Defining the limits of immunotherapy in early small-cell lung cancer

Immunotherapy given during and after chemoradiation did not improve survival for study participants with limited-stage, small-cell lung cancer (SCLC) according to the results of an international clinical trial, NRG-LU005, led by NRG Oncology in collaboration with the Alliance for Clinical Trials in Oncology. The results are published in the Journal of Clinical Oncology.

The trial did not meet its primary endpoint as the addition of the immunotherapy agent atezolizumab to chemotherapy and radiation did not significantly improve survival for those with limited-stage SCLC. However, twice-daily radiation therapy was associated with improved survival in this population.

We are still learning how best to use immunotherapy in limited-stage, small-cell lung cancer. Concurrent immunotherapy with chemoradiotherapy did not improve survival, but we did not find worsened outcomes or unexpected safety signals."

Helen J. Ross, MD, Professor and Director, Research and Clinical Trials, Rush Cancer Center

Ross has also served as co-principal investigator of LU005 and the Alliance lead investigator.

"Radiation was given either once or twice daily based on investigator's choice. Although not randomized, our analysis of the radiation fractionation schedule provides indirect evidence that twice-daily radiation therapy may make a difference in outcomes," Dr. Ross added. "Clinical trials dating to the 1990s showed that twice-daily radiation therapy can improve survival for patients with limited-stage SCLC, but only about 20 percent of patients in the U.S. receive this approach."

Management of limited-stage, small-cell lung cancer has historically relied on chemotherapy delivered concurrently with radiation therapy. While immunotherapy has improved treatment for extensive-stage SCLC, at the time LU005 was developed, it remained unknown whether moving immunotherapy into earlier, potentially curable stages would offer benefit.

The LU005 study was designed to address this question, while also ensuring rigorous radiation quality assurance and broad patient eligibility. Importantly, unlike previous trials that enrolled only patients who completed chemoradiation without progression, LU005 allowed enrollment after a single cycle of chemotherapy, capturing real‑world patients earlier and ensuring that radiation plans could be centrally reviewed.

LU005 enrolled 544 patients between May 2019 and December 2023 across 218 sites in the United States and Japan. Participants were assigned to receive either standard concurrent chemoradiation alone or chemoradiation plus atezolizumab intravenously every three weeks starting with the first study cycle, which was the second cycle of chemotherapy.

Thoracic radiation was delivered using one of two schedules: 45 Gy administered twice daily over three weeks, or 66 Gy administered once daily over six-and-a-half weeks. The primary endpoint of the study was overall survival, with key secondary endpoints including progression‑free survival, distant metastasis‑free survival, objective response rate, local control, and safety.

The addition of atezolizumab did not improve progression-free or overall survival. The median overall survival was 36.1 months in the chemoradiation‑alone arm and 31.1 months in the chemoradiation plus atezolizumab arm. Median progression‑free survival was 11.4 months for chemoradiation alone and 12.1 months for the atezolizumab group.

Both arms demonstrated survival outcomes that exceeded those of earlier landmark trials in this population. The 36.1‑month median overall survival in the standard chemoradiation arm represents one of the longest survival outcomes ever reported in a randomized study in people with limited-stage SCLC.

An interesting finding in LU005 was the consistent survival benefit associated with twice‑daily radiation therapy. Even though twice‑daily radiation is supported by decades of evidence, adoption of the regimen in routine practice remains low, partially due to logistical challenges for patients, caregivers and providers. In LU005, while the choice of fractionation was left to the treating investigators, twice‑daily radiation was associated with substantially better survival than once‑daily radiation, regardless of immunotherapy use.

In the chemoradiation‑alone arm, patients receiving once‑daily radiation had a 51 percent higher risk of death compared to those treated twice daily. A similar trend favoring twice‑daily radiation was also observed in the atezolizumab arm.

"By combining contemporary trial methodology, a robust sample size, and stringent quality assurance requirements, LU005 provides one of the strongest modern validations that 45 Gy delivered twice daily should remain the preferred thoracic radiation schedule for patients with limited-stage SCLC," Dr. Ross said.