Ceralasertib Plus Durvalumab Demonstrates Limited Activity in PD-L1-Resistant Advanced Melanoma

Clinical Summary: 

• Design/Population: This randomized phase 2 trial evaluated ceralasertib plus durvalumab versus ceralasertib monotherapy in patients with unresectable or metastatic cutaneous, acral, or mucosal melanoma whose disease had progressed during prior anti–PD-L1 therapy with or without anti–CTLA-4 treatment.
• Key Outcomes: Both treatment arms demonstrated low objective response rates, with the combination failing to meet the prespecified efficacy threshold. Median progression-free and overall survival numerically favored ceralasertib plus durvalumab, while both regimens were well tolerated. Exploratory analyses suggested that higher baseline tumor CD8-positive T-cell infiltration was associated with improved overall survival.
• Clinical Relevance: These findings indicate limited activity of ceralasertib, either alone or combined with durvalumab, in PD-L1-resistant advanced melanoma while highlighting potential biomarkers that may help identify patients more likely to benefit from ATR inhibition.

Results from the phase 2 MONETTE trial demonstrated that ceralasertib, administered alone or in combination with durvalumab, produced limited clinical activity in patients with anti–PD-L1-resistant advanced melanoma.

“Immunotherapies targeting PD-1, its ligand, PD-L1, and CTLA-4 produce durable clinical benefit in melanoma… however, a substantial proportion of patients eventually develop primary or secondary resistance to immune checkpoint inhibitor therapies,” stated Max Schlaak, MD, Charité – Universitätsmedizin Berlin, Germany, and coauthors. “Data suggest that ceralasertib, a potent and selective oral inhibitor of the ataxia-telangiectasia and Rad3-related (ATR) DNA damage response kinase, may overcome resistance to prior immunotherapy.”

In this multicenter trial, patients with unresectable or metastatic cutaneous, acral, or mucosal melanoma who experienced disease progression during prior anti–PD-L1 therapy, with or without anti–CTLA-4 treatment, were randomized 2:1 to receive 240 mg of ceralasertib twice daily on days 1 through 7 either alone or in combination with 1,500 mg of durvalumab on day 8 of each 28-day cycle The primary end point was objective response rate (ORR). Key secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

At analysis, the ORR was 9.3% with ceralasertib plus durvalumab and 5.8% with ceralasertib alone. The ORR observed with the combination did not meet the prespecified efficacy threshold. Median PFS was 2 months with ceralasertib plus durvalumab and 1.9 months with ceralasertib monotherapy. Median OS was 16 months and 12.3 months, respectively. 

Exploratory biomarker analyses demonstrated that higher baseline tumor CD8-positive T-cell infiltration was associated with longer OS across both treatment arms. Investigators also observed transient cyclical changes in circulating CD14-positive monocytes and plasma growth differentiation factor 15 (GDF-15) levels during ceralasertib treatment, suggesting pharmacodynamic immune modulation.

“Both ceralasertib plus durvalumab and ceralasertib monotherapy demonstrated low response rates in anti–PD- (L)1–resistant advanced melanoma,” concluded Dr Schlaak et al. “Although outcomes were limited… both regimens were well tolerated, and exploratory biomarker analyses suggested a possible trend whereby higher baseline pretreatment tumor CD8+ T-cell counts might be linked to improved OS across both treatment arms.”

Source: 

Schlaack M, Cimminiello C, Pigozzo J, et al. MONETTE: A randomized phase II study of ceralasertib plus durvalumab or ceralasertib monotherapy in patients with advanced melanoma resistant to PD-(L)1 inhibition. Clin Can Res. Published online: May 29, 2026. doi: 10.1158/1078-0432.CCR-25-3951