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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 BRAFV600 in melanoma1,2. 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 BRAFV600 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.

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Fig. 1: CONSORT diagram.
Fig. 2: Progression-free survival.
Fig. 3: Overall survival.
Fig. 4: PFS in patients with detectable and undetectable BRAFV600 ctDNA at baseline assigned to continuous and intermittent dosing.

Data availability

All data (to replicate every analysis in the manuscript and any Supplementary Information) will be posted to the NCI NCTN Data Archive per NCTN policy (https://nctn-data-archive.nci.nih.gov). Patient-level data, including a data dictionary, will be available within 6 months of publication through the United States NCTN/NCORP Data Sharing Archive (https://nctn-data-archive.nci.nih.gov) following the Data Sharing Archive policies. De-identified patient-level data, including the numbers, tables and figures in the paper, will be made available. The protocol (including the statistical analysis plan in section 11 of the protocol) and the informed consent form are available in the Supplementary Information.

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Acknowledgements

We gratefully acknowledge B. Suttle and D. Ouellet for their work on the pharmacokinetic modeling for dabrafenib and trametinib. We also acknowledge M. Voi, T. Haas and E. Gasal from Novartis for their critical reading of the manuscript and for their helpful comments. S1320 is an intergroup trial led by the SWOG Cancer Research Network with funding and supervision from the National Cancer Institute’s Cancer Therapeutics Evaluation Program (NCI-CTEP). Research reported in this publication was supported by NCI/NIH awards CA180888, CA180819, CA180820, CA180850, CA239767, CA189808, CA46282, CA189858, CA189830, CA233230, CA189829, CA189954, CA189860, CA189822, CA189953, CA180834, CA189809, CA189957 and CA189958 (to SWOG), R35 CA197633 (to A.R.) and P01 CA244118 (to A.R. and R.S.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Glaxo-Smith-Kline, the manufacturer of dabrafenib and trametinib at the time of study initiation, reviewed and approved the study protocol and provided the study drugs to NCI-CTEP. Novartis, the manufacturer of the study drugs at the time of study completion, reviewed and commented on the final study manuscript. All data analysis was completed by M.O. and J.M. at the SWOG statistical center. All authors had full access to all of the study data and they had sole responsibility for the decision to submit the paper for publication and for the contents of the submitted manuscript.

Author information

Affiliations

Authors

Contributions

A.P.A. served as principal investigator for the study. A.R. served as the cooperative group leader for the study. A.P.A., A.R., J.M. and M.O. designed the study. A.P.A., A.R. and M.O. wrote the manuscript. R.S.L. participated in study design and also made substantive contributions to manuscript revisions. M.O. and J.M. were primarily responsible for data analysis. A.I.D., J.M.M., T.-G.T., R.C., K.K., G.C.D., J.I.C., M.J.M, D.F.M., C.L., B.A.F., R.G., A.H.-M., L.D. and K.F.G. accrued patients, contributed to data collection and participated in manuscript development.

Corresponding author

Correspondence to Alain P. Algazi.

Ethics declarations

Competing interests

A.P.A.—research support, advisory board member, consultant, shareholder and honorarium recipient, OncoSec. Advisory board member and stock shareholder for Valitor Biosciences. Advisory board member and honorarium recipient for Regeneron and Array. Research support from Acerta, Amgen, AstraZeneca, BMS, Dynavax, Genentech, Idera, Incyte, ISA, LOXO, Merck, Novartis, Sensei and Tessa. M.O.—consultant for Merck, Daiichi Sanko and Glycomimetics. DSMC member for Celgene and Glycomimetics. A.I.D.—research funding from GSK, Novartis, Merck, BMS, Incyte and Checkmate. Consultant for Pfizer, Roche, Incyte, BioNTech, Merck and BMS. J.M.M.—consultant and honorarium recipient for Array. Grant support/contractor for Merck. Research support from Sanofi, Polynoma, Amgen, AstraZeneca, Incyte, Macro Genics and BMS. Research support and advisory board member for EMD Serono. K.K.—research support from Merck, BMS, Immunocore, Medpace and Novartis. G.C.D.—speakers bureau for Novartis, BMS and Merck. J.I.C.—speakers bureau for BMS and Merck. Research support to institution BMS, Aveo, Argos Therapeutics, Genentech/Roche and Nektar. Immediate family member is employed full time by BMS. K.F.G.—consulting for BMS, Genentech, Castle Biosciences, Novartis, Array and Pfizer. R.S.L.—research support from Array, Merck, Novartis, OncoSec and BMS. Honorarium recipient from Amgen. A.R.—consultant/independent contractor and honorarium recipient: Amgen, Chugai, Merck, Novartis and Sanofi. Advisor/board member and honorarium recipient: Arcus, Bioncotech, Compugen, CytomX, ImaginAb, Isoplexis, Merus, Rgenix, Lutris, PACT Pharma and Tango Therapeutics. Stock shareholder (self-managed): Arcus, Compugen, CytomX and Merus. Research support from Agilent and BMS.

Additional information

Peer review information Javier Carmona was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

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).

Supplementary information

Reporting Summary

Supplementary Data 1

S1320 protocol first and last versions, initial and revised statistical analysis plans, summaries of changes, and informed-consent form with addendum.

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Algazi, A.P., Othus, M., Daud, A.I. et al. Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial. Nat Med 26, 1564–1568 (2020). https://doi.org/10.1038/s41591-020-1060-8

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