Early approval of Jazz Pharmaceuticals’ small cell lung cancer (SCLC) drug Zepzerka may be in jeopardy again.
Jazz said Friday that the Phase 3 Lagoon trial failed in its primary endpoint of overall survival.
This trial tested Zepzerka alone or in combination with irinotecan (Camptosar) as a second-line treatment for metastatic SCLC. As a comparison group, the researchers chose either topotecan (hycamtin) or irinotecan. Besides Zepzerka, the three drugs involved in this study are chemotherapy.
A Phase 3 failure would jeopardize Zepzerka’s initial FDA approval, an accelerated approval it received six years ago for previously treated SCLC based on tumor regression data from a single-arm Phase 2 trial.
Since then, a phase 3 trial called Atlantis, which was supposed to be a confirmatory trial for the indication, showed no overall survival benefit for Zepzerka and doxorubicin compared with physician’s choice chemotherapy for second-line SCLC.
The FDA allowed Zepzelka to remain on the market despite the debacle. In rejecting a citizen petition to halt the drug’s use in 2022, the agency noted that the Atlantis study used a lower dose of Zepzerka than the approved version and that there is an unmet medical need in second-line SCLC.
Turning to the current Lagoon study, zepzerka monotherapy was tested at its currently approved strength, while irinotecan combination therapy used a lower dose.
Results for Zepzerka monotherapy were even worse than the control group, with a 19% higher risk of death, Jazz said. Median survival for patients receiving Zepzerka alone was 8.7 months, compared to 10.7 months for patients in the control group.
Zepzerka irinotecan showed a small numerical improvement in overall survival of 9.8%, but it did not meet statistical significance, according to Jazz.
In its final pitch, Jazz noted in a June 12 press release that the Lagoon trial was conducted in a broader patient population than the original Phase 2 trial by including patients with a history of brain metastases.
“Zepzerka’s efficacy in selected patients without a history of central nervous system disease was comparable to the control group and outperformed its historical predecessor,” the company said.
Even in patients without brain metastases, results with single-agent Zepzerka were worse than controls. Within this subgroup, patients who received Zepzerka monotherapy had a median survival of 9.6 months, which was shorter than the 10.7 months recorded in the control group. Results were slightly better in the zepzerka-irinotecan group, with a median overall survival of 11.1 months and an improved risk of death of only 7.8%.
Interestingly, the magnitude of mortality risk reduction with the Zepzelca combo was better in the overall population than in patients with and without CNS metastases. The anomaly occurred because the overall analysis used stratified analysis, but not the individual subgroups, Jazz told Fierce.
Jazz said it would share Lagoon’s results with the FDA and discuss next steps with the agency regarding second-line indications. The company licensed the U.S. rights to Zepzelca from PharmaMar, which conducted the Lagoon trial.
The failure of the second line will not affect Zepzerka’s other FDA green light. Full approval granted in 2025 allows Zepzerka in combination with Roche’s Tecentriq as first-line maintenance therapy for patients with advanced SCLC. In the Phase 3 IMforte trial, the combination significantly reduced the risk of death by 27% compared to Tecentriq alone.
For the Jazz, Zepzelka’s sales in the first quarter of 2026 were $101 million, up 60% year-over-year. The company cited the prevalence of first-line maintenance settings as a key driver of growth, “partially offset by reduced second-line usage.”
In late 2025, the FDA reversed its previous conditional approval and granted traditional approval to Amgen’s T-cell engager Imdeltora for previously treated advanced-stage SCLC.
During Jazz’s first-quarter earnings call in May, Chief Commercial Officer Samanta Pearce said the company expects second-line use of Zepzerka to continue to decline “due to competition and a decline in Zepzerka-naive patients.”
The company said Friday that the Lagoon failure does not affect its 2026 outlook.
