Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial

Abstract

Background: Head and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting.

Methods: The phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria.

Results: From November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III-IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3-4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR.

Conclusions: Neoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach.

Trial registration number: ClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759.

Keywords: clinical trials as topic; head and neck neoplasms; immunotherapy.

Figure 1

Characteristics of treatment response. Change from baseline in the sum of target lesion diameters according to adapted RECIST v1.1 in evaluable patients in the (A) HPV-positive (n=25) and (B) HPV-negative (n=24) cohorts. Dashed horizontal lines indicate 30% target lesion reduction (consistent with a partial response in the absence of new lesions) and 20% increase (consistent with progressive disease). An open square indicates truncation of percent change at +100%. Note that radiographic responses were measured using adapted RECIST v1.1 comprising a single on-treatment imaging scan before surgery, with no confirmatory scan performed. Detailed per-patient data are provided in online supplemental tables S4 and S5. CPS, combined positive score; HPV, human papillomavirus; MPR, major pathologic response; NA, not available; pCR, pathological complete response; pPR, pathologic partial response; PD-L1, programmed cell death ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors. ^aBased on central pathology review. ^bPatient received only one neoadjuvant dose of nivolumab. ^cFollowing database lock, patient was found to have received planned post-nivolumab biopsy instead of complete surgical resection.

Figure 2

Tumor regression in a 76-year-old white man with stage IVA HPV-negative HNSCC (T4aN0M0; patient no. 37 per online supplemental table S5). The tumor was PD-L1 positive (tumor PD-L1 ≥1% and CPS >1) and originated in the larynx. (A) Evidence of primary tumor regression on CT scans (red circles) after receipt of two doses of nivolumab preoperatively. The tumor measured 51×44 mm at baseline and 41×27 mm at day 22. (B) On day 37, the patient underwent surgery as originally planned (total laryngectomy with bilateral neck dissection, ypT4aN0), revealing a pathologic partial response (pPR) by central pathology review. Representative H&E staining of primary tumor specimen (final magnification ×200) illustrating treatment response. Keratin granuloma (within black circle are multinucleated giant cells surrounding acellular keratin and microcalcifications) surrounded by dense fibrosis. Black arrow points to a keratin granuloma adjacent to the thyroid cartilage with osseous metaplasia. This area shows no viable squamous cell carcinoma. Adjuvant radiotherapy was administered to the primary tumor site as standard-of-care at the investigator’s discretion. At 3.9 years of follow-up, this patient remains alive and tumor-free per the investigator. CPS, combined positive score; HPV, human papillomavirus; PD-L1, programmed cell death ligand 1.

Figure 3

Recurrence-free survival in patients with HNSCC who were reported as undergoing surgery in the HPV-positive (n=18) and HPV-negative (n=20) cohorts. Median follow-up for patients from date of surgery was 33.1 months (range, 18.2–51.4) and 36.3 months (range, 1.9–53.3), respectively. In the HPV-positive cohort, there were two tumor recurrences. In the HPV-negative cohort, there were five tumor recurrences and three deaths from disease progression (n=1) or adverse events unrelated to neoadjuvant nivolumab or protocol surgery (n=2). HPV, human papillomavirus; NE, not estimable; NR, not reached; RFS, recurrence-free survival. ^aAfter database lock, one patient in the HPV-negative cohort was found to have received a planned post-nivolumab biopsy instead of complete surgical resection; RFS for this patient was 14.5 months.

Figure 4

Overall survival in patients with HNSCC who were reported as undergoing surgery in the HPV-positive (n=18) and HPV-negative (n=20) cohorts. Median follow-up for these cohorts was 34.3 months (range, 19.1 to 52.3) and 37.1 months (range, 2.7 to 53.9), respectively. In the HPV-positive cohort, there were no on-study deaths. In the HPV-negative cohort, there were nine on-study deaths from disease progression (n=6) or adverse events unrelated to neoadjuvant nivolumab or protocol surgery (n=3). HPV, human papillomavirus; NE, not estimable; NR, not reached; OS, overall survival. ^aAfter database lock, one patient in the HPV-negative cohort was found to have received a planned post-nivolumab biopsy instead of complete surgical resection; OS for this patient was 49.8 months.