Trial of Intermittent Dabrafenib/Trametinib Dosing for BRAF-Mutated Melanoma Fails

By Megan Brooks

May 07, 2020

NEW YORK (Reuters Health) - A new study has dashed hopes that intermittent dosing of BRAF inhibitor dabrafenib and the MEK inhibitor trametinib would be as effective as continuous dosing of the drugs in patients with advanced BRAF-mutated melanoma.

In the randomized phase-2 trial, continuous dosing of dabrafenib and trametinib appeared to lead to improved progression-free survival (PFS) compared with intermittent dosing, although the finding was not statistically robust, Dr. Alain Algazi reported April 27 at the American Association for Cancer Research (AACR) virtual annual meeting.

"The PFS advantage in favor of continuous dosing was observed in younger and older patients, men and women, patients with and without prior immune-checkpoint-inhibitor therapy, and in patients with normal and elevated baseline LDH levels," Dr. Algazi of the University of California, San Francisco, said during a press briefing.

The dabrafenib/trametinib combination yields objective responses in most patients with BRAF-mutated melanoma, but acquired resistance limits the duration of response. Studies in mice have suggested that intermittent dosing might be as effective and delay acquired resistance.

But that did not pan out in the SWOG S1320 study, which "represents a large-scale, real-world test of intermittent-dosing hypothesis," Dr. Algazi said.

The study enrolled 249 patients with advanced BRAF-mutated melanoma. All patients received continuous dabrafenib and trametinib for eight weeks. The 206 "non-progressing" patients were randomly allocated to either continuous treatment or intermittent dosing of both drugs on a three-week-off, five-week-on schedule. Baseline patient characteristics were well balanced between the two groups.

The median PFS was longer with continuous versus intermittent dosing (9.0 months vs. 5.5 months; hazard ratio, 1.36; 80% confidence interval, 1.10 to 1.66; P=0.063).

Overall survival did not differ between the groups; at a median follow-up of two years, median overall survival was 29.2 months in both arms. More patients in the intermittent arm stopped treatment due to disease progression (84% vs. 77%; P=0.34).

Toxicity was similar in both arms, despite a decrease in drug exposure in the intermittent therapy arm.

"Despite the solid scientific rationale, this randomized clinical trial demonstrated that continuous dosing was better than intermittent dosing," study chief and AACR President Dr. Antoni Ribas told the briefing.

"The idea of prescribing therapy intermittently made sense," Dr. Ribas, of the University of California, Los Angeles, added in a statement. "Cancer cells wouldn't have enough time to get used to it and become resistant - a notion that was supported scientifically by well-conducted studies in the laboratory. This clinical study illustrates the importance of ultimately testing hypotheses in human patients."

"What works in pre-clinical studies doesn't always work in real-world clinical studies," Dr. Algazi said in the statement. "In melanoma research, we're all trying to figure out ways to optimize these targeted drugs and find a way around resistance so people live longer. We're going to have to keep at it because the current standard of continuous dosing seems to hold the most benefit."

The study was sponsored by the National Cancer Institute. Novartis Pharmaceuticals, which makes dabrafenib and trametinib, provided the study drugs and partial funding to support the study through a Collaborative Research and Development Agreement between NCI and Novartis. Dr. Algazi and Dr. Ribas have disclosed financial relationships with Novartis.

SOURCE: AACR 2020 annual meeting, presented April 27, 2020.