Intensity-Modulated Reirradiation Therapy With Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial

Authors

Nabil F. Saba

Stuart J. Wong

Tahseen Nasti

Ashley Alesia McCook-Veal

Mark W. McDonald

William A. Stokes

Allyson M. Anderson

Asari Ekpenyong

Manali Rupji

Marin Abousaud

Soumon Rudra

James E. Bates

Jill S. Remick

Nikhil P. Joshi

Neil M. Woody

Musaddiq Awan

Jessica L. Geiger

Aditya Shreenivas

Julia Samsa

Matthew Christopher Ward

Nicole C. Schmitt

Mihir R. Patel

Kristin A. Higgins

Yong Teng

Conor E. Steuer

Dong M. Shin

Yuan Liu

Rafi Ahmed

Shlomo A. Koyfman

Doi

10.1001/jamaoncol.2024.1143

PMID: 38780927 · DOI: 10.1001/jamaoncol.2024.1143 · Journal: JAMA Oncology (2024; 10(7):896-904) · Trial: NCT03521570

TL;DR

This multicenter, single-arm, nonrandomized phase 2 trial (NCT03521570) evaluated intensity-modulated reirradiation therapy (IMRT) combined with concurrent and maintenance nivolumab in 51 evaluable patients with locoregionally recurrent or second primary head and neck squamous cell carcinoma (HNSC) meeting MIRI Recursive Partitioning Analysis (RPA) class 1 or 2 criteria. At a median follow-up of 24.5 months, the estimated 1-year progression-free survival was 61.7% (95% CI, 49.2%–77.4%), rejecting the null hypothesis of 1-year PFS <43.8% (1-arm log-rank P = .002). Toxicity was manageable with only 6 (11.8%) grade ≥3 treatment-related adverse events and no grade 5 events, supporting further evaluation of PD-1 checkpoint blockade with reirradiation in this population PMID:38780927.

Cohort & data

  • Design: Multicenter, single-arm, open-label, nonrandomized phase 2 trial conducted at Winship Cancer Institute (Emory University), Cleveland Clinic, and Medical College of Wisconsin; accrual July 11, 2018 – August 12, 2021; data analyzed June–December 2023 PMID:38780927.
  • Sample size: 62 consented and screened; 11 excluded (9 ineligible, 2 elected alternative therapy); 51 evaluable patients received treatment PMID:38780927.
  • Cancer type: Recurrent or second primary head and neck squamous cell carcinoma (HNSC) arising in a previously irradiated field (≥40 Gy to >50% of anticipated target volume, with prior radiation completed >6 months prior). Primary disease sites: oral cavity 16 (31%), oropharynx 14 (27%), larynx/hypopharynx 13 (25%), nasopharynx 6 (12%), unknown 2 (3.9%) PMID:38780927.
  • RPA stratification: MIRI Recursive Partitioning Analysis class 1 in 23 (45%) and class 2 in 27 (53%); class 3 patients excluded PMID:38780927.
  • Demographics: Median (IQR) age 62 (56–67) years; 42 (82%) male; 41 (80%) White, 7 (14%) Black/African American, 3 (5.9%) Asian; ECOG 0–1 in 49 (95%) PMID:38780927.
  • p16/HPV status: 6 (12%) p16-positive, 9 (18%) p16-negative, 36 (71%) not applicable/unknown PMID:38780927.
  • Prior therapy: 38 (75%) had salvage surgery; 36 (71%) had neck dissection PMID:38780927.
  • Assays / correlative data: Central PD-L1 IHC 22C3 pharmDx (Agilent) with combined positive score on tumor tissue; multiparameter flow cytometry of peripheral blood mononuclear cells (PBMCs) at baseline, before each nivolumab infusion during radiation, and at weeks 18, 30, 52, and 104 to monitor CD4+, CD8A+, FOXP3+, PDCD1 (PD-1)+, and MKI67 (Ki-67)+ T-cell subsets PMID:38780927.
  • Dataset: No cBioPortal study was used; this is primary clinical-trial data from NCT03521570.

