MATRiX: A randomized phase II trial of tuvusertib (ATR inhibitor) with or without avelumab in advanced anti-PD(L)-1 refractory Merkel cell carcinoma.

Abstract

LBA9514 Background: Advanced Merkel cell carcinoma (MCC) often responds to anti-PD-(L)1, but patients (pts) with immune checkpoint inhibitor (ICI)-refractory disease have poor outcomes and few therapy options. MCC has defects in G1 checkpoint control, proliferates rapidly, and is reliant on S/G2 checkpoints such as ATR (ataxia telangiectasia mutated and Rad3-related). Inhibiting ATR can promote immunogenic cell death. MATRiX (MCC refractory to immunotherapy treated with ATR inhibitor ± avelumab) is a multicenter, NCI-sponsored, randomized, open-label phase II trial evaluating tuvusertib, an ATR inhibitor, alone (Arm 1) or in combination with avelumab (Arm 2) in anti-PD-(L)1-refractory MCC, NCT05947500. Methods: Pts were randomized 1:1 using a permuted-block design. Arm 1 received tuvusertib 180 mg PO on days 1-14 of each 21-day cycle. Arm 2 received tuvusertib as in Arm 1, plus avelumab 1600 mg IV every 21 days. Pts with disease progression in Arm 1 were eligible to cross over to Arm 2. The planned sample size (N=50; 25 per Arm) provided >80% power to observe a statistically significant (1-sided level of 0.15) difference in the primary endpoint, progression-free survival (PFS), assuming a hazard ratio of 0.5. Secondary endpoints were overall response rate (ORR), duration of response, and overall survival (OS). Data cutoff: January 20, 2026. Results: From 5/2024 to 9/2025, 35 subjects (median age 73) received therapy: Arm 1, n=10; Arm 2, n=25. One pt was deemed ineligible post-randomization and excluded from all analyses. 18 pts (53%) had primary ICI-refractory disease, and 22 (65%) had ≥2 prior systemic therapies. Arm 1 met prespecified futility criteria (0/10 responses) and was closed early. No objective responses were observed among 4 pts who crossed over to Arm 2. Among 24 eligible pts in Arm 2, 1 complete and 4 partial responses [ORR 20.8% (95% CI: 7.1-42.2%)] were observed, including 4 primary and 1 acquired ICI-resistant cases. 4 of 5 responders remained progression-free at cutoff (182-273 days from treatment initiation); 1 relapsed at 479 days. One-year estimates were PFS 0% (Arm 1) and 26.4% (Arm 2; 95% CI: 10.8-45.1%) and OS 29.2% (Arm 1; 1.5-69.8%) and 36.5% (Arm 2; 7.8-67.2%), respectively. Grade ≥3 treatment-emergent adverse events occurred in 80% of pts in Arm 1 and 58% in Arm 2; the most common were lymphopenia (20% vs 21%), anemia (50% vs 17%), fatigue (20% vs 17%), pain (10% vs 17%), and infection (0% vs 17%). Safety profiles were consistent with previous reports for these agents. Conclusions: Tuvusertib with avelumab demonstrated antitumor activity in anti-PD-(L)1-refractory MCC, inducing durable clinical benefit in ICI-resistant metastatic pts with limited salvage options. No signal of anticancer efficacy was observed with ATRi monotherapy. These findings warrant further investigation of ATRi in combination with immunotherapy in ICI-refractory MCC. Clinical trial information: NCT05947500 .