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Clinical Trial
. 2022 Jan;10(1):e003747.
doi: 10.1136/jitc-2021-003747.

Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer

Markus Hecht  1   2   3 , Markus Eckstein  2   4 , Sandra Rutzner  5   2   3 , Jens von der Grün  6 , Thomas Illmer  7 , Gunther Klautke  8 , Simon Laban  9 , Matthias G Hautmann  10 , Thomas B Brunner  11 , Bálint Tamaskovics  12 , Axel Hinke  13 , Jian-Guo Zhou  5   2   3 , Benjamin Frey  5   2   3 , Anna-Jasmina Donaubauer  5   2   3 , Ina Becker  5   2   3 , Sabine Semrau  5   2   3 , Arndt Hartmann  2   4 , Panagiotis Balermpas  6 , Wilfried Budach  12 , Udo S Gaipl  5   2   3 , Heinrich Iro  2   3   14 , Antoniu-Oreste Gostian #  2   3   14 , Rainer Fietkau #  5   2   3
Affiliations
Clinical Trial

Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer

Markus Hecht et al. J Immunother Cancer. 2022 Jan.

Abstract

Purpose: The first aim of the trial is to study feasibility of combined programmed death protein ligand 1/cytotoxic T-lymphocyte-associated protein 4 inhibition concomitant to radiotherapy. In addition, efficacy of the entire treatment scheme consisting of induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy (RIT) after intratumoral CD8 +immune cell-based patient selection will be analyzed.

Methods: Patients with stage III-IVB head and neck squamous cell carcinoma were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30 mg/m² days 1-3, docetaxel 75 mg/m² day 1, durvalumab 1500 mg fix dose day 5 and tremelimumab 75 mg fix dose day 5. Patients with increased intratumoral CD8 +immune cell density or pathological complete response (pCR) in the rebiopsy entered RIT up to a total dose of 70 Gy. Patients received further three cycles of durvalumab/tremelimumab followed by eight cycles of durvalumab mono (every 4 weeks). The intended treatment for patients not meeting these criteria was standard radiochemotherapy outside the trial. Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80%.

Results: Between September 2018 and May 2020, 80 patients were enrolled (one excluded). Out of these, 23 patients had human papilloma virus (HPV)-positive oropharyngeal cancer. Median follow-up was 17.2 months. After induction chemoimmunotherapy 41 patients had pCR and 31 had increased intratumoral CD8 +immune cells. Of 60 patients entering RIT (primary endpoint cohort), 10 experienced imiting toxic (mainly hepatitis) and four discontinued for other reasons, resulting in a feasibility rate of 82%. The RIT cohort (n=60) had a progression-free survival (PFS) rate at one and 2 years of 78% and 72%, respectively, and an overall survival rate at one and 2 years of 90% and 84%, respectively. Patients with HPV-positive oropharyngeal cancers had greater benefit from RIT with a 2-year PFS rate of 94% compared with 64% for HPV-negative oropharyngeal cancers and other locations. In the entire study cohort (n=79) the 2-year PFS rate was 68% (91% for HPV-positive oropharynx vs 59% for others). Toxicity grade 3-4 mainly consisted of dysphagia (53%), leukopenia (52%) and infections (32%).

Conclusions: The trial met the primary endpoint feasibility of RIT. Induction chemo-immunotherapy followed by chemotherapy-free RIT after intratumoral CD8 +immune cell-based patient selection has promising PFS.

Trial registration number: The trial was registered with ClinicalTrials.gov (identifier: NCT03426657). The trial was conducted as investigator-sponsored trial (IST).

Keywords: radioimmunotherapy.

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Conflict of interest statement

