Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial

Abstract

Importance: Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression.

Objective: To assess safety and objective response rate of durvalumab combined with tremelimumab.

Design, setting, and participants: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific.

Interventions: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy.

Main outcomes and measures: Safety and tolerability and efficacy measured by objective response rate.

Results: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively.

Conclusions and relevance: In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way.

Trial registration: clinicaltrials.gov Identifier: NCT02319044.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Siu reported receiving consulting or advisory fees from Merck, Pfizer, Celgene, AstraZeneca/Medimmune, Morphosys, and Roche, grant or research support from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingleheim, Regeneron, GlaxoSmithKline, Roche, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, and AbbVie (institution); Dr Siu’s spouse holds stock in Agios. Dr Even reported receiving consulting or advisory fees from AstraZeneca, Bristol-Myers Squibb, Innate Pharma, Merck Serono, and Merck Sharpe & Dohme and receiving travel, accommodations, or expenses from Merck Serono. Dr Mesía reported receiving consulting or advisory fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Serono, and Merck Sharp & Dohme, and speaking fees from AstraZeneca, Bristol-Myers Squibb, and Merck Serono. Dr Saba reported receiving consulting or advisory fees from Pfizer, Lilly, and Bristol-Myers Squibb and speaking fees from Merck. Dr Ready reported receiving consulting or advisory fees from AbbVie, AstraZeneca, Bristol-Myers Squibb, Celgene, and Merck. Dr Braña reported receiving research funding from Merck Sharp & Dohme Corp, Bristol-Myers Squibb, AstraZeneca, KURA, Gliknik, Pfizer, Orion, GlaxoSmithKline, Janssen, Novartis, and Celgene; speaking fees from Bristol-Myers Squibb, AstraZeneca, and Merck Serono; and travel fees from AstraZeneca and Merck Serono. Dr Zandberg reported receiving research funding from AstraZeneca/MedImmune (institution), Bristol-Myers Squibb (institution), Gliknik (institution), MacroGenics (institution), and Merck (institution). Dr Gilbert reported receiving honoraria from TRM Oncology, consulting or advisory fees from AstraZeneca and TRM Oncology, research funding from AstraZeneca (institution), Bristol-Myers Squibb (institution), Merck (institution), and Pfizer (institution), and travel, accommodations, and expenses from TRM Oncology. Dr Mehanna reported receiving research funding from AstraZeneca and consulting or advisory fees from Merck Sharp & Dohme Corp. Dr Jarkowski reported being an employee of AstraZeneca and Bristol-Myers Squibb and having stock or other ownership in AstraZeneca. Dr Melillo reported being an employee and having stock or other ownership in AstraZeneca. Dr Armstrong reported being an employee and having stock or other ownership in AstraZeneca. Dr Wildsmith reported being an employee and having stock or other ownership in AstraZeneca. Dr Fayette reported receiving honoraria from AstraZeneca, Bristol-Myers Squibb, and Merck and receiving consulting or advisory fees from Bristol-Myers Squibb and travel, accommodations, and expenses from AstraZeneca and Bristol-Myers Squibb. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

All patients randomized are included in the full analysis set (FAS). EAS indicates evaluable analysis set; SAS, safety analysis set. aThese patients did not meet all inclusion criteria, including programmed death ligand 1 low or no tumor expression, or met at least 1 of the exclusion criteria.

Figure 2.. Kaplan-Meier Estimates of Progression-Free Survival and Overall Survival

Hatching on plots indicates censored data. aStratified log rank test.