Key findings

  • Primary endpoint met: Estimated 1-year PFS was 61.7% (95% CI, 49.2%–77.4%); lower bound of 90% CI was 46.2%, also greater than the historical 43.8% benchmark. Null hypothesis (1-year PFS < 43.8%) rejected by 1-sided 1-sample log-rank test P = .002 PMID:38780927.
  • Median PFS: 20.7 months (95% CI, 12.0–30.8); 2-year PFS 43.2% (95% CI, 29.8%–62.6%) PMID:38780927.
  • Overall survival: Median OS 21 months (95% CI, 19.3–30.8); 1-year OS 84.4% (95% CI, 74.4%–95.7%); 2-year OS 48.4% (95% CI, 34.2%–68.6%) — favorable vs. MIRI historical control (2-year OS 42% for RPA class 1, 29% for RPA class 2) PMID:38780927.
  • Subgroup (nonsurgical): 1-year PFS was 75% (95% CI, 54.1%–100%) in patients without salvage surgery vs. 56.9% (95% CI, 42.5%–76.2%) in those with surgery — a hypothesis-generating trend favoring the nonsurgical cohort compared with the MIRI estimate of 35% PMID:38780927.
  • Tolerability: 6 (11.8%) patients had grade ≥3 treatment-related adverse events; most common was lymphopenia in 2 (3.9%), and 1 (2%) each had colitis, diarrhea, infective myositis, oral mucositis, myasthenia gravis, and nausea. No grade 5 events were reported PMID:38780927.
  • Any-grade toxicities: fatigue 82.4%, radiation dermatitis 58.8%, dysphagia 54.9%, oral mucositis 49.0%, dry mouth 47.1% PMID:38780927.
  • Compliance: Median (IQR) nivolumab cycles delivered: 10 (7–15); target was 15 doses over 52 weeks. 20 patients completed therapy; 31 discontinued (21 progressive disease, 7 AE, 2 withdrawal, 1 noncompliance) PMID:38780927.
  • Quality of life: FACT-G and FACT-H&N scores remained stable and consistent across all assessed time points (baseline, end of IMRT, weeks 18, 30, 52, 104); Cronbach α >0.7 for all FACT subscales PMID:38780927.
  • PD-L1 correlation: CD274 (PD-L1) combined positive score <20 vs. ≥20 showed no significant correlation with PFS (68.8% vs. 59.2% at 1 year, P = .86) or OS (94.4% vs. 84.3% at 1 year, P = .74) — divergent from the recurrent/metastatic setting where PD-L1 CPS predicts single-agent PD-1 inhibitor benefit PMID:38780927.
  • Peripheral T-cell biomarker trend: Patients with a ≥1.5-fold increase from baseline in peripheral blood CD4+ T cells co-expressing PDCD1 (PD-1) and MKI67 (Ki-67) at week 2 or 4 trended toward worse PFS (HR 2.09, 95% CI 0.77–5.66, P = .14; median PFS 16.0 vs. 27.1 months) PMID:38780927.
  • FOXP3+ T-cell surge: Patients with FOXP3+ T-cell surge had a 41% higher expected hazard (PFS HR 1.42, 95% CI 0.60–3.29, P = .43; 1-year PFS 60% vs. 64.2%) — not statistically significant PMID:38780927.
  • CD8+ T-cell surge: No correlation with PFS (CD8A surge HR 0.84, 95% CI 0.33–2.11, P = .71; 1-year PFS 63.5% with surge vs. 55.0% without) PMID:38780927.

Genes & alterations

This trial does not profile tumor genomic alterations; correlative analyses focus on peripheral blood immune-cell markers and tumor PD-L1 protein expression.

  • CD274 (PD-L1) — Central tumor tissue IHC using the 22C3 pharmDx assay, scored by combined positive score (CPS). CPS <20 vs. ≥20 did not predict PFS or OS benefit in this reirradiation context, unlike in R/M HNSCC with single-agent PD-1 blockade PMID:38780927.
  • PDCD1 (PD-1) — Target of nivolumab; surface expression measured on peripheral blood T cells by flow cytometry. Co-expression with MKI67 on CD4+ T cells defined the early proliferative response cutoff (>1.5-fold fold-change from baseline) PMID:38780927.
  • MKI67 (Ki-67) — Proliferation marker in the flow panel; surge in PD-1+Ki-67+CD4+ T cells trended with worse PFS, inverting expectations from lung cancer and melanoma where such surges track with benefit PMID:38780927.
  • CD4 — Peripheral CD4+ T-cell compartment; ≥1.5-fold proliferative surge post–cycle 1 defined “responders” for the biomarker correlative analysis, which trended toward worse outcome PMID:38780927.
  • CD8A — Peripheral CD8+ T-cell compartment; no correlation with PFS observed PMID:38780927.
  • FOXP3 — T regulatory cell marker; FOXP3+ T-cell surge trended toward worse PFS (HR 1.42, P = .43) PMID:38780927.

