Addition of nivolumab to stereotactic ablative radiotherapy in early-stage non-small cell lung cancer

For patients with inoperable stage I or II node-negative non–small-cell lung cancer (NSCLC), the standard therapy is stereotactic ablative radiotherapy (SABR) but recurrences remain common. Compared SABR alone, the addition of nivolumab to SABR (I-SABR) was now found to significantly improve event-free survival at 4-years in early-stage treatment-naïve or lung parenchymal recurrent node-negative NSCLC with tolerable toxicity.

Although stereotactic ablative radiotherapy (SABR) offers a high local control with low toxicity for patients with inoperable early-stage non-small cell lung cancer (NSCLC), relapses frequently occur, particularly for lesions >3 cm, multiple primaries, and recurrent disease. Immunotherapy generally reduces recurrence and improves survival in patients with stage III NSCLC after chemoradiotherapy, but its utility in patients with stage I and II disease is unclear. To gain more knowledge on this matter, a phase II, open-label trial comparing SABR alone to SABR with immunotherapy (I-SABR) for patient with early-stage NSCLC was conducted in Texas, USA.

Study design

Patients aged 18 years or older with histologically proven treatment-naive stage IA–IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) or isolated parenchymal recurrences (N0M0 after prior definitive surgery or radiotherapy/chemotherapy) were eligible for inclusion. Key exclusion criteria were previous receipt of immune checkpoint inhibitors and contraindications to SABR and/or immunotherapy. Participants were randomly assigned (1:1) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 hours after, the first SABR fraction). The primary endpoint of the study was 4-year event-free survival (EFS). Patients were followed with chest CT or PET/CT and clinical visits every 3 months for 2 years, then every 6 months for 3 years, and then annually.

Results

Out of the 156 patients that were randomly assigned to treatment, 141 actually received the assigned treatment. Patient characteristics were generally well balanced between the treatment arms, although patients in the I-SABR arm tend to have a larger tumour size (median 2.0 vs. 1.7 cm) and more frequently had recurrent disease (24% vs. 16% of patients). After a median follow-up of 33 months, the 4-year EFS improved from 53% with SABR to 77% with I-SABR (HR[95%CI]: 0.42[0.22-0.80], p= 0.0080 for patients in the intention-to-treat population, HR[95%CI]: 0.38[0.19-0.75], p= 0.0056 for the per-protocol population). In the per-protocol population, the I-SABR group had significantly better event-free survival among patients with a tumour size of ≤ 2 cm (HR[95%CI]: 0.35[0.14–0.86], p= 0.023) and a non-significant trend toward improvement among those with a tumour size of > 2 cm (HR[95%CI]: 0.40[0.14–1.20], p= 0.374). A significant benefit was observed among patients with treatment-naive early-stage disease (HR[95%CI]: 0.32[0.14–0.74], p= 0.008) but not among 28 patients with isolated parenchymal recurrent disease (HR[95%CI]: 0.52[0.15–1.85], p= 0.312). Interestingly, also the EFS benefit of I-SABR for PD-L1-negative cases (N= 61) remained statistically significant (HR[95%CI]: 0.27[0.09-0.81], p= 0.012).

No grade ≥3 adverse events were reported for SABR. However, 10 patients in the I-SABR group experienced grade 3 immunological adverse events that were related to nivolumab. There was no grade 3 and only 2 cases of grade 2 pneumonitis in the I-SABR arm. The most common adverse event was fatigue.

Conclusion

The addition of nivolumab to SABR significantly improved event-free survival at 4 years in patients with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. Although I-SABR thus has the potential to become a treatment option in these patients, further confirmation from a number of currently accruing phase III trials is required.

Reference

Chang J, et al. Nivolumab After Stereotactic Ablative Radiotherapy for Early-Stage Non-Small Cell Lung Cancer: Randomized I-SABR Trial. Presented at WCLC 2023; Abstract OA12.04