Extensive-stage small cell lung cancer: progress, slowly but surely

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. It is highly lethal due to its aggressive biology with rapid growth, early metastasis and high rate of relapse (1). The current standard of care for previously untreated extensive-stage small cell lung cancer (ES-SCLC) is the combination of a platinum agent (cisplatin/carboplatin) with etoposide in combination with a programmed death-ligand 1 (PD-L1) inhibitor, followed by maintenance therapy with the PD-L1 inhibitor, based on results from IMpower133 (atezolizumab) and CASPIAN (durvalumab) trials (2,3). The addition of immunotherapy to platinum-etoposide has led to moderate improvement in overall survival (OS) compared to chemotherapy alone. However, despite a high initial response rate ranging 50–70%, patients relapse and the median OS is approximately 12 months with standard chemoimmunotherapy (2,3). Hence, there is a critical need to develop approaches to improve OS.

Maintenance therapy has the potential to consolidate the initial good response, delay progression and thereby leading to improvement in OS. Multiple maintenance strategies have been tested in SCLC: nivolumab-ipilimumab (4), talazoparib-atezolizumab (5), and rovalpituzumab tesirine (6). Unfortunately, none of these trials was successful in improving outcomes. To address these issues, IMforte, a randomized phase 3 study evaluating the efficacy and safety of lurbinectedin and atezolizumab as maintenance therapy for ES-SCLC, was conducted (7). The primary endpoints of the study were progression-free survival (PFS) and OS from randomization.

Lurbinectedin is a synthetic alkylating agent that inhibits the binding of oncogenic transcription factors to their recognition sequences. It was granted accelerated approval by the U.S. Food and Drug Administration (FDA) based on the results of a phase 2 single-arm basket trial, which showed a response rate of 35% and median PFS of 3.7 months in patients with relapsed SCLC (8,9). Lurbinectedin has shown synergy with PD-L1 inhibitors by remodeling the tumor microenvironment, inducing long-term T-cell memory and higher rate of tumor regression in early phase studies which provided the rationale for IMforte study to evaluate the efficacy of lurbinectedin plus atezolizumab vs. atezolizumab alone as first-line maintenance therapy (10,11).

The IMforte study enrolled patients with ES-SCLC without brain metastasis and randomized them to either lurbinectedin and atezolizumab or atezolizumab alone, if they did not have disease progression after 4 cycles of carboplatin, etoposide and atezolizumab. In this trial 660 patients were enrolled and 571 patients completed induction treatment. Of these, 483 patients were randomly assigned to either lurbinectedin-atezolizumab (n=242) or atezolizumab (n=241). The baseline characteristics were well balanced between the two arms. The addition of lurbinectedin to atezolizumab improved the median PFS to 5.4 months [95% confidence interval (CI): 4.2–5.8] from 2.1 months (95% CI: 1.6–2.7) in atezolizumab group [hazard ratio (HR): 0.54, 95% CI: 0.43–0.67; P<0.0001]. The median OS was 13.2 months (95% CI: 11.9–16.9) in experimental arm compared to 10.6 months (95% CI: 9.5–12.2) in the control arm [HR: 0.73, 95% CI: 0.57–0.95; P=0.017]. This translated to a 27% reduction in the risk of death. The IMforte study is the first to show that combination chemoimmunotherapy (lurbinectedin/atezolizumab) improves OS in ES-SCLC patients without progression after induction therapy.

Although the IMforte study showed encouraging results, significant challenges remain in the use of maintenance therapy for managing ES-SCLC. In the IMforte study, the combination of lurbinectedin and atezolizumab resulted in increased toxicity. The incidences of grade 3–4 treatment-related adverse events (AE) (26% vs. 6%) and treatment-related serious AEs (12% vs. 4%) were significantly higher in the lurbinectedin plus atezolizumab group. There were more frequent dose reductions or interruptions in the lurbinectedin plus atezolizumab arm than in the atezolizumab arm (38% vs. 14%). A more recent update of the IMforte study reported the patterns of disease progression (PD) and efficacy by tumor burden (12). A higher proportion of patients in the combination arm developed brain metastases (27% vs. 10%), while atezolizumab alone was associated with an increased proportion of liver metastases (14% vs. 3%). Despite an increased proportion of patients developing brain metastases, the median time to development of brain metastases was longer in the combination arm (4.3 vs. 2.8 months).

