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589 Xevinapant plus nivolumab in patients with advanced solid tumors who progressed on prior anti–PD-1/PD-L1 treatment: results of a dose-optimization, exploratory phase 1b/2 trial
  1. Emiliano Calvo Aller1,
  2. Glenn Hanna2,
  3. Maria Vieito Villar3,
  4. Caroline Even4,
  5. Victor Moreno5,
  6. Chul Kim6,
  7. Shuchi Gulati7,
  8. Daniel Morgensztern8,
  9. Ana Acuna-Villaorduna9,
  10. Philippe Cassier10,
  11. Dennie Jones11,
  12. Florilene Bouisset12,
  13. Daniela Sahlender12,
  14. Elisabeth Rouits12,
  15. Dany Spaggiari12,
  16. Lars Damstrup12 and
  17. Carlos-Alberto Gomez-Roca13
  1. 1START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain
  2. 2Dana-Farber Cancer Institute, BOSTON, MA, United States
  3. 3Hospital Universitari Vall d'Hebron, Barcelona, Spain
  4. 4Institut Gustave Roussy, Villejuif, Val de Marne, France
  5. 5Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
  6. 6Georgetown University – Lombardi Comprehensive Cancer Center, Washington, DC, DC, United States
  7. 7University of Cincinnati, Cincinnati, OH, United States
  8. 8Washington University, School of Medicine, St. Louis, MO, United States
  9. 9Montefiore Medical Center PRIME, Bronx, NY, United States
  10. 10Centre Léon Bérard, Lyon, Rhone, France
  11. 11University of Florida, Gainesville, FL, United States
  12. 12Debiopharm International SA, Lausanne, Switzerland
  13. 13Institut Claudius Regaud, Toulouse, Haute Garonne, France


Background Anticancer agents that render cancer cells susceptible to apoptosis and increase antitumor immunity may enhance clinical responses to immune checkpoint inhibitors. In this phase 1b/2 trial, we investigated the antitumor activity and safety of xevinapant, a first-in-class, potent, oral, small-molecule inhibitor of apoptosis proteins inhibitor which restores cancer cell sensitivity to apoptosis, in combination with the anti-PD-1 antibody nivolumab.

Methods Eligible patients had histologically confirmed advanced or metastatic solid tumors that progressed on prior anti–PD-1/PD-L1 treatment, including small cell lung cancer (cohort 1), squamous cell carcinoma of the head and neck (cohort 2), gastrointestinal cancers with known microsatellite-high (MSI-H)/mismatch repair deficiency (MMRd) or other DNA-damage response (DDR) abnormalities (cohort 3), or platinum-resistant epithelial ovarian, endometrial, primary peritoneal or cervical cancer (with known MSI-H/MMRd, BRCA1/2 mutations, or other DDR abnormalities; cohort 4). In the dose-escalation part of the trial (part A), patients received xevinapant 150 or 200 mg/day on days 1-10 and days 15-24 plus nivolumab 240 mg on days 1 and 15 of a 28-day cycle. The primary objective of part A was to determine the recommended phase 2 dose (RP2D). In the phase 2 basket trial (part B), patients received xevinapant plus nivolumab at the RP2D; the primary endpoint was objective response rate (ORR).

Results Eleven patients were enrolled in part A; 3 patients received xevinapant 150 mg/day and 8 received 200 mg/day. No dose-limiting toxicities during the observation period (28 days) or grade ≥3 treatment-related adverse events (TRAEs) were reported. The RP2D was established as xevinapant 200 mg/day (days 1-10 and 15-24) plus nivolumab 240 mg (days 1 and 15) per 28-day cycle.1 In part B, 35 patients (n=8 cohorts 1-3, n=11 cohort 4) received xevinapant plus nivolumab at the RP2D. Most patients (60.0%) had stage IV disease and all patients had received prior chemotherapy treatment. At data cutoff (April 6, 2022), the ORR was 2.9%, with 1 partial response (cohort 4; endometrial cancer); 15 patients (42.9%) had stable disease. Thirty-four patients (97.1%) had discontinued treatment; the most common reason was disease progression (26 patients; 74.3%). Median PFS across cohorts was 1.9 months (95% CI, 1.7-2.7); median OS was 11.7 months (95% CI, 6.0-15.9). TRAEs occurred in 30 patients (85.7%); grade ≥3 TRAEs in 9 patients (25.7%). No treatment-related deaths were reported.

Conclusions Xevinapant plus nivolumab had a tolerable safety profile in patients with heavily pretreated solid tumors but limited clinical activity in this immunotherapy-refractory population.

Acknowledgements This trial was sponsored by Debiopharm. Medical writing support was provided by Sophie Saunders of ClinicalThinking and was funded by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

Trial Registration NCT04122625 (


  1. Azaro Pedrazzoli AB, Moreno V, Gomez-Roca CA, et al. Safety and efficacy of Debio 1143, an antagonist of inhibitor of apoptosis proteins (IAPs), in combination with nivolumab in a phase Ib/II trial in patients (pts) failing prior PD-1/PD-L1 treatment. Ann Oncol 2020;31(Suppl 4):Abstract 560P.

Ethics Approval The trial protocol was approved by the independent ethics committee or institutional review board at each participating center.

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