The following article features coverage from the American Association for Cancer Research (AACR) 2020 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

A continuous dosing regimen of dabrafenib plus trametinib prolonged progression-free survival (PFS) compared with an intermittent dosing schedule among patients with advanced BRAFV600E/K mutated melanoma, according to results from the phase S1320 presented at the American Association for Cancer Research (AACR) Virtual Annual Meeting I 2020.

Although BRAF/MEK inhibition yields high response rates, most patients acquire treatment resistance. Preclinical data suggest that intermittent dosing may deselect tumor cells that require trametinib for their growth, thereby delaying acquired resistance. The aim of this study was to determine if intermittent dosing of dabrafenib and trametinib improved PFS compared with continuous dosing.

“S1320 represents a large-scale, real-world test of the intermittent dosing hypothesis,” Alain P. Algazi, MD, of the University of California at San Francisco, and lead author and presenter of the study, said.

The phase 2 S1320 trial treated all patients with continuous dabrafenib and trametinib for 8 weeks, then 206 patients without progressive disease were randomly assigned to receive continuous dosing or intermittent dosing with a 3-week-off, 5-week-on schedule.


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Patient characteristics were similar at baseline, with a median patient age of 60 years, 36% were male, and 98% were white. There was prior exposure to immune checkpoint inhibition in 30% of patients. The tumor response to dabrafenib and trametinib is commonly observed at 8 weeks.

“It is important to note that there was no statistically significant difference in the initial tumor response between treatment arms,” Dr Alain said. The complete response rate after the 8-week run-in with dabrafenib and trametinib was 12% and 10% with continuous and intermittent dosing, respectively.

Intermittent dosing was associated with poorer PFS, with a median of 5.5 months from randomization compared with 9.0 months with continuous dosing (hazard ratio [HR], 1.36; 80% CI, 1.10-1.66; P =.063). The p-value was within the prespecified α of 0.02, indicating that the PFS with continuous dosing was superior to that with intermittent dosing. This benefit was observed across most subgroups.

“Although the study was not powered to detect differences in overall survival, it is notable that the overall survival curves were very similar between the 2 arms,” Dr Algazi said. The median OS was 29.2 months from randomization for both continuous and intermittent dosing.

The frequency of adverse events was similar between groups, except that fatigue and fever occurred more frequently in the continuous dosing arm.

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Dr Alain concluded with theories for why the results did not support the hypothesis, including that the long half-life of trametinib may have prevented the rapid withdrawal of drug that may have been needed to see a beneficial effect with intermittent dosing.

Discussant Charles L. Sawyers, MD, of the Howard Hughes Medical Institute, agreed, stating that the intermittent schedule may not have adequately tested the hypothesis because the half-life of trametinib may have prevented rapid drug withdrawal.

Disclosures: Some of the presenting authors disclosed financial relationships with pharmaceutical and/or medical companies. For a full list of disclosures, please refer to the study abstract.

Read more of Cancer Therapy Advisor‘s coverage of AACR 2020 meeting by visiting the conference page.

Reference

Algazi A, Othus M, Daud A, et al. SWOG S1320: Improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma. Presented at: American Association for Cancer Research Virtual Annual Meeting I; April 27-28, 2020. Abstract CT013.