Key perioperative/window-of-opportunity immunotherapy trials in resectable HNSCC.
| Setting | Trial/Study | Phase & design | Population (N) | Regimen & timing | Primary endpoint(s) | Key efficacy results | Feasibility (surgery) | Safety (selected) |
|---|---|---|---|---|---|---|---|---|
| Frontline, resectable LA-HNSCC | KEYNOTE-689 [10] (perioperative pembrolizumab) | Phase III; open-label randomized (pembro + SOC vs. SOC) | Resectable, LA-HNSCC (N = 714; randomized 363 vs. 351) | Neoadj pembro 200 mg q3w × 2 → surgery → adjuvant RT ± cisplatin (SOC) + pembro planned concomitantly with postop RT/CRT then continued (total 15 adjuvant cycles planned) | EFS sequentially in CPS ≥ 10, CPS ≥ 1, then total population | EFS @36 mo: CPS ≥ 10: 59.8% vs. 45.9% (HR 0.66; P = 0.004); CPS ≥ 1: 58.2% vs. 44.9% (HR 0.70; P = 0.003); total: 57.6% vs. 46.4% (HR 0.73; P = 0.008). Path response after neoadj + surgery (pembro arm, total population): MPR 9.4%, pCR 3.0%; 0% in control by blinded review. | Surgery completion: 88.4% (pembro) vs. 87.7% (control). Surgery delays: 38 vs. 10; median time to surgery 3.0 vs. 1.9 weeks. | Grade ≥ 3 TRAEs: 44.6% vs. 42.9%; deaths due to AE 1.1% vs. 0.3%. Potentially immune-mediated AEs grade ≥ 3: 10.0% (pembro). |
| Frontline, resectable HPV-unrelated/p16 | Uppaluri et al., 2020 [13] (neoadj ± adjuv pembrolizumab) | Phase II; multicenter | Resectable, LA HPV-unrelated HNSCC (N = 36) | Neoadj pembro 200 mg once → surgery 2–3 weeks later → planned postop (chemo) RT; high-risk pathology planned adjuvant pembro q3w × 6 | Coprimary: pTR-2 (≥ 50% regression) (all pts) and 1-year relapse rate in high-risk pathology | pTR-2: 22%; pTR-1: 22%; any pTR ≥ 10%: 44%; pCR: 0%. 1-year relapse rate in high-risk: 16.7% (95% CI reported in paper). | Abstract reports no unexpected surgical delays/complications. | Abstract reports no serious (grade 3–4) AEs and no unexpected surgical delays/complications. |
| Frontline, resectable p16 LA-HNSCC | Wise-Draper et al., 2022 [14] (peri-pembrolizumab) | Phase II; open-label, nonrandomized; safety lead-in | Resectable HNSCC including p16 oropharynx; clinical stage high-risk features (N = 92) | Neoadj pembro 200 mg 7–21 days pre-op → surgery → adjuvant RT (60–66 Gy) + pembro q3w × 6; high-risk also got weekly cisplatin 40 mg/m2 | 1-year DFS | 1-year DFS: 97% (intermediate-risk) vs. 66% (high-risk) at median follow-up 28 months. Pathologic response associated with improved 1-year DFS (93% vs. 72%; HR 0.29; 95% CI 0.11–0.77). | Feasibility assessed via DLT defined as pembro-attributable delay to SOC (> 7 days surgery, > 3 days RT, > 7 days cisplatin). | “No new safety signals” in abstract; DLT framework specified. |
| Frontline, resectable HPV+/HPV− | CheckMate 358 [15] (neoadj nivolumab) | Phase I/II; nonrandomized | Resectable HNSCC (N = 52; 26 HPV+, 26 HPV−) | Nivolumab 240 mg days 1 & 15 → surgery planned day 29 (± 7) | Primary: safety/tolerability; protocol-defined TRAE-related surgical delay > 4 weeks | No pCR by site/central review. Centrally evaluable: HPV+: MPR 5.9% + pPR 17.6% (= 23.5%); HPV−: pPR 5.9%. | No protocol-defined TRAE-related surgical delay (> 4 weeks). | Grade 3–4 TRAEs: 19.2% (HPV+) and 11.5% (HPV−). |
| Frontline, oral cavity SCC | Schoenfeld et al., 2020 [16] (nivo vs. nivo + ipi) | Phase II; open-label randomized (single center) | Untreated oral cavity SCC (N = 29; randomized 14 vs. 15) | Nivolumab 3 mg/kg weeks 1 & 3 ± ipilimumab 1 mg/kg week 1 → surgery 3–7 days after cycle 2 | Coprimary: safety (incl surgical delays) and volumetric response | Evidence of response in both arms: volumetric response 50% vs. 53%; RECIST response 13% vs. 38%; pathologic response 54% vs. 73%. Major/complete path response > 90%: 1 (nivo) vs. 3 (combo). | Median cycle 1 → surgery: 19 days (range 7–21); no surgical delays. | Grade 3–4 events: 2 (nivo) vs. 5 (combo). One postoperative death judged unrelated to study treatment (reported in paper). |
| Frontline (mostly) + some recurrent; major surgery planned | IMCISION [17] (nivolumab ± ipilimumab) | Phase Ib/IIa; nonrandomized | Primary or recurrent resectable HNSCC (N = 32) | 2 doses: nivolumab 240 mg weeks 1 & 3 ± ipilimumab 1 mg/kg week 1 → surgery week 5–6 | Phase Ib: feasibility (resect ≤ week 6); Phase IIa: pathologic response | MPR: 17% (nivo mono) vs. 35% (combo) (reported overall/phase IIa as described in paper). | Surgery not delayed or suspended for any patient in phase Ib. | Grade 3–4 irAEs: 33% (nivo mono) vs. 38% (combo). MPR definition required ≤ 10% residual viable tumor and 90–100% decrease in viable tumor cells from baseline biopsy to on-treatment specimen (study’s conservative classification). |
