Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck

Abstract

Purpose: Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition [anti-PD-1, nivolumab (N), and anti-KIR, lirilumab (L)] before and after salvage surgery to improve disease-free survival (DFS).

Patients and methods: In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling.

Results: Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response (P = 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8-71.7) and 1-year OS was 85.7% (95% CI, 66.3-94.4). Two-year DFS and OS were 64% and 80% among pathologic responders.

Conclusions: (Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted.See related commentary by Sacco and Cohen, p. 435.

Figure 1.

Kaplan–Meier curves showing (A) DFS reported in months from the time of salvage surgery to the first of any disease recurrence, death, or censored at last follow-up. B, OS reported in months from the time of salvage surgery to death from any cause, or censored at last follow-up. DFS stratified by (C) pathologic response (PPR = partial pathologic response, ≤50% tumor viability; MPR = major pathologic response, ≤10% tumor viability) and (D) number of adjuvant cycles of immunotherapy received (maximum of 6).

Figure 2.

A, Waterfall plot showing objective radiologic response rate to one dose of neoadjuvant nivolumab plus lirilumab in patients with relapsed, resectable SCCHN (RECIST v1.1). B, Viable tumor quantification (%) at the time of salvage surgery following neoadjuvant immunotherapy, arranged by degree of pathologic response (≤50%, partial response; ≤10% major response). HPV, human papillomavirus. C, Preimmunotherapy right posterior tongue biopsy (patient ID #22) showing keratinizing, invasive squamous cell carcinoma (200×; left) and a post-op hemi-glossectomy specimen with extensive fibrosis in the prior tumor bed with an area of necrosis and a few multinucleated giant cells noted in the upper left region (200×; right). D, Tumor and immune cell PD-L1 expression CPS in both the initial preimmunotherapy recurrence specimen and paired salvage tumor specimen, arranged by descending % tumor viability.

Figure 3.

A, Swimmer plot showing 13 of 28 evaluable patients with evidence of biopsy-proven recurrent disease (above) and N = 15 without recurrent disease (below) after (neo)adjuvant immunotherapy followed by salvage surgery and adjuvant immunotherapy for up to six cycles with anti–PD-1/KIR combination therapy. Each row or bar represents an individual study patient with their time from the start of immunotherapy to date of salvage surgery indicated. The time from surgery to the end of up to six cycles of immunotherapy (28-day cycles) is displayed. Positive margin status at the time of salvage surgery (with tumor on ink) is noted. HPV (human papillomavirus)-positive disease is denoted by a “+.” The date of biopsy-proven recurrence (if applicable) is plotted along with last known follow-up (censored) or date of death. B, Clinicopathologic features of individuals experiencing recurrence (N = 13) sorted by pathologic downstaging from pre-op (clinical stage) to post-op (pathologic stage), margin status (positive defined as tumor on ink), lymph node status (ENE = extranodal extension) if sampled, and number (#) of adjuvant cycles of immunotherapy received post-op (six total cycles were planned; 28-day cycle length).

Figure 4.

Mutational landscape plot showing the most commonly mutated genes arranged by frequency (top to bottom). Each column represents an individual patient's tumor sample obtained at the time of salvage surgery, following neoadjuvant immunotherapy grouped from left to right based on disease status (disease-free or recurrence). The bar graph at the top of the figure shows TMB in mutations/Mb. The color-coded top row tiles indicate key clinicopathologic features, including primary site of initial disease (OC, oral cavity; OPC, oropharynx; “+” human papillomavirus positive; LAR, larynx; HYPO, hypopharynx), radiologic response to neoadjuvant immunotherapy prior to salvage surgery (RECIST v1.1), pathologic response graded by degree of viable tumor remaining in the surgical specimen (≤50%, partial response and ≤10% major response), and PD-L1 CPS determined from the salvage surgical specimen.