No somatic mutation, copy-number, fusion, or gene-panel profiling was performed.

Clinical implications

  • Efficacy signal for PD-1 blockade with reirradiation: Adding concurrent and maintenance nivolumab to IMRT-based reirradiation met the primary PFS endpoint against MIRI historical controls, and 2-year OS (48.4%) compared favorably with historical IMRT-only outcomes (RPA class 1 42%, class 2 29%). The authors position this as the first prospective trial of IMRT reirradiation + PD-1 blockade and call for confirmatory randomized trials PMID:38780927.
  • Safety supports further development: Grade ≥3 treatment-related AEs in only 12% and no grade 5 events in a heavily pretreated population suggest acceptable tolerability; stable FACT-G and FACT-H&N QOL across 104 weeks supports patient acceptability PMID:38780927.
  • Biomarker caveat for PD-L1: Unlike the recurrent/metastatic HNSCC setting, PD-L1 CPS (22C3) did not stratify benefit here — suggesting that tumor PD-L1 expression may be a less reliable biomarker when PD-1 blockade is combined with reirradiation in a previously irradiated field PMID:38780927.
  • Hypothesis-generating peripheral biomarker: An early PD-1+Ki-67+CD4+ T-cell surge in peripheral blood trended with worse outcome — opposite to reports in lung cancer and melanoma — suggesting context-dependent interpretation of peripheral T-cell pharmacodynamic markers for checkpoint immunotherapy. Warrants prospective validation PMID:38780927.
  • Subgroup signal in nonsurgical patients: Nonsurgical patients had numerically superior 1-year PFS (75% vs. 56.9%); the authors hypothesize this may reflect sparing of regional lymphatics and preservation of immunomodulatory capacity, but the subset was not powered for formal inference PMID:38780927.

Limitations & open questions

  • Nonrandomized, single-arm design with historical-control comparison to the MIRI cohort — differences in RPA class distribution (45%/53% class 1/2 here vs. 28%/72% in MIRI), systemic-therapy sequencing heterogeneity, and differing follow-up-time definitions limit direct comparability PMID:38780927.
  • Small sample (n=51) was not powered for subgroup analyses (p16 status, RPA class, PD-L1 CPS, peripheral immune biomarkers); all biomarker findings are hypothesis-generating PMID:38780927.
  • No tumor genomic profiling: the trial did not evaluate somatic alterations, tumor mutational burden, or HPV-integration features that could modify immunotherapy response in HNSCC.
  • Optimal sequencing and duration of PD-1 blockade with reirradiation remain unsettled — whether radiation adds to longevity in the context of immunotherapy is not clear, and combining the two could increase toxicity risk PMID:38780927.
  • Paradoxical peripheral T-cell surge (CD4+PD-1+Ki-67+) tracking with worse PFS contradicts published reports in other solid tumors; mechanism (regulatory skew? exhaustion phenotype? lymphatic drainage effects from prior radiation?) is unresolved.
  • Generalizability to RPA class 3 (excluded) and to unresectable-only cohorts is unknown.

Citations from this paper used in the wiki

  • “The estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P=.002 within a 1-year timeframe.” — Abstract / Results, JAMA Oncol 2024;10(7):896.
  • “The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis.” — Abstract / Results.
  • “A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed.” — Abstract / Results.
  • “No statistically significant correlation was found between PD-L1/combined positive score of less than 20 vs 20 or more and PFS (68.8% vs 59.2% at 1-year, P=.86) or OS (94.4% vs 84.3% at 1-year, P=.74).” — Biomarker Correlative Analysis, p. 900.
  • “To our knowledge, this nonrandomized controlled trial is the first prospective clinical trial of IMRT-based reirradiation therapy in combination with concurrent and maintenance nivolumab in patients with locoregionally recurrent HNSCC.” — Discussion, p. 900.
  • “Class 1 included patients with more than 2 years between the first and planned second radiation therapy courses and managed with resection followed by postoperative reirradiation, whereas class 2 included patients with unresected tumors of more than 2 years…” — Introduction, p. 897 (MIRI RPA definition reused for eligibility).

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