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Clinical efficacy and single-cell analysis of combined BRAF, MEK, and PD-1 inhibition in BRAFV600E colorectal cancer patients
Background
While combinations of BRAF inhibitors with EGFR and/or MEK inhibitors have improved efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and durability is limited. Preclinical and correlative studies suggest that targeting BRAF signaling in combination with immune checkpoint inhibition (ICI) could enhance activity.
Methods
BRAFV600E CRC patients at the Massachusetts General Hospital Cancer Center and the Dana-Farber Cancer Institute were treated with spartalizumab (PDR001) 400mg IV q28d, dabrafenib 150mg PO BID, and trametinib 2mg PO daily. Single-cell RNAseq (scRNAseq) was performed on paired baseline and day 15 tumor biopsies and patient-derived organoids were established from baseline biopsies.
Results
37 of 40 planned BRAFV600E CRC patients have been enrolled (5 MSI, 32 MSS). 5 had prior therapy with BRAF inhibitors and/or immunotherapy. Median age was 63 (range 35-87) and 20 (54%) were female. Treatment was well-tolerated with fever, rash, and diarrhea as the most common AEs. ORR was 27% (10/37), disease control rate (DCR) 70%, and PFS 5.5 months, which compares favorably to the historical 12% ORR and PFS 3.5 months of dabrafenib plus trametinib alone in BRAFV600E CRC, as well as the current FDA-approved standard (encorafenib plus cetuximab) of 20% ORR and 4.3 months PFS. 49% (19/37) patients remained on therapy for >6 months, and one MSS patient remained on therapy >2 years with -100% reduction by RECIST. Among 28 MSS patients with no prior BRAF inhibitor or ICI, response rate was 25% (7/28), DCR 75%, and PFS 5.6 months. scRNAseq of paired pre-treatment and day 15 on-treatment biopsies revealed significant increase in T-cell infiltration and a reduction in tumor cell number at day 15 in patients with PFS >6 months, but not in patients with 6 months, but not in PFS 6 months vs. 6 months vs. < 6 months. However, when organoids were treated with a more optimal targeted core (BRAF/ERK inhibition) that could effectively suppress MAPK signaling in all models, significant induction of immune programs were observed in all organoids regardless of PFS.
Conclusions
Spartalizumab, dabrafenib, and trametinib showed favorable efficacy relative to historical controls in BRAFV600E CRC patients, suggesting the potential for clinical cooperativity between BRAF-targeting and ICI. scRNAseq of paired tumor biopsies identified tumor-intrinsic induction of key immune programs upon MAPK inhibition in patients with PFS >6 months as a potential mechanism underlying improved efficacy. More effective BRAF-MAPK inhibition in patient-derived organoids drove greater induction of immune programs across all models, suggesting that future clinical trials combining ICI with more effective BRAF-targeted regimens are warranted.
Clinical trial identification
NCT03668431.
Legal entity responsible for the study
The authors.
Funding
Study was funded by Novartis and Stand Up to Cancer.
Disclosures
R. Corcoran: Advisory / Consultancy: Abbvie, Amgen, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, AstraZeneca, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Cogent Biosciences, Elicio, Erasca, Fog Pharma, Genentech, Guardant Health, Ipsen, Kinnate Biopharma, LOXO, Merrimack, Mirati Therapeutics, Natera, Navire, Nested Therapeutics, N-of-one/Qiagen, Novartis, nRichDx, Remix Therapeutics, Revolution Medicines, Roche, Roivant, Shionogi, Shire, Spectrum Pharmaceuticals, Symphogen, Syndax, Tango Therapeutics, Taiho, Theonys, Warp Drive Bio, Zikani Therapeutics; Research grant / Funding (self): Research Funding: Asana (ended 2019), AstraZeneca (ended 2019), Lilly, Novartis, Pfizer; Shareholder / Stockholder / Stock options: Avidity Biosciences, C4 Therapeutics, Cogent Biosciences, Erasca, Kinnate Biopharma, Interline Therapeutics, Nested Therapeutics, nRichDx, Remix Therapeutics, Revolution Medicines, and Theonys. S. Chao: Full / Part-time employment: GV. P. Enzinger: Advisory / Consultancy: Arcus Biosciences, Astellas Pharma, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb/Celgene, Celgene, Coherus Biosciences, Daiichi Sankyo, Five Prime Therapeutics, IDEAYA Biosciences, ISTARI Oncology, Legend Biotech, Lilly, loxo, Merck, Novartis, Ono Pharmaceutical, SERVIER, Taiho Pharmaceutical, Takeda, Turning Point Therapeutics, Xencor, Zymeworks. S. Klempner: Advisory / Consultancy: Astellas, BMS, Daichi Sankyo, Lilly, Merck, Mersana, Natera, Pieris, sanofi-aventis, MBrace; Shareholder / Stockholder / Stock options: Turning Point Therapeutics. A. Parikh: Advisory / Consultancy: Eli Lilly, Pfizer, Inivata, Biofidelity, and Guardant. ; Leadership role: DSMC for a Roche Trial; Research grant / Funding (institution): PureTech, PMV Pharmaceuticals, Plexxicon,Takeda, BMS, Mirati, Novartis, Genentech, Natera, and Daiichi Sankyo; Shareholder / Stockholder / Stock options: Equity in C2I Genomics. All other authors have declared no conflicts of interest.
