Abstract CT182: Neoadjuvant immuno-radiotherapy (NIRT) in head and neck cancer: Phase I/Ib study of combined PD-1/SBRT prior to surgical resection
Authors: Leidner Rom , Bell R. Bryan , Young Kristina , Curti Brendan , Couey Marcus , Patel Ashish , Watters Amber , Xiao Hong , Bifulco Carlo , Piening Brian , Morris George , Rushforth Lessli , Brucker Dawn , Nemeth Shorin , Gough Michael , Crittenden Marka 
Published: August 2019

Abstract
Background: Standard treatment of locally advanced HPV-associated oropharyngeal HNSCC includes definitive chemoRT or surgery followed by risk-adapted adjuvant RT +/- chemo. These approaches provide high rates of long term survival, but are associated with significant subacute as well as long term morbidity. Therefore, increasing efforts have been directed at exploring alternative approaches. Combined SBRT and PD-1 blockade may have particularly favorable properties for anti-tumor immune response in HNSCC (Gough 2009). We present phase I safety & efficacy data from the NIRT trial of neoadjuvant nivolumab/SBRT in oropharyngeal p16+ HNSCC (NCT03247712).
Methods: Patients with p16+ oropharyngeal or unknown primary HNSCC, with clinical indications for adjuvant RT, or upfront TORS ineligible due to tumor size, could enroll. Patients received Nivo 240mg IV q2wks x3 prior to surgery, with SBRT to GTV+3mm delivered between Nivo doses 1 & 2, in two dose finding cohorts (n=5 each): 8Gy x5 daily (M-F) and de-escalated 8Gy x3 (M,W,F). Surgery was performed 5 weeks post-SBRT followed by adjuvant Nivo 480mg IV q4wks x3, starting 4 weeks post-op. The primary endpoint was &lt; 33% unplanned surgical delay; the secondary endpoint was pathologic response by irPRC (Cottrell 2018).
Results: There were no unplanned surgical delays. All patients had radiologic evidence of decreased tumor size prior to surgery, but none showed a CR by RECIST. Remarkably, the pathologic CR rate was 100% in the 8Gy x 5 cohort (5/5) and 80% In the 8 Gy x 3 cohort (4/5), with the remaining patient achieving MPR (major pathologic response; &lt;10% residual viable tumor). G3 toxicity was observed after surgery in both cohorts but was higher in the 8 Gy x 5 cohort. No G4 or higher toxicity was observed. Interestingly, G2 adrenal insufficiency was observed in 50% (5/10), a higher rate than previously reported with PD-1 blockade for recurrent/metastatic HNSCC. Notably, patients did not experience xerostomia or ageusia rates associated with standard adjuvant radiation in HNSCC. Tissue responses were characterized by robust inflammatory infiltrates into the regression bed and cholesterol clefts, as previously described. Circulating immune cells, baseline tissue, end of RT biopsy and surgical specimen were analyzed using flow cytometry and RNAseq to characterize of immunologic changes over time. There have been no local or distant failures, but median follow up remains &lt; 1 year.
Conclusions: Neoadjuvant combined PD-1/SBRT to GTV+3mm dosed at either 8Gy x5 (M-F) or 8Gy x3 (M,W,F) did not delay HNSCC surgery in this Phase I trial (n=10; five per dose). Potent anti-tumor response was observed in all cases (CR=9 + MPR=1). A high response rate and lower toxicity profile favors the 8Gy x3 cohort for development. This study represents a major paradigm shift in the approach to treatment of locally advanced p16+ oropharyngeal cancers.
Citation Format: Rom Leidner, R. Bryan Bell, Kristina Young, Brendan Curti, Marcus Couey, Ashish Patel, Amber Watters, Hong Xiao, Carlo Bifulco, Brian Piening, George Morris, Lessli Rushforth, Dawn Brucker, Shorin Nemeth, Michael Gough, Marka Crittenden. Neoadjuvant immuno-radiotherapy (NIRT) in head and neck cancer: Phase I/Ib study of combined PD-1/SBRT prior to surgical resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT182.