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Sequential Imatinib and Anti-PD-1 Therapy in KIT-Altered Melanoma: Mechanistic Insights and Clinical Benefit

ABSTRACT: KIT is a key oncogenic driver in triple-wildtype melanoma and represents a rational therapeutic target for KIT inhibitors such as imatinib. However, the tumor immune microenvironment in KIT-altered melanoma and optimal strategies to integrate immunotherapy remain poorly defined. In this study, we found that melanomas harboring KIT mutations or amplifications exhibited reduced CD8⁺ T cell infiltration, indicative of an immune-cold phenotype. Imatinib treatment reversed this Immunosuppressive microenvironment by enhancing CD8⁺ T cell infiltration and cytotoxic activity. Furthermore, imatinib upregulated O-GlcNAc transferase (OGT), which functions as a protein lactyltransferase and increased PD-L1 expression through lysine lactylation, thereby sensitizing tumors to anti–PD-1 therapy. Based on these findings, we conducted an open-label, single-arm phase II clinical trial in patients with advanced or metastatic KIT-altered melanoma. Patients received imatinib monotherapy as induction for six weeks, followed by combination therapy with toripalimab, an anti–PD-1 antibody. The combiniation therapy was well-tolerated and demonstrated encouraging clinical activity, with an objective response rate (ORR) of 59.4% in the overall cohort, 73.9% in patients with exon 11/13 mutations, and 100% in those with exon 11 mutation plus amplification—markedly higher than the ORRs of 23.3% with imatinib monotherapy and 25.7% with anti–PD-1 monotherapy. Median progression-free survival and overall survival were 8.2 months (95% CI, 6.5–9.9) and 15.1 months (95% CI, 13.1–20.8), respectively. These results support the use of imatinib as an immune-sensitizing induction therapy prior to PD-1 blockade in KIT-altered melanoma and highlight the therapeutic relevance of OGT-mediated PD-L1 regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303456 | GEO | 2026/07/23

REPOSITORIES: GEO

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Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network.

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Sequential Imatinib and Anti-PD-1 Therapy in KIT-Altered Melanoma: Mechanistic Insights and Clinical Benefit

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