Phase 3 LAGOON Trial Fails to Confirm Survival Benefit of Lurbinectedin in Relapsed SCLC

The phase 3 LAGOON trial (NCT05153239) did not meet its primary end 1point of overall survival (OS) in patients with relapsed metastatic small cell lung cancer (SCLC) treated with lurbinectedin (Zepzelca).¹ The trial evaluated lurbinectedin as monotherapy and in combination with irinotecan against investigators' choice of topotecan or irinotecan in the second-line setting. No new safety signals were identified, though the results raise questions about the drug's continued accelerated approval in this indication.

Primary End Point Results

The LAGOON trial enrolled 724 patients across more than 200 sites globally, including sites in the United States, Canada, and Europe, randomized 1:1:1 to 3 treatment arms. Patients received either lurbinectedin 3.2 mg/m² as monotherapy (the approved US dose), lurbinectedin 2.0 mg/m² in combination with irinotecan 75 mg/m², or investigators' choice of topotecan or irinotecan.

Median OS in the overall population was 8.7 months with lurbinectedin monotherapy (n = 240), 10.9 months with the lurbinectedin-irinotecan combination (n = 242), and 10.7 months with the control arm (n = 242). The hazard ratio (HR) for lurbinectedin monotherapy vs control was 1.190 (95% CI, 0.959-1.476), and the HR for the combination vs control was 0.902 (95% CI, 0.729-1.115). Neither comparison reached statistical significance.

Patient Population and Subgroup Findings

An important contextual factor is that LAGOON enrolled a broader population than the phase 2 pivotal trial that supported lurbinectedin's accelerated approval, most notably by including patients with a history of central nervous system (CNS) involvement. When the subgroup without CNS metastases was examined separately, outcomes were more comparable between arms: median OS was 9.6 months with monotherapy, 11.1 months with the combination, and 10.7 months in the control group, with HRs of 1.106 (95% CI, 0.875-1.398) and 0.922 (95% CI, 0.729-1.166), respectively.

Conversely, patients with a history of CNS metastases fared notably worse on lurbinectedin monotherapy. In this subgroup, median OS was 7.1 months with lurbinectedin monotherapy versus 10.3 months in the control arm (HR, 1.791; 95% CI, 1.162-2.760). The combination arm performed more similarly to control in this subgroup (10.5 vs 10.3 months; HR, 1.107; 95% CI, 0.724-1.692).

Safety Profile

The overall safety data were more favorable for lurbinectedin monotherapy than for either the combination arm or the control. Treatment-related adverse events (TRAEs) occurred in 78.5% of patients receiving lurbinectedin monotherapy, compared with 95.0% for the lurbinectedin-irinotecan combination and 93.8% for the control arm. Grade 3 or higher TRAEs were observed in 35.0% of patients in the monotherapy arm, 62.6% in the combination arm, and 64.4% in the control arm.

Regulatory Implications

Lurbinectedin received accelerated approval from the US Food and Drug Administration (FDA) in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy, based on objective response rate and duration of response data from the phase 2 pivotal trial.² The LAGOON trial was conducted as a postmarketing requirement to confirm clinical benefit in that indication.

Jazz Pharmaceuticals has shared the LAGOON results with the FDA and indicated it will discuss next steps regarding its postmarketing requirements for the second-line SCLC indication. The company did not specify whether it would seek voluntary withdrawal or await FDA guidance, and the second-line accelerated approval has not been revoked at the time of this publication.

"Relapsed SCLC is an aggressive cancer with a poor prognosis and patients continue to need treatment options, including in later lines of therapy. We thank the investigators, trial sites and patients who were involved in the LAGOON trial, along with our partner, PharmaMar," said Rob Iannone, MD, MSCE, executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals, in a news release. "[Lurbinectedin] is an important treatment in SCLC and, based on the strength of the IMforte trial [NCT05091567] results, we believe its most beneficial use is in the first-line maintenance setting in combination with immunotherapy given the rapid progression of metastatic SCLC after first-line chemotherapy induction."

Established Approval in First-Line Maintenance Unaffected

The negative LAGOON results do not affect lurbinectedin's full FDA approval for a distinct indication. In October 2025, the FDA granted full approval to lurbinectedin in combination with atezolizumab (Tecentriq) or atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza) as maintenance treatment for adults with extensive-stage SCLC (ES-SCLC) whose disease has not progressed following first-line induction therapy with atezolizumab, carboplatin, and etoposide.

That approval was based on the phase 3 IMforte trial, which demonstrated statistically significant improvements in both OS and progression-free survival (PFS) for the lurbinectedin-atezolizumab combination vs atezolizumab alone as maintenance therapy.³ The combination reduced the risk of disease progression or death by 46% and the risk of death by 27% compared with atezolizumab maintenance alone.

REFERENCES

1. Jazz Pharmaceuticals Provides Update on Zepzelca® (lurbinectedin) Phase 3 LAGOON Trial in Second-Line Small Cell Lung Cancer. News release. Jazz Pharmaceuticals. June 12, 2026. Accessed June 15, 2026. https://tinyurl.com/43kzc4pu

2. FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer. News release. US FDA. June 16, 2020. Accessed June 15, 2026. https://tinyurl.com/5h5rpn92

3. FDA approves lurbinectedin in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs for extensive-stage small cell lung cancer. News release. US FDA. October 2, 2025. Accessed June 15, 2026. https://tinyurl.com/45j99bym