Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i

Abstract

Immune and targeted therapies achieve long-term survival in metastatic melanoma; however, new treatment strategies are needed to improve patients’ outcomes1,2. We report on the efficacy, safety and biomarker analysis from the single-arm safety run-in (part 1; n = 9) and biomarker (part 2; n = 27) cohorts of the randomized, placebo-controlled, phase 3 COMBI-i trial (NCT02967692) of the anti-PD-1 antibody spartalizumab, in combination with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Patients (n = 36) had previously untreated BRAF V600-mutant unresectable or metastatic melanoma. In part 1, the recommended phase 3 regimen was identified based on the incidence of dose-limiting toxicities (DLTs; primary endpoint): 400 mg of spartalizumab every 4 weeks plus 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily. Part 2 characterized changes in PD-L1 levels and CD8+ cells following treatment (primary endpoint), and analyzed additional biomarkers. Assessments of efficacy and safety were key secondary endpoints (median follow-up, 24.3 months). Spartalizumab plus dabrafenib and trametinib led to an objective response rate (ORR) of 78%, including 44% complete responses (CRs). Grade ≥3 treatment-related adverse events (TRAEs) were experienced by 72% of patients. All patients had temporary dose modifications, and 17% permanently discontinued all three study drugs due to TRAEs. Early progression-free survival (PFS) events were associated with low tumor mutational burden/T cell–inflamed gene expression signature (GES) or high immunosuppressive tumor microenvironment (TME) GES levels at baseline; an immunosuppressive TME may also preclude CR. Overall, the efficacy, safety and on-treatment biomarker modulations associated with spartalizumab plus dabrafenib and trametinib are promising, and biomarkers that may predict long-term benefit were identified.

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Fig. 1: Baseline biomarker results from biopsy specimens based on PFS.
Fig. 2: Baseline and on-treatment biomarker analyses based on PFS and RECIST response.

Data availability

Novartis is committed to sharing, with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. This trial data availability is in accordance with the criteria and process described on ClinicalStudyDataRequest.com. Publicly available databases utilized for the biomarker analyses in this study include RefSeq (https://www.ncbi.nlm.nih.gov/refseq/), dbSNP (https://www.ncbi.nlm.nih.gov/snp/), MSigDB C2 Canonical Pathways (https://www.gsea-msigdb.org/gsea/msigdb), the Exome Sequencing Project (http://evs.gs.washington.edu/EVS/), the Exome Aggregation Consortium (now part of gnomAD, https://gnomad.broadinstitute.org/) and COSMIC (https://cancer.sanger.ac.uk/cosmic).

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Acknowledgements

We thank the patients and their families for their participation. We also thank the study site staff, additional investigators, R. Leary, C. Unitt and S. Mahan (Next Generation Diagnostics) for their contributions. We thank K. Gibbs for biomarker sample management, as well as A. Savchenko, J. Choi, C. Wong, B. Fu, G. Gorgun and R. Ramesh for support with biomarker analyses. We thank Navigate Biopharma for DNA and RNA extraction, as well as HistoGeneX and Bioagilytix for biomarker testing. We also thank M. Voi (Novartis Pharmaceuticals) for guidance and critical review. We thank A. Lytle and A. Ghiretti (ArticulateScience LLC) for providing medical writing support, which was funded by Novartis Pharmaceuticals Corporation in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp3). COMBI-i (NCT02967692) is sponsored by Novartis Pharmaceuticals.

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C.R., D.S., H.A.T., J.C.B., E.G. and G.V.L. conceived or designed the work. R.D., C.L., V.A., M.M., P.D.N., A.A., E.R., N.Y., C.R., D.S., H.A.T., P.A.A., A.R., N.P., C.D.C., K.T.F., D.G., A.M., J.C.B., E.G. and G.V.L. acquired, analyzed or interpreted the data. R.D., C.L., A.A., E.R., N.Y., C.R., D.S., H.A.T., A.R., K.T.F., J.C.B., E.G. and G.V.L. drafted or substantively revised the work.

Corresponding author

Correspondence to Reinhard Dummer.

