Adding Pembrolizumab to SBRT Does Not Improve EFS in Early-Stage NSCLC

The addition of pembrolizumab (Keytruda) to stereotactic body radiotherapy (SBRT) did not improve event-free survival (EFS) compared with SBRT alone in patients with inoperable stage I or II non–small cell lung cancer (NSCLC), according to results from the phase 3 KEYNOTE-867 trial (NCT03924869) published in the Journal of Clinical Oncology.¹ On the basis of the benefit-risk profile, the trial was stopped early, and all study treatment was discontinued.

What was the efficacy of pembrolizumab plus SBRT?

At the prespecified first interim analysis—which became the final analysis after the study was stopped for futility (data cutoff, June 11, 2024)—the median EFS was 31.2 months (95% CI, 22.5-39.1) in the SBRT-plus-pembrolizumab arm and 28.3 months (95% CI, 19.8-33.1) in the SBRT-plus-placebo arm, a difference that was not statistically significant (HR, 0.92; 95% CI, 0.69-1.24; P = .29). Because EFS was not significant, the overall survival (OS) hypothesis was not formally tested; the OS point estimate did not favor the pembrolizumab arm (HR, 1.33; 95% CI, 0.93-1.90), with a median OS of 54.7 months (95% CI, 33.5-not reached [NR]) vs NR (95% CI, 44.4-NR).

There was no difference between arms in the time to death or distant metastases (HR, 1.02; 95% CI, 0.74-1.42), and in an end-of-study analysis, disease-specific survival was not improved (HR, 1.44; 95% CI, 0.75-2.76). Subgroup and post hoc analyses suggested that pembrolizumab may improve EFS and OS among those younger than 65 years, although this group comprised less than 15% of the study population and the confidence intervals were wide.

What were the safety findings from KEYNOTE-867?

Among patients who received at least 1 dose of study treatment, grade 3 to 5 treatment-related adverse events (AEs) occurred in 46 of 226 (20.4%) in the pembrolizumab arm vs 8 of 218 (3.7%) in the placebo arm, and treatment-related AEs of any grade occurred in 73.5% vs 50.0%. There were 5 treatment-related deaths (2.2%), all in the pembrolizumab arm (3 cases of pneumonia and 1 each of bronchopneumopathy and pneumonitis); no treatment-related deaths occurred in the placebo arm. Treatment-related AEs led to discontinuation in 15.9% vs 2.3% of patients.

All-cause pneumonitis was more frequent in the pembrolizumab arm (20.8% vs 10.6%), whereas the incidence of radiation pneumonitis was similar between arms (9.7% vs 9.2%); most events were grade 1 or 2. The most common treatment-related AEs with pembrolizumab were hypothyroidism (13.7%), rash (12.4%), pruritus (11.9%), and fatigue (11.5%).

“[I]nterim analysis results of the KEYNOTE-867 study did not support the combination of SBRT plus pembrolizumab for the treatment of unresected stage I or II NSCLC," wrote lead author Salma K. Jabbour, MD, of the Department of Radiation Oncology at Rutgers Cancer Institute, with study coinvestigators.¹ “EFS and OS were not improved with the addition of pembrolizumab to SBRT, and the combination was associated with greater toxicity, compared with SBRT alone.”

How was KEYNOTE-867 designed?

KEYNOTE-867 was a phase 3, randomized, double-blind study conducted at 193 sites worldwide. Adults with untreated, unresected, stage I or II NSCLC that was inoperable—or who declined surgery—were randomly assigned 1:1 to thoracic SBRT delivered over no more than 2 weeks, administered concomitantly with pembrolizumab at 200 mg (n = 227) or placebo (n = 221) once every 3 weeks for up to 17 cycles. A total of 448 patients were randomly assigned between September 2019 and January 2024; the median age was 73.0 years, and 82.4% of patients were medically inoperable. Patients with ultra-centrally located tumors were excluded.

The primary end point was EFS by blinded independent central review. Secondary end points included OS, time to distant metastases or death, safety, and participant-reported outcomes, and disease-specific survival was a tertiary end point.

In patient-reported outcome analyses, global health status and physical and role functioning scores decreased from baseline to week 24 in both arms, with no clinically meaningful differences between groups.

The authors noted that, although immunotherapy following chemoradiation has improved outcomes in locally advanced NSCLC, as in the phase 3 PACIFIC trial (NCT02125461) of durvalumab (Imfinzi) consolidation, the benefit of concomitant radiotherapy and immunotherapy has not been established, with the phase 3 PACIFIC-2 study (NCT03519971) of concurrent durvalumab showing no benefit.^2,3 A phase 2 study (NCT03110978 ) of SBRT with or without nivolumab (Opdivo) had reported improved 4-year EFS, but differences in design—including a shorter immunotherapy duration and a higher proportion of small tumors—may account for the divergent results.⁴ Full results from the ongoing phase 3 PACIFIC-4 study (NCT03833154) of SBRT plus durvalumab are awaited to further clarify the role of immunotherapy added to SBRT in early-stage NSCLC.

References

1. Jabbour SK, Sótér S, Eaton M, et al. KEYNOTE-867: a phase III, randomized, double-blind study of stereotactic body radiotherapy with pembrolizumab for unresected stage I or II non–small cell lung cancer. J Clin Oncol. Published online October 28, 2026. doi:10.1200/JCO-26-00404
2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937
3. Bradley JD, Sugawara S, Lee KH, et al. Simultaneous durvalumab and platinum-based chemoradiotherapy in unresectable stage III non–small cell lung cancer: the phase III PACIFIC-2 study. J Clin Oncol. 2025;43(33):3610-3621. doi:10.1200/JCO-25-00036
4. 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. 2023;402(10405):871-881. doi:10.1016/S0140-6736(23)01384-3. Erratum in: Lancet. 2023;402(10405):850. doi:10.1016/S0140-6736(23)01852-4