Adding a PD-L1 inhibitor to a standard targeted therapy for patients with untreated BRAF V600 mutation–positive advanced melanoma led to significantly improved progression-free survival, according to findings presented at the American Association for Cancer Research Virtual Annual Meeting Part I: April 27–28, 2020. The results add to evidence that combining immune checkpoint blockade with MEK–BRAF inhibition produces more clinically meaningful survival benefits than either MEK–BRAF or immune checkpoint inhibition alone.

Adding a PD-L1 inhibitor to standard targeted therapy for patients with untreated BRAF V600 mutation–positive advanced melanoma led to significantly improved progression-free survival (PFS), according to findings presented at the American Association for Cancer Research Virtual Annual Meeting Part I: April 27–28, 2020. The results add to evidence that combining immune checkpoint blockade with MEK–BRAF inhibition produces more clinically meaningful survival benefits than either MEK–BRAF or immune checkpoint inhibition alone.

In the IMspire 150 trial, 514 patients with BRAF V600 mutation–positive, treatment-naïve stage IIIc/IV melanoma were randomized to receive a targeted therapy combination of the MEK inhibitor cobimetinib (Cotellic; Genentech) and the BRAF inhibitor vemurafenib (Zelboraf; Genentech)—alone or with the anti–PD-L1 antibody atezolizumab (Tecentriq; Genentech). Both PFS and median duration of response (DOR) were significantly higher in the atezolizumab group than the control arm—15.1 months vs. 10.6 months, and 21 months vs. 12.6 months, respectively.

“The combination of BRAF and MEK inhibitors offers the advantage of higher response rates that are unfortunately short-lived for many patients, while immune checkpoint inhibitors provide more durable responses but have lower response rates,” said lead investigator Grant McArthur, PhD, of the Peter MacCallum Cancer Centre, Melbourne, Australia, who presented the findings. “These data led us to the hypothesis that combining BRAF and MEK with immune checkpoint inhibition might overcome the clinical limitation of the individual classes of therapy and potentially lead to more durable responses.”

The IMspire 150 study shows that triple therapy can trigger an impressive DOR, said trial discussant Charles Sawyers, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. However, he noted that the BRAF–MEK inhibitor comparator arm may have lost relevance based on recent results from the Checkmate 067 trial, which reported sustained long-term survival benefits over 5 years in patients treated with a checkpoint blockade targeting PD-1 and CTLA4, compared with PD-1 inhibition alone.

The trial offers a valuable opportunity to test the theory that MEK–BRAF inhibition releases a “gold mine of tumor antigens” that activate an immune response following checkpoint blockade, Sawyers said.

As shown in preclinical data collected by the IMspire 150 investigators, T-cell infiltrate increases in patients who receive only kinase inhibitors. In addition, in certain contexts, MEK inhibition has been shown to increase the expression of HLA class 1 expression in tumor cells, which theoretically could improve antigen presentation to T cells, Sawyers explained.

“I'm quite excited about developments in technology, such as single-cell RNA sequencing and spatial transcriptomics, that allow us to look very precisely and accurately at tumor samples obtained from patients in a trial like this one,” he added. “I look forward to seeing those tools applied to this and similar studies.” –Janet Colwell

©2020 American Association for Cancer Research.
2020
American Association for Cancer Research.