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