with previously treated disease, including many with microsatellite-stable disease for whom immune checkpoint inhibitors (ICI) are typically ineffective. Median progression-free survival (PFS) was 4.3 months, and median overall survival (OS) was 13.6 months.
Single-cell RNA sequencing experiments revealed that inhibition of BRAF and MEK—both members of the MAPK signaling pathway—led to tumor-intrinsic induction of genes involved in interferon responses, antigen presentation, and chemokine activity. Patients who responded to the triplet therapy also exhibited a deeper degree of MAPK suppression.
The results validate preclinical studies that highlighted the potential for cooperativity between MAPK inhibition and immune checkpoint blockade in BRAF-mutant cancers. They also suggest that adding ICIs to standard targeted therapies can prolong survival for patients with BRAFV600E-altered colorectal cancer, a subtype of the disease that carries a dismal prognosis.
The researchers “make a compelling argument for that,” says Zev Wainberg, MD, of the University of California, Los Angeles, who was not involved in the study.
However, the use of MEK inhibitors in the triple-drug cocktail is unlikely to find widespread clinical acceptance, given that the combination of a BRAF inhibitor (encorafenib; Braftovi; Array BioPharma) plus an EGFR inhibitor (cetuximab; Erbitux; Lilly) has recently become the standard of care for previously treated BRAFV600E-mutated colorectal cancer—and that approved doublet has also shown promising signs of clinical activity when paired with checkpoint blockade.
Van Morris, MD, and his colleagues at The University of Texas MD Anderson Cancer Center in Houston, reported at meetings last year that the combination of encorafenib and cetuximab with the anti–PD-1 agent nivolumab (Opdivo; Bristol Myers Squibb) yielded responses in 11 of 22 evaluable patients, with a median PFS of 7.4 months and a median OS of 15.1 months.
“The two studies synergize well with each other,” Morris says. Both the MD Anderson and the MGH teams found that strong MAPK inhibition—whether with anti-BRAF/EGFR or anti-BRAF/MEK combinations—augments tumor-directed immune responses in patients with microsatellite-stable disease receiving ICIs. But, the EGFR-containing drug regimen has a “clearer path to development at this time.”
A randomized phase II trial involving encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite-stable BRAFV600E-altered metastatic colorectal cancer is currently enrolling patients at sites across the United States. –Elie Dolgin
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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