| Frontline, oral cavity SCC | Ju et al., 2022 [18] (camrelizumab + apatinib) | Phase I; single-arm | LA resectable OSCC (N = 20) | Camrelizumab 200 mg q2w + apatinib 250 mg daily × 3 cycles → surgery | Primary: safety and MPR (≤ 10% residual viable tumor) | MPR: 40% (8/20). Post-hoc 18-month locoregional recurrence 10.5% and survival 95% (reported; follow-up limited). | One reported surgery delay (7 days) due to unexplained troponin elevation (resolved). | No neoadjuvant therapy-related grade ≥ 3 AEs reported in paper’s primary safety summary. |
| Frontline, LA-HNSCC (China; mixed subsites) | Zhang et al., 2022 [19] (chemo + camrelizumab) | Phase II; single-center single-arm | Resectable stage III–IVB HNSCC (N = 30; 27 underwent surgery) | Chemo + camrelizumab every 21 days × 3 → surgery (1–4 weeks after neoadj) → adjuvant RT | Coprimary: pCR rate and safety | ORR: 96.7% (29/30).pCR: 37.0% (95% CI 19.4–57.6).MPR: 74.1% (95% CI 53.7–88.9).12-mo DFS: 95.8% (95% CI 73.9–99.4). | 27/30 underwent surgery “without delay”; R0 resection 92.6% (25/27). | Grade 3 neoadjuvant TRAEs: rash/pruritis/thrombocytopenia (each 3.3%); no grade 4/5. Surgical complication: delayed wound healing 18.5%. |
| Salvage/Recurrent, resectable | Hanna et al., 2022 [20] (nivo + lirilumab peri-salvage) | Phase II; single-arm | Recurrent, resectable HNSCC undergoing salvage surgery (N = 28; 96% prior radiation) | Nivolumab 240 + lirilumab 240 once 7–21 days pre-op → salvage surgery → 6 cycles adjuvant nivo + liri | Primary: 1-year DFS | Pathologic response: 43% overall (MPR 14% [≤ 10% viability], PPR 29% [≤ 50% viability]); 1-year DFS: 55.2%; 1-year OS: 85.7% (reported). | No delays to surgery reported in abstract. | Grade 3 + AEs: 11% (reported). |
| Salvage/recurrent, resectable | Leddon et al., 2022 [21] (adjuvant nivolumab post-salvage) | Phase II; open-label; multi-institutional | Recurrent, resectable HNSCC post-salvage resection (N = 39) | Enroll ≤ 6 weeks post-op → adjuvant nivolumab planned for 6 cycles of 480 mg every 28 days (or equivalent dosing per protocol) | Primary: 2-year DFS vs. historical | 2-year DFS: 71.4% (95% CI 57.8–88.1). 2-year OS (from salvage surgery): 77.7% (95% CI 64.1–94.2). | Not a neoadjuvant study (feasibility pertains to completing planned adjuvant therapy). | Grade 3–4 TRAEs: 7.7% (3/39); 8% discontinued due to side effects; no treatment-related deaths reported during study follow-up. |
Summary of key perioperative and window-of-opportunity immunotherapy trials in resectable HNSCC across frontline and salvage/recurrent settings. For each study, the table reports trial phase/design, population characteristics (including subsite and HPV/p16 enrichment when specified), perioperative regimen and timing (neoadjuvant window, surgery timing, and adjuvant therapy backbone), primary endpoint(s), and selected efficacy, feasibility, and safety outcomes. “Feasibility” is reported using each study’s stated definition (e.g., protocol-defined TRAE-related surgical delay thresholds vs. any delay), and “safety” summarizes selected grade ≥ 3 treatment-related and/or irAEs as reported. Pathologic response metrics (e.g., pTR categories, MPR, pCR, pPR) and their definitions vary across trials and are presented as defined in the original reports; therefore, cross-trial comparisons should be interpreted cautiously given heterogeneity in populations, endpoints, and reporting windows. AE: adverse event; CI: confidence interval; CPS: combined positive score; CRT: chemoradiotherapy; DFS: disease-free survival; DLT: dose-limiting toxicity; EFS: event-free survival; HNSCC: head and neck squamous cell carcinoma; HPV: human papillomavirus; HR: hazard ratio; irAE: immune-related adverse event; LA: locally advanced; MPR: major pathologic response; ORR: objective response rate; OS: overall survival; OSCC: oral squamous cell carcinoma; p16: p16 immunohistochemistry surrogate for human papillomavirus-associated disease; pCR: pathologic complete response; pPR: pathologic partial response; pTR: pathologic tumor response; q2w: every 2 weeks; q3w: every 3 weeks; RT: radiotherapy; SCC: squamous cell carcinoma; SOC: standard of care; TRAE: treatment-related adverse event.