A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours

Abstract

Background: We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers.

Methods: There were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response.

Results: Of the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells.

Conclusions: HFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy.

Clinical trial registration: NCT02303990 ( www.clinicaltrials.gov ).

Conflict of interest statement

Merck, which manufactures pembrolizumab, provided the drug for free and provided personnel support via an investigator-sponsored research agreement to A.M. The authors declare no competing interests.

Figures

Fig. 1

Trial schema and stratification. Patients were stratified by histology and whether they had received prior PD-1 or PDl-1 therapy. Within each stratum, the first six patients received 8 Gy × 3 to a single lesion and the second six patients received 17 Gy × 1

Fig. 2

Images for responder with non-small cell lung cancer. Patient 15 was diagnosed with non-small cell lung cancer metastatic to the bone and was given carboplatin/paclitaxel x 6 cycles with a good response and then given palliative radiation to the right lung mass (37.5 Gy). He developed a mass in the ileum and received gemcitabine/navelbine but progressed. He received nivolumab to which he had a good response initially. (a) Chest CT scan after 4 months on nivolumab. CT scan 2 months later showed progression of disease in the chest. CT scan done 2 months after this showed further progression of disease (b). At this time, nivolumab was discontinued, and he was enrolled on our pembrolizumab HFRT study. He underwent a planning FDG PET/CT scan that established his baseline disease status (c, d). He received pembrolizumab and then radiation (8 Gy × 3) to an abdominal mass (c) followed by continued pembrolizumab. A repeat PET/CT scan was performed 6 months after radiation (e, f) showing response in non-irradiated lesions which had previously progressed on PD-1 blockade prior to study entry

Fig. 3

Pharmacodynamic immune response to anti-PD-1+ radiation. (a) Timeline of treatment and blood collections; D0 is pre-treatment and D10–14 is post RT. Panels b–d show flow cytometric data from 4 patients in stratum 2 treated with 8 Gy × 3 (patients 1, 3, 5, 6). (b) Ki67 in CD8 T cells pre- and post-RT from a representative stratum 2 patient and all 4 patients (c) Ki67 in PD-1+ versus PD-1− CD8 T cells pre- and post-RT. (d) Frequency of PD-1+CTLA4+CD8 T cells pre- and post-RT of a representative stratum 2 patient and all 4 patients (e) Phenotypic expression of CD8 T cells in the peripheral blood at days 11 and 84 of patient 15 (Fig. 2) who was treated with 8 Gy  × 3