Pathologic Responses to Stereotactic Ablative Radiotherapy in Combination With Nivolumab for Early Stage NSCLC: A Phase 2 Study.

Introduction: Stereotactic ablative radiotherapy (SABR) is routinely used in patients with early stage NSCLC who are not candidates for surgery. Despite excellent local tumor control, it is associated with a high rate of regional and distant recurrences. Combining stereotactic radiotherapy with PD-1 inhibitors has demonstrated encouraging results for patients with curative intent, but how it affects the tumor microenvironment and pathologic response remains unclear. Methods: We designed a phase II, open-label, single-arm study aimed to evaluate the efficacy and safety of neoadjuvant nivolumab combined with SABR in patients with NSCLC measuring up to 4 cm, without positive lymph nodes. Patients were required to be eligible for surgery, with adequate pulmonary and cardiovascular function. Nivolumab was administered at 360 mg every 21 days for three doses, combined with SABR, which was initiated concomitantly with the first cycle. Patients subsequently underwent surgical resection 10 weeks after the last dose of radiation. The primary end point was the pathologic complete response (pCR) rate at surgery. Secondary end points included major pathologic response (MPR) rate, safety, event-free survival, and overall survival at 12 months and a comprehensive biomarker analysis. Results: A total of 25 patients were enrolled between November 2019 and February 2022. The mean age was 68 years, and 68% were female. The mean tumor size at baseline was 2.47 cm. A total of 24 patients fully completed the experimental therapy and proceeded with surgery. The primary end point of pCR was achieved by 19 of 24 patients (79.2%; 95% confidence interval: 57%-92%, Conclusions: The neoadjuvant combination of three doses of nivolumab and SABR produced a high pCR rate in stage I NSCLC. Further research is warranted to evaluate this treatment modality in patients with medically inoperable NSCLC and whether surgery could be safely omitted for patients who are candidates for resection.