Elsevier

The Lancet

Volume 394, Issue 10212, 23–29 November 2019, Pages 1929-1939
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(19)32222-6Get rights and content

Summary

Background

Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum–etoposide) in treatment-naive patients with ES-SCLC.

Methods

This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum–etoposide; durvalumab plus tremelimumab plus platinum–etoposide; or platinum–etoposide alone. All drugs were administered intravenously. Platinum–etoposide consisted of etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL per min or cisplatin 75–80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum–etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum–etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum–etoposide group versus the platinum–etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing.

Findings

Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum–etoposide group and 269 to the platinum–etoposide group. Durvalumab plus platinum–etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59–0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5–14·8) in the durvalumab plus platinum–etoposide group versus 10·3 months (9·3–11·2) in the platinum–etoposide group, with 34% (26·9–41·0) versus 25% (18·4–31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum–etoposide group and 166 (62%) of 266 in the platinum–etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.

Interpretation

First-line durvalumab plus platinum–etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received.

Funding

AstraZeneca.

Introduction

Small-cell lung cancer (SCLC) accounts for 13–17% of all diagnosed cases of lung cancer and is characterised by rapid proliferation, high growth fraction, and early development of widespread metastases.1, 2 Less than 7% of patients with SCLC remain alive at 5 years after diagnosis.2, 3 Extensive-stage SCLC (ES-SCLC) accounts for about two-thirds of all cases of SCLC.1 For more than three decades, the standard first-line treatment has consisted of etoposide plus either cisplatin or carboplatin (platinum–etoposide), with few alternatives.4, 5, 6, 7 Despite initial response rates of up to 78% for patients treated with platinum–etoposide,8, 9 most patients relapse within 6 months of completing initial treatment and median overall survival is about 10 months.4, 8, 10 Outside of Japan, the current standard-of-care treatment in the second-line setting is topotecan,5, 6 which is associated with poor outcomes (response rates of 5% and a 1-year survival rate of 9% in patients with platinum-refractory disease),11 emphasising the significant unmet need for improved first-line therapies.

Research in context

Evidence before this study

We searched PubMed on July 8, 2019, for clinical trials published in English with the terms “PD-1” OR “PD-L1” OR “pembrolizumab” OR “nivolumab” OR “atezolizumab” OR “durvalumab” OR “avelumab” AND “extensive-disease” OR “extensive-stage” AND “first-line” OR “previously untreated” OR “treatment-naive” AND “small-cell lung cancer” OR “SCLC”, selecting relevant publications published within the past 5 years (Jan 1, 2014, to July 8, 2019). We also searched the abstracts from the 2018 and 2019 American Society of Clinical Oncology Annual Meetings, the 2018 European Society for Medical Oncology Congress, and the 2018 World Conference on Lung Cancer using the same search terms. We identified one study of atezolizumab plus carboplatin–etoposide (IMpower133), which indicated the therapeutic value of immunotherapy targeting the programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) pathway to treat patients with extensive-stage small-cell lung cancer (ES-SCLC) in the first-line setting.

Added value of this study

The phase 3, randomised, open-label CASPIAN study showed a statistically significant improvement in overall survival (primary study endpoint) with first-line durvalumab and etoposide plus either cisplatin or carboplatin (platinum–etoposide) versus platinum–etoposide alone in patients with ES-SCLC at a planned interim analysis. To our knowledge, this is the first phase 3 study of anti-PD-1 or anti-PD-L1 in patients with ES-SCLC that permitted the use of investigator's choice of either cisplatin or carboplatin as the platinum component in platinum–etoposide and that allowed up to six cycles of platinum–etoposide (consistent with routine clinical practice) in the control group, compared with four cycles in the durvalumab plus platinum–etoposide group.

Implications of all the available evidence

In CASPIAN, the addition of durvalumab to platinum–etoposide as first-line treatment for patients with ES-SCLC resulted in consistent and durable clinical benefit across overall survival, progression-free survival, and objective response, compared with a clinically relevant control group that is reflective of current global clinical practice for this challenging-to-treat disease. Our results align with those from the IMpower133 trial of atezolizumab plus carboplatin–etoposide, while providing significant progress in offering the flexibility of platinum choice in combination with immunotherapy, expanding treatment options for patients and physicians.

Immunotherapy targeting the programmed cell death 1 (PD-1, also known as PDCD1) and programmed cell death ligand 1 (PD-L1, also known as CD274) pathway has demonstrated clinical activity for patients with ES-SCLC, including as first-line treatment.12 Durvalumab, a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80,13 is indicated for the treatment of patients with unresectable, stage 3 non-small-cell lung cancer following platinum-based chemoradiotherapy.14, 15, 16, 17 In early-phase clinical trials, durvalumab, both as monotherapy and in combination with the anti-cytotoxic T lymphocyte-associated antigen-4 antibody, tremelimumab, showed durable clinical activity and a manageable safety profile in patients with pretreated ES-SCLC, including those with relapsed or refractory disease.18, 19, 20

In CASPIAN, we assessed the efficacy and safety of durvalumab, with or without tremelimumab, in combination with platinum–etoposide for the first-line treatment of patients with ES-SCLC. We report results from a planned interim analysis of overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide alone; the durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide alone comparison is proceeding to final analysis.

Section snippets

Study design

This randomised, open-label, sponsor-blind, phase 3 trial was performed at 209 sites in 23 countries across Europe, Asia, North America, and South America. The study was done in accordance with the International Conference on Harmonisation good clinical practice guidelines, the Declaration of Helsinki, and applicable local regulations with approval from an independent ethics committee or institutional review boards. The protocol and all modifications were approved by relevant ethics committees

Results

Between March 27, 2017, and May 29, 2018, 972 patients were screened, of whom 167 were excluded and 805 were randomly assigned to durvalumab plus platinum–etoposide (n=268), durvalumab plus tremelimumab plus platinum–etoposide (n=268), and platinum–etoposide alone (n=269; figure 1). At the time of the planned interim overall survival analysis, the independent data monitoring committee recommended that the durvalumab plus platinum–etoposide and platinum–etoposide groups be unmasked to the

Discussion

The CASPIAN trial met its primary endpoint of overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide at the planned interim analysis. Durvalumab plus platinum–etoposide demonstrated a statistically significant and clinically meaningful improvement in overall survival versus platinum–etoposide alone, with an HR of 0·73 (95% CI 0·59–0·91; p=0·0047). Overall survival benefit was observed across all clinically relevant patient subgroups. Consistent with the results for

Data sharing

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy.

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    A complete list of investigators who enrolled patients in CASPIAN is provided in the appendix (pp 2–3)

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