Elsevier

The Lancet Oncology

Volume 22, Issue 6, June 2021, Pages 824-835
The Lancet Oncology

Articles
Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial

https://doi.org/10.1016/S1470-2045(21)00149-2Get rights and content

Summary

Background

Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15–45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab.

Methods

We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I–IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual.

Findings

Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8–22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3–71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2–79·6]; p<0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3–4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3–4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported.

Interpretation

Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial.

Funding

AstraZeneca.

Introduction

Blockade of the PD-1–PD-L1 immune checkpoint has revolutionised the treatment of patients with advanced non-small-cell lung cancer (NSCLC).1, 2 The progress in the treatment of advanced NSCLC disease has increased interest in using immune checkpoint blockade at even earlier disease stages.3 Several phase 2 trials have reported the use of anti-PD-1 or anti-PD-L1-blocking antibodies as neoadjuvant therapy in patients with early-stage NSCLC with major pathological response as the primary endpoint.4, 5, 6, 7, 8, 9 In a small pilot trial, Forde and colleagues reported an encouraging major pathological response rate of 45% after two preoperative cycles of nivolumab in 22 patients with early-stage lung cancer.4 However, major pathological response rates reported in more recent larger trials are in the range of 14–20%.5, 6, 7, 8 For example, in a preliminary report on the Lung Cancer Mutational Consortium trial of preoperative atezolizumab in stages IB–IIIA NSCLC, Kwiatkowski and colleagues reported a major pathological response rate of 18% in the first 101 patients.5 Investigators of the Neostar trial reported a response rate of 22% in patients treated by three preoperative cycles of nivolumab.6 In 2020, investigators of the PRINCEPS trial, which evaluated preoperative atezolizumab, reported a major pathological response rate of 14% in 30 patients; and those of the IONESCO trial, which evaluated preoperative durvalumab, reported a major pathological response rate of 18% in 50 patients.8, 9 These major pathological response rates are similar to those reported after neoadjuvant chemotherapy alone and highlight the need to explore additional approaches to enhance the efficacy of immune checkpoint blockade.10 Further improvements in major pathological response rates might be accomplished by dual checkpoint inhibition,6, 11 albeit at the price of enhanced toxicity, or by combining immune checkpoint blockade with chemotherapy.12, 13 Two small phase 2 trials of neoadjuvant immune checkpoint blockade combined with chemotherapy in early-stage NSCLC reported a major pathological response in 57% and 73% of their intention-to-treat populations.12, 13 Good preclinical and recent clinical evidence in advanced NSCLC for stereotactic body radiotherapy at doses of three fractions of 8 Gy might be a potent immunomodulator, enhancing the efficacy of the immune response facilitated by immune checkpoint blockade.14, 15, 16, 17, 18, 19 Radiotherapy enhances immune response through multiple proposed mechanisms, including induction of immunogenic cell death with release of neoantigens, upregulation of major histocompatibility complex (MHC) and enhanced antigen presentation, activation of dendritic cells and enhanced antigen cross presentation, modulation of checkpoint expression, and increased T-cell infiltration into the tumour.14

Here we report the results of, to our knowledge, the first randomised neoadjuvant trial in early-stage NSCLC evaluating the safety and efficacy of stereotactic body radiotherapy (8 Gy × 3 fractions), as a proposed immunomodulator that enhances the anti-tumour immune response associated with immune checkpoint blockade by durvalumab.

Section snippets

Study design and participants

We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). Patients were eligible if they had a biopsy-proven diagnosis of NSCLC with clinical stages I to IIIA (according to the 7th edition of the American Joint Committee on Cancer staging system) that was deemed

Results

Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened of whom 60 (63%) met the eligibility criteria and were enrolled and randomly assigned to the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30; figure 1). Demographic, clinical, and pathological variables were well balanced between both groups (table 1). Since PD-L1 expression was not a prespecified stratification factor, more patients with PD-L1-negative tumours (PD-L1 expression <1%) were

Discussion

In this population of patients with operable clinical stages I–IIIA NSCLC, the preoperative combination of immune checkpoint blockade and radiotherapy to the primary tumour resulted in a significant and clinically meaningful increase in the proportion of patients with a major or complete pathological response. In contrast to prevailing strategies, combining immunotherapy with stereotactic body radiotherapy might be associated with a more favourable safety profile and higher patient compliance

Data sharing

The trial protocol did not include a data sharing plan; therefore, data from the trial will not be shared publicly, as data sharing was not included when ethical approval was requested.

Declaration of interests

NKA reports stock options from TMRW, Angiocrine Bioscience, and View Point Medical; and is on the research advisory committee for AstraZeneca. AS reports personal fees from AstraZeneca, Blueprint Medicines, Genentech, Medtronic, and Takeda. JLP reports leadership and stock options from TMRW, Angiocrine Bioscience, and View Point Medical. BMS reports personal fees from AstraZeneca, Pfizer, Flame Biosciences, Gala Therapeutics, Bristol Myers Squibb, and Ribon Therapeutics; and is on the board of

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