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MONETTE: A Randomized Phase II Study of Ceralasertib plus Durvalumab or Ceralasertib Monotherapy in Patients with
Max Schlaak1, Carolina Cimminiello2, Jacopo Pigozzo3
1Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Berlin, Germany.
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.
Insights
Ceralasertib showed low response rates in advanced melanoma resistant to immunotherapy. Combination therapy with durvalumab did not significantly improve outcomes compared to ceralasertib alone.
Area of Science:
- Oncology
- Pharmacology
- Immunotherapy
Background:
- Ceralasertib, an ATR kinase inhibitor, is investigated for overcoming resistance to anti-PD-(L)1 and anti-CTLA-4 immunotherapies.
- Melanoma patients often develop resistance to standard immunotherapies, necessitating novel treatment strategies.
Purpose of the Study:
- To evaluate the efficacy and safety of ceralasertib in combination with durvalumab versus ceralasertib monotherapy.
- To assess the potential of ceralasertib to overcome resistance in advanced melanoma patients progressing on prior immunotherapy.
Main Methods:
- A Phase II randomized study enrolled patients with unresectable or metastatic melanoma resistant to anti-PD-(L)1 therapy.
- Patients received either ceralasertib plus durvalumab or ceralasertib monotherapy.
- Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were primary and secondary endpoints. Biomarker analyses were conducted.
Main Results:
- The ORR was 9.3% for ceralasertib plus durvalumab and 5.8% for ceralasertib monotherapy, both below the minimum threshold.
- Median PFS was 2.0 months versus 1.9 months, and median OS was 16.0 months versus 12.3 months, respectively.
- Both regimens were well-tolerated. Exploratory analyses suggested a correlation between baseline CD8+ T cell counts and improved OS, and potential effects of ceralasertib on monocytes and GDF-15 levels.
Conclusions:
- Ceralasertib, both as monotherapy and in combination with durvalumab, demonstrated limited efficacy in patients with advanced melanoma resistant to anti-PD-(L)1 therapy.
- Further research into biomarkers and combination strategies may be warranted for this patient population.
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