The generalizability of IMforte study also warrants careful consideration. There was high pre-randomization dropout of patients in the study, with 27% (177 of 660 patients) of enrolled patients in the induction phase excluded from the randomization to maintenance phase due to disease progression, toxicity or clinical decline. While this is attributable to the nature of the disease, it also undermines the need to develop better treatment approaches in general for these patients. A more problematic aspect of the study design was the exclusion of patients with brain metastasis at baseline. Brain metastases are present in approximately 15% of patients with ES-SCLC at diagnosis and this increases to 40–50% during the disease course. The presence of brain metastases is associated with poor prognosis in ES-SCLC (13,14). Lurbinectedin also has limited efficacy in patients with brain metastases as indicated by a previous study (15). The IMforte study excluded patients with known brain metastases both at initial screening for the induction therapy and prior to enrollment in the maintenance phase, without specifically evaluating the intracranial response to induction treatment. This limits the applicability of IMforte study to the broader patient population in real-world settings.

Critics of the study may also argue that this was not true maintenance, but rather early second-line therapy. Maintenance therapy is typically administered to patients who achieve disease control (response or stable disease) after induction chemotherapy and before progression, whereas second-line therapy is initiated after documented progression. In the IMforte trial, crossover between treatment arms was not permitted and only 9% of patients in the atezolizumab group received lurbinectedin upon progression. The absence of crossover limits the interpretation of the benefits of concurrent lurbinectedin with atezolizumab compared with sequential use of lurbinectedin after progression. However, it must be remembered that only a small minority of patients ever receive second-line therapy. In a real-world outcomes study of around 6,000 SCLC patients, only 19% of patients received second-line treatment (16). In that context, it is important that patients receive as many active agents as possible during the course of their disease to improve outcomes.

These drawbacks notwithstanding, IMforte is the first study to demonstrate improvement, albeit incremental, in OS with maintenance therapy in patients with ES-SCLC. However, given the highly aggressive nature of SCLC, advances in first-line and maintenance therapy must extend beyond the incremental benefits. Future strategies should aim to improve tolerability, prolong treatment durability and achieve substantial gain in survival outcomes.

Tarlatamab has been approved by the FDA for the treatment of ES-SCLC with disease progression during or after platinum-based chemotherapy (17). The DeLLphi-303 phase 1b study of tarlatamab in combination with a PD-L1 inhibitor (atezolizumab or durvalumab) as first-line maintenance therapy in ES-SCLC patients showed encouraging safety and durable response with median PFS of 5.6 months and median duration of disease control of 9.3 months (17). A phase 3 trial (DeLLphi-305) evaluating tarlatamab plus durvalumab as first-line maintenance therapy is ongoing (18).

Multiple novel agents are currently being investigated in SCLC. Ifinatamab deruxtecan, an antibody-drug conjugate, is being studied in combination with atezolizumab with or without carboplatin in ES-SCLC in the first-line setting (IDeate-Lung03, NCT06362252). Obrixtamig, a BiTE therapy (DAREON-8, NCT06077500), LSD1 inhibitor iadademstat with atezolizumab or durvalumab for SCLC (NCT06287775) and PARP inhibitor (olaparib) and immunotherapy (durvalumab) with carboplatin, etoposide with or without radiation therapy (NCT04728230) are under investigation. Precision medicine approaches are also being explored in SCLC treatment. The phase 2 SWOG S1929 trial (NCT04334941) tested a combination of atezolizumab plus talazoparib in SLFN11-positive patients in the maintenance setting, and the phase 2 SWOG S2409 (PRISM) trial (NCT06769126) uses the molecular subtypes of SCLC based on gene expression to guide subtype-specific maintenance therapy.

In conclusion, the IMforte study represents an important advancement in the management of ES-SCLC, highlighting the potential of maintenance therapy to improve outcomes in this aggressive disease and is a new standard for first-line maintenance treatment. Nevertheless, its applicability may be limited in patients who have brain metastases or are frail and less able to tolerate cytotoxic chemotherapy. Future studies aimed at refining both induction and maintenance strategies, particularly through biomarker-driven approaches, will be critical to advancing toward more effective and personalized care for patients with ES-SCLC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-113/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-113/coif). A.K.G. reports research support from Merck, Mirati Therapeutics, Poseida Inc, Imugene Inc., Apexigen, NEKTAR Pharmaceuticals, Pfizer, Boehringer-Ingelheim and IOVANCE Therapeutics; consulting fees from AstraZeneca, Jazz Pharmaceuticals, Cardinal Health, Zai Lab, Pfizer, Amgen, Catalyst Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi Genzyme and Merck; and receipt of drug from Chimerix. The other author has no conflicts of interest to declare.

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