Lurbinectedin Maintenance in SCLC: Insights from the IMforte Trial

The IMforte study (NCT05091567) represents a potentially practice-changing development in the maintenance treatment of extensive-stage small cell lung cancer (SCLC). By randomizing patients who had not progressed on carboplatin-etoposide and atezolizumab (Tecentriq) induction to either lurbinectedin (Zepzelca) plus atezolizumab or atezolizumab alone, the trial demonstrated meaningful improvements in both progression-free survival (PFS) and overall survival (OS), raising important questions about how, and in whom, this regimen should be adopted.

During a live Community Case Forum^TM, Carl Gay, MD, PhD, assistant professor in the Department of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center, walks through the trial design and eligibility criteria, reviews the efficacy and safety data, and offers his perspective on patient selection, including which patients may be poor candidates for indefinite cytotoxic therapy and how clinicians might adapt the regimen in practice.

This is part 2 of a 2-part series.

Register today to join a Case-Based Roundtable near you.

Targeted Oncology: Could you discuss the design of the IMforte study?

Carl Gay, MD, PhD: It's important to remember this is a maintenance design, so when you look at the PFS and OS data, this is from maintenance—not from the initial diagnosis. It's not a head-to-head comparison with the CASPIAN [NCT03043872] or IMpower133 [NCT02763579] regimen. Patients who had not progressed during the induction phase of carboplatin-etoposide and atezolizumab were randomized 1:1 to either lurbinectedin plus atezolizumab every 3 weeks or atezolizumab every 3 weeks and treated until progression or intolerance.¹

What were the eligibility criteria?

A few key eligibility criteria are worth mentioning. Patients had to be newly diagnosed with extensive-stage disease. One thing that may come up in discussion is that this study excluded patients with brain metastases, which is not a trivial subgroup in small cell lung cancer. There were stratification factors including performance status, [lactate dehydrogenase (LDH)], liver metastases, and [prophylactic cranial irradiation (PCI)]—though the application of PCI in the extensive-stage setting is fairly controversial. Those factors were balanced between the 2 groups. Looking at the demographic data for IMforte, the majority of patients on induction therapy had a response—about 88%—which speaks to the remarkable activity of carboplatin-etoposide.

Could you discuss the findings?

Looking at the PFS data, this is PFS from the point of starting maintenance therapy, so approximately 3 months should be added to the beginning. There is a very clear separation of the curves, with a hazard ratio of 0.54—a strong result, representing about a 3-plus month improvement in PFS. I don't think that's surprising; continuing cytotoxic therapy for a chemo-sensitive disease would be expected to offer some progression-free benefit.

OS is the more critical question. Continuing chemotherapy to keep disease at bay is not unexpected, but there is a meaningful [OS] benefit—about a 2.5-month improvement, not unlike what we saw with the addition of tarlatamab [Imdelltra] or lurbinectedin in other settings. If those were considered practice-changing, it seems reasonable that this would be as well. The control arm performed about as expected based on IMpower133, with 10.6 months of [OS]. Adding the maintenance period brings the total to roughly 13 to 14 months, consistent with the original IMpower133 data of 12 to 13 months.

In subgroup analyses, there are no major factors that suggest a group that clearly should or should not receive lurbinectedin. Nearly everything falls to the left, favoring lurbinectedin plus atezolizumab. Liver metastases, which are thought to portend a worse prognosis and may challenge immunotherapy responses, did not appear to attenuate the benefit of lurbinectedin. As expected, continuing cytotoxic therapy produced a higher response rate—almost double—with most responses being partial responses rather than complete responses, but not trivial.

What was the tolerability and safety of the regimen?

Looking at discontinuation rates, there are no major factors that stand out. Most patients who received subsequent therapy went on to chemotherapy. About 6% of patients in the lurbinectedin arm discontinued therapy compared to 3% in the control arm—a slight increase, but lower than many of us anticipated for an indefinite cytotoxic therapy strategy. There were more dose reductions, adjustments, and treatment pauses in the lurbinectedin arm, largely driven by cytopenias, which is expected. Dose adjustments for immunotherapy are rarely needed.

The adverse event [AE] profile is what you would expect. There are AEs specific to cytotoxic therapy that are more common in the lurbinectedin arm—nausea, cytopenias, fatigue—that would not arise with immunotherapy alone. That is the calculus for both physicians and patients: whether this is sustainable long-term. As oncologists, we have extensive experience managing these AEs. Nothing unique emerges here that we haven't seen before or can't manage. The question of whether patients and the health care system are willing to take on that management burden is worth discussing.

Are there any patients you would consider good or bad candidates for the IMforte regimen?

That's a discussion that should come up for every patient. The patients I'm thinking about are those who, "limp to the finish line"—patients where you're not sure they'll make it through 3 or 4 cycles of platinum-etoposide. It's difficult to then recommend that patient start an indefinite cytotoxic regimen. Whether there's benefit in trying it until they fail, vs recognizing early that it's not appropriate to start, is something that will play out over the next year or two as we gain experience with this regimen.

Would you consider starting with immunotherapy alone, waiting for some marrow recovery, and then adding lurbinectedin?

That's a really interesting point. In the IMforte study, there was about a 5-week interval—rather than the usual 3 to 4 weeks—before transitioning to maintenance therapy, giving patients a little extra time for marrow recovery. Whether you would consider adding lurbinectedin at dose 2 or 3 of atezolizumab, if the patient wasn't quite ready at the start but subsequently rebounded, seems clinically reasonable. We don't have data to support or refute that approach, but it makes more sense than starting lurbinectedin in a patient presenting pancytopenic just because the trial protocol called for initiating it with the first dose of maintenance therapy. That's a place for clinical judgment: add it back in once the patient has recovered.

REFERENCE

1. Paz-Ares L, Borghaei H, Liu SV, et al. Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2025 Jun 14;405(10495):2129-2143. doi: 10.1016/S0140-6736(25)01011-6. Epub 2025 Jun 2. PMID: 40473449.