Immunotherapy Should Come After Radiation in SCLC

WASHINGTON — Timing matters when it comes to combining immunotherapy with chemoradiation in limited-stage small cell lung cancer (SCLC), according to the phase 3 NRG-LU005 trial presented at the American Society for Radiation Oncology (ASTRO) 2024 Annual Meeting.

Investigators did not find a significant survival benefit among patients who received atezolizumab simultaneously with chemoradiation compared with those who received chemoradiation alone.

The recent findings follow those from the ADRIATIC trial, which found that starting durvalumab, another programmed death-ligand 1 inhibitor, several weeks after the end of chemoradiation extended median overall survival by 22.5 months over chemoradiation alone — 56 months vs 33.5 months — in limited-stage SCLC.

NRG-LU005’s principal investigator Kristin Higgins, MD, did not think the survival outcomes between the two trials differed because durvalumab works better than atezolizumab; both have strong records in SCLC. Rather, radiation — a known immunosuppressive — likely tamped down the immune response needed for atezolizumab to work, indicating that the immune system may require time to recover from radiation before giving immunotherapy, Higgins explained.

The takeaway is that giving immunotherapy concurrently with chemoradiation “is not the way to go,” said Higgins, a radiation oncologist at City of Hope Cancer Center Atlanta, Newnan, Georgia. “We need to give it after completion of chemoradiation.”

Study discussant Kenneth Rosenzweig, MD, chair of radiation oncology at Mount Sinai School of Medicine, New York City, agreed that “the timing of immunotherapy is crucial.”

In the current open-label, randomized study, patients had received one cycle of chemotherapy (platinum/etoposide) before trial registration and were then randomized 1:1 to concurrent chemoradiation (n = 270) or concurrent chemoradiation plus atezolizumab 1200 mg intravenous (n = 274).

Patients had Tx-4, N0-3, M0 disease and were stratified by chemotherapy (cisplatin or carboplatin), radiation fractionation schedule (66 Gy once daily vs 45 Gy twice daily), sex, and performance status (0-1 vs 2).

Among patients receiving atezolizumab, the agent was given every 3 weeks for a maximum of 17 cycles (or about 1 year) until progression or intolerable side effects. Atezolizumab therapy began during the second of four cycles of chemotherapy, the same point when thoracic radiation began. In the control arm, patients received chemoradiation followed by observation.

At 3 years, the overall survival rate was 44.7% in the atezolizumab group vs 50.3% in the control arm. Median overall survival was about 6 months shorter in the atezolizumab group — 33.1 months vs 39.5 months in the control group — but the difference was not significant (hazard ratio [HR], 1.11; 95% CI, 0.85-1.45).

Median progression-free survival was similar in both groups — 12 months with atezolizumab vs 11.5 months without. The cumulative incidence of local failure at 2 years was 13.1% with atezolizumab vs 14.4% without (HR, 0.84; 95% CI, 0.50-1.40). A complete or partial response was achieved in about 59% of both groups.

Grade 3 or higher pneumonitis was more prevalent in the atezolizumab group (5.6% vs 3.1%), but the researchers reported no concerning safety signals for atezolizumab plus chemoradiation.

However, the trial found that giving radiation twice a day instead of once improved survival, regardless of whether patients received atezolizumab. Among the 47.2% of patients who had twice-daily radiation, median overall survival was 35.4 months vs 28.3 months in those who received once-daily radiation (HR, 1.44; 95% CI, 1.10-1.89).

Rosenzweig said the results put the question of once-daily vs twice-daily radiation “back on the table.”

Twice-a-day radiation is “still just as inconvenient as it was in the 90s” when the issue debated, but it’s “something we should strongly look at again” given the trial results, Rosenzweig said.

To give patients “the best shot,” Higgins said, twice-daily radiation “should be considered the optimal radiation choice for patients with limited-stage small cell lung cancer.”

The work was funded by the National Cancer Institute and Genentech/Roche, maker of atezolizumab. Higgins is an advisor/consultant to AstraZeneca, Regeneron, Janssen, and Picture Health. Rosenzweig had no disclosures.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected].