April 15 2020
Article by Jennifer Hsing Choe, MD, of Duke University’s Duke Cancer Institute
Patient outcomes are excellent for early stage non-smoker HPV-positive oropharynx cancers treated with definitive concurrent cisplatin and radiation. However, significant morbidity related to acute and long-term toxicities from standard chemoradiation regimens have led to controversy and a number of investigations into treatments that reduce the risks of toxicity without sacrificing efficacy. These strategies have included reduced radiation dosing and alternate concurrent systemic therapy regimens, including immune checkpoint therapy or cetuximab. The approach to treatment de-intensification remains a hotly debated subject where randomized phase III data has not yet been established that would guide de-intensification protocols into routine clinical practice. While phase II data have been promising, the results of the phase III RTOG 1016 study demonstrating the inferiority of cetuximab/RT to cisplatin/RT in HPV+ positive oropharynx cancers only further reinforced the need for validated phase III results to support treatment de-intensification.
Open to accrual since July 2019, NRG-HN005 is a randomized phase II/III trial with the initial phase II portion designed to guide treatment arms in phase III. The trial will directly compare clinical outcomes related to de-intensification strategies in HPV-positive oropharyngeal disease through use of both reduced intensity radiation and/or nivolumab therapy. Similar to NRG-HN004 in cisplatin-ineligible patients, immune checkpoint therapy is added to augment RT-induced immunogenic cell death and mitigate the immunosuppressive tumor phenotype associated with radiation.
The phase II study is comprised of three arms evaluating various combinations of reduced dose radiation and in combination with nivolumab in patients with early stage HPV-positive oropharynx cancer (8th edition Stage I-II, excluding T0, T1-2 N0, or any N2). The control arm (arm 1) utilizes the standard 70 Gy (delivered over an accelerated radiation course) with cisplatin; the 2 experimental arms test a reduced radiation dose of 60 Gy with either cisplatin (arm 2) or the anti-PD1 inhibitor nivolumab (arm 3).Cisplatin would be administered at 100 mg/m2 for 2 cycles based on RTOG 1016 (Gillison et al, 2018).Inclusion of one or both experimental arms for the phase III portion would be guided by the treatments that had non-inferior PFS in the phase II component. The non-inferior PFS primary endpoint will be carried through both phases, but the phase III study will also support a co-primary endpoint evaluating quality of life, including dysphagia.
The phase III data generated from this study is potentially practice-changing and may provide pivotal guidance on treatment choice in early stage HPV-positive oropharynx cancers in non-smokers.
NRG-HN005 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.