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.

Melanoma has long represented a unique challenge in oncology. In its early stages, it can often be cured with surgery alone, resulting in excellent survival outcomes. Its biology is complex and heterogeneous, often including mutations such as BRAF and NRAS, which partly explain its high immunogenicity but also its capacity to relapse. For many decades, the standard approach in resectable stage III melanoma was surgery first, followed by adjuvant therapy. In the last decade, the development of immune checkpoint inhibitors created the opportunity to treat patients before surgery. The neoadjuvant approach is based on the hypothesis that treatment of the intact tumor may enhance antitumor immune priming and activation. The first prospective neoadjuvant studies, including OpACIN and OpACIN-neo, showed high pathological response rates with ipilimumab plus nivolumab and introduced pathological response as an early marker of long-term benefit. The PRADO study showed that treatment response could guide the extent of surgery required. The SWOG S1801 trial demonstrated better event-free survival with perioperative pembrolizumab compared to adjuvant therapy alone. Lastly, the phase III NADINA trial showed that neoadjuvant ipilimumab plus nivolumab followed by response-adapted adjuvant therapy significantly improves outcomes. Biomarkers such as PD-L1, IFN-γ signature, tumor mutational burden and imaging (PET scan) appear promising to predict response, but none have been sufficiently validated for routine clinical practice.

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.

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.

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.

The role of adjuvant therapy in stage III melanoma is well established in clinical practice. Because stage IIB–IIC melanoma carries a risk of recurrence and melanoma-specific mortality comparable to that of stage III disease, adjuvant approaches have also been developed for patients with thick stage II tumors. Both pembrolizumab and nivolumab have demonstrated efficacy in reducing the risk of local and distant recurrence in patients with high-risk stage II melanoma, whereas evidence supporting the use of BRAF-MEK inhibitors in this setting remains inconclusive. Combinations of immune checkpoint inhibitors, as well as immunotherapy combined with mRNA-based vaccines, are currently under investigation in clinical trials. However, given the non-trivial risk of immune-related adverse events, careful selection of patients with stage II disease who are most likely to derive meaningful benefit from adjuvant therapy is essential. In this context, several clinicopathologic variables and gene expression profiling-based prognostic tools have been proposed to refine risk stratification. To date, however, none of these instruments have been incorporated into routine clinical practice, and no validated predictive biomarkers are available. Accordingly, optimal patient selection for adjuvant therapy remains an important unmet clinical need in early-stage melanoma.