Evaluating Which Patients Benefit From Maintenance Chemo in ES-SCLC

Extensive-stage small cell lung cancer (ES-SCLC) often responds to frontline therapy but more research is being done on how to best maintain this response and proceed with additional therapy. At a Community Case Forum event in Frisco, Texas, Wade T. Iams, MD, MSCI, director of lung cancer research at Greco-Hainsworth Centers for Research of Tennessee Oncology, reviewed the outcomes of the phase 3 IMforte trial (NCT05091567). After discussing the efficacy and safety findings from this trial, Iams considered questions brought up by the trial about distinguishing the benefit of lurbinectedin (Zepzelca) maintenance compared with giving it in the second line and determining the cost vs benefit of an additional therapy for these patients.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: What can be interpreted from the subsequent therapies given in the IMforte trial?

Wade T. Iams, MD, MSCI: Any time you have a survival benefit…of 2.5-to-3-month improvement in overall survival [OS], a key question is, what subsequent therapies did the control group and the intervention group get? Looking at the subsequent therapies, there was a 10% increase in receipt of subsequent therapy; 55% of patients in the atezolizumab [Tecentriq] group got subsequent therapy vs 45% in the lurbinectedin plus atezolizumab group.¹ [There was] a little bit of a shift there, but with the key caveat that very few of the patients in the atezolizumab group received lurbinectedin subsequently. Only about 10% of patients in the atezolizumab group got lurbinectedin because it was an international study where lurbinectedin was not significantly available.

How do you know if adding lurbinectedin as maintenance improves OS vs giving it in the second line?

The answer is, we don’t know. Only 10% of patients in the atezolizumab arm got lurbinectedin on relapse, so that’s frustrating that we don’t have the answer to the difference that sequencing would make. I was at Vanderbilt [University Medical Center] for 6 years with thoracic medical oncology…and my main research was in circulating tumor DNA [ctDNA] in SCLC, trying to think about ways that could help in the clinic to use ctDNA. We don’t use ctDNA in SCLC, so we put together a subset of patients, and we would try to collect longitudinal ctDNA in all our patients with SCLC. [When] we analyzed ctDNA longitudinally in ES-SCLC, 70% of patients with ES-SCLC still had detectable ctDNA after 4 cycles.² Biomarker studies are hard to get done…but someone who has minimal residual disease [MRD] may be the one who benefits from escalating therapy at that point. Something that like that would be interesting.

It goes back to the study design. It makes sense to give the trial compounds to the patients who would have qualified for the trial. Patients who would have fallen off at this point are not appropriate for maintenance lurbinectedin, but speculating percentage-wise in our clinic, what percent of patients are getting to this point where they would be a trial candidate after they finish 4 cycles of chemotherapy/immunotherapy? I’ve had this discussion in different contexts. In Nashville, I would say 60% to 70%; in Memphis, they felt like the percentage may be lower there. I think it just depends on the general comorbidities and the patient population of the area.

What rationale is there to use lurbinectedin as maintenance chemotherapy, as opposed to continuing carboplatin?

I think we’re treating MRD that’s present in enough patients to drive a progression-free survival and OS [benefit]. I would hypothesize potentially this is just because it’s a different mechanism, but I think of this as a lighter chemotherapy. We’re treating MRD, and that’s enough to push the curves in all comers. I wish we could identify which patients had the MRD that we needed to treat. There may be something to the change of mechanism and retreating MRD, but it could be similar if you just did more of the platinum doublet.

How can you ensure the benefit is worth the cost of added therapy?

I think that’s an important point. ctDNA studies [done] prospectively are the ideal [solution] because in big groups, they take away treatment from the patients who don’t need it, and they give it to patients

who do need it.

It’s a small, marginal benefit, for sure. The other direction on ctDNA [is that] we’re getting to a point where, for the time being, the next-generation sequencing companies have sold their data anonymously to pharmaceutical [companies]…not charging people. But at some point, that’s going to end, and what’s the [cost] going to be?

The other perspective that I think is interesting is, could we have better biomarkers for SCLC subtypes that determine response? There are 2 neuroendocrine subtypes that are more chemo-sensitive and 2 non-neuroendocrine subtypes that are much less common.³ It makes sense when we think about platinum response being so high. But I also wonder if we could look at the SCLC subtypes, and potentially patients who still had a chemo-sensitive subtype at completion of induction could be included here.

[My research was] looking at circulating tumor cells post 4 cycles of chemoimmunotherapy to see who still had the neuroendocrine subtype and who transformed to non-neuroendocrine subtype.⁴ Because over time in SCLC, there are some data from MD Anderson Cancer Center showing subtypes change over time as you expect, and they change to non-neuroendocrine chemo-resistant sometimes, which we know intuitively from seeing these patients’ trajectory; they become chemo-resistant.³ I don’t know that we’ll have a biomarker that’s able to better guide us, but that’s the best I can do for ways to make it more cost effective.

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DISCLOSURES: Iams previously reported consulting or advisory role with Sanofi, Elevation Oncology, AstraZeneca, NovoCure, Catalyst, Janssen, Takeda, Bristol Myers Squibb, Mirati, Chardan Consulting, Curio Science, Defined Health, G1 Therapeutics, Genentech, Jazz Pharmaceuticals, Outcomes Insights, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA.

REFERENCES

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;405(10495):2129-2143. doi:10.1016/S0140-6736(25)01011-6

2. Iams WT, Kopparapu PR, Yan Y, et al. Blood-Based Surveillance Monitoring of Circulating Tumor DNA From Patients With SCLC Detects Disease Relapse and Predicts Death in Patients With Limited-Stage Disease. JTO Clin Res Rep. 2020;1(2):100024. Published 2020 Mar 12. doi:10.1016/j.jtocrr.2020.100024

3. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39(3):346-360.e7. doi:10.1016/j.ccell.2020.12.014

4. Groves SM, Ildefonso GV, McAtee CO, et al. Archetype tasks link intratumoral heterogeneity to plasticity and cancer hallmarks in small cell lung cancer. Cell Syst. 2022;13(9):690-710.e17. doi:10.1016/j.cels.2022.07.006