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Competing interests

R.D. reports intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron and Alligator outside the submitted work. C.L. reports research funding from Roche and BMS, speakers bureau for Roche, BMS, MSD, Amgen, Novartis and Pierre Fabre, and consulting and advisory roles for BMS, MSD, Roche, Novartis, Merck Serono, Sanofi and Pierre Fabre. V.A. reports advisory roles for BMS, Merck Serono, MSD, Novartis, Roche, Nektar and Pierre Fabre, and received speaker’s fees from BMS, Merck, MSD and Novartis, and travel support from BMS, MSD and Onco-Sec. M.M. reports consulting or advisory roles for MSD, Roche, BMS and Pierre Fabre and research funding from Roche, Novartis and BMS. P.D.N. reports advisory roles for BMS, Immunocore, Merck, MSD, Novartis and Pfizer, speaker’s bureaux for BMS and Novartis and steering committee membership for Immunocore, Merck and Novartis. A.A. reports personal fees and other from BMS, MSD, Roche, Novartis, Merck, Sanofi, Amgen and Pierre Fabre, outside the submitted work. E.R. reports consulting or advisory roles for Amgen, Bayer, BMS, MSD, Merck, Novartis, Pierre Fabre, Roche and Sanofi; reception of honoraria from Amgen, Bayer, BMS, MSD, Merck, Novartis, Pierre Fabre, Roche and Sanofi; speaker’s bureaux for Amgen, BMS, MSD, Merck, Novartis, Pierre Fabre and Sanofi; research funding from Amgen, BMS, MSD, Novartis, Pierre Fabre and Roche; travel support from Amgen, BMS, MSD, Merck, Novartis, Pierre Fabre, Roche and Sanofi; and President of the Austrian Cancer Aid/Styria. N.Y. reports consulting and advisory roles for Novartis, Ono, BMS and MSD, honoraria from Novartis, Ono, BMS and MSD and institutional research support from Novartis, Ono, BMS, MSD and Takara-Bio. C.R. reports consulting or advisory roles for BMS, Roche, Amgen, Novartis, Pierre Fabre, MSD, Sanofi, Biothera, CureVac and Merck. D.S. reports research funding from Novartis and BMS. H.A.T. reports consulting or advisory roles for Novartis, BMS, Roche-Genentech, Merck and Array BioPharma and research funding from BMS, Novartis, Merck, GlaxoSmithKline, Genentech/Roche and Celgene. P.A.A. reports consulting or advisory roles for BMS, Roche-Genentech, MSD, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar and Boehringer Ingelheim, research funding from BMS, Roche-Genentech and Array and travel support from MSD. A.R. reports serving as a consultant/independent contractor for, and being the recipient of honoraria from, Amgen, Chugai, Merck, Novartis and Sanofi; advisory roles and receipt of honoraria from Arcus, Bioncotech, Compugen, CytomX, ImaginAb, Isoplexis, Merus, Rgenix, Lutris, PACT Pharma and Tango Therapeutics; self-managed stock shareholder in Arcus, Compugen, CytomX and Merus; and research support from Agilent and BMS. K.T.F. reports advisory roles for Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals, X4 Pharmaceuticals, PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Stattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros and Vibliome; consulting roles for Lilly, Novartis, Genentech, BMS, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre and Debiopharm; research funding from Novartis and Sanofi; and stock shareholder in Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals, X4 Pharmaceuticals, PIC Therapeutics, Fount, Shattuck Labs, Apricity, Oncoceutics, Fog Pharma, Tvardi, xCures, Monopteros and Vibliome. N.P. reports employment at Novartis Healthcare Pvt. Ltd. C.D.C. reports employment with, and stock in, Novartis Pharmaceuticals. D.G. reports employment with Novartis Institutes for BioMedical Research. A.M. reports employment by Novartis and stock or ownership in Novartis and BMS. J.C.B. reports employment by, and stock ownership in, Novartis, and is a coinventor on a patent application related to reported biomarker subgroups of interest. E.G. reports employment by, and stock ownership in, Novartis. G.V.L. reports consultant advisory roles for Aduro Biotech, Inc., Pierre Fabre Medicament, BMS, Amgen, MSD, Novartis Pharma, Array BioPharma, Syneos and Sandoz Biopharmaceuticals. All authors received support for third-party medical writing and editorial assistance provided by ArticulateScience LLC and funded by Novartis Pharmaceuticals Corporation.

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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.

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Extended data

Extended Data Fig. 1 Study designs for (a) part 1 and (b) part 2 of COMBI-i.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; CD, cluster of differentiation; CNS, central nervous system; DCR, disease control rate; DLT, dose-limiting toxicity; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; FFPE, formalin-fixed paraffin-embedded; ORR, overall response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death ligand 1; PFS, progression-free survival; PK, pharmacokinetics; Q4W, every 4 weeks; Q8W, every 8 weeks; QD, once daily; RECIST, Response Evaluation Criteria in Solid Tumors; RP3R, recommended phase 3 regimen; S, screening; ULN, upper limit of normal.a BRAF V600 mutation was assessed based on local testing (followed by central confirmation using the bioMérieux THxID-BRAF assay). b With systemic therapy including checkpoint inhibitors, targeted therapy, chemotherapy, biologic therapy, tumor vaccine therapy, or investigational treatment for unresectable or metastatic melanoma; prior intralesional, adjuvant, or neoadjuvant therapy was allowed if completed ≥ 6 months prior to start of study treatment, and prior radiation therapy was allowed if completed ≥ 4 weeks prior to start of study treatment. c DL-1b: DLT observation period starts on cycle 2, day 1 (C2D1 [day 29]). Patients who did not tolerate dabrafenib and/or trametinib and discontinued during the first 4 weeks were to be replaced due to insufficient exposure.

