In the phase II I-SABR trial reported in The Lancet, Chang et al found that the addition of nivolumab to stereotactic ablative radiotherapy (SABR) improved event-free survival in patients with previously untreated stage I or II or isolated parenchymal recurrent node-negative non–small cell lung cancer (NSCLC).
As stated by the investigators, “[SABR] is the standard treatment for medically inoperable early-stage NSCLC, but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear.”
Study Details
In the open-label trial, 156 patients (intent-to-treat [ITT] population) from three hospitals in the integrated MD Anderson Cancer Network were randomly assigned between June 2017 and March 2022 to receive SABR alone (n = 78) or SABR plus nivolumab (I-SABR group; n = 78). In the per-protocol population of 141 patients, 66 were in the I-SABR group and 75 were in the SABR group. Patients had treatment-naive stage IA to IB (tumor size ≤ 4 cm, N0M0), stage IIA (tumor size ≤ 5 cm, N0M0), or stage IIB (tumor size > 5 cm and ≤ 7 cm, N0M0) disease, or isolated parenchymal recurrences (tumor size ≤ 7 cm, TanyNanyM0 before definitive surgery or chemoradiotherapy).
SABR was given at 50 Gy in 4 once-daily fractions or 70 Gy in 10 once-daily fractions, with simultaneous integrated boosts to internal gross tumor volume if dose-volume constraints for radiation-sensitive organs could be met. Nivolumab was given at 480 mg every 4 weeks (beginning on the same day as the first SABR fraction) for a total of four cycles. In the first 6 months of the trial, prior to approval of the subsequent nivolumab regimen, nivolumab was given at 240 mg every 2 weeks for seven planned cycles. The primary endpoint was 4-year event-free survival, analyzed in the per-protocol and ITT populations.
KEY POINTS
- In the per-protocol population, the addition of nivolumab to SABR significantly improved event-free survival.
- The 4-year event-free survival rate was 77% vs 53%.
Event-Free Survival
Median follow-up was 33 months (95% confidence interval [CI] = 28.7–38.1 months). In the per-protocol population, 4-year event-free survival was 77% (95% CI = 66%–91%) in the I-SABR group vs 53% (95% CI = 42%–67%) in the SABR group (hazard ratio [HR] = 0.38, 95% CI = 0.19–0.75, P = .0056). In analysis adjusting for the stratification factors of Eastern Cooperative Oncology Group performance status, tumor size, lung cancer history, and histology, the benefit in the I-SABR group remained significant (HR = 0.36, 95% CI = 0.18–0.74, P = .0054).
In the ITT population, 4-year event-free survival was significantly better in the I-SABR group (HR = 0.42, 95% CI = 0.22–0.80, P = .0080). In the per-protocol population, the I-SABR group had significantly better event-free survival among patients with a tumor size of ≤ 2 cm (HR = 0.35, 95% CI = 0.14–0.86, P = .0230) and a nonsignificant trend toward improvement among those with a tumor size of > 2 cm (HR = 0.40, 95% CI = 0.14–1.20, P = .10). A significant benefit was observed among patients with treatment-naive early-stage disease (HR = 0.32, 95% CI = 0.14–0.74, P = .0077) but not among 28 patients with isolated parenchymal recurrent disease (HR = 0.52, 95% CI = 0.15–1.85, P = .31).
Adverse Events
No treatment-related grade 4 or 5 adverse events were observed in either group. No treatment-related grade 3 events were observed in the SABR group. A total of 10 patients (15%) in the I-SABR group had treatment-related grade 3 adverse events, most commonly fatigue (n = 2). No patients in either group discontinued SABR due to adverse events; five patients did discontinue treatment with nivolumab (8%). No grade 3 pneumonitis was observed.
The investigators concluded, “Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase III trials is required.”
Joe Y. Chang, MD, of the Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet Oncology.
Disclosure: The study was funded by Bristol Myers Squibb and MD Anderson Cancer Center Alliance, the National Cancer Institute, and others. For full disclosures of the study authors, visit thelancet.com.
