Small cell lung cancer: a therapeutic update in the era of immunotherapy and beyond—a narrative review

Introduction

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma characterized by rapid growth, early dissemination, and frequent relapse. In the United States, SCLC accounts for approximately 11–13% of all lung cancers, corresponding to an estimated 29,000–30,000 new cases annually (1,2). The age-adjusted incidence rate has declined steadily over recent decades, from 9.0 per 100,000 in 2000 to 4.6 per 100,000 in 2020, paralleling reductions in smoking prevalence (1). The median age at diagnosis is 69 years, and women now represent approximately half of new cases (1,3). SCLC is strongly associated with tobacco use, although approximately 2% of cases occur in never-smokers (4).

At the molecular level, SCLC is characterized by very frequent TP53 alteration and high rates of RB1 inactivation, and it exhibits four main transcriptional subtypes driven by ASCL1, NEUROD1, POU2F3, and an inflamed subtype (SCLC-I). Unlike non-small cell lung cancer (NSCLC), PD-L1 expression is variable and not predictive of response to immune checkpoint inhibitors (ICIs) (5). SCLC can arise de novo or through histologic transformation from EGFR- or ALK-mutant NSCLC, with transformed cases carrying a particularly poor prognosis (5). Clinically, SCLC may present with respiratory symptoms, paraneoplastic syndromes (e.g., syndrome of inappropriate antidiuretic hormone secretion (SIADH), Cushing’s syndrome), or neurologic manifestations like Lambert-Eaton myasthenic syndrome. Diagnosis involves imaging and biopsy, with histology showing small, mitotically active cells and neuroendocrine marker expression (e.g., CD56, synaptophysin).

For accurate staging and treatment planning, patients should undergo thoracic and abdominal computed tomography (CT), brain magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT. SCLC is classified as limited stage (LS)-SCLC or extensive stage (ES)-SCLC based on tumor confinement to one hemithorax (with or without hilar nodal involvement) that can be encompassed within a single radiation field. The definition of LS-SCLC was expanded by the International Association for the Study of Lung Cancer (IASLC) in 1986 to include disease involving contralateral mediastinal and supraclavicular nodes and ipsilateral pleural effusion (6,7). The TNM staging system, which stages tumors by primary tumor size, node positivity, and distant metastases, closely aligns with the IASLC staging, with stages I through III corresponding to LS-SCLC and stage IV representing ES-SCLC.

Recently, new treatment strategies have changed the treatment paradigm, prompting the need to review current and emerging therapeutic strategies. This review aims to summarize the latest evidence on SCLC treatment across all disease stages, focusing on multimodal therapy and novel agents. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-104/rc).

Methods

We performed a comprehensive literature search to identify clinical trials, meta-analyses, guidelines, and key translational studies related to SCLC. Searches were conducted in PubMed, Embase, and the Cochrane Library for articles published up to 1 April 2025, with pivotal publications and late-breaking abstracts considered through July 2025 (Table 1). The core search strategy combined Medical Subject Headings (MeSH) and free-text terms for “small cell lung carcinoma” or “small cell lung cancer” with treatment concepts including “chemotherapy”, “immunotherapy”, “radiotherapy”, “surgery”, “targeted therapy”, “bispecific T-cell engager”, and “antibody-drug conjugate”.

Boolean operators were used, for example: (“small cell lung carcinoma” [MeSH] OR “small cell lung cancer” OR SCLC) AND (“chemotherapy” OR “etoposide” OR “platinum”) AND (“immunotherapy” OR “checkpoint inhibitor” OR “PD-1” OR “PD-L1” OR “CTLA-4”).

No language restrictions were applied at the database level; when relevant studies were published in non-English journals, data were extracted from the full text or, if not available, from English abstracts. Abstracts from major scientific meetings (ASCO, ESMO, ASTRO; 2020–2025) were screened for late-breaking or unpublished data. Study selection focused on randomized controlled trials, phase II-III clinical trials, pivotal phase I studies, meta-analyses, and major clinical practice guidelines.

Limited stage SCLC (LS-SCLC)

Limited stage I–IIA (T1–2N0M0)

Early-stage SCLC (T1–2N0M0) is uncommon and represents only a small minority of cases. Multidisciplinary discussion involving medical oncologists, radiation oncologists and thoracic surgeons is strongly recommended to determine the optimal treatment for patients with LS-SCLC, especially in early-stage disease (8). International guidelines recommend local therapy as the initial treatment approach for this selected group, followed by systemic treatment and postoperative radiotherapy if positive margins are present. Surgical resