Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial

Abstract

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAF^V600 in melanoma^1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAF^V600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.

Extended Data Fig. 1. Pharmacokinetic modeling.

a. Model of plasma concentrations of trametinib, dabrafenib, and dabrafenib metabolites during a 2-week washout period (preceded by steady-state dosing) and after resumption of treatment. b. Trametinib levels are predicted to remain higher than the level of quantification, but they are predicted to fall below the target effective concentration. A 3-week washout was selected for S1320 to ensure an adequate time period with subtherapeutic exposure to trametinib. Trametinib levels are predicted to reach steady-state within 4 weeks of resuming the medication.

Extended Data Fig. 2. Patient characteristics.

Patient characteristics among randomized patients. Median (interquartile range) and N (%) reported. Two-sided p-values from Wilcoxon (quantitative covariates) and Fisher exact (categorical covariates) reported.

Extended Data Fig. 3. Survival after disease progression.

Survival after disease progression in patients randomized to the continuous and intermittent dosing arms. Hazard ratio (HR), 80% confidence interval (shaded regions), and two-sided Wald-test p-values (p) from Cox regression model stratified by randomization stratification factors reported.

Extended Data Fig. 4. Baseline characteristics and progression-free survival.

Multivariable Cox regression model of the association of baseline characteristics with progression-free survival; two-sided Wald p-values reported.

Extended Data Fig. 5. Adverse events.

All adverse events assessed as possibly, probably, and definitely related to study treatment. On the continuous therapy arm, 38 patients (36%) experienced grade 3 adverse events, and 7 (7%) experienced grade 4 events, while on the intermittent therapy arm, 31 patients (31%) experienced grade 3 adverse events, and 3 (3%) experienced grade 4 events (p=0.46 for grade 3, p=0.33 for grade 4). The most common grade 3–4 adverse event across both arms was fatigue. There was a significant difference in the incidence of grade 3 and 4 pyrexia, (6 patients on continuous dosing vs 1 patient on intermittent dosing, p<0.001).

Figure 1.

CONSORT diagram.

Figure 2:

A. Progression-free survival. The median PFS after randomization (8 weeks after the start of treatment) was 9.0 months in the continuous dosing arm and 5.5 months in the intermittent dosing arm.. Hazard ratio (HR), 80% confidence interval (shaded regions), and two-sided Wald-test p-values (p) from Cox regression model stratified by randomization stratification factors reported. B. Progression-free survival by subgroup; hazard ratio (HR), 80% confidence interval (CI), and two-sided Wald-test p-values (p) from Cox regression model; no adjustment was made for multiple comparisons.

Figure 3.

A. Overall survival. The median OS after randomization (8 weeks after the start of treatment) was 29.2 months in the continuous dosing arm and 29.2 months in the intermittent dosing arm. Hazard ratio (HR), 80% confidence interval (shaded regions), and two-sided Wald-test p-values (p) from Cox regression model stratified by randomization stratification factors reported. B. Overall survival by subgroup; hazard ratio (HR), 80% confidence interval (CI), and two-sided Wald-test p-values (p) from Cox regression model; no adjustment was made for multiple comparisons.

Figure 4.

Progression-free survival in patients with detectable and undetectable circulating BRAF^V600 tumor DNA (ctDNA) at baseline in patients assigned to continuous intermittent dosing. Detection of ctDNA prior to therapy was associated with worse PFS (median BRAF^V600 ctDNA positive = 5.8; 95% CI: 4.2–9.6 months, BRAF^V600 ctDNA negative = 21.4 mos; 95% CI 10.4-NA; measured from start of treatment on study, p=0.001), two-sided p-value from Cox regression model Wald-test).