High Recurrence for HPV-Positive Oropharyngeal Cancer With Neoadjuvant Radiation Therapy to Gross Disease Plus Immunotherapy: Analysis From a Prospective Phase Ib/II Clinical Trial

Abstract

Moderate reduction of radiation to elective volumes has demonstrated encouraging results for human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPSCC). However, it remains unknown whether omitting elective volume radiation completely can maintain adequate locoregional control. This trial (NCTXXX) assessed outcomes of Stereotactic Body Radiation Therapy (SBRT) to the gross disease without elective volume irradiation combined with durvalumab and tremelimumab before surgery in patients with HPV+ OPSCC. This phase Ib/II trial included patients with previously untreated locally advanced HPV+ OPSCC from September 2019 to March 2021. Patients received neoadjuvant durvalumab±tremelimumab for 2 doses, with the first dose concurrent with SBRT of 25 Gy in 5 fractions to gross disease only, prior to TransOral Robotic Surgery, followed by adjuvant durvalumab for up to 4 cycles. The primary endpoint was safety/efficacy for the phase Ib portion; and two-year progression-free survival for the phase II portion. This report describes patterns of failure after early closure of the trial following a separate study demonstrating a lack of efficacy of durvalumab±tremelimumab in the metastatic/recurrent setting. Nineteen patients were enrolled (phase Ib: 6; phase II: 13). Three were treated with durvalumab only while 16 with durvalumab+tremelimumab. Median follow-up was 12.7 months. No safety signals were seen. Overall, 18 out of 19 (95%) achieved a clinical to pathological downstaging, and 9 (47%) had a pathological complete response (pCR). Five patients (26%) developed locoregional recurrence, with a median time to recurrence was 3 months. Failing to achieve pCR was significantly associated with locoregional recurrence (p=0.033). None developed distant metastasis. Neoadjuvant SBRT delivered only to the gross tumor before surgery is associated with a high early risk of lymph node recurrence in HPV+ OPSCC despite concurrent/adjuvant immunotherapy. The results caution against omitting elective volume irradiation even in this group of patients with relatively favorable prognosis.