STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network

Abstract

Mutated oncogenic KIT is a therapeutic target in melanoma. We conducted a multicenter phase II trial on the KIT inhibitor nilotinib in patients with unresectable melanoma harboring KIT alteration. The primary endpoint was the response rate (complete response or partial response following Response Evaluation Criteria in Solid Tumors criteria) at 6 months. Pharmacodynamic studies using KIT sequencing, qPCR array, and immunostaining of downstream KIT effectors were performed during treatment. Twenty-five patients were included and received 400 mg oral nilotinib twice daily. At 6 months, nilotinib induced tumor response in four patients. The best overall response rate was 20% and the disease control rate was 56%, limited to patients harboring exon 11 or 13 mutations. Four patients exhibited durable response, including three persisting (3.6 and 2.8 years for two patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in signal transducer and activator of transcription (STAT) 3 phosphorylation and its effectors (BCL-2, MCL-1) in tumors during follow-up was significantly associated with clinical response. In the KIT-mutated melanoma cell line M230, nilotinib reduced STAT3 signaling and STAT inhibitors were as efficient as KIT inhibitors in reducing cell proliferation. Our study evidences a significant association between STAT3 inhibition and response to nilotinib, and provides a rationale for future research assessing STAT inhibitors in KIT-mutated melanoma.

KIT and Melanoma: Biological Insights and Clinical Implications

“…63 Five studies were conducted using this drug, in which all patients received orally nilotinib 400 mg twice a day. 56,[64][65][66][67] The most recent study was a phase II clinical trial conducted by the French Skin Cancer Network on 25 patients. 65 At 6 months after nilotinib initiation, only four patients were responsive to nilotinib (ORR: 16%, 90% CI: 5.6-33.0%), including one CR patient and three PR patients.…”

“…56,[64][65][66][67] The most recent study was a phase II clinical trial conducted by the French Skin Cancer Network on 25 patients. 65 At 6 months after nilotinib initiation, only four patients were responsive to nilotinib (ORR: 16%, 90% CI: 5.6-33.0%), including one CR patient and three PR patients. Out of the other 21 patients, six experienced progression and 15 died with an estimated PFS of 6.0 months and a median OS of 13.2 months (95% CI: 5.6-19.9 months).…”

Atypical BRAF and NRAS Mutations in Mucosal Melanoma

“…Treatment with KIT inhibitors resulted in a trend toward improved response in melanoma patients, with response rates of approximately 20%. Despite the clinical benefit achieved with KIT inhibition in select patients with melanoma harboring KIT mutations, most patients ultimately experience disease progression [9,10,11,12,13,14]. Immunotherapy has recently emerged as a promising treatment modality for cutaneous melanomas.…”

Molecular and Immune Biomarkers for Cutaneous Melanoma: Current Status and Future Prospects

“…Several trials based on targeting with kinase inhibitors c-KIT showed consistent results, obtaining an ORR of 16-29% and a median OS of 12-13 months [7][8][9][10]. Other studies investigating nilotinib, a small molecule more potent than imatinib in inhibiting KIT, showed promising clinical activity [11,37,38]. The global, single-arm, phase II TEAM trial showed 26.2% ORR (all partial responses) and OS of 18 months [11].…”