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Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials

https://doi.org/10.1016/S2213-2600(20)30391-XGet rights and content

Summary

Background

Radiotherapy might augment systemic antitumoral responses to immunotherapy. In the PEMBRO-RT (phase 2) and MDACC (phase 1/2) trials, patients with metastatic non-small-cell lung cancer were randomly allocated immunotherapy (pembrolizumab) with or without radiotherapy. When the trials were analysed individually, a potential benefit was noted in the combination treatment arm. However, owing to the small sample size of each trial, differences in response rates and outcomes were not statistically significant but remained clinically notable. We therefore did a pooled analysis to infer whether radiotherapy improves responses to immunotherapy in patients with metastatic non-small-cell lung cancer.

Methods

Inclusion criteria for the PEMBRO-RT and MDACC trials were patients (aged ≥18 years) with metastatic non-small-cell lung cancer and at least one unirradiated lesion to monitor for out-of-field response. In the PEMBRO-RT trial, patients had previously received chemotherapy, whereas in the MDACC trial, patients could be either previously treated or newly diagnosed. Patients in both trials were immunotherapy-naive. In the PEMBRO-RT trial, patients were randomly assigned (1:1) and stratified by smoking status (<10 vs ≥10 pack-years). In the MDACC trial, patients were entered into one of two cohorts based on radiotherapy schedule feasibility and randomly assigned (1:1). Because of the nature of the intervention in the combination treatment arm, blinding to radiotherapy was not feasible in either trial. Pembrolizumab was administered intravenously (200 mg every 3 weeks) with or without radiotherapy in both trials. In the PEMBRO-RT trial, the first dose of pembrolizumab was given sequentially less than 1 week after the last dose of radiotherapy (24 Gy in three fractions), whereas in the MDACC trial, pembrolizumab was given concurrently with the first dose of radiotherapy (50 Gy in four fractions or 45 Gy in 15 fractions). Only unirradiated lesions were measured for response. The endpoints for this pooled analysis were best out-of-field (abscopal) response rate (ARR), best abscopal disease control rate (ACR), ARR at 12 weeks, ACR at 12 weeks, progression-free survival, and overall survival. The intention-to-treat populations from both trials were included in analyses. The PEMBRO-RT trial (NCT02492568) and the MDACC trial (NCT02444741) are registered with ClinicalTrials.gov.

Findings

Overall, 148 patients were included in the pooled analysis, 76 of whom had been assigned pembrolizumab and 72 who had been assigned pembrolizumab plus radiotherapy. Median follow-up for all patients was 33 months (IQR 32·4–33·6). 124 (84%) of 148 patients had non-squamous histological features and 111 (75%) had previously received chemotherapy. Baseline variables did not differ between treatment groups, including PD-L1 status and metastatic disease volume. The most frequently irradiated sites were lung metastases (28 of 72 [39%]), intrathoracic lymph nodes (15 of 72 [21%]), and lung primary disease (12 of 72 [17%]). Best ARR was 19·7% (15 of 76) with pembrolizumab versus 41·7% (30 of 72) with pembrolizumab plus radiotherapy (odds ratio [OR] 2·96, 95% CI 1·42–6·20; p=0·0039), and best ACR was 43·4% (33 of 76) with pembrolizumab versus 65·3% (47 of 72) with pembrolizumab plus radiotherapy (2·51, 1·28–4·91; p=0·0071). Median progression-free survival was 4·4 months (IQR 2·9–5·9) with pembrolizumab alone versus 9·0 months (6·8–11·2) with pembrolizumab plus radiotherapy (hazard ratio [HR] 0·67, 95% CI 0·45–0·99; p=0·045), and median overall survival was 8·7 months (6·4–11·0) with pembrolizumab versus 19·2 months (14·6–23·8) with pembrolizumab plus radiotherapy (0·67, 0·54–0·84; p=0·0004). No new safety concerns were noted in the pooled analysis.

Interpretation

Adding radiotherapy to pembrolizumab immunotherapy significantly increased responses and outcomes in patients with metastatic non-small-cell lung cancer. These results warrant validation in a randomised phase 3 trial.

Funding

Merck Sharp & Dohme.

