944TiP Randomized phase II study of immune stimulation with pembrolizumab and radiotherapy of recurrent and/or metastatic head and neck squamous cell carcinoma : The IMPORTANCE trial

PD-1-inhibitors were found effective in large clinical trials in first- and second-line therapy of recurrent and/or metastatic head and neck squamous cell carcinoma (rmHNSCC). Despite relative low objective response rates (ORR), overall survival (OS) improved significantly. It is generally assumed, that an improvement of the ORR will directly result in a further improvement of OS. Radiotherapy (RT) not only kills tumor cells, but also changes the tumor cell phenotype and the tumor microenvironment, which might result in induction of anti-tumor immune responses. In preclinical experiments the combination of RT and PD-1/PD-L1 pathway blockade improved local tumor control, and also induced systemic tumor immunity. Consequently, metastases distant from the irradiated tumor responded after RT and the survival rate of the animals improved. Thus, local RT, acting as in situ vaccination, is probably able to improve the ORR to pembrolizumab (P) in rmHNSCC. IMPORTANCE (NCT03386357) is an open-label, randomized, prospective, multicenter phase II clinical trial of P with or without local RT in patients (pts) with rmHNSCC after progression to platinum-based therapy or as first line treatment if CPS≥1. All pts will receive P 200 mg administered every third week until confirmed disease progression according to iRECIST criteria, unacceptable toxicity, pts’ wish to stop therapy or a maximal treatment time of 12 months. Pts in treatment arm A will receive RT of one, two or three tumor lesions with a total tumor volume of at least 2 ml (if possible, ≥5 ml) intended to induce immunogenic tumor cell death. RT will be performed conventionally with single doses of 3 Gy to a total dose of 36 Gy. Pts in arm B will only receive P. The objectives are to show that addition of local RT of 1-3 lesions to P improves the ORR, duration of response, progression free survival and OS. Further objective is the assessment of distinct immune changes, safety and tolerability of the combination of P and RT. Recruitment started in July 2018 and is ongoing. Until March 2023, 100 pts were randomized. The planned sample size is 130 patients, the recruitment is estimated to be completed by January 2024. NCT03386357, released: 29.12.2017. Dean of the Medical Faculty of the Friedrich-Alexander University Erlangen-Nürnberg. MSD Merck Sharp & Dohme.