Neoadjuvant durvalumab plus SBRT safe, effective for lung cancer subset
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The addition of neoadjuvant durvalumab to stereotactic body radiotherapy appeared safe and conferred a nearly 55% major pathologic response rate among patients with early-stage non-small cell lung cancer.
In addition, the major pathologic response rate increased to more than 70% when patients with EGFR mutations were excluded from the analysis, according to phase 2 study results published in The Lancet Oncology.
“There is preclinical work showing lower-dose radiation can modulate the tumor immune microenvironment in a way that sensitizes the tumor cells to immune checkpoint inhibition. We wanted to test that hypothesis in patients with early-stage lung cancer,” Nasser K. Altorki, MD, chief of thoracic surgery at Weill Cornell Medicine, told Healio.
Investigators evaluated whether use of SBRT enhanced the antitumor immune response of durvalumab (Imfinzi, AstraZeneca) among 60 patients with early-stage NSCLC. Researchers randomly assigned patients 1:1 to two cycles of neoadjuvant durvalumab via IV every 3 weeks dosed at 1.12 g either alone (n = 30; median age, 71 years; 53% men) or combined with SBRT (8 Gy in three fractions) to the primary tumor immediately before the first cycle of durvalumab (n =30; median age, 70 years; 50% men). Patients without systemic disease progression then underwent surgical resection.
Major pathologic response in the primary tumor served as the primary endpoint.
Eighty-seven percent of patients in each group underwent surgical resection after a median 5.3 weeks from the first cycle of durvalumab.
Researchers reported a major pathologic response rate of 53.3% (95% CI, 34.3-71.7) in the combination group compared with 6.7% (95% CI, 0.8-22.1) among those in the durvalumab-alone group, a difference that met statistical significance (crude OR = 16; 95% CI, 3.2-79.6).
Fifty percent of those in the combination group with a major pathologic response achieved a complete pathologic response, researchers noted.
In a post hoc analysis that excluded 10 patients with EGFR mutations, the rate of major pathologic response increased to 71% in the combination group — which included a 38% complete pathologic response rate — compared with 10% in the monotherapy group.
Clinicians withheld treatment with the second dose of durvalumab for 10% of patients in the combination group due to immune-related adverse events, including grade 3 hepatitis, grade 2 pancreatitis and grade 3 fatigue and thrombocytopenia.
Grade 3 to grade 4 adverse events were more common in the combination group (20% vs. 17%) and two patients in each group experienced serious adverse events, including one each of pulmonary embolism and stroke in the durvalumab-alone group and one each of pancreatitis and fatigue in the combination group.
Researchers observed no treatment-associated deaths or deaths within 30 days of surgery.
“The pathologic response rates we observed are close to those reported after immune checkpoint inhibitors plus chemotherapy. However, the treatment is of shorter duration and accompanied by fewer adverse events,” Altorki said. “We need to confirm these findings in larger, preferably randomized, trials. We are now expanding the trial to a larger multicenter cohort.”
More accurate patient selection and stratification for various treatment regimens will likely further improve outcomes in this setting, according to an accompanying editorial by Boris Sepesi, MD, FACS, and Tina Cascone, MD, PhD, both researchers at The University of Texas MD Anderson Cancer Center.
“Biomarkers should inevitably have a role in novel trial design to identify nonresponders,” the editorial authors wrote. “Studies investigating potential biomarkers of clinical benefit from neoadjuvant immune-based treatments are ongoing and encompass pre-therapy and post-therapy tumor and nodal tissues, longitudinal blood samples, serial imaging for radioimmunogenomics, as well as tumor and human microbiome. Many novel immunotherapy-based strategies evidently provide greater benefit than standard chemotherapy alone, yet many trials have not excluded patients whose tumors harbor targetable genomic alterations, except for EGFR and ALK aberrations. ... Patients with operable tumors harboring actionable genomic alterations should be enrolled in neoadjuvant targeted therapy studies and these efforts are already underway through the Lung Cancer Mutation Consortium and other clinical trials.”
For more information:
Nasser K. Altorki, MD, can be reached at NewYork-Presbyterian/ Weill Cornell Medical Center, New York, NY 10023; email: nkaltork@med.cornell.edu.
References:
Altorki NK, et al. Lancet Oncol. 2021;doi:10.1016/S1470-2045(21)00149-2.
Sepesi B and Cascone T. Lancet Oncol. 2021;doi:10.1016/S1470-2045(21)00261-8.
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