Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8

Abstract

Background: To determine safety and efficacy of single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab in stage III-IVB head and neck cancer.

Methods: Patients received a single cycle of cisplatin 30 mg/m² on days 1-3 and docetaxel 75 mg/m² on day 1 combined with durvalumab 1500 mg fix dose on day 5 and tremelimumab 75 mg fix dose on day 5. Patients with pathologic complete response (pCR) in the rebiopsy after induction treatment or at least 20% increase of intratumoral CD8+ cell density in the rebiopsy compared with baseline entered radioimmunotherapy with concomitant durvalumab/tremelimumab. The objective of this interim analysis was to analyze safety and efficacy of the chemoimmunotherapy-induction treatment before radioimmunotherapy.

Results: A total of 57 patients were enrolled, 56 were treated. Median pretreatment intratumoral CD8+ cell density was 342 cells/mm². After induction treatment, 27 patients (48%) had a pCR in the rebiopsy and further 25 patients (45%) had a relevant increase of intratumoral CD8+ cells (median increase by a factor of 3.0). Adverse event (AE) grade 3-4 appeared in 38 patients (68%) and mainly consisted of leukopenia (43%) and infections (29%). Six patients (11%) developed grade 3-4 immune-related AE. Univariate analysis computed p16 positivity, programmed death ligand 1 immune cell area and intratumoral CD8+ cell density as predictors of pCR. On multivariable analysis, intratumoral CD8+ cell density predicted pCR independently (OR 1.0012 per cell/mm², 95% CI 1.0001 to 1.0022, p=0.016). In peripheral blood CD8+ cells, the coexpression of programmed death protein 1 significantly increased especially in patients with pCR.

Conclusions: Single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab is feasible and achieves a high biopsy-proven pCR rate.

Keywords: CD8-Positive T-lymphocytes; Phase II as topic; clinical trials; combined modality therapy; head and neck neoplasms; radioimmunotherapy.

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, 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); 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). 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). 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). A Hinke conflict of interest with Roche (honoraria). SS conflict of interest with Strycker (stock); Varian (stock); Abbot (stock); Crispr Techn. (stock); Pfizer (stock); Merck Serono (stock); Symrise (stock); Ortho (honoraria, advisory role, speakers’ bureau, research funding, travel expenses); PharmaMar (speakers’ bureau, travel expenses); Haema (speakers’ bureau). A Hartmann 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). USG conflict of interest with AstraZeneca (advisory role, research funding); BMS (advisory role); MSD (research funding); Sennewald Medizintechnik (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).

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Duration of adverse events (AEs) ≥grade 3. The swimmer plot presents the duration of AE ≥grade 3 separated in conventional AE and immune-related AE (irAE) on patients level. Each bar represents an individual patient. Toxicity was assessed from study inclusion until the end of the restaging period (day before the first fraction of radiotherapy) or the safety follow-up (before subsequent treatment). *This patient denied further treatment after complete response (CR); after a follow-up of 12 months, the tumor is still in CR.

Figure 2

Consolidated Standards of Reporting Trials (CONSORT) diagram and treatment response. (A) CONSORT diagram including pathologic treatment response. pCR, pathologic complete response. (B) Radiographic response in dependence of baseline intratumoral CD8+ cell density (CD8↑, preinduction CD8 density above median; CD8↓, preinduction CD8 density below median). The radiographic response was evaluated according to RECIST 1.1 criteria. Tumor responses were measured at baseline and at the restaging before radiotherapy. The values shown are the percentage change in the sum of longest diameters. Each bar represents one patient. CR, complete response; PR, partial response; SD, stable disease.

Figure 3

Histological parameters associated with treatment response. HE and immunohistochemical CD8 staining (brown) of representative patients. Residual tumors (ReTu) without immunologic response typically showed no tumor-infiltrating immune cells preinduction and postinduction neither in the HE nor in the CD8 staining. In residual tumors with immunological response, an increase of intratumoral immune cells is typically found both in HE and CD8 staining postinduction compared with preinduction. In patients who developed pCR, tumor-infiltrating immune cells are typically present preinduction and even increase post-induction. Comparison of (B) intratumoral CD8+ cell density, (C) programmed cell death ligand 1 (PD-L1) tumor cell area (TC area) and (D) PD-L1 immune cell area (IC area) in patients with residual tumor (ReTu) and pathologic complete response (pCR). Changes of (E) intratumoral CD8+ cell density, (F) PD-L1 TC area and (G) PD-L1 IC area before and after induction treatment in patients with residual tumor. (H) Peripheral blood concentration of CD8+ cells before and after induction treatment in patients with ReTu and pCR. (J) PD-1 coexpression of peripheral blood CD8+ cells before and after induction treatment in patients with ReTu and pCR.