Pathologic response to neoadjuvant sequenced, lymphatic-sparing SBRT plus pembrolizumab in HPV-negative head and neck squamous cell carcinoma.

6084 Background: The Neoadjuvant Immuno-Radiotherapy Trial (NIRT-2) is a phase II study, conducted at 2 institutions, that evaluated in patients (pts) with locoregionally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) whether the combination of neoadjuvant sequenced, lymphatic sparing stereotactic body radiation therapy (SBRT) delivered to gross tumor volume (GTV) plus pembrolizumab is effective in enhancing major pathologic response (MPR) compared to historical controls of anti-PD-1 alone. Methods: 27 pts with resectable clinical stage III-IVA HPV-negative HNSCC who would warrant adjuvant RT per the investigators were enrolled. Neoadjuvant therapy consisted of SBRT 8Gy X 3 delivered over 1 week (GTV +/-3mm) followed by 3 cycles of pembrolizumab (200mg) prior to definitive surgical resection + neck dissection at week 7. Standard of care adjuvant RT +/- chemotherapy was administered based on pathologic staging, followed by adjuvant pembrolizumab for 6 months (14 doses). The primary endpoint was MPR (defined as </=10% viable tumor cells), assessed using a single-arm Simon Two-stage design to test the hypothesis that SBRT would improve MPR to pembrolizumab from 22%, rejecting the null hypothesis if 10 or more responses (37%) are observed in 27 pts (Type 1 error 5%, 90% power, alternative rate 50%). Secondary endpoints included pathologic down-staging allowing for surgical de-escalation and omission of adjuvant RT. Results: The study completed enrollment (N=27) on January 17, 2025, at which time 22 pts had completed surgery. 22/27 (81%) pts enrolled were clinically staged as T3/T4 and 8/27 (30%) were N2b/c (AJCC 8th Ed). Pathologic down-staging was observed in 16/22 (73%) pts, which permitted surgical de-escalation (no tracheostomy or free flap, >50% organ preservation) in 11 pts (50%). 16/22 (73%, one-sided 95% CI =53%-100%, p<.0001) had a MPR, of which 6 had a pathologic complete response (pCR), thus meeting the study's primary endpoint of 10 MPR. Adjuvant RT was omitted in 17/22 (77%) pts. All pts remain disease-free at a median follow-up of 8.5 months (IQR=3.9, 21.2; range=0-32). Conclusions: Neoadjuvant sequenced, lymphatic sparing SBRT followed by pembrolizumab led to notable pathologic down-staging allowing for surgical de-escalation and omission of adjuvant RT. Clinical trial information: NCT04938609 .