Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1–Low/Negative Recurrent or Metastatic HNSCC

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

The effects and safety of PD‐1/PD‐L1 inhibitors on head and neck cancer: A systematic review and meta‐analysis

“…Literature search and review of reference lists identified 697 relevant articles. After screening and eligibility assessment, we included in the systematic review and meta‐analysis a total of nine clinical trials involving the group (n = 1018) of patients treated with PD‐1/PD‐L1 inhibitors and the group (n = 369) receiving standard‐of‐care treatment, comprising two randomized controlled trial and seven single arm trials (Figure ) . The PD‐1/PD‐L1 inhibitors used included pembrolizumab (n = 4), nivolumab (n = 1), cemiplimab (n = 0), atezolizumab (n = 1), avelumab (n = 0), and durvalumab (n = 3).…”

FOLFOX Chemotherapy Ameliorates CD8 T Lymphocyte Exhaustion and Enhances Checkpoint Blockade Efficacy in Colorectal Cancer

“…Relief of exhaustion in tumor infiltrating lymphocytes is currently under intensive study as a therapeutic method due to significant advancements in the care of patients with melanoma, non-small cell lung cancer, and others using PD-1 and CTLA-4 checkpoint blockade (13). However, the majority of patients does not respond nor achieve durable responses to this therapy, including most CRC patients (14)(15)(16)(17)(18). This may be related to the plastic vs. terminal dysfunctional stage of patients' TILs.…”

Fatal Adverse Events Associated With Programmed Cell Death Ligand 1 Inhibitors: A Systematic Review and Meta-Analysis

“…Thereinto, 1,936 records were screened by the title and abstract after removing the duplicates. Eventually, 26 studies with 6,896 unique individuals were collected following perusing the full texts (Antonia et al, 2016;Fehrenbacher et al, 2016;Balar et al, 2017;Peters et al, 2017;Powles et al, 2017;Barlesi et al, 2018;Choueiri et al, 2018;Dirix et al, 2018;Garassino et al, 2018;Horn et al, 2018;Liu et al, 2018;McDermott et al, 2018;Pal et al, 2018;Patel et al, 2018;Powles et al, 2018;Schmid et al, 2018;Siu et al, 2018;Socinski et al, 2018;Spigel et al, 2018;Chung et al, 2019;Eng et al, 2019;Hong et al, 2019;Kim, 2019;Motzer et al, 2019;Rini et al, 2019;West et al, 2019). In sum, 74 cases of fatal adverse events associated with PD-L1 inhibitors were documented.…”

“…Furthermore, a study regarding durvalumab exhibited seven treatment-related death, three of which mixed six fatal causes (Kim, 2019). Additionally, two studies included all patients with a positive status of PD-L1 (Peters et al, 2017;Spigel et al, 2018), whereas only one study that PD-L1 status was a negative status (Siu et al, 2018). Each of the following five kinds of cancers only included a qualified article: SCLC, pancreatic cancer, colorectal cancer, gastric or gastroesophageal junction cancer, and head and neck squamous cell carcinoma (HNSCC) (Horn et al, 2018;Siu et al, 2018;Chung et al, 2019;Eng et al, 2019;Hong et al, 2019).…”