Stereotactic ablative radiotherapy (SABR) combined with immunotherapy (I-SABR) significantly improved event-free survival (EFS) in patients with early-stage or lung parenchymal recurrent node-negative non-small cell lung cancer (NSCLC) compared with the use of Sabr alone, according to a randomized phase II trial.

In the per-protocol analysis, the 4-year EFS rate was 77% with I-SABR versus 53% with SABR alone at a median follow-up of 33 months (HR 0.38, 95% CI 0.19-0.75, P=0.0056), reported Joe Y. Chang, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

Findings from the intention-to-treat analysis were similar (HR 0.42, 95% CI 0.22-0.80, P=0.008), they noted in The Lancet.

“Collectively, the results of this trial imply that the combined method of I-SABR might represent an enhanced therapeutic option for early-stage NSCLC or lung parenchymal recurrences, and provide an important precedent as phase III trials in this population continue to accrue,” wrote Chang and colleagues.

In subgroup analyses, there were significant improvements in EFS with I-SABR in participants with tumors 2 cm or less (HR 0.35, 95% CI 0.14-0.86, P=0.023), with a non-significant trend towards improvement for patients with tumors larger than 2 cm (HR 0.40, 95% CI 0.14-1.20, P=0.10). There was no effect of size of the gross tumor volume on EFS (HR 0.99, 95% CI 0.98-1.02, P=0.90).

There was also a significant improvement in EFS among patients with treatment-naive early-stage disease (HR 0.32, 95% CI 0.14-0.74, P=0.0077), with no discernible difference in patients with isolated parenchymal recurrent NSCLC, which the authors attributed to low case numbers.

Moreover, while the EFS benefit in patients with PD-L1-positive tumors was more pronounced, patients with PD-L1-negative tumors also saw a significant benefit (HR 0.27, 95% CI 0.09-0.81, P=0.012).

Recurrences of any type as first event occurred in 36% of patients in the SABR group compared with 12% in the I-SABR group. Second primary lung cancer was seen in 8% and 3%, respectively. Thirteen patients died by the end of the study (nine in the SABR group and four in the I-SABR group), but overall survival data were not mature.

In a commentary accompanying the study, Eric D. Brooks, MD, of the University of Florida College of Medicine in Jacksonville, noted that the trial results “show a potentially practice-changing approach using systemic immunotherapy after curative local treatment. Although this is only a phase II trial, the results are long-awaited, and finally support the much-needed use of effective and safe systemic therapy for early-stage disease.”

For this study, Chang and colleagues randomized 156 patients with pathologically confirmed stages IA-IIB NSCLC or isolated parenchymal recurrences who were unable or unwilling to undergo surgery from June 2017 to March 2022, and 141 patients received their assigned therapy. Median age was 72 years, and the majority were women and white. Most had an Eastern Cooperative Oncology Group performance status score of 0-1.

Patients were randomly assigned 1:1 to receive SABR with or without four cycles of nivolumab (Opdivo; 480 mg once every 4 weeks, with the first dose on the same day as, or within 36 hours after, the first SABR fraction).

While there were no grade ≥3 adverse events among patients in the SABR-alone group, 15% of patients in the I-SABR group experienced grade 3 immunological adverse events related to nivolumab, the most frequent of which was fatigue. No grade ≥4 adverse events were reported in either group.

No participants in either group prematurely discontinued SABR. Toxicity resulted in withholding or delaying nivolumab for the subsequent cycle in five patients in the I-SABR group.

Chang and team acknowledged several limitations to the study, including its small sample size. Being a phase II study, it was conducted at few hospitals, was not double-blinded or placebo-controlled, and did not use masked independent central review of imaging. Furthermore, they noted that the study was not adequately powered to address the efficacy of the I-SABR regimen for patients with EGFR mutations or other oncogenic drivers “for which targeted agents are known to be effective in the metastatic setting.”

Thus, the results do not preclude the need for large-volume multicenter phase III studies that are ongoing, they said.