MONETTE Trial Reports Low Response Rates in PD-(L)1-Resistant Melanoma

Key Takeaways

• Response rates were low in both study arms in anti–PD-(L)1–resistant advanced melanoma.
• Median progression-free survival was brief in both groups, while median overall survival was 16.0 months and 12.3 months.
• Both regimens were described as well tolerated in the abstract-level report.
• Exploratory biomarker findings suggested possible associations involving baseline tumor CD8+ T cells, circulating CD14+ monocytes, and GDF-15.

In the MONETTE phase 2 study, objective response rates were 9.3% with ceralasertib plus durvalumab and 5.8% with ceralasertib alone in unresectable or metastatic cutaneous, acral, or mucosal melanoma that had progressed during anti–PD-(L)1 therapy, with or without anti–CTLA-4. The combination arm did not reach the prespecified minimum threshold for response, and antitumor activity was limited in this enrolled population.

MONETTE randomly assigned patients in a 2:1 ratio to ceralasertib plus durvalumab or ceralasertib monotherapy. In both groups, ceralasertib was given at 240 mg twice daily on days 1 to 7 of each 28-day cycle. The combination arm also received durvalumab 1,500 mg intravenously on day 8 every 28 days in Clinical Cancer Research. The primary endpoint was objective response rate, with progression-free survival, overall survival, and safety as key secondary endpoints.

Objective response rate was 9.3% with the combination, with a 95% CI of 4.3 to 16.9, and 5.8% with monotherapy, with a 95% CI of 1.2 to 15.9. Median progression-free survival was 2.0 months with the combination and 1.9 months with monotherapy. The hazard ratio for progression-free survival was 0.80, with a 95% CI of 0.54 to 1.18, and median overall survival was 16.0 months versus 12.3 months. The hazard ratio for overall survival was 0.81, with a 95% CI of 0.49 to 1.37, and response rates remained low in anti–PD-(L)1–resistant advanced melanoma.

Median progression-free survival confidence intervals were 1.9 to 3.5 months for the combination and 1.9 to 3.1 months for monotherapy. Median overall survival confidence intervals were 10.5 months to not calculated for the combination and 9.5 months to not calculated for monotherapy. Investigators noted that both regimens were well tolerated, although detailed adverse-event listings were not provided in the abstract. Overall, the efficacy and safety findings reflected limited clinical activity in this setting.

Exploratory analyses suggested a possible association between higher baseline pretreatment tumor CD8+ T-cell counts and improved overall survival across both arms. Ceralasertib treatment was also associated with transient cyclical changes in circulating CD14+ monocytes and GDF-15 plasma levels.

These observations were limited to exploratory biomarker findings from baseline tumor and circulating measures, along with on-treatment circulating biomarkers. They remained hypothesis-level findings within a trial with limited reported clinical activity.