MONETTE: A Randomized Phase II Study of Ceralasertib plus Durvalumab or Ceralasertib Monotherapy in Patients with Advanced Melanoma Resistant to PD-(L)1 Inhibition

Introduction: Data suggest that ceralasertib, a potent and selective oral inhibitor of the ATR DNA damage response kinase, may overcome resistance to prior immunotherapy. Methods: In this phase II study, patients with unresectable or metastatic melanoma of cutaneous, acral or mucosal subtype and confirmed progression during anti-PD-(L)1 therapy with or without anti-CTLA-4 were randomized 2:1 to ceralasertib 240 mg BID on days 1-7 then durvalumab 1500 mg IV on day 8, every 28 days or ceralasertib 240 mg BID on days 1-7, every 28 days. The primary endpoint was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses of baseline (tumor and circulating) and on-treatment (circulating only) biomarkers were conducted. Results: ORR was 9.3% (95% confidence interval [CI], 4.3-16.9) for ceralasertib plus durvalumab (below the prespecified minimum threshold) and 5.8% (95%CI, 1.2-15.9) for ceralasertib monotherapy; median PFS was 2.0 months (95%CI, 1.9-3.5) versus 1.9 months (95%CI, 1.9-3.1) (hazard ratio [HR], 0.80; 95%CI, 0.54-1.18); and median OS was 16.0 months (95%CI, 10.5-NC) versus 12.3 months (95%CI, 9.5-NC) (HR, 0.81; 95%CI, 0.49-1.37). Both regimens were well tolerated. Exploratory analyses indicated a possible link between higher baseline pre-treatment tumor CD8+ T cell counts and improved overall survival across both arms and suggested that ceralasertib treatment may induce transient, cyclical changes in circulating CD14+ monocytes and GDF-15 plasma levels. Conclusion: Both ceralasertib plus durvalumab and ceralasertib monotherapy demonstrated low response rates in anti-PD-(L)1-resistant advanced melanoma.