IN A POPULATION of heavily pretreated patients with recurrent or metastatic head and neck cancer and low or negative programmed cell death ligand 1 (PD-L1) expression, durvalumab (Imfinzi) monotherapy demonstrated an overall response rate of 9.2%, consistent with that of single-agent programmed cell death protein 1 (PD-1) inhibitors in second-line settings. According to data presented at the 2018 Multidisciplinary Head and Neck Cancer Symposium,¹ investigators observed no difference in clinical activity between durvalumab alone and the combination of durvalumab and tremelimumab, with both arms showing clinically relevant overall survival. Low or negative PD-L1 expression was defined as PD-L1 staining in less than 25% of tumor cells. 

Lillian Siu, MD, FASCO

“Results from the randomized, phase II CONDOR trial suggest the immune checkpoint blocker durvalumab is safe and shows encouraging antitumor activity as second-line treatment in tumors with low or negative PD-L1,” said Lillian Siu, MD, FASCO, lead author of the study as well as a senior medical oncologist at Princess Margaret Cancer Centre and Professor of Medicine at the University of Toronto. “Nevertheless, we need to see how these overall survival curves pan out as well as the results from the ongoing randomized phase III EAGLE trial to determine efficacy in this population.” 

The safety and efficacy of durvalumab monotherapy in head and neck tumors that express high levels of PD-L1 were already demonstrated in the phase II HAWK trial,² the authors noted, but this was the first trial to show similar findings for the immune checkpoint inhibitor in patients with low or negative PD-L1 expression. 

As Dr. Siu reported, head and neck squamous cell carcinoma commonly has an inflamed phenotype with T-cell infiltration, which may benefit from immunotherapy. With durvalumab, a human immunoglobulin G1 (IgG1) monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, and tremelimumab, a selective human IgG2 monoclonal antibody inhibitor of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) that promotes T-cell activity but does not deplete regulatory T cells, the CONDOR trial focused on two targets. 

“Combining anti–PD-L1 and anti–CTLA-4 antibodies have shown enhanced preclinical antitumor activity over either agent alone, indicating the two pathways are not redundant,” Dr. Siu explained. “There is also an unmet need for effective treatment options for patients with PD-L1–low or negative–expressing tumors, due to the serious and life-threatening nature of the disease.” 

CONDOR Trial Details 

FOR THE RANDOMIZED, phase II CONDOR trial, investigators enrolled patients with recurrent or metastatic head and neck squamous cell carcinoma (oral cavity, oropharynx, hypopharynx, or larynx) following disease progression of one prior platinum-based regimen in the recurrent/metastatic setting. Eligible patients had low or negative PD-L1 expression. Patients were stratified by human papillomavirus (HPV) and smoking status and randomized to one of three treatment arms: (1) durvalumab monotherapy (10 mg/kg, intravenously [IV] every 2 weeks); (2) tremelimumab monotherapy (10 mg/kg IV every 4 weeks), or (3) combination of durvalumab plus tremelimumab ([20 mg/kg every 4 weeks + 1 mg/kg every 4 weeks] 4 cycles, then 10 mg/kg durvalumab every 2 weeks). 

Responses were measured using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included the duration of response and overall survival. 

As Dr. Siu reported, 267 patients were randomized to the three arms, and median follow-up was 5.8 months. The majority of patients had metastatic disease (64%) vs recurrent disease (36%), and 28.1% of patients had HPV-positive disease. In addition, 40% of patients were light or never smokers, and the majority had a good performance status. 

Toxicity 

TREATMENT-RELATED adverse events of any grade were seen in 57.9% of patients in the durvalumab plus tremelimumab arm, 63.1% of patients in the durvalumab arm, and 55.4% of patients in the tremelimumab arm. According to Dr. Siu, the frequency of treatment-related adverse events was slightly lower in patients receiving durvalumab monotherapy. Grade 3 or 4 treatment-related adverse events occurred in 15.8% of patients in the combination arm, 12.3% of patients in the durvalumab arm, and 16.9% of patients in the tremelimumab arm—all with low frequency, Dr. Siu observed. 

“Toxicity was manageable and consistent with that of similar immunotherapeutic agents, either in combination or alone,” said Dr. Siu, who noted very few patients discontinued treatment as a result of the study drugs. “There was only one treatment-related death in the combination arm, and this was due to acute respiratory failure.” 

Response and Survival 

ACCORDING TO Dr. Siu, durvalumab showed encouraging antitumor activity both alone and in combination with tremelimumab. Patients treated with durvalumab monotherapy had an overall response rate of 9.2%, and those treated with the combination therapy had an overall response rate of 7.8%. Patients treated with tremelimumab alone had a 1.6% overall response rate. Of the 17 patients who experienced a partial response to treatment, 10 responses are still ongoing, said Dr. Siu, who noted the response rate for durvalumab monotherapy was consistent with that of other single-agent PD-1/PD-L1 inhibitors in this setting. 

Median overall survival was 7.6 months for the combination arm, 6.0 months for durvalumab monotherapy, and 5.5 months for tremelimumab monotherapy. There was no observed difference in clinical activity between durvalumab alone and durvalumab in combination with tremelimumab, Dr. Siu reported. 

“These results add to the body of evidence that durvalumab is tolerable and has demonstrated encouraging clinical activity across a range of tumors, including in heavily pretreated recurrent or metastatic head and neck cancer,” said Dr. Siu. “Follow-up duration is still fairly short,” Dr. Siu added, “so it will be interesting to see how these survival curves evolve over time.” 

DISCLOSURE: Dr. Siu has been a consultant for AstraZeneca/MedImmune, Boehringer Ingelheim, Celgene, Merck, and Pfizer and has received grant/research support from AstraZeneca/MedImmune, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, and Pfizer. 

REFERENCES 

1. Siu L, Even C, Mesía R, et al: A randomized, open-label, multicenter, global phase 2 study of durvalumab, tremelimumab, or durvalumab plus tremelimumab in patients with PD-L1 low/negative recurrent or metastatic head and neck squamous cell carcinoma: CONDOR. 2018 Multidisciplinary Head and Neck Cancer Symposium. Abstract 1. Presented February 15, 2018. 

2. Zandberg DP, Jarkowski A, Emeribe UA, et al: A Phase 2, multicenter, single-arm, global study of MEDI4736 monotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: HAWK (NCT02207530). 2015 ASCO Annual Meeting. Abstract TPS6086. Presented May 30, 2015.