As reported in The Lancet Oncology by Jonathan W. Goldman, MD, of the David Geffen School of Medicine at University of California Los Angeles, and colleagues, updated results from the phase III CASPIAN trial show maintained improvement in overall survival with first-line durvalumab plus platinum/etoposide (EP) vs EP in patients with extensive-stage small–cell lung cancer (SCLC).¹ In a primary overall survival analysis, no significant benefit vs EP was observed with the addition of tremelimumab to the durvalumab regimen.

Jonathan W. Goldman, MD

The trial supported the March 2020 approval of durvalu-mab for use in combination with etoposide and either carboplatin or cisplatin for 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 plus tremelimumab plus EP (n = 268), durvalumab plus EP (n = 268), or EP (n = 269). The two primary endpoints were overall survival for durvalumab plus EP vs EP and for durvalumab/tremelimumab plus EP vs EP in the intention-to-treat population.

At the previously reported interim analysis,² durvalumab plus EP was associated with a significant improvement in overall survival vs EP, with a hazard ratio 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 for durvalumab/tremelimumab plus EP vs EP, 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 EP group vs 10.5 months (95% CI = 9.3–11.2 months) in the EP group (hazard ratio [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 EP group vs 10.5 months (95% CI = 9.3–11.2 months) in the EP 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 EP group and 32.0% (95% CI = 26.5%–37.7%) in the durvalumab plus EP group vs 24.8% (95% CI = 19.7%–30.1%) in the EP 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 EP group (HR = 0.84, 95% CI = 0.70–1.01 vs EP group), 5.1 months (95% CI = 4.7–6.2 months) in the durvalumab plus EP group (HR = 0.80, 95% CI = 0.66–0.96 vs EP group), and 5.4 months (95% CI = 4.8–6.2 months) in the EP 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. In 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 EP group (odds ratio [OR] = 1.02, 95% CI = 0.72–1.44, vs EP group), 68% of the durvalumab plus EP group (OR = 1.53, 95% CI = 1.08–2.18 vs EP group), and 58% of the EP 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% (death, febrile neutropenia, and pulmonary embolism in two each and enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death in one each), 2% (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis in one each), and 1% of patients (pancytopenia and thrombocytopenia in one each).

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.” 

DISCLOSURE: The study was funded by AstraZeneca. Dr. Goldman has served in a consulting or advisory role for Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Clovis Oncology, Genentech/Roche, Lilly, Trovagene, and Vortex Biosciences; has participated in a speakers’ bureau for Merck; has received institutional research funding from AbbVie, Advaxis, Array BioPharma, AstraZeneca/MedImmune, Bristol Myers Squibb, Corvus Pharmaceuticals, Genentech/Roche, Lilly, and Spectrum Pharmaceuticals; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca.

REFERENCES

1. Goldman JW, Dvorkin M, Chen Y, et al: Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): Updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. December 4, 2020 (early release online).

2. Paz-Ares L, Dvorkin M, Chen Y, et al: Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): A randomised, controlled, open-label, phase 3 trial. Lancet 394:1929-1939, 2019.