Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (33020648)
Authors Dummer R, Lebbé C, Atkinson V, Mandalà M, Nathan PD, Arance A, Richtig E, Yamazaki N, Robert C, Schadendorf D, Tawbi HA, Ascierto PA, Ribas A, Flaherty KT, Pakhle N, Campbell CD, Gusenleitner D, Masood A, Brase JC, Gasal E, Long GV
Title Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i.
Journal Nature medicine
Vol
Issue
Date 2020 Oct 05
URL
Abstract Text 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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600X melanoma predicted - sensitive Dabrafenib + Spartalizumab + Trametinib Phase III Actionable In a Phase III trial (COMBI-i), the combination of Tafinlar (dabrafenib), Mekinist (trametinib), and Spartalizumab (PDR001) resulted in an objective response rate of 78% (28/36, 16 complete, 12 partial), disease control rate of 94% (34/36), and median progression-free survival of 23 months in patients with BRAF V600-mutant metastatic melanoma, including 29 patients (81%) harboring BRAF V600E and 4 patients (11%) harboring BRAF V600K (PMID: 33020648; NCT02967692). 33020648