MONETTE: A Randomized Phase II Study of Ceralasertib plus Durvalumab or Ceralasertib Monotherapy in Patients with Advanced Melanoma Resistant to PD-(L)1 Inhibition

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.

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Journal
Clinical Cancer Research
Published
2026-04-21
DOI
https://doi.org/10.1158/1078-0432.ccr-25-3951
Primary Topic
Melanoma and MAPK Pathways
Type
article
Field-Weighted Citation Impact
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article

MONETTE: A Randomized Phase II Study of Ceralasertib plus Durvalumab or Ceralasertib Monotherapy in Patients with Advanced Melanoma Resistant to PD-(L)1 Inhibition

Emma Jane Dean, Jacek Mackiewicz, Mario Mandalà, William Sharfman et al.
Clinical Cancer Research
Melanoma and MAPK Pathways
article

MONETTE: A Randomized Phase II Study of Ceralasertib plus Durvalumab or Ceralasertib Monotherapy in Patients with Advanced Melanoma Resistant to PD-(L)1 Inhibition

Emma Jane Dean, Jacek Mackiewicz, Mario Mandalà, William Sharfman, Urwah Noor, Jeeyun Lee, Sebastian Haferkamp, Paolo A. Ascierto, Sonia Iyer, Fabrizio Carnevale‐Schianca, Max Schlaak, Stephan Grabbe, Jacopo Pigozzo, Shahneen Kaur Sandhu, Jessica Cecile Hassel, Victoria Atkinson, Roy Rabbie, Antoni Ribas, Katy K. Tsai, P Rutkowski
article en

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.

Clinical Cancer Research
Poznan University of Medical Sciences (PL), University of California, Los Angeles (US), University of California, San Francisco (US), Johannes Gutenberg University Mainz (DE), Heidelberg University (DE), University of Perugia (IT), Peter MacCallum Cancer Centre (AU), Princess Alexandra Hospital (AU), Samsung Medical Center (KR), Johns Hopkins University Applied Physics Laboratory (US), University Hospital Regensburg (DE), AstraZeneca (South Korea) (KR), University Medical Center of the Johannes Gutenberg University Mainz (DE), Istituto Oncologico Veneto (IT), AstraZeneca (Singapore) (SG), AstraZeneca (Poland) (PL), Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT), Princess Alexandra Hospital (GB), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Candiolo Cancer Institute (IT), European Institute of Oncology (IT), University of San Francisco (US), Charité - Universitätsmedizin Berlin (DE), Heidelberg University (US)
AstraZeneca
Good health and well-being
Openalex Percentile: Top 17%
Melanoma and MAPK Pathways
DOIOpen Access PDFOpenAlex
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