Continuous dosing with dabrafenib and trametinib improved progression-free survival in patients with BRAF-mutated advanced melanoma compared with an intermittent-dosing strategy, according to results of the phase II SWOG S1320 randomized trial reported at the opening Plenary Session of the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting.¹ Median progression-free survival from the time of randomization was 9 months for continuous dosing vs 5.5 months for intermittent dosing (P = .063).

Alain Algazi, MD

“Continuous dosing of dabrafenib and trametinib yields superior progression-free survival compared to intermittent dosing. This advantage was observed in all subgroups,” said Alain Algazi, MD, of the University of California, San Francisco. “Toxicity was similar despite decreased drug exposure in the intermittent arm. This was a large-scale, real-world test, with patients drawn from 68 centers over a 5-year period using a commonly prescribed BRAF and MEK inhibitor combination regimen.”

BRAF and MEK inhibitor combinations induce rapid remissions in about two-thirds of patients with advanced BRAF-mutated melanoma, but early relapses are common. In mouse models, vemurafenib-­resistant cells grew more slowly with intermittent dosing, suggesting this strategy could prevent or delay resistance, he explained.

Study Details

The open-label, phase II SWOG S1320 study randomly assigned 206 patients with advanced BRAF V600E/K–positive melanoma to receive either continuous dosing or intermittent dosing of the BRAF/MEK inhibitor combination. After an 8-week lead-in period on continuous dosing, patients who achieved an objective response or stable disease were randomly assigned to receive continuous treatment for 8 weeks (n = 105) or intermittent dosing of dabrafenib/trametinib on a 5-week-on, 3-week-off schedule (n = 101).

Baseline characteristics were well balanced between the two arms. The median age was 58 years in the continuous arm and 62 years in the intermittent arm. In the two arms, respectively, 59% and 69% were male, and 89% and 97% were white. Almost all patients had an EGOG performance status of 0 or 1. About 30% of patients in each arm had received prior immune checkpoint inhibitor therapy.

“Typically, we can see responses in 8 weeks,” Dr. Algazi said. “There were no statistically significant differences in initial tumor responses between the two arms.” At the time of analysis, 84 patients in each arm had discontinued therapy primarily due to disease progression.

Progression-free survival was significantly longer in patients receiving continuous vs intermittent therapy, with a median of 9 months vs 5.5 months, respectively (P = .063). The effect on progression-free survival was similar across all subgroups, including younger and older patients, men and women, patients with and without prior checkpoint inhibitor therapy, and patients with normal and elevated lactate dehydrogenase (LDH) levels at baseline.

The overall survival curves were similar in the two arms. At a median follow-up of 2 years, the median overall survival was 29.2 months in each arm, and there were 47 deaths in each arm. The effect on survival was similar across all patient subgroups, with no differences based on age, gender, LDH level, or prior checkpoint inhibitor exposure.

Postprogression Survival

Postprogression and overall survival favored the intermittent arm, but the explanation for this finding was elusive. There was no difference in postprogression exposure to anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) or anti–programmed cell death protein 1 (PD-1) antibodies in the two arms, so subsequent immunotherapy could not explain this difference. Neither could prior exposure to checkpoint inhibitors, since 30% of patients in each arm of the study had previously received these agents.

“Although interesting, overall survival or postprogression survival findings should be considered hypothesis-generating at this point,” Dr. Algazi stated.

Treatment-related adverse events observed in more than 10% of patients included fever, fatigue, and chills. There was one case of grade 3 chills in both arms; grade 3 fever was reported in six patients in the continuous arm and one in the intermittent arm.

“Why was our finding different from preclinical studies?” Dr. Algazi continued. One possibility is there was decreased exposure in the intermittent arm, and 8 weeks may be too short a time for resistant clones to develop. The development of non-MAPK resistance pathways may provide an explanation, since intermittent dosing may not address that. Moreover, he said the long half-life of trametinib (4 days in humans) may preclude the rapid decrement in exposure required to achieve effective drug withdrawal.

Additional Comments

Antoni Ribas, MD, PhD

In a press release, Antoni Ribas, MD, PhD, senior author of the trial, AACR President-Elect, and Professor of Medicine at the David Geffen School of Medicine at UCLA, ­commented:

“The idea of prescribing therapy intermittently made sense. 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, which is the underlying reason for the existence of [National Cancer Institute]–funded groups like SWOG.” 

DISCLOSURE: Dr. Algazi reported financial relationships with OncoSec, Valitor Biosciences, Regeneron, Array, Acerta, Amgen, AstraZeneca, BMS, Dynavax, Genentech, Idera, Incyte, ISA, Loxo Oncology, Merck, Novartis, Sensei, and Tessa. Dr. Ribas reported financial relationships with Amgen, Bristol-Myers Squibb, Chugai, Dynavax, Genentech, Merck, Nektar, Novartis, Roche, Sanofi, Advaxis, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, RAPT Therapeutics, ImaginAb, Isoplexis, Kite-Gilead, Lutris-Pharma, Merus, PACT Pharma, Rgenix, and Tango Therapeutics.

REFERENCE

1. Algazi AP, Othus M, Daud AI, et al: Continuous compared to intermittent dosing with BRAF and MEK inhibitors in patients with BRAF mutated melanoma. 2020 AACR Virtual Meeting. Abstract CT013. Presented April 27, 2020.