As reported in The Lancet Oncology by Goldman et al, updated results from the phase III CASPIAN trial showed maintained improvement in overall survival with first-line durvalumab plus platinum/etoposide vs platinum/etoposide in patients with extensive-stage small cell lung cancer (SCLC). However, the addition of tremelimumab to durvalumab plus platinum/etoposide did not significantly improve outcomes vs platinum/etoposide.

The trial supported the March 2020 U.S. Food and Drug Administration approval of durvalumab for use in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage SCLC.

Study Details

In the open-label international trial, 805 treatment-naive patients were randomly assigned 1:1:1 between March 2017 and May 2018 to receive durvalumab and tremelimumab plus platinum/etoposide (n = 268), durvalumab plus platinum/etoposide (n = 268), or platinum/etoposide (n = 269). The two primary endpoints were overall survival for durvalumab plus platinum/etoposide vs platinum/etoposide, and overall survival for durvalumab/tremelimumab plus platinum/etoposide vs platinum/etoposide in the intention-to-treat population.

At the previously reported interim analysis, durvalumab plus platinum/etoposide was associated with a significant improvement in overall survival vs platinum/etoposide, with a hazard ratio (HR) of 0.73 (P = .0047). As of data cutoff for the current analysis in January 2020, median follow-up for overall survival in censored patients was 25.1 months (interquartile range = 22.3–27.9 months), representing an additional 11 months of follow-up from the interim analysis. For the primary overall survival analysis of durvalumab/tremelimumab plus platinum/etoposide vs platinum/etoposide, statistical significance was set at a P value < .0418.

Overall Survival

In the primary analysis, median overall survival was 10.4 months (95% confidence interval [CI] = 9.6­–12.0 months) in the durvalumab/tremelimumab plus platinum/etoposide group vs 10.5 months (95% CI = 9.3–11.2 months) in the platinum/etoposide group (HR = 0.82, 95% CI = 0.68­–1.00; P = .045).

In the updated analysis, median overall survival was 12.9 months (95% CI = 11.3–14.7 months) in the durvalumab plus platinum/etoposide group vs 10.5 months (95% CI = 9.3–11.2 months) in the platinum/etoposide group (HR = 0.75, 95% CI = 0.62–0.91; nominal P = .0032).

Overall survival at 18 months was 30.7% (95% CI = 25.2%–36.4%) in the durvalumab/tremelimumab plus platinum/etoposide group and 32.0% (95% CI = 26.5%–37.7%) in the durvalumab plus platinum/etoposide group vs 24.8% (95% CI = 19.7%–30.1%) in the platinum/etoposide group. In post hoc analyses, 12- and 24-month overall survival rates were 43.8%, 52.8%, and 39.3%, respectively, and 23.4%, 22.2%, and 14.4%, respectively.

Progression-Free Survival and Response Rates

Median progression-free survival was 4.9 months (95% CI = 4.7–5.9 months) in the durvalumab/tremelimumab plus platinum/etoposide group (HR = 0.84, 95% CI = 0.70–1.01 vs platinum/etoposide group), 5.1 months (95% CI = 4.7–6.2 months) in the durvalumab plus platinum/etoposide group (HR = 0.80, 95% CI = 0.66­–0.96 vs platinum/etoposide group), and 5.4 months (95% CI = 4.8–6.2 months) in the platinum/etoposide group. Rates at 6 and 12 months were 43.2%, 45.4%, and 45.8%, respectively, and 16.9%, 17.9%, and 5.3%, respectively. At post hoc analysis, rates at 24 months were 11.5%, 11.0%, and 2.9%, respectively.

In post hoc analyses, confirmed objective response was observed in 58% of the durvalumab/tremelimumab plus platinum/etoposide group (odds ratio [OR] = 1.02, 95% CI = 0.72–1.44 vs platinum/etoposide group), 68% of the durvalumab plus platinum/etoposide group (OR = 1.53, 95% CI = 1.08–2.18 vs platinum/etoposide group), and 58% of the platinum/etoposide group. The estimated percentages of responders remaining in response at 12 and 24 months were 24.9%, 23.2%, and 7.3%, respectively, and 17.2%, 13.5%, and 3.9%, respectively.

Safety Profiles

Safety profiles of the study regimens were consistent with those previously reported. The most common grade ≥ 3 adverse events in the three groups were neutropenia (32%, 24%, and 33%) and anemia (13%, 9%, and 18%). Serious adverse events were reported in 45%, 32%, and 36% of patients. Treatment-related deaths occurred in 5%, 2%, and 1% of patients.

The investigators concluded: “First-line durvalumab plus platinum/etoposide showed sustained overall survival improvement vs platinum/etoposide, but the addition of tremelimumab to durvalumab plus platinum/etoposide did not significantly improve outcomes vs platinum/etoposide. These results support the use of durvalumab plus platinum/etoposide as a new standard of care for the first-line treatment of extensive-stage SCLC.”

Luis Paz-Ares, MD, of the Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by AstraZeneca. For full disclosures of the study authors, visit thelancet.com.