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Clinical Trial
. 2021 May;9(5):e002485.
doi: 10.1136/jitc-2021-002485.

Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma

Rom Leidner  1   2 , Marka Crittenden  1   2   3 , Kristina Young  1   2   3 , Hong Xiao  4 , Yaping Wu  4 , Marcus A Couey  1 , Ashish A Patel  1   5 , Allen C Cheng  5 , Amber L Watters  1 , Carlo Bifulco  1   2   4 , George Morris  2 , Lessli Rushforth  2 , Shorin Nemeth  1 , Walter J Urba  1   2 , Michael Gough  1   2 , R Bryan Bell  6   2
Affiliations
Clinical Trial

Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma

Rom Leidner et al. J Immunother Cancer. 2021 May.

Abstract

Background: Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone.

Methods: The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Eligible patients were treated with neoadjuvant SBRT at a total dose of either 40 Gy in 5 fractions or 24 Gy in 3 fractions, delivered in a 1-week timespan, with or without nivolumab, prior to definitive surgical resection. Patients were then planned for treatment with adjuvant nivolumab for 3 months. The primary safety endpoint was unplanned delay in surgery considered to be at least possibly related to neoadjuvant treatment. The primary efficacy endpoints included pathological complete response (pCR), major pathological response (mPR), and the rate of clinical to pathological downstaging after neoadjuvant treatment.

Results: Twenty-one patients underwent neoadjuvant treatment, which was well tolerated and did not delay surgery, thus meeting the primary endpoint. Tissue responses were characterized by robust inflammatory infiltrates in the regression bed, plasma cells and cholesterol clefts. Among the entire study group, the mPR and pCR rate was 86% and 67%, respectively. Clinical to pathological downstaging occurred in 90% of the patients treated.

Conclusion: These data demonstrate that radiation delivered only to the gross tumor volume combined with immunotherapy was safe, resulted in a high rate of mPR and should be further evaluated as a locally focused neoadjuvant therapy for patients with head and neck cancer.

Trial registration number: This study is registered with clinicaltrials.gov (NCT03247712) and is active, but closed to patient accrual.

Keywords: combination; drug therapy; head and neck neoplasms; immunotherapy; radioimmunotherapy.

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Conflict of interest statement

Competing interests: The Earle A. Chiles Research Institute receives research funding from Bristol-Myers Squibb, none of which was used in the conduct of this trial; and AstraZeneca. RSL reports grants from Bristol Myers Squibb, personal fees from Merck, personal fees from Sanofi, personal fees from Regeneron, personal fees from Oncolys, outside the submitted work; MRC reports research grants from Jounce Therapeutics, grants from Nanobiotix, outside the submitted work. KHY reports non-financial support and material support for clinical trial from Eli Lilly; sponsored project agreement and institutional grant support from Bristol-Myers Squibb; and other support from AstraZeneca, outside the submitted work; CBB reports a consultant/advisory relationship with PrimeVax and Bristol-Myers Squibb; stock ownership and scientific board membership in PrimeVax and BioAI; and holds a patent on image processing systems and methods for displaying multiple images of a biological specimen that was outside the submitted work; WJU reports grants from Bristol-Myers Squibb, grants and other institutional support from Galectin Therapeutics, grants and other institutional support from Astra Zeneca, grants and other institutional support from Prometheus, grants and other institutional support from Merck, outside the submitted work; MJG reports grants from Bristol Myers Squibb, grants from Mavupharma, outside the submitted work; RBB reports grants and personal fees from Bristol Myers Squibb, grants and personal fees from Merck, personal fees from Regeneron, outside the submitted work. All other authors declare no competing interests.

Figures

Figure 1
Figure 1
Neoadjuvant Immuno-Radiotherapy Trial (NIRT) schema. GTV, gross tumor volume; HNSCC, head and neck squamous cell carcinoma; HPV, human papilloma virus; IV, intravenous; MPR, major pathological response; pCR, pathological complete response; SBRT, stereotactic body radiation therapy; SOC, standard of care.
Figure 2
Figure 2
Toxicity swimmers plot. (A) Timing of neoadjuvant nivolumab and stereotactic body radiation therapy (SBRT) are indicated prior to resection. Extent of follow-up is shown in blue, and known recurrences are indicated. Grade 3 or greater pain requiring opiates are indicated in red. Unplanned temporary gastrostomy tube placement is indicated in green. In cohort 4, g-tubes were placed intraoperatively, per routine, to facilitate postoperative free-flap wound healing. Grade 2 or higher adrenal insufficiency requiring corticosteroid use is indicated in yellow. (B) RECIST response at surgery. The y-axis represents per cent tumor response, delineated by cohort and pathological response (indicated by black dots below). (C) Pathological response at surgery. The y-axis represents per cent pathological response in either the primary tumor site or metastatic lymph node, delineated by cohort. cPR, pathological complete response; HPV, human papilloma virus; mPR, major pathological response.
Figure 3
Figure 3
CT imaging of a 63-year-old man (NIRT008) with cT2N1M0 HPV+ squamous cell carcinoma (SCC) of the tonsil. (A) Pretreatment axial image demonstrating primary tumor involving the palatine tonsil. (B) Pretreatment CT demonstrating right metastatic lymphadenopathy. (C) Radiation isodose plan to GTV+2–3 mm. (D) Post treatment CT demonstrating partial radiographic response by RECIST (−71%) with near complete resolution of the primary tumor. (E) Post treatment radiographic response in level II lymph nodes. Neoadjuvant treatment resulted in pathological complete response (pCR) in the primary and major pathological response (mPR) in the largest metastatic lymph node (<10% viable tumor cells).
Figure 4
Figure 4
Representative photomicrographs of resection specimens illustrating features of pathological response in the regression bed of HPV+ subjects. (A) Fibrosis and plasma cell infiltration in metastatic lymph node (NIRT006, cohort 1) with pathologic complete response (pCR) (magnification ×200). (B) Giant cells (arrow) and fibrosis in primary tumor (NIRT008, cohort 2) with pCR (magnification ×200). (C) Residual viable tumor (arrow) in metastatic lymph node (NIRT008, cohort 2, %RVT=5) with major pathological response (mPR) (magnification ×200). (D) Necrosis (left, arrow), calcification (star) and histiocytes (right, arrow) in metastatic lymph node (NIRT010, cohort 2) with pCR (magnification ×100). (E) Cholesterol clefts (arrow) with giant cells in primary tumor (NIRT010, cohort 2) with pCR (magnification ×100). (F) Residual viable tumor (arrow) in metastatic lymph node (NIRT019, cohort 3, %RVT=5) with mPR (magnification ×200).
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