Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial

Abstract

Background: In this phase I/II trial, we evaluated the safety and effectiveness of pembrolizumab, with or without concurrent radiotherapy (RT), for lung and liver lesions from metastatic non-small cell lung cancer (mNSCLC).

Methods: Patients with lung or liver lesions amenable to RT plus at least one additional non-contiguous lesion were included regardless of programmed death-ligand 1 (PD-L1) status. Pembrolizumab was given at 200 mg every 3 weeks for up to 32 cycles with or without concurrent RT. Metastatic lesions were treated with stereotactic body RT (SBRT; 50 Gy in 4 fractions) if clinically feasible or with traditionally fractionated RT (45 Gy in 15 fractions) if not. The primary end point was the best out-of-field lesion response, and a key secondary end point was progression-free survival (PFS).

Results: The median follow-up time was 20.4 months. One hundred patients (20 phase I, 80 phase II) were evaluable for toxicity, and 72 phase II patients were evaluable for treatment response. No patients in the phase I group experienced grade 4-5 events; in the phase II group, two had grade 4 events and nine had grade 3 events. The ORR in the combined-modality cohort (irrespective of RT schema) was 22%, vs 25% in the pembrolizumab group (irrespective of receipt of salvage RT) (p=0.99). In the concurrent pembrolizumab+RT groups, the out-of-field ORRs were 38% in the pembrolizumab+SBRT group and 10% in the pembrolizumab+traditional RT group. When examining the pembrolizumab-alone patients, the out-of-field ORRs were 33% in those designated to receive salvage SBRT (if required) and 17% for salvage traditional RT. In all patients, the median PFS for pembrolizumab alone was 5.1 months (95% CI 3.4 to 12.7 months), and pembrolizumab/RT (regardless of schema) was 9.1 months (95% CI 3.6 to 18.4 months) (p=0.52). An exploratory analysis revealed that for patients with low PD-L1 expression, the median PFS was 4.6 vs 20.8 months for pembrolizumab with and without RT, respectively (p=0.004).

Conclusions: Concurrent immunoradiotherapy for mNSCLC is safe, although larger trials are required to address which patients benefit most from RT.

Trial registration number: NCT02444741.

Keywords: immunotherapy; lung neoplasms; radioimmunotherapy; radiotherapy.

Conflict of interest statement

Competing interests: JW, JVH, MA and JYC have received research grants from Bristol-Myers Squibb. JW has received grants from Merck. JVH also received research funding from AstraZeneca and Spectrum Pharmaceuticals. MA has also received research funding from Lilly, Novartis and GSK. JW is a co-founder of Healios, MolecularMatch and OncoResponse; he is on the scientific advisory board of RefleXion Medical, Mavupharma, Alpine Immune Sciences and Checkmate Pharmaceuticals; he has received grants from Varian and OncoResponse; he has also received laboratory research support from Bristol-Myers Squibb, Merck, Aileron, Nanobiotix and Checkmate Pharmaceuticals; he has ownership interest in OncoResponse. VP is advisory board members for Bristol-Myers Squibb. JYC is a shareholder of Global Oncology One. JVH has ownership interest in Cardinal Spine and Bio-Tree.

© 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

Out-of-field overall response rates (ORRs) for patients with metastatic non-small cell lung cancer evaluated with immune-related response criteria, stratified according to the treatment received. RT, radiotherapy; SBRT, stereotactic body RT.

Figure 2

Progression-free survival (PFS) times in (A) all patients, (B) patients with disease amenable to stereotactic body RT (SBRT) and (C) patients with disease requiring traditional radiotherapy (RT).

Figure 3

Out-of-field overall response rates (ORRs) and progression-free survival (PFS) in the (A and B) high-programmed death-ligand 1 (PD-L1) expression group, (C and D) low-PD-L1 expression group and (E and F) PD-L1-negative group. RT, radiotherapy.