Extended Data Fig. 2 Best percent change from baseline in sum of diameters by local investigator review (N = 36).

A total of 33 patients experienced a reduction in the size of the target lesion. One patient with SD had a best percent change of 0% in the target lesion. Best percent change in the target lesion was not available for 1 patient with PD. Best percent change in target lesion could not be calculated for 1 additional patient as best overall response was unknown. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Extended Data Fig. 3 Time-to-event analyses, including (a) DOR, (b) PFS, and (c) OS, in patients enrolled in parts 1 and 2 of COMBI-i (N = 36).

12- and 24-month DOR rates were 80% (95% CI, 59%-91%) and 53% (95% CI, 29%-73%); 12- and 24-month PFS rates were 67% (95% CI, 49%-80%) and 41% (95% CI, 23%-59%); 12- and 24-month OS rates were 86% (95% CI, 70%-94%) and 74% (95% CI, 56%-86%). DOR, duration of response; PFS, progression-free survival; NE, not estimable; OS, overall survival.

Extended Data Fig. 4 Markers of response to immunotherapy were not associated with CR.

Baseline T-cell–inflamed GES levels and TMB in samples from patients with and without a CR. For T-cell–inflamed GES: n = 27 independent tumor biopsy specimens (CR, n = 14; no CR, n = 13). For TMB: n = 24 independent tumor biopsy specimens (CR, n = 12; no CR, n = 12). Box plots show median, first and third quartiles (boxes), and range up to 1.5 times IQR from the bounds of the box [whiskers]. Points beyond 1.5 times IQR from the bounds of the box are plotted individually. For T-cell–inflamed GES: CR, 4.90 (4.31-5.27) [3.48-6.09]; no CR, 4.87 (3.99-5.30) [2.88-6.65]. For TMB: CR, 7.196 (5.957-9.205) [3.365-13.479]; no CR, 7.209 (6.639-9.140) [3.539-10.533]. Descriptive P values are based on a two-sided Wilcoxon rank sum test (T-cell–inflamed GES: W = 89, effect size -0.04 [95% CI, -0.75-0.83]; TMB: W = 79, effect size 0.05 [95% CI, -2.40-2.85]); no adjustments were made for multiple comparisons. CPM, counts per million; CR, complete response; GES, gene expression signature; IQR, interquartile range; TMB, tumor mutational burden.

Extended Data Fig. 5 Correlative analysis of GES levels and tumor shrinkage following treatment with spartalizumab in combination with dabrafenib and trametinib.

Association between a, T-cell–inflamed GES levels and b, PI3K pathway gene expression and best overall tumor reduction, based on Spearman correlation coefficient. n = 27 independent tumor biopsy specimens. CPM, counts per million; GES, gene expression signature.

Extended Data Fig. 6 Evidence of immune activation during treatment with spartalizumab in combination with dabrafenib and trametinib.

a, Analysis of intratumoral density of CD8+ cells for available paired tumor biopsy specimens (n = 9) at baseline and on treatment using exploratory H-score analysis. Scale bars = 100 μm. b, Modulation of plasma IFN-γ following treatment with spartalizumab plus dabrafenib plus trametinib. Of the 27 independent plasma specimens analyzed, 25 showed elevated IFN-γ levels on treatment, while the other 2 showed a slight decrease. Box plot shows median, first and third quartiles (boxes), and range up to 1.5 times IQR from the bounds of the box [whiskers]. Points beyond 1.5 times IQR from the bounds of the box are plotted individually. Baseline, 1.78 (1.06-2.37) [1.06-4.19]. On treatment, 6.08 (3.65-7.88) [1.69-10.51]. IFN, interferon; IHC, immunohistochemistry; IQR, interquartile range.

Supplementary information

Supplementary Information

Supplementary Tables 1–8 and Figs. 1–3.

Reporting Summary

Supplementary Tables

Supplementary Tables 9–11. Full listings of all gene sets for which P < 0.05 in unbiased analyses (Table 9: PFS ≤12 months versus all others; Table 10: CR versus all others; Table 11: on-treatment modulations).

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Dummer, R., Lebbé, C., Atkinson, V. et al. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Nat Med 26, 1557–1563 (2020). https://doi.org/10.1038/s41591-020-1082-2

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