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Zepzelca Plus Tecentriq Boosts Survival in First-Line ES-SCLC Care

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Key Takeaways

  • Zepzelca plus Tecentriq improved PFS and OS in ES-SCLC patients compared to Tecentriq alone, with a median PFS of 5.4 months versus 2.1 months.
  • The combination therapy showed a median OS of 13.2 months, compared to 10.6 months with Tecentriq monotherapy, indicating a clinically meaningful benefit.
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Among patients with ES-SCLC, first-line maintenance therapy with Zepzelca plus Tecentriq led to improvements in PFS and OS versus Tecentriq alone.

First-line Zepzelca plus Tecentriq led to survival improvements versus Tecentriq alone in patients with ES-SCLC: © stock.adobe.com.

First-line Zepzelca plus Tecentriq led to survival improvements versus Tecentriq alone in patients with ES-SCLC: © stock.adobe.com.

Among patients with extensive-stage small cell lung cancer (ES-SCLC), first-line maintenance therapy with Zepzelca (lurbinectedin) combined with Tecentriq (atezolizumab) led to improvements in both progression-free survival (PFS) and overall survival (OS) compared with Tecentriq alone, according to primary findings from the phase 3 IMforte trial which were shared at the 2025 ASCO Annual Meeting.

The median PFS with the doublet (242 patients treated) was 5.4 months by independent review facility (IRF) assessment versus 2.1 months with the monotherapy (241 patients treated), translating to a 46% reduction in the risk of disease progression or death. The six-month IRF-PFS rates in the respective arms were 41.2% and 18.7%; at 12 months, these rates were 20.5% and 12.0%.

A clinically meaningful OS benefit was also observed with the addition of Zepzelca to Tecentriq versus Tecentriq alone, at a median of 13.2 months versus 10.6 months, respectively. The 12-month OS rate with the doublet was 56.3% versus 44.1% with the monotherapy.

“IMforte is the first phase 3 study to show PFS and OS improvement with first-line maintenance treatment for ES-SCLC, highlighting the potential of Zepzelca plus Tecentriq to become a new standard of care [SOC] for first-line maintenance therapy in patients with this aggressive and difficult-to-treat disease,” Dr. Luis Paz-Ares, of Hospital Universitario 12 de Octubre, H12O-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc, in Madrid, Spain, said in a press briefing ahead of the meeting.

Underscoring the Unmet Need

Glossary

Overall survival (OS): the length of time from either the date of diagnosis or the start of treatment for a disease that patients diagnosed are alive.

Progression-free survival (PFS): the length of time during and after the treatment that a patient lives with the disease but it does not get worse.

Overall response rate (ORR): the proportion of patients who have a partial or complete response to therapy.

ECOG performance status: describes a patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability.

Myelosuppression: the decrease in production of cells responsible for providing immunity, carrying oxygen and normal blood clotting.

Febrile neutropenia: the development of fever, often with other signs of infection, in a patient with neutropenia.

SCLC represents approximately 15% of all lung cancer cases, and 70% of these cases are extensive-stage disease, according to Paz-Ares. For these patients, SOC treatment is comprised of induction etoposide, platinum, and an immune checkpoint inhibitor (ICI) in the form of Tecentriq or Imfinzi (durvalumab), followed by maintenance treatment with the same ICI. Although patients respond to induction, many will experience early disease progression and poor survival. Earlier phase trials have shown that when Zepzelca is paired with ICIs, it is active with favorable tolerability.

Shining a Light on IMforte: Eligibility, Treatment, End Points

The global, open-label, randomized, phase 3 trial enrolled patients with ES-SCLC who had not previously received systemic treatment, who did not have central nervous system metastases, and who have an ECOG performance status of 0 or 1 (660 patients). They received induction treatment with Tecentriq plus carboplatin and etoposide for four cycles every three weeks.

