At the 2024 Annual Meeting of the American Society for Radiation Oncology (ASTRO), the second interim analysis of the Phase III NRG-LU005 trial revealed the importance of timing when combining immunotherapy with chemoradiotherapy for limited-stage small cell lung cancer (SCLC). The findings showed no significant survival benefits for patients who received atezolizumab concurrently with chemoradiotherapy (cCRT) compared to those who received cCRT alone.

In contrast, the ADRIATIC trial found that starting the PD-L1 inhibitor durvalumab a few weeks after completing chemoradiotherapy extended median overall survival (OS) by 22.5 months (56 months vs 33.5 months) compared to chemoradiotherapy alone for patients with limited-stage SCLC. According to NRG-LU005’s lead investigator, Dr. Kristin Higgins from City of Hope Cancer Center Atlanta, the differing survival outcomes between NRG-LU005 and ADRIATIC were not due to durvalumab being more effective than atezolizumab; both agents have shown promising results in SCLC. Instead, Higgins suggested that radiotherapy, a known immunosuppressant, might hinder the immune response necessary for atezolizumab to work effectively. This indicates that the immune system may need recovery time post-radiotherapy before beginning immunotherapy. Therefore, simultaneous use of immunotherapy and chemoradiotherapy “is not a viable strategy,” and immunotherapy should be administered after completing chemoradiotherapy. During the 2024 ASTRO meeting, Kenneth Rosenzweig, Director of Radiation Oncology at Mount Sinai School of Medicine and NRG-LU005 discussant, emphasized the critical importance of timing in administering immunotherapy.

Study Design and Key Findings

In the open-label, randomized NRG-LU005 trial, patients received one round of chemotherapy (platinum/etoposide) before enrollment and were then randomized 1:1 to receive either concurrent cCRT (n=270) or cCRT plus intravenous atezolizumab at 1200 mg (n=274). Eligible patients had Tx-4, N0-3, M0 SCLC and were stratified based on chemotherapy (cisplatin or carboplatin), radiotherapy regimen (66 Gy once daily vs 45 Gy twice daily), gender, and performance status (0-1 vs 2). Atezolizumab was administered every three weeks for up to 17 cycles (approximately one year), until disease progression or intolerable toxicity. Atezolizumab treatment began during the second round of chemotherapy, concurrent with chest radiotherapy, while the control group underwent observation post-cCRT.

Results

• After three years, the OS rate for the atezolizumab group was 44.7% versus 50.3% for the control group. Median OS was approximately six months shorter in the atezolizumab group (33.1 months vs 39.5 months), but this difference was not statistically significant (Hazard Ratio [HR]=1.11; 95% CI: 0.85-1.45).
• Median progression-free survival (PFS) was similar between the two groups: 12 months for the atezolizumab group versus 11.5 months for the control group.
• Median distant metastasis-free survival (DMFS) was 13.2 months in the cCRT group and 16.8 months in the atezolizumab+cCRT group (HR=0.95; 95% CI: 0.75-1.21).
• The cumulative incidence of local recurrence at two years was 13.1% in the atezolizumab group versus 14.4% in the control group (HR=0.84; 95% CI: 0.50-1.40). Approximately 59% of patients in both groups achieved complete response (CR) or partial response (PR).
• Higher rates of grade ≥3 pneumonia were observed in the atezolizumab group (5.6% vs 3.1%), but no major safety signals were reported from combining atezolizumab with chemoradiotherapy.

The trial also indicated that patients who received twice-daily radiotherapy had higher survival rates compared to those receiving once-daily radiotherapy, regardless of atezolizumab treatment. Median OS was 35.4 months for patients receiving twice-daily radiotherapy versus 28.3 months for those receiving once-daily radiotherapy (HR=1.44; 95% CI: 1.10-1.89).

Conclusion and Future Perspectives

Dr. Rosenzweig highlighted that the results of NRG-LU005 bring the question of once-daily versus twice-daily radiotherapy “back to the forefront.” He acknowledged the inconvenience of twice-daily radiotherapy, as it was in the 1990s, but emphasized that based on the trial’s findings, it is “something we should seriously consider again.” Dr. Higgins concluded that twice-daily radiotherapy “should be considered the optimal radiotherapy option for patients with limited-stage SCLC” to give them the “best chance” at successful treatment.

These findings underscore the importance of carefully timing immunotherapy in combination with chemoradiotherapy to maximize survival outcomes for patients with limited-stage SCLC.