IMforte Trial Maintenance Regimen Extends Survival for ES-SCLC

Adding immunotherapy to platinum-based chemotherapy is an established standard of care for extensive-stage small cell lung cancer (ES-SCLC). More research is being done on maintenance and subsequent therapy for this patient population with poor survival outcomes. 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, spoke with oncologists about trials of chemoimmunotherapy and additional options that have been found to prolong outcomes in this setting. He highlighted the distinct elements of the trial design of the phase 3 IMforte trial (NCT05091567) and how to interpret its efficacy and safety outcomes in this patient population.

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Targeted Oncology: Could you describe the study design for the IMforte trial?

Wade T. Iams, MD, MSCI: The end points we’re going to look at, in terms of progression-free survival [PFS] and overall survival [OS], are shifted compared with the [immunotherapy trials]. This is because the randomization point for IMforte, which is adding lurbinectedin [Zepzelca] to the atezolizumab [Tecentriq] maintenance, was after they finished their 4 cycles of induction carboplatin and atezolizumab without progression. So they weeded out the patients with refractory disease, which are a small subgroup, up to 20% of patients, but there are some patients who unfortunately are just refractory from the get-go.

So those patients are not allowed [on the trial]. It’s only patients who have already completed their 4 cycles of induction without progression, either partial response or stable disease. At that point, they’re randomly assigned to either atezolizumab maintenance or atezolizumab plus lurbinectedin on the typical dosing for relapse at 3.2 mg/m² and the typical every-3-weeks schedule. There was 1 other key feature to note, because in the relapsed setting, we’ve had more options. In the IMforte study, granulocyte colony–stimulating factor [G-CSF] was recommended for all patients, and nearly all patients in the lurbinectedin cohort got essentially prophylactic pegfilgrastim [Neulasta]. That was a key feature, that G-CSF support was given to basically all patients in the lurbinectedin cohort. Another key feature was patients without brain metastases were excluded from the trial…. Otherwise, prophylactic cranial irradiation [PCI] was at investigator’s discretion. In the extensive stage, we are not doing PCI for these patients anyway.

What were the key characteristics of the study cohorts?

[There were approximately] 240 patients in each arm, and a similar balance of high-risk features, such as liver metastasis.¹ That 3-month point is key; in my mind, I always have the 12 to 13 months in the IMpower133 [NCT02763579] and CASPIAN [NCT03043872] for OS median vs about 10 months.^2,3 We have to add 3 months to what we’re going to see here based on the timing of the randomization in the study. Also helpful to note, most patients in the in the study responded to platinum, so only about 10% of patients in each cohort had stable disease.¹ These are the responders to platinum, etoposide, and checkpoint inhibitor that we’re looking at.

What were the efficacy outcomes with lurbinectedin?

The first end point we will look at is PFS, and then OS. When you look at the PFS between the cohort of patients who got lurbinectedin and maintenance vs patients who got atezolizumab maintenance alone, we see significant difference in the median PFS from after the completion of induction of 5.4 months vs 2.1 months. We saw the median induction time was the same 3.2 months in each group, so you basically add 3 months to each of those, and you get about 8 months if you do lurbinectedin maintenance, vs the same 5 months that we saw IMpower133 and CASPIAN for the atezolizumab group, with an HR of 0.54 [95% CI, 0.43-0.67; P < .0001]. We can see over time that patients are ultimately [experiencing progression]. There’s not that same tail of the curve that we’re going to see with the tarlatamab [Imdelltra] curves and other immunotherapies in SCLC. In that sense, the immunogenic component is important to consider in the patient’s treatment journey.

When we look at OS, there was also a significant improvement. The median OS…was 13.2 months vs 10.6 months [HR, 0.73; 95% CI, 0.57-0.95; P = .0174]. At first glance, you would say that’s similar to IMpower133 and CASPIAN, but that’s from the time of completion of their 3 months of induction, so it’s more like a comparison of 16 months vs 13 months. The control arm actually performed a little bit better than the checkpoint inhibitor cohorts had performed in IMpower133 and CASPIAN, but still about a 2.5-to-3-month improvement in median OS.

Remember, 88% of patients had already had a radiographic response to their platinum, etoposide, and atezolizumab. About 20% of the patients in the lurbinectedin arm had a further objective response, and about 10% of patients in the atezolizumab arm had a further objective response. You can see some delay in response to checkpoint inhibitors, so that may explain that cohort. I think the 20% probably [includes] an additional 10% who had some degree of more active macroscopic disease who then responded to lurbinectedin.

What were the safety outcomes with the dual maintenance therapy?

Homing in on the grade 3 or 4 treatment-related adverse events [TRAEs] is the way that I like to do it. We have a significant increase in grade 3 or 4 TRAEs in the lurbinectedin arm [25.6% vs 5.8% with atezolizumab alone]. It’s mostly cytopenias, even in the face of G-CSF, but it’s anemia, thrombocytopenia, and also some patients with increased fatigue. Another outcome that I like to look at is discontinuation of the study drug due to AEs. I think that’s also a marker of overall tolerance of that treatment, and we see much closer numbers. It’s from 3% [with atezolizumab alone] vs about 6% of patients discontinuing any drug due to AEs. The grade 3 or 4 rates were certainly increased in the lurbinectedin cohort, but [there was] a much smaller difference in discontinuation in the lurbinectedin cohort. One interesting observation…I don’t have a good mechanistic hypothesis, but when we look at atezolizumab, AEs of special interest requiring steroids, which are…presumably immune-related AEs, we saw 16% in the lurbinectedin plus atezolizumab arm vs 8% in the atezolizumab [arm]. Maybe there is something to that…adding chemotherapy to checkpoint inhibitors exposes more antigen and can cause more immune response.

But thinking about grade 3 or 4 toxicities and overall toxicities…[the most common] are anemia, thrombocytopenia, and—even with G-CSF—neutropenia. We know neutropenia is one of the main associated toxicities…so there was still a fair amount of grade 3 or 4 neutropenia, same for thrombocytopenia. When we drill down to what our grade 3 or 4 events are increased with lurbinectedin, I think none of us would be surprised. The largest non-cytopenia is fatigue, which we see with lurbinectedin. [There is] possibly some gastrointestinal toxicity, but it’s usually mild, and the febrile neutropenia rates are key. With the caveat that…over 90% of patients in the lurbinectedin arm got G-CSF, the febrile neutropenia rate was 1.7% compared with 0% with the checkpoint inhibitor cohort. Grade 3 or 4 infections were similar; 6.6% vs 5%, [respectively]; universal G-CSF support is the key to remember for this dataset.

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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. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055

3. Paz-Ares L, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open. 2022;7(2):100408. doi:10.1016/j.esmoop.2022.100408