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Cited by 342Lung Cancer Diagnosis and TreatmentCancer Immunotherapy and BiomarkersLung Cancer Research Studies

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

Altorki, Nasser K, McGraw, Timothy E, Borczuk, Alain C, Saxena, Ashish, Port, Jeffrey L, Stiles, Brendon M, Lee, Benjamin E, Sanfilippo, Nicholas J +11 more·2021·The Lancet Oncology
DOI 10.1016/s1470-2045(21)00149-2
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Abstract

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.

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Authors
Altorki, N. K., McGraw, T. E., Borczuk, A. C., Saxena, A., Port, J. L., Stiles, B. M., Lee, B. E., Sanfilippo, N. J., Scheff, R. J., Pua, B. B., Gruden, J. F., Christos, P. J., Spinelli, C., Gakuria, J., Uppal, M., Binder, B., Elemento, O., Ballman, K. V., & Formenti, S. C.
Affiliations
NewYork–Presbyterian Hospital (US)
Corresponding author
Altorki, Nasser K
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2021-06
Volume
22
Issue
6
Pages
824-835
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(21)00149-2
OpenAlex
W3163414580
Cited by
342
References
37
Citations by year
2026: 30 · 2025: 58 · 2024: 70 · 2023: 85 · 2022: 76 · 2021: 23
FWCI
41.23
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • The Lancet Oncology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • MedImmune
  • Lung Cancer Research Foundation
  • Bristol-Myers Squibb
  • Weill Cornell Medical College (1-UL1-TR002384-01)
  • Eli Lilly and Company
  • Takeda Pharmaceuticals U.S.A.
  • AstraZeneca
  • Janssen Pharmaceuticals
  • Angiocrine Bioscience
  • Merck
  • GlaxoSmithKline
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords
early-stage non-small cell lung cancer, neoadjuvant immunotherapy, durvalumab, stereotactic body radiotherapy, PD-L1 inhibitors, major pathological response, immunomodulation, surgical resection, tumor immune microenvironment, PD-L1 expression, tumor-infiltrating lymphocytes, tumour-associated macrophages, tumor-associated neutrophils
MeSH terms
Adolescent, Adult, Aged, Antibodies, Monoclonal, Carcinoma, Non-Small-Cell Lung, Combined Modality Therapy, Female, Humans, Male, Middle Aged, Neoplasm Staging, Radiosurgery, Neoadjuvant Therapy, Young Adult, B7-H1 Antigen

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