Addition of Lurbinectedin Improves Duration of Maintenance in ES-SCLC

The phase 3 IMforte trial(NCT05091567) demonstrated benefit for expanding on maintenance immunotherapy in extensive-stage small cell lung cancer (ES-SCLC) by adding the chemotherapy lurbinectedin (Zepzelca). During a live Community Case Forum event in Saddle Brook, New Jersey, Joshua K. Sabari, MD, assistant professor at NYU Grossman School of Medicine in New York, looked beyond the survival outcomes and discussed key areas including subgroup analysis, response, and safety. He highlighted the durability of response that is rarely seen in this setting; though only a small number of patients have persistent benefit, identifying these patients could allow more optimal use of the available therapies.

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

CASE SUMMARY

A 73-year-old woman presented with dyspnea on mild exertion, productive cough, chest pain, fatigue, anorexia, and a recent, unintentional 18-lb weight loss​.

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Medical history:

• Hypertension, well controlled on candesartan/hydrochlorothiazide daily​
• Forty-five pack-year smoking history and current smoker​

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Staging: T3N3M1b, stage IV​

• Extensive-stage small cell lung cancer​ (ES-SCLC)
• ECOG performance status: 1​

Focused physical examination:​

• Dullness to percussion and diminished breath sounds on auscultation over the posterior lung fields​

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Imaging studies:​

• Chest radiograph: left hilar mass and a 5.4-cm left upper lobe (LUL) opacity​
• Contrast chest CT reveals several masses with irregular margins in the LUL (largest measuring 6.1 cm involving the chest wall) and contralateral hilar plus mediastinal lymphadenopathy​.
• ¹⁸F-FDG PET/CT demonstrates avid FDG uptake in LUL, hilum, mediastinal, and supraclavicular lymph nodes and several hepatic lesions​.
• Brain MRI: negative​

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Percutaneous image-guided liver biopsy:

• Histopathology consistent with SCLC (chromogranin and synaptophysin positive; Ki-67, 90%)​

Targeted Oncology: What did the OS subgroup analysis of the IMforte trial show?

No matter what subset you look at in this patient population, across all subsets, there is a benefit to the addition of lurbinectedin.^1,2 There was a benefit in both patients with and without baseline liver metastases. You could say that for those patients with the highest burden of disease, [we should] give…maintenance lurbinectedin, but here you see a benefit even in those patients with less burden of disease. Across all clinical characteristics, there was an improvement in the utilization of maintenance lurbinectedin and atezolizumab.

What was the tumor response rate in the maintenance phase?

If you look at the objective confirmed response rate, it’s [nearly] 20%. That doesn’t seem high, but remember, these are patients already with a partial response, complete response, or stable disease. We saw an additional regression from the last scan with lurbinectedin/atezolizumab. With atezolizumab alone, the response rate was only 10%. How do you have a response rate with atezolizumab alone [in the maintenance phase]? Maybe those patients were in response or close to that. You can imagine what a response is and how we think about the depth of response in this patient population. Stability…is really what I care about here. If you add the response and the stable disease, that’s 19% plus 55%, so we’re talking about 75% [disease control rate].

But these are patients who are already responding. How much more response are you going to get in that patient population? If you look at atezolizumab maintenance, the disease control rate there is much lower. We’re talking about stable disease of 37.4% and then the response rate of 10.4%, so that’s about 47%. I like disease control rate, but if it’s disease control rate at 3 months or a month, it’s less important to me than at 6 months.

What is the significance of the subsequent therapies received in both arms?

This is also important, because if you got lurbinectedin and atezolizumab, did those patients then not go on to get other therapies? Whereas if you got atezolizumab, did you go on to get other [therapies]…? [The number of] patients who discontinued maintenance treatment was 197 [of 242] for lurbinectedin and atezolizumab and 208 [of 241] for atezolizumab alone [Table²]. At the time of clinical cutoff in this study, no patient in the lurbinectedin and atezolizumab arm vs 22 patients [9.1%] in the atezolizumab arm received follow-up lurbinectedin treatment.… When this was published, there was no use…of tarlatamab [Imdelltra] in this clinical trial. But now tarlatamab is approved in the second line.

What were the safety outcomes with the addition of lurbinectedin?

These are the safety data for the IMforte regimen using atezolizumab plus lurbinectedin. If you look at adverse events leading to discontinuation, it’s 6.2% for lurbinectedin and atezolizumab vs 3.3% for atezolizumab, so there is a doubling in discontinuation rates. However, there is an improvement in PFS and OS. When you look at dose interruption or modification, there is almost a 3-fold increase—38% for lurbinectedin and atezolizumab vs about 14% for atezolizumab alone. It’s a chemotherapeutic, so you need to dose reduce; you need to manage patients appropriately.

But if you look at the median duration of treatment in months, it’s double for the lurbinectedin and atezolizumab arm vs atezolizumab. So not only do you get more lurbinectedin, you get more atezolizumab, too, because patients are living longer and are on therapy longer—a [median of] over 4 months for lurbinectedin and atezolizumab vs a median of 2.1 months of atezolizumab alone. That number always shocks me, because when I give atezolizumab maintenance alone, I know that after 2 or 3 cycles, in our first scan, we see progressive disease. Thirty, 40, or maybe even 50% have progression by their scan after cycle 4. I usually get it 9 weeks later; some people get it 3 months later. At 12 weeks, you’re going to almost always see progressive disease on that scan. There’s a small number of patients who are far out, where they have no progression, and that’s great. How do we select out those patients? We don’t have that information, those clinical or biologic characteristics, yet in 2025.

Looking at the different adverse events for lurbinectedin and atezolizumab vs atezolizumab, just to highlight febrile neutropenia, it is only 2% for lurbinectedin and atezolizumab vs 0% for atezolizumab alone. If you look at infusion reactions, a lot of people are worried that if you give chemotherapy and atezolizumab, you are going to see higher rates of infusion reactions. It is very similar—6.6% for lurbinectedin and atezolizumab vs 5% for atezolizumab alone.

These are chemotherapy-like toxicities that I think we know how to manage and deal with. It’s mostly the hematologic toxicity that jumps out, and nausea, which is a chemotherapy-like adverse event. Fatigue [occurred in] 8% for atezolizumab vs 20% for atezolizumab plus chemotherapy. Most of these are grades 1 and 2; the rates of grades 3 and 4 are much lower in this population.

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_{DISCLOSURES: Sabari previously reported a consulting or advisory role with AbbVie, AstraZeneca, Genentech/Roche, Janssen, Loxo/Eli Lilly and Company, Medscape, Mirati Therapeutics, Pfizer, Regeneron, Sanofi, and Takeda Pharmaceuticals; and institutional support from Janssen, Loxo/Eli Lilly and Company, Mirati Therapeutics, and Regeneron.}

_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. Paz-Ares LG, Borghaei H, Liu SV, et al. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): primary results of the phase 3 IMforte trial. J Clin Oncol. 2025;43(suppl 16):8006. doi:10.1200/JCO.2025.43.16_suppl.8006}