Joe Y. Chang, MD

In a phase II trial (I-SABR) reported in The Lancet, Joe Y. Chang, MD, of the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center, Houston, and colleagues found that the addition of immunotherapy with nivolumab to stereotactic ablative radiotherapy (SABR) improved event-free survival in patients with previously untreated stage I to II or isolated parenchymal recurrent node-negative non–small cell lung cancer (NSCLC).¹

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 network were randomly assigned between June 2017 and March 2022 to receive SABR alone (n = 78) or with nivolumab immunotherapy (I-SABR group; n = 78). In the per-protocol population of 141 patients, 66 were in the I-SABR group and 75 in the SABR group. Patients had treatment-naive stage IA or IB (tumor size ≤ 4 cm, N0M0), stage IIA (tumor size ≤ 5 cm, N0M0), or stage IIB (tumor size > 5 cm and ≤ 7 cm, N0M0) or isolated parenchymal recurrences (tumor size ≤ 7 cm) NSCLC (T_anyN_anyM0 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.

Event-Free Survival

Median follow-up was 33 months (95% confidence interval [CI] = 28.7–38.1 months). In the per-protocol population, the 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, the 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 up to 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 larger than 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). No effect of size of gross tumor volume was observed (HR = 0.99, 95% CI = 0.98–1.02, P = .90).

In an exploratory subgroup analysis, the event-free survival benefit of I-SABR was augmented in patients with PD-L1–positive tumors, with no recurrences observed in 15 patients in the I-SABR group vs 5 of 16 in the SABR group. Benefit of I-SABR was also significant in PD-L1–negative patients (n = 61; HR = 0.27, 95% CI = 0.09–0.81, P = .012).

In the per-protocol population, recurrence of any type as the first event occurred in 27 of 75 patients (36%) in the SABR group vs 8 of 66 patients (12%) in the I-SABR group. Local recurrence was observed in 13% vs 0%; regional recurrence, in 11% vs 6%; and distant recurrence, in 16% vs 3%. Second primary lung cancer was observed in 8% vs 3% of patients.

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 (2 patients). Adverse events led to discontinuation of SABR treatment in no patients in either group and to discontinuation of nivolumab in five patients (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.” 

DISCLOSURE: The study was funded by Bristol Myers Squibb and the MD Anderson Cancer Center Alliance, National Cancer Institute, and others. Dr. Chang reported no conflicts of interest.

REFERENCE

1. Chang JY, Lin SH, Dong W, et al: Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: An open-label, randomised, phase 2 trial. Lancet. July 18, 2023 (early release online).