April 15 2020
Article by Jennifer Hsing Choe, MD, of Duke University’s Duke Cancer Institute
The best treatment option remains unclear for locoregionally advanced head and neck squamous cell (HNSCC) patients who require concurrent chemoradiation but are not eligible for cisplatin due to comorbidities and age. While concurrent treatment of radiation therapy with the EGFR inhibitor cetuximab has usually been favored for these patients, RTOG 1016 (Gillison et al, 2018) recently confirmed the superiority of cisplatin over cetuximab for definitive chemoradiation for HPV-positive oropharyngeal disease. Alternative effective options from cisplatin for multi-modality treatment of definitive HNSCC patients remain unclear.
NRG-HN004 is a randomized phase II/III study which compares a cetuximab/radiation therapy standard- of-care control arm to a durvalumab/radiation therapy experimental arm to evaluate PFS and OS primary endpoints in cisplatin-ineligible patients with locoregionally advanced HNSCC. The study opened to accrual in December 2017, and preliminary results of the 10-patient safety lead-in presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting reported that the combination of radiation therapy with durvalumab was safe and feasible in this population. No DLTs were seen, and the adverse event profile was comparable to previous immune checkpoint therapies.
The study is now actively enrolling in the phase II portion. For the phase II and III portions, the patients will be randomized to durvalumab/radiation therapy or cetuximab/radiation therapy with radiation given as a standard 70 Gy in 35 daily fractions over 7 weeks.
Radiation may synergize with immune checkpoint therapy through enhanced immunogenic cell death and blockade of radiation-induced PDL1 expression. Building on this premise, NRG-HN004 will provide evidence of whether PDL1 inhibition with radiation represents a viable therapeutic option for cisplatin-ineligible HNSCC patients. While combining anti-PDL1 agent durvalumb with anti-CTLA4 therapy tremelimumab missed its mark on OS improvement in the phase III study in head and neck cancer, the PACIFIC trial in NSCLC (Antonia et al, NEJM 2018) provided proof of concept that adding adjuvant durvalumab to radiation therapy could significantly improve overall survival. This trial seeks to demonstrate whether this benefit can translate to head and neck cancers. Additionally, secondary objectives will also compare quality of life measures, including swallowing dysfunction, a major source of long-term morbidity related to head and neck treatment.
The results of NRG-HN004 will provide clinical guidance on treatment choice for locoregionally advanced HNSCC patients who are medically unfit for standard-of-care cisplatin. Positive findings may be leveraged for additional multi-modality studies that partner radiation with immune checkpoint therapy, including the perioperative setting.
2019 ASCO Abstract
NRG-HN004 on Clinicaltrials.gov
Gillison ML, Trotti AM, Harris J, et al. Radiotherapy Plus Cetuximab or Cisplatin in Human Papillomavirus Positive Oropharyngeal Cancer (NRG Oncology RTOG 1016): a Randomised, Multicentre, Non-Inferiority Trial. Lancet. 2019;393(10166):40-50.
Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350.