Abstract 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.
Schlaak et al. (Tue,) studied this question.