Patients were screened again and those with an ongoing complete response/partial response or stable disease after induction treatment and an ECOG performance status of 0 or 1 went on to receive maintenance treatment (483 patients). These patients were randomly assigned to receive 1200 mg of intravenous Tecentriq every three weeks with or without 3.2 mg/m2 of Zepzelca. Treatment continued until disease progression or intolerable toxicity.

Notably, no crossover was allowed. Patients were stratified by performance status (zero versus one), lactate dehydrogenase (≤ upper limit of normal [ULN] versus > ULN), liver metastases at baseline induction (yes versus no), and receipt of prophylactic cranial irradiation (yes versus no).

The trial’s primary end points were IRF-PFS and OS, and secondary end points comprised investigator-assessed PFS, objective response rate, duration of response and safety. Efficacy was evaluated from randomization into the maintenance phase of the design. Investigators assessed safety from day one of cycle one of treatment.

Additional Efficacy Revelations

Investigator-assessed PFS aligned with what was reported with regard to IRF assessment. The median PFS with Zepzelca plus Tecentriq was 5.4 months versus 2.7 months with Tecentriq monotherapy.

Safety Spotlight

All-cause side effects were reported in 97.1% of those on the combination arm versus 80.8% of those on the monotherapy arm, with 38.0% and 22.1% of these respective effects being grade 3 (serious; interferes with a person's ability to do basic things) or 4 (severe; requires hospitalization). Treatment-related grade 3 or 4 side effects were experienced by more patients in the investigative arm versus those in the control arm, at 25.6% versus 5.8%, respectively.

Twelve patients who received the doublet experienced grade five (death) side effects versus six patients who received the monotherapy; they were treatment related for two patients in the investigative arm and one patient in the control arm. More serious side effects occurred with the doublet versus the monotherapy (31.0% versus 17.1%).

Side effects led to dose interruption or modification of any drug for 38.0% of those in the investigative arm versus 13.8% of those in the control arm; they led to discontinuation of any drug for 6.2% and 3.3% of patients, respectively.

“The safety profile of Zepzelca plus Tecentriq was manageable, with mostly low-grade AEs and low treatment discontinuation rates,” Paz-Ares said. “No clinically meaningful increase in immune-related [side effects] was observed [with the addition of Zepzelca],” he noted.

The most common side effects experienced by at least 10% of those in the Zepzelca/Tecentriq and Tecentriq-alone arms were nausea (36.4% verus 4.2%), anemia (31.8% verus 6.7%), fatigue (20.2% verus 7.9%), decreased appetite (16.9% verus 6.7%), decreased platelet count (15.3% verus 2.9%), diarrhea (14.0% verus 7.5%), vomiting (13.6% verus 2.5%), asthenia (12.8% verus 6.3%), thrombocytopenia (12.8% verus 1.7%), decreased neutrophil count (12.8% verus 1.3%), constipation (12.0% verus 6.3%) and neutropenia (10.7% verus 1.7%).

“You see a clear increase for those patients treated with Zepzelca/Tecentriq, particularly [side effects] related to the Zepzelca — nausea, vomiting, diarrhea, asthenia, and also some more myelosuppression,” Paz-Ares noted. “Concerning myelosuppression, that was one of the main concerns, we have seen febrile neutropenia only in 1.7% of cases.”

He added that grade 3 or 4 infections and infestations occurred in 6.6% of those who received the doublet versus 5.0% of those who were given the monotherapy.

Topline Takeaway

“I think it’s important to note that at least in the United States, Zepzelca is FDA approved in the second-line setting, and so, with the results of this study, we would anticipate that it would be moved into the first-line maintenance setting — so, moving it into an earlier line before there is progression on the first-line therapy,” Dr. Julie R. Gralow, chief medical officer and executive vice president of ASCO, commented. “The study is important because both PFS and OS were increased. But I would point out, while this is a next step, PFS is still quite low in both arms, and we need to work on additional ways of advancing this even further. So, it is a small next step; it is extending the time that the tumor doesn’t progress and the amount of time that the patients are living, but we need to do more research in ES-SCLC, as well.”

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