Primary results of the phase II CheckRad-CD8 trial: First-line treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) with double checkpoint blockade and radiotherapy dependent on intratumoral CD8+ T-cell infiltration.
Authors: Markus Hecht, Markus Eckstein, Sandra Rutzner, Jens von der Grün, Thomas Illmer, Gunther Klautke, Simon Laban, Matthias G. Hautmann, Thomas Brunner, Balint Tamaskovics, Axel Hinke, Benjamin Frey, Sabine Semrau, Arndt Hartmann, Panagiotis Balermpas, Wilfried Budach, Udo S Gaipl, Heinrich Iro, Antoniu-Oreste Gostian, Rainer Fietkau
Journal: Journal of Clinical Oncology (2021)

6007 Background: Inhibition of the PD-1/PD-L1 pathway is efficient in recurrent/metastatic HNSCC. Targeting the immune checkpoint CTLA-4 may be synergistic to radiotherapy. This trial studies feasibility and efficacy of combined PD-L1/CTLA-4 blockade concomitant to induction chemotherapy and radiotherapy. Methods: Patients with previously untreated stage III-IVB (AJCC 8 th edition) HNSCC were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30mg/m² d1-3, docetaxel 75mg/m² d1, durvalumab 1500mg fix dose d5 and tremelimumab 75mg fix dose d5. Patients with at least 20% increase of intratumoral CD8+ immune cell density or pathological complete response (pCR) in the re-biopsy (performed on d22-26) entered radio-immunotherapy (RIT) up to a total dose of 70Gy. Patients received further three cycles of durvalumab/tremelimumab (q4w, two concomitant and one subsequent) followed by eight cycles of durvalumab mono (q4w). Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80% (i.e. dose limiting toxicity/DLT ≤20%; exclusion of patients with other reasons than DLT for treatment discontinuation; feasibility unacceptable if ≤65%). The calculated sample size was 57 patients to enter RIT. Main secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Between Sep 2018 and Mai 2020, 80 patients were enrolled (one excluded). Median age was 60 years, 33 patients (42%) were current smokers, 43 patients (54%) had oropharyngeal tumors (53% p16 positive), 44 patients (56%) were stage IV. Median follow up was 12.5 months. After induction chemo-immunotherapy 41 patients had pCR and 31 an intratumoral CD8+ immune cell increase. Of 60 patients entering RIT (primary endpoint cohort), 10 received DLT and 4 discontinued for other reasons. The feasibility rate of the RIT cohort until cycle 6 was 82%, meeting the primary endpoint of ≥80% (95% confidence interval (CI), one-sided (lower boundary): 72%). The RIT cohort had a PFS rate at 1 year of 79% (CI 69-90%) and at 2 years of 73% (CI 61-87%) and an OS rate at 1 year of 89% (CI 81-98%) and at 2 years of 86% (CI 77-97%). The entire study cohort had a PFS rate at 1 year of 75% (CI 65-85%) and at 2 years of 68% (CI 58-81%) and an OS rate at 1 year of 86% (CI 78-95%) and at 2 years of 80% (CI 70-91%). Toxicity (treatment-related or un-related) ≥grade 3 appeared in 75 patients (95%) and mainly consisted of dysphagia (53%), leucopenia (48%) and infections (29%). DLT mainly consisted of hepatitis (10%). Conclusions: The trial met the primary endpoint feasibility. CD8+ T cell-based pathological patient selection after induction therapy identifies patients with promising PFS rates after chemotherapy-free RIT. Clinical trial information: nct03426657.