Competing interests: MH conflict of interest with Merck Serono (advisory role, speakers’ bureau, honoraria, travel expenses, research funding); MSD (advisory role, speakers’ bureau, honoraria, travel expenses, research funding); AstraZeneca (research funding); Novartis (research funding); BMS (advisory role, honoraria, speakers’ bureau); Teva (travel expenses). ME conflict of interest with Diaceutics (employment, honoraria, advisory role, speakers’ bureau, travel expenses); Cepheid (research funding, advisory role); AstraZeneca (honoraria, advisory role, speakers’ bureau, travel expenses); Roche (honoraria, travel expenses); MSD (honoraria, speakers’ bureau); GenomicHealth (honoraria, advisory role, speakers bureau, travel expenses); Astellas (honoraria, speakers’ bureau); Janssen-Cilag (honoraria, advisory role, research funding, travel expenses); Stratifyer (research funding, patents). SR conflict of interest with AstraZeneca (research funding); MSD (research funding). GK conflict of interest with BMS (advisory role); Lilly (advisory role); Roche (advisory role). SL conflict of interest with AstraZeneca (honoraria, advisory role); BMS (honoraria, advisory role, speakers’ bureau); MSD (honoraria, advisory role); Merck Serono (honoraria, speakers’ bureau); ISA-Pharmaceuticals (research funding). MGH conflict of interest with Roche (stock); Varian (stock); Sanofi (stock); AstraZeneca (honoraria); BMS (honoraria, advisory role); MSD (honoraria, advisory role); Merck Serono (honoraria); Celgene (honoraria). AHi conflict of interest with Roche (honoraria). SS conflict of interest with Strycker (stock); Varian (stock); Abbot (stock); Crispr Techn. (stock); Pfitzer (stock); Merck Serono (stock); Symrise (stock); Ortho (honoraria, advisory role, speakers’ bureau, research funding, travel expenses); PharmaMar (speakers’ bureau, travel expenses); Haema (speakers’ bureau). AHa. conflict of interest with BMS (honoraria, advisory role); MSD (honoraria, advisory role); Roche (honoraria, advisory role, research funding); AstraZeneca (honoraria, advisory role, research funding); Boehringer Ingelheim (honoraria); Abbvie (honoraria); Cepheid (advisory role, research funding); Quiagen (advisory role); Janssen-Cilag (honoraria, advisory role, research funding); Ipsen (honoraria, advisory role); NanoString Technologies (advisory role, research funding, expert testimony); Illumina (advisory role); 3DHistech (advisory role); Diaceutics (advisory role); BioNTech (research funding). WB conflict of interest with BMS (advisory role); MSD (advisory role); Merck Serono (advisory role); Pfitzer (advisory role); AstraZeneca (advisory role). UG conflict of interest with AstraZeneca (advisory role, research funding); BMS (advisory role); MSD (research funding); Sennewald Medizintechnik (advisory role, travel expenses). RF conflict of interest with MSD (honoraria, advisory role, research funding, travel expenses); Fresenius (honoraria); BrainLab (honoraria); AstraZeneca (honoraria, advisory role, research funding, travel expenses); Merck Serono (advisory role, research funding, travel expenses); Novocure (advisory role, speakers’ bureau, research funding); Sennewald (speakers’ bureau, travel expenses). The other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
CONSORT diagram. *Radiotherapy to a cumulative dose of at least 66.0/59.4/50.8 Gy. CD8, CD8 +intratumoral immune cells. CONSORT, Consolidated Standards of Reporting Trials; DLT, dose-limiting toxicity; IT, immunotherapy; pCR, pathologic complete response; RIT, radioimmunotherapy; RT, radiotherapy.
Figure 2
Figure 2
Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS). Kaplan-Meier estimates of (A) PFS and (B) OS of the radioimmunotherapy (RIT) cohort. Kaplan-Meier estimates of (C) PFS and (D) OS of the entire study cohort. Tick marks indicate censored observations.
Figure 3
Figure 3
Predictive immune parameters of treatment failure. Comparison of the histological parameters (A) intratumoral CD8 +cell density as determined by immunohistochemistry, (B) programmed cell death ligand 1 (PD-L1) tumor cell area (TC area), (C) PD-L1 immune cell area (IC area) and the liquid immune parameters (D) dendritic cells (DC; LIN-/HLA-DR+), (E) myeloid DCs (mDC; LIN-/HLA-DR+/CD11c high, CD1c-, CD123 low), (F) double negative T cells (DNT; CD3+/CD4-/CD8-), and (G) HLA-DR +B cells (CD19+/CD20+) in patients with locoregional tumor recurrence, residual locoregional disease or distant metastases (RRM) and without RRM (non-RRM). HLAD-DR, human leukocyte antigen – DR isotype.
See this image and copyright information in PMC

References

    1. Burtness B, Harrington KJ, Greil R, et al. . Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019;394:1915–28. 10.1016/S0140-6736(19)32591-7 - DOI - PubMed
    1. Ferris RL, Blumenschein G, Fayette J, et al. . Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856–67. 10.1056/NEJMoa1602252 - DOI - PMC - PubMed
    1. Machiels J-P, Tao Y, Burtness B, et al. . Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Future Oncol 2020;16:1235–43. 10.2217/fon-2020-0184 - DOI - PubMed
    1. Yu Y, Lee NY. Javelin head and neck 100: a phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer. Future Oncol 2019;15:687–94. 10.2217/fon-2018-0405 - DOI - PMC - PubMed
    1. Lee NY, Ferris RL, Psyrri A, et al. . Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 2021;22:450–62. 10.1016/S1470-2045(20)30737-3 - DOI - PubMed

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