Editor's Note: As immunotherapy continues to make breakthroughs in treating malignant tumors, it has significantly improved the survival rates of melanoma patients. However, there remains an urgent need to develop new drugs and optimize immunotherapy strategies for patients resistant or intolerant to current treatments. At the ongoing 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, several studies focused on new treatment strategies for immunotherapy-resistant melanoma patients. Oncology Frontier invited Professor Yu Chen from Fujian Cancer Hospital to analyze these cutting-edge studies, revealing the important roles and potential applications of new therapies in this challenging melanoma subtype.Background: The NCT03161431 study aimed to evaluate the efficacy and safety of SX-682 (CXCR1/2 inhibitor) combined with pembrolizumab (pem) in metastatic melanoma (mMEL) patients with disease progression on PD-1 inhibitors.
Methods: Participants: Melanoma patients with disease progression during PD-1 inhibitor treatment, including mucosal melanoma and asymptomatic brain metastases. The study employed a dose-escalation and expansion design to assess the safety and efficacy of pem and SX-682 (25-400 mg, po, bid, q3w) in metastatic melanoma patients. The dose-escalation cohort received 21 days of SX-682 monotherapy (MONO). During combination (COMBO) treatment, efficacy was evaluated every 2 cycles using RECIST 1.1. Primary endpoints: Safety, AEs, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD). Secondary endpoints: Objective response rate (ORR, CR+PR), disease control rate (DCR, CR+PR+SD), and overall survival (OS).
Results: As of October 2023, 51 patients were enrolled and treated: Median age 65 years (24-91), 55% male, 61% with elevated LDH, 39% BRAF mutations. All patients had prior anti-PD-1 therapy; 73% had anti-PD-1 and anti-CTLA-4 therapy, and 45% had received 3 or more lines of treatment. COMBO cohort dose expansion: 25 mg bid (n=3), 50 mg bid (n=3), 100 mg bid (n=6), 150 mg bid (n=8), 200 mg bid (n=31). At 200 mg, ORR for 19 evaluable patients was 21% (4 PRs), and DCR was 63% (8 SDs, 4 PRs). DCR significantly depended on SX-682 dose: 0% for ≤100 mg (0/9), 50% for 150 mg (3/6, P=0.0440), and 63% for 200 mg (12/19, P=0.0028). All 15 DCR patients had progressed on anti-PD-1 and anti-CTLA-4 therapy. Median OS was longer in the 200 mg cohort compared to ≤100 mg (14.7 vs. 7.4 months; 95% CI: 10.5-NR vs. 5.0-NR, n=31 vs. 10).
Safety: No DLT or MTD during MONO treatment. Any-grade and grade 3/4 treatment-related AEs (TRAEs) occurred in 75% and 43% of patients, respectively. TRAE-related discontinuation occurred in 20% of patients (25% for grade 3/4 TRAEs, 12% for DC due to rash, transaminase elevation). No infection-related warnings were noted.
Conclusion: The combination of SX-682 and pem demonstrated good clinical efficacy and acceptable toxicity in melanoma patients with progression on prior anti-PD-1 and anti-CTLA-4 therapy.
Expert Commentary: Melanoma is a highly aggressive malignancy with high mortality and morbidity. Targeted and immunotherapy advancements over the past two decades have significantly improved survival for melanoma patients. Currently, single-agent PD-1 or CTLA-4 combined with PD-1 therapy is the standard first-line treatment for advanced cutaneous melanoma, widely used in Western countries. Despite significant first-line PFS improvements, some patients exhibit primary resistance, and many with initial response eventually develop acquired resistance. Therefore, exploring strategies to overcome resistance has become a focus in recent years.
Mechanistically, CXCR1/2 inhibitors like SX-682 can improve the tumor microenvironment by inhibiting MDSC transport. The 2022 ASH meeting showcased SX-682’s preliminary efficacy in myelodysplastic syndrome. A 2023 Nature publication reported that SX-682 combined with immune checkpoints LAG3 and 41BB led to complete tumor remission in pancreatic cancer models, laying the groundwork for further research. This study explored SX-682 combined with PD-1 re-challenge in immunotherapy-resistant cutaneous melanoma. A significant portion of the cohort had prior CTLA-4+PD-1 therapy, with a notable DCR improvement with increased SX-682 doses. The 200 mg dose showed 21% clinical response and 63% DCR, with prolonged median OS compared to lower doses. These promising results and good tolerability support further research.
Several questions remain for future studies: the duration of disease control in responsive and controlled patients, potential biomarkers in the tumor microenvironment or peripheral blood to enrich for responders, and clinical response in PD-1 primary-resistant subtypes like acral and mucosal melanomas. Overall, SX-682 adds a new strategy for melanoma treatment, and we anticipate further translational research and phase II results.
