Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jan 5;29(1):15-24.
doi: 10.1093/oncolo/oyad247.

Combined RAF and MEK Inhibition to Treat Activated Non-V600 BRAF-Altered Advanced Cancers

Naryan Rustgi  1 , Ann Maria  2 , Nicolas Toumbacaris  3 , HuiYong Zhao  4 , Katherine Kargus  5 , Morgan Bryant  2 , Alexandra Waksmundzki  2 , Ilinca Aricescu  6 , Robert A Lefkowitz  7 , Bob T Li  2 , Joanne Chou  3 , Marinela Capanu  3 , Elisa de Stanchina  4 , Sandra Misale  8 , Jinru Shia  9 , Rona Yaeger  2
Affiliations

Combined RAF and MEK Inhibition to Treat Activated Non-V600 BRAF-Altered Advanced Cancers

Naryan Rustgi et al. Oncologist. .

Abstract

Background: Cancers with non-V600 BRAF-activating alterations have no matched therapy. Preclinical data suggest that these tumors depend on ERK signaling; however, clinical response to MEK/ERK inhibitors has overall been low. We hypothesized that a narrow therapeutic index, driven by ERK inhibition in healthy (wild-type) tissues, limits the efficacy of these inhibitors. As these mutants signal as activated dimers, we further hypothesized that RAF inhibitors given concurrently would improve the therapeutic index by opposing ERK inhibition in normal tissues and not activate ERK in the already activated tumor.

Materials and methods: Using cell lines and patient-derived xenografts, we evaluated the effect of RAF inhibition, alone and in combination with MEK/ERK inhibitors. We then undertook a phase I/II clinical trial of a higher dose of the MEK inhibitor binimetinib combined with the RAF inhibitor encorafenib in patients with advanced cancer with activating non-V600 BRAF alterations.

Results: RAF inhibition led to modest inhibition of signaling and growth in activated non-V600 BRAF preclinical models and allowed higher dose of MEK/ERK inhibitors in vivo for more profound tumor regression. Fifteen patients received binimetinib 60 mg twice daily plus encorafenib 450 mg daily (6 gastrointestinal primaries, 6 genitourinary primaries, 3 melanoma, and 2 lung cancer; 7 BRAF mutations and 8 BRAF fusions). Treatment was well tolerated without dose-limiting toxicities. One patient had a confirmed partial response, 8 had stable disease, and 6 had radiographic or clinical progression as best response. On-treatment biopsies revealed incomplete ERK pathway inhibition.

Conclusion: Combined RAF and MEK inhibition does not sufficiently inhibit activated non-V600 BRAF-mutant tumors in patients.

Keywords: BRAF; MEK; precision medicine; translational research.

PubMed Disclaimer

Conflict of interest statement

Bob T. Li has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly; has served as a consultant/advisory board member for Roche, Biosceptre International, Thermo Fisher Scientific, Mersana Therapeutics, Hengrui Therapeutics, and Guardant Health; has received research funds to his institution from Genentech, Bolt Biotherapeutics, Daiichi Sankyo, Hengrui Therapeutics, Illumina, BioMed Valley Discoveries, AstraZeneca, GRAIL, Lilly, and Amgen; has received academic travel support from Amgen, Jiangsu Hengrui Medicine, and MORE Health; and is an inventor on 2 institutional patents at MSK (US62/685,057, US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. Joanne Chou is an investigator on a research study sponsored by or related to Paige AI and reports that MSK holds equity in and has licensed intellectual property related to digital pathology slides and algorithm development to Paige. Sandra Misale has served as a consultant for Boehringer Ingelheim and has received research support to her institution from Boehringer Ingelheim and Daiichi Sankyo. Jinru Shia is a consultant for Paige AI. Rona Yaeger has served as an advisor for Amgen, Natera, Array BioPharma/Pfizer, Mirati Therapeutics, and Zai Lab and has received research support to her institution from Array BioPharma/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, and Mirati Therapeutics. The other authors indicated no financial relationships.

Figures

Figure 1.
Figure 1.
Effect of RAF inhibitors in activated non-V600 BRAF-mutant tumors. (A) Immunoblots showing dose response after 1-hour treatment with the RAF inhibitor encorafenib on downstream signaling in a panel of activating non-V600 BRAF-mutant cell lines. The BRAF V600E melanoma cell line A375 is representative of a sensitive line, and the KRAS G12V colon cell line SW620 is representative of a resistant line. (B) Growth curves for patient-derived xenografts with activating non-V600 BRAF mutants treated with vehicle control or the RAF inhibitor PLX7420. Five mice were treated in each group. Error bars indicate SEM. Abbreviation: BID: twice daily.
Figure 2.
Figure 2.
Effect of combined RAF and MEK/ERK inhibition in activated non-V600 BRAF-mutant patient-derived xenograft. (A). Growth curves for BRAF K601E colon patient-derived xenograft treated with the indicated therapies. Four to five mice were treated in each group. (B) Mean mouse weight during treatment course. Error bars indicated SEM. Abbreviation: QD: once daily; BID: twice daily.
Figure 3.
Figure 3.
Combined RAF/MEK inhibitor trial for patients with advanced cancers with activated non-V600 BRAF mutations. (A) Study schema. (B) Waterfall plot showing best response by RECIST assessment. (C) Swimmer plot showing duration of treatment with time at each dose level marked. Abbreviation: DLT: dose-limiting toxicity; QD: once daily; BID: twice daily.
Figure 4.
Figure 4.
Correlative studies of pharmacodynamic markers of pathway inhibition in patient tumors. (A) Reverse transcription-polymerase chain reaction (RT-PCR) measurements of transcript levels of the ERK output genes, DUSP6, SPRY2, and ETV1, in pretreatment and on-treatment (day 7) biopsies. (B) Summary of immunohistochemical analysis of pretreatment and on-treatment samples. (C) Representative images of immunohistochemical staining.
See this image and copyright information in PMC

References

    1. Food and Drug Administration. FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grant...
    1. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596-599. 10.1038/nature09454 - DOI - PMC - PubMed
    1. Yao Z, Torres NM, Tao A, et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell. 2015;28(3):370-383. 10.1016/j.ccell.2015.08.001 - DOI - PMC - PubMed
    1. Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703-713. 10.1038/nm.4333 - DOI - PMC - PubMed
    1. Joseph EW, Pratilas CA, Poulikakos PI, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci USA. 2010;107(33):14903-14908. 10.1073/pnas.1008990107 - DOI - PMC - PubMed

MeSH terms