Atezolizumab, when administered concurrently with chemoradiation, did not improve overall survival (OS) or progression-free survival (PFS) in patients with limited-stage small cell lung cancer (LS-SCLC), according to results from the phase 3 NRG-LU005 trial presented at the 2024 ASTRO Annual Meeting.
The international NRG-LU005 trial randomized 544 patients 1:1 to receive either platinum/etoposide every 3 weeks for 3 cycles plus thoracic radiotherapy (45 Gy twice daily or 66 Gy daily) with or without intravenous atezolizumab. Atezolizumab was then administered every 3 weeks for up to 1 year in the experimental arm. The primary endpoint was OS, with secondary endpoints including PFS, objective response rate, and distant metastasis-free survival (DMFS).
The median OS was 39.5 months (95% CI, 27.5-not reached) with concurrent chemoradiation (CRT) alone versus 33.1 months (95% CI, 27.8-43.9) with the addition of atezolizumab (HR, 1.11; 95% CI, 0.85-1.45; P = .7640). The median PFS was 11.5 months (95% CI, 10.7-13.4) and 12.0 months (95% CI, 10.8-15.1) in each respective arm (HR, 1.00; 95% CI, 0.80-1.25; P = .9542).
Timing of Immunotherapy Matters
These findings contrast with recent data from the ADRIATIC trial, which demonstrated that durvalumab, another immunotherapy agent, improved OS when administered after chemoradiation in LS-SCLC. This suggests that the timing of immunotherapy relative to chemoradiation is critical.
"The introduction of immunotherapy marked the first significant breakthrough in treating small cell lung cancer treatment in decades. Now, we see that if you give immunotherapy concurrently with chemoradiation, it does not yield the same survival benefit as it does when we add it after standard treatment," said Kristin A. Higgins, MD, chief clinical officer at City of Hope Cancer Center Atlanta, and the presenting author of the study.
Impact of Radiation Schedule
Interestingly, the NRG-LU005 trial also revealed that twice-daily radiation (45 Gy) was associated with improved survival compared to once-daily radiation (66 Gy), regardless of atezolizumab administration. The median OS for patients who received twice-daily radiotherapy was 35.4 months (95% CI, 32.3-NR) vs 28.3 months (95% CI, 21.7-40.6) with once-daily radiation (HR, 1.44; 95% CI, 1.10-1.89; P = .0075).
Safety Profile
Most patients in both the CRT alone and CRT/atezolizumab arms experienced adverse events (AEs), with any-grade AEs occurring in 99.0% and 99.6% of patients, respectively. Grade 3/4 AEs were observed in 92.5% and 86.5% of patients, respectively. AEs leading to death occurred in 1.6% and 9.0% of patients from each arm. Notably, there were 4 grade 5 immune-related AEs in the CRT/atezolizumab arm.
Implications for Clinical Practice
While concurrent atezolizumab did not improve survival outcomes in LS-SCLC, the finding regarding radiation schedule could influence clinical practice. "Twice-daily radiation did show improved survival and could be the optimal choice of radiation fractionation," Higgins noted. Further research is needed to elucidate the optimal sequencing and combination strategies for immunotherapy and chemoradiation in LS-SCLC.
