Maintenance Lurbinectedin Raises Stakes of Checkpoint Choice in ES-SCLC

Adding a checkpoint inhibitor to platinum and etoposide extends survival by only a few months in patients with extensive-stage small cell lung cancer (ES-SCLC), and the choice among agents has often felt interchangeable. The phase 3 IMforte trial (NCT05091567) of maintenance lurbinectedin (Zepzelca) added to atezolizumab (Tecentriq) after induction links the first-line decision to what comes next. However, the pivotal trial excluded patients with brain metastases and measured survival from randomization rather than from the start of treatment, which complicates counseling.

In a live Community Case Forum event in Louisville, Kentucky, Wade Iams, MD, MSCI, director of lung cancer research at Tennessee Oncology in Nashville, reviewed first-line chemoimmunotherapy and maintenance data and moderated discussion of a 73-year-old woman with ES-SCLC and liver metastases. Iams emphasized that the maintenance survival figures must be read against a clock that starts about 3 months after induction begins.

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This article is part 1 of a 2-part series from a Community Case Forum event.

CASE SUMMARY

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

Past Medical/Social History

• Hypertension, well controlled on candesartan/hydrochlorothiazide once daily
• 45 pack-year smoking history and current smoker
• Staging: T3N3M1b – IV
• ES-SCLC

Initial Diagnostic Workup

• ECOG performance status: 1
• Focused physical examination: Dullness to percussion and diminished breath sounds on auscultation over the posterior lung fields
• 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 chest wall) and contralateral hilar + mediastinal lymphadenopathy
  • 18F-fluorodeoxyglucose (FDG) PET/CT demonstrates avid FDG uptake in LUL, hilum, mediastinal and supraclavicular lymph nodes and several hepatic lesions
  • Brain MRI negative
• Percutaneous image-guided liver biopsy: Histopathology consistent with SCLC (chromogranin and synaptophysin positive; Ki-67 90%)

EVENT RECAP

When asked which first-line regimen they would recommend, 58.3% of 12 respondents chose platinum, etoposide, and atezolizumab, whereas 33.3% chose durvalumab (Imfinzi) in place of atezolizumab; 1 respondent chose platinum and etoposide alone. One oncologist said insurers had refused durvalumab in some patients who were also receiving lurbinectedin, so the oncologist moved to atezolizumab induction to keep the maintenance option open. Arvinda Padmanabhan, MD, of Baptist Health Lexington in Lexington, Kentucky, described following habit: "I started out with [atezolizumab] and just kind of stuck with it."

Iams presented data from the trials: in the IMpower133 trial (NCT02763579), atezolizumab added to carboplatin and etoposide for 4 cycles, followed by atezolizumab maintenance, improved median overall survival (OS) to 12.3 months from 10.3 months with chemotherapy alone (HR, 0.76; 95% CI, 0.60-0.95; P = .0154) at a median follow-up of 22.9 months; the 18-month OS rate was 34% vs 21%.¹ At an earlier analysis, median progression-free survival (PFS) was 5.2 months vs 4.3 months (HR, 0.77; 95% CI, 0.62-0.96; P = .02).² In the CASPIAN trial (NCT03043872), durvalumab with platinum and etoposide improved median OS to 12.9 months from 10.5 months (HR, 0.71; 95% CI, 0.60-0.86; nominal P = .0003), and the 36-month OS rate was 17.6% vs 5.8% at a median follow-up of 39.4 months.³ The trials had different follow-up, and CASPIAN allowed cisplatin as well as carboplatin, so the results cannot be compared directly.

Iams described the benefit of the class as modest: “I think the checkpoint inhibitors as a whole are a small marginal benefit, and then some have just gotten lucky enough to hit statistical significance in their trial.” Padmanabhan said long-term survivors remained uncommon in practice, adding, "you still see a home run, but it's not pushing the numbers up."

Participants generally favored stopping induction at 4 cycles, Padmanabhan said. Lee Hicks, MD, of Versailles, Kentucky, noted that patients put off by chemotherapy need the goal set at the first visit, because maintenance lurbinectedin, though better tolerated than induction, is still chemotherapy.

For patients who reach maintenance, NCCN guidelines suggest considering lurbinectedin with atezolizumab in those with at least stable disease after 4 cycles of induction chemoimmunotherapy, an ECOG performance status of 0 or 1, and no history of brain metastases.⁴

In the IMforte trial, patients who completed induction with carboplatin, etoposide, and atezolizumab were randomly assigned to maintenance lurbinectedin plus atezolizumab or atezolizumab alone. At a median follow-up of 15.0 months, the combination improved median OS to 13.2 months (95% CI, 11.9-16.4) from 10.6 months (95% CI, 9.5-12.2; HR, 0.73; 95% CI, 0.57-0.95; P = .017) and median PFS assessed by independent review to 5.4 months from 2.1 months (HR, 0.54; 95% CI, 0.43-0.67; P ≤ .0001).⁵ Because the clock started at randomization, a median of 3.2 months after induction began, Iams said patients should be counseled that the medians are roughly 3 months longer from the first day of treatment. In an exploratory subgroup, the OS HR was 0.70 (95% CI, 0.48-1.00) for patients with liver metastases at induction baseline and 0.76 (95% CI, 0.54-1.07) for those without; the trial was not powered for subgroup comparisons.

The cost was greater toxicity; these safety differences were descriptive. Grade 3 or 4 adverse events occurred in 38.0% of patients receiving lurbinectedin plus atezolizumab vs 22.1% with atezolizumab, adverse events led to discontinuation in 6.2% vs 3.3%, and dose interruption or modification occurred in 38.0% vs 13.8%. Prophylactic granulocyte colony-stimulating factor (G-CSF) was given to patients on the combination, and febrile neutropenia occurred in 1.7% vs 0%.

Padmanabhan said patients felt better during maintenance than during induction and tolerated the combination better than single-agent lurbinectedin, while advising growth factor support because lurbinectedin is fairly immunosuppressive when given with a checkpoint inhibitor. One participant reported seeing more outliers with progression-free intervals of 8 to 10 months on the combination, with no tolerability concerns.

Chandler Park, MD, of Norton Cancer Institute in Elizabethtown, Kentucky, asked whether Iams would follow the trial for a patient who presents with brain metastases. Iams noted that the trial design left him without prospective data but said he would still use the regimen and added, "The patients with small cell brain [metastases] aren't TKI [tyrosine kinase inhibitor] patients. They're going to need local therapy." Though some trials of B7-H3 agents have shown potential in this subset of patients, Iams remained skeptical of relying on systemic therapy for brain metastases.

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DISCLOSURES: Iams previously reported consultancy or advisory board participation for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Catalyst Pharmaceuticals, Daiichi Sankyo, Eli Lilly, EMD Serono, Galvanize Therapeutics, Genentech, Gilead Sciences, Janssen, Johnson & Johnson, Merck, Partner Therapeutics, Pfizer, and Regeneron; and speakers’ bureau participation for AbbVie, Amgen, Jazz Pharmaceuticals, Novocure, and Nuvation Bio.

REFERENCES

1. 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

2. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064

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

4. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 1.2027. Accessed November 5, 2026. https://tinyurl.com/353m69xe

5. 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