LAUSR

BACKGROUND: Combining anti-PD-1/L1 antibodies and agents that restore cancer cell susceptibility to apoptosis may enhance antitumor activity. We report results from a phase 1b dose-expansion cohort of xevinapant, a first-in-class, oral, small-molecule IAP (inhibitor of apoptosis protein) inhibitor that restores cancer cell sensitivity to apoptosis, and avelumab (anti-PD-L1) in pts with advanced NSCLC. METHODS: The recommended phase 2 dose (RP2D; 28-day cycles of xevinapant 200 mg/day [days 1-10 and 15-24] + avelumab 10 mg/kg [days 1 and 15]) was previously established during the dose-escalation part of this phase 1, open-label study. In this dose-expansion cohort, pts with advanced NSCLC who progressed on first-line (1L) platinum-based chemotherapy (CTx) or anti-PD-1/L1 ± platinum-based CTx received xevinapant (at RP2D) + avelumab for 13 cycles. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics (PK). RESULTS: 38 pts were treated: most had squamous cell carcinoma (45%) or adenocarcinoma (42%) of the lung, 11% had prior anti-PD-L1 therapy, 71% were men, and median age was 62 years (range, 35-75). 1 pt completed 13 cycles, and 37 permanently discontinued treatment; most common reasons were progressive disease (PD; 70%) and adverse events (AEs; 27%). ORR was 10.5% (95% CI 2.9-24.8). Best overall response (BOR): 4 pts had a confirmed partial response (PR), 19 had stable disease, and 15 had PD. Median DoR in responders was 15.9 months (95% CI 3.5-29.7); DCR was 60.5% (95% CI 43.4-76.0). Median PFS was 3.5 months (95% CI 1.9-5.1); median OS was 9.4 months (95% CI 6.7-16.2). Most pts (n=37; 97.4%) had treatment-emergent AEs (TEAEs); 21 (55.3%) had grade ≥3. Most common TEAEs were decreased appetite (n=13; 34.2%) and ALT increase (n=11; 28.9%). Nine pts died due to TEAEs; none were considered treatment-related. Xevinapant and avelumab PK were comparable to monotherapy at the same doses. In exploratory biomarker analyses, plasma IL-10 levels increased during the study treatment period. In blood, activated CD4 T cells and Tregs increased during cycle 1, and activated CD8 T cells increased during the treatment period; however, these did not correlate with antitumor activity. In tumor samples, low Ki67 expression was associated with BOR of PR (n=4), and increases in macrophages, Tregs, Th1 cells, and dendritic cells were associated with disease control. CONCLUSION: Xevinapant + avelumab had tolerable safety in pts with advanced NSCLC who progressed on 1L platinum-based CTx or anti-PD-1/L1 ± platinum-based CTx; however, the study did not meet its primary endpoint as antitumor activity was comparable to historic data for avelumab second-line monotherapy. Citation Format: Quincy Chu, Tudor Ciuleanu, Rodryg Ramlau, Daniel Renouf, Rosalyn Juergens, Ewa Kalinka, Piotr Sawrycki, Jonathan Bramson, Brad Nelson, Rafael Crabbé, Daniela A. Sahlender, Philippa Crompton, Elisabeth Rouits, Dany Spaggiari, Franck Brichory, Luke Piggott, Mike Schenker, Glenwood Goss. Xevinapant plus avelumab in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Phase 1b dose-expansion results and exploratory biomarker analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT202.