Intratumoral (IT) ruxotemitide (LTX‑315) in combination with pembrolizumab in patients with unresectable advanced melanoma refractory to PD-1/PD-L1 therapy: Final results from the ATLAS-IT-05 study

Background: Advanced unresectable cutaneous melanoma refractory to prior immunotherapy is associated with poor prognosis and limited treatment options. Ruxotemitide, an oncolytic peptide, induces immunogenic cell death and remodels the tumor microenvironment to enhance antitumor immunity. Preclinical and early clinical data support synergistic activity with PD-1 blockade. This Phase 2 study evaluated intratumoral (IT) ruxotemitide in combination with pembrolizumab in patients with unresectable advanced or metastatic melanoma accessible for IT injection after prior checkpoint inhibitor (CPI) failure. Methods: This was an open-label, single-arm Phase 2 study enrolling adults with stage IIIB-IV (M1b) cutaneous melanoma and at least one injectable lesion (cutaneous, subcutaneous, lymph node, or intramuscular). Patients received IT ruxotemitide (up to seven injections during the first 29 days) in combination with pembrolizumab 200 mg IV every 3 weeks until disease progression or for up to 24 months. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and safety. Results: Twenty-three patients were enrolled, with a median age of 68 years (range, 42-91 years). Over half (52.1%) of pts had received three or more prior lines of therapy, and all had previous CPI treatment. Twenty-two patients were evaluable for efficacy. ORR was 13.6% (80% CI, 5.1-27.9). The clinical benefit rate was 36.4%. All responses were durable, lasting more than 24 months. Median PFS was 6.3 months. The safety profile was consistent with known effects of IT immunotherapy and pembrolizumab. The most common treatment emergent adverse events (TEAEs) were injection-site reactions (95.7%), fatigue (30%), pruritus (26.1%), hypotension (26.1%), and anemia (21.7%). No TEAEs led to treatment discontinuation. Conclusions: IT ruxotemitide plus pembrolizumab demonstrated durable antitumor activity and manageable safety in heavily pretreated patients with CPI-refractory advanced or metastatic melanoma with injectable disease. These findings support further clinical evaluation of this combination in melanoma.