Introduction

Systemic treatment of metastatic non-small-cell lung cancer continues to evolve rapidly, with immunotherapy (with or without chemotherapy) now being a cornerstone of first-line treatment.1, 2, 3, 4 However, the benefit of immunotherapy has been largely driven by a subset of patients with striking and durable responses to immunotherapeutic agents.5 Between 17% and 48% of patients respond to immunotherapy-based approaches, leaving the need to investigate further options for non-responders.1, 3, 4

To improve outcomes for patients who do not respond to immunotherapy, efforts have been aimed at combining immunotherapy with radiotherapy. There is ample mechanistic evidence that radiotherapy can enhance the immune response in this setting.6, 7, 8, 9, 10, 11, 12, 13 Central to this notion is the idea of the abscopal effect, which refers to systemic (out of the radiotherapy field) antineoplastic effects caused by local radiotherapy. Biologically, radiotherapy enhances systemic release of antigens from tumour tissue, which are recognised by antigen-presenting cells and subsequently presented to T lymphocytes (particularly, CD8 cytotoxic T cells). Priming and activation of these cells causes a systemic immune response against tumour tissue, both locally and systemically. Moreover, sublethal doses of radiotherapy have been mechanistically shown to more favourably modulate the tumour microenvironment so as to better attract T cells (eg, possibly by reducing the inhibitory signal transforming growth factor β), and low doses attenuate high-dose radiotherapy-induced immunosuppressive cell signalling (eg, macrophage repolarisation to the M1 subtype).14, 15, 16, 17, 18

Despite cumulative preclinical and clinical data, randomised evidence is scant for whether combining radiotherapy with immunotherapy for metastatic non-small-cell lung cancer improves response rates, outcomes, or both over immunotherapy alone. In the PEMBRO-RT trial,19 no differences in response rates were noted when pembrolizumab was combined with radiotherapy versus pembrolizumab alone (36% vs 18%; p=0·07), although a proportionally greater effect was seen in PD-L1 negative patients (22% vs 4%; p=0·14). In the MDACC trial,20 no differences in outcomes were discerned between groups in the overall population (median progression-free survival 5·1 months with immunotherapy alone vs 9·1 months with immunotherapy plus radiotherapy; p=0·52), but a proportionally greater effect was seen on response rate (38% vs 10%; p=0·11) and progression-free survival (20·8 months vs 6·8 months; p=0·03) when radiotherapy of 50 Gy in four fractions was applied.

The relatively small sample sizes in both the PEMBRO-RT and MDACC trials were a limitation to the detection of potentially significant differences in response rates and outcomes when analysed individually. Although several randomised trials are ongoing to investigate addition of radiotherapy to various immunotherapy agents, PEMBRO-RT and MDACC are the only known completed randomised comparisons of immune checkpoint inhibition alone versus immune checkpoint inhibition combined with radiotherapy in metastatic non-small-cell lung cancer. We therefore did a pooled analysis of findings from these two trials to better assess the clinical endpoints.

Section snippets

Study design and participants

PEMBRO-RT is a phase 2, multicentre (three sites), randomised trial led by the Netherlands Cancer Institute (Amsterdam, Netherlands). MDACC is a phase 1/2, single-centre, randomised trial done at the M D Anderson Cancer Center (Houston, TX, USA). Patients (aged ≥18 years) were eligible for either study if they had metastatic non-small-cell lung cancer with at least one unirradiated lesion (to monitor the out-of-field response). Patients in both trials were immunotherapy-naive. In the PEMBRO-RT

Results

Between July 1, 2015, and March 31, 2018, 92 patients were assessed for eligibility in the PEMBRO-RT trial, of whom 76 were randomised. Between Sept 1, 2015, and Aug 31, 2018, 100 patients were assessed for eligibility to the MDACC trial, of whom 72 were randomised. Figure 1 shows selection of patients in both trials. Data for 148 patients were pooled for this analysis. 76 patients received pembrolizumab alone (median follow-up 33 months [IQR 31·7–34·3]) and 72 received pembrolizumab plus

Discussion

Our pooled analysis of the PEMBRO-RT19 and MDACC20 randomised trials is, to our knowledge, the largest assessment of prospectively obtained data in patients with metastatic non-small-cell lung cancer who were randomised to pembrolizumab with or without radiotherapy. Our findings showed that addition of radiotherapy to immunotherapy with pembrolizumab significantly increased response rates of unirradiated lesions, which led to significantly higher progression-free survival and overall survival.

Data sharing

The protocols of the MDACC and PEMBRO-RT trials are available in appendix 2 and appendix 3, resepctively. All other data, including study participant data, the data dictionary, the statistical analysis plan, and informed consent, will not be shared.

References (20)

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