Roy Rabbie

Purpose: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.Patients and 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 twice daily on days 1 to 7 and then durvalumab 1,500 mg intravenously on day 8, every 28 days or ceralasertib 240 mg twice daily on days 1 to 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–not calculated (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 pretreatment tumor CD8+ T-cell counts and improved OS across both arms and suggested that ceralasertib treatment may induce transient, cyclical changes in circulating CD14+ monocytes and GDF-15 plasma levels.Conclusions:Both ceralasertib plus durvalumab and ceralasertib monotherapy demonstrated low response rates in anti–PD-(L)1–resistant advanced melanoma.

Supplementary tables including inclusion/exclusion criteria, representativeness of study participants, objective response rate by stratification factors and melanoma subtype, AEs, SAEs, AESIs, Baseline patient and disease characteristics in PD-L1 biomarker evaluable population, CD8/Ki67 evaluable population, baseline circulating immune cell population and GDF-15 evaluable population.

Study treatment discontinuation criteria and Flow Cytometry Immunophenotyping.

MONETTE study design, Baseline tumor sample and blood samples, DoR, best percentage change from baseline in target lesion size, OS in PD-L1 and CD8/Ki67 biomarker evaluable populations, micrographs of PD-L1 expression and CD8+/Ki67 cells, baseline area of CD8+ T cells, Ki67+ cells, and proliferating CD8+ Ki67 + T cells in the central tumor region, OS in the baseline circulating immune cell biomarker population, longitudinal pharmacodynamic effects on T cells, OS in GDF-15 biomarker population and baseline GDF-15 as a prognostic marker for OS in monotherapy and combination therapy.

Purpose: 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. Patients and 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 twice daily on days 1 to 7 and then durvalumab 1,500 mg intravenously on day 8, every 28 days or ceralasertib 240 mg twice daily on days 1 to 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–not calculated (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 pretreatment tumor CD8+ T-cell counts and improved OS across both arms and suggested that ceralasertib treatment may induce transient, cyclical changes in circulating CD14+ monocytes and GDF-15 plasma levels. Conclusions: Both ceralasertib plus durvalumab and ceralasertib monotherapy demonstrated low response rates in anti–PD-(L)1–resistant advanced melanoma.

Supplementary Table S5. Normalized Counts of transcripts in GRAMD1B KO and NT cells.

Supp Table S6 Differentially Expressed Genes

Supp Table S3 has a List of Oligonucleotides Sequences

Supp Table S4 has a list of antibodies and other resources

Validation of gramd1b depletion in zebrafish cells and tumors.