The accelerated approval for Jazz Pharmaceuticals’ small cell lung cancer (SCLC) drug Zepzelca may once again be in jeopardy.
Friday, Jazz said the phase 3 Lagoon trial has failed on its primary endpoint of overall survival.
The trial tested Zepzelca either alone or in combination with irinotecan (Camptosar) as a second-line treatment for metastatic SCLC. For the comparator arm, investigators chose between topotecan (Hycamtin) or irinotecan. Besides Zepzelca, the three agents involved in the study are chemotherapy.
The phase 3 flop threatens Zepzelca’s initial FDA go-ahead—an accelerated approval earned six years ago in previously treated SCLC based on tumor shrinkage data from a phase 2 single-arm study.
Since then, what was originally meant to be the indication’s confirmatory trial, a phase 3 called Atlantis, failed to show an overall survival benefit for Zepzelca and doxorubicin compared with physician’s choice of chemotherapy in second-line SCLC.
The FDA allowed Zepzelca to stay on the market despite the flop. In rebuffing a citizen petition calling for the drug’s withdrawal in 2022, the agency noted that the Atlantis study used a lower dose of Zepzelca than its approved version, and that an unmet medical need exists in second-line SCLC.
Moving to the current Lagoon study, Zepzelca monotherapy was tested at its currently approved strength, while its irinotecan combo used a lower dose.
According to Jazz, Zepzelca monotherapy performed even worse than the control arm, with a 19% higher risk of death. Patients who got Zepzelca alone lived a median 8.7 months, versus 10.7 months for those in the control arm.
Zepzelca-irinotecan showed a numerical but marginal overall survival benefit with a 9.8% improvement, which didn’t meet statistical significance, according to Jazz.
In a last-ditch pitch, Jazz noted in its June 12 press release that by including patients with a history of brain metastases, the Lagoon trial was conducted in a broader patient population than the drug’s original phase 2 study.
“Efficacy of Zepzelca in the subset of patients without a history of CNS involvement was more comparable to the control arm, which performed better than historical precedent,” the company said.
Even in patients without brain metastases, single-agent Zepzelca did worse than control. Within this subgroup, those who got Zepzelca monotherapy lived a median 9.6 months, shorter than the 10.7 months recorded in the control arm. The Zepzelca-irinotecan group did slightly better with a median overall survival of 11.1 months and a small 7.8% improvement in death risks.
Interestingly, the magnitude of Zepzelca combo’s death-risk reduction was better in the overall population than in patients with and those without CNS metastases. The overall analysis used stratified analysis, while the individual subgroups used unstratified analysis, causing the anomaly, Jazz told Fierce.
Jazz said it has shared the Lagoon results with the FDA and will discuss next steps with the agency regarding the second-line indication. The company licensed U.S. rights to Zepzelca from PharmaMar, which conducted the Lagoon trial.
The second-line flop won’t affect Zepzelca’s other FDA go-ahead. In a full approval granted in 2025, Zepzelca in combination with Roche’s Tecentriq is allowed as first-line maintenance treatment for patients with extensive-stage SCLC. In the phase 3 IMforte trial, the combo significantly reduced the risk of death by 27% compared with Tecentriq alone.
For Jazz in the first quarter of 2026, Zepzelca sales jumped 60% year over year to $101 million. The company cited uptake in the first-line maintenance setting as the main driver of growth, which was “partially offset by a decline in second line use.”
In late 2025, the FDA granted traditional approval to Amgen’s T-cell engager Imdelltra in previously treated extensive-stage SCLC, converting a previous conditional nod.
During Jazz’s first-quarter earnings call in May, Chief Commercial Officer Samantah Pearce said the company expects continued decline in Zepzelca’s second-line use “due to competition and fewer Zepzelca-naïve patients.”
The company said Friday that the Lagoon fail do not impact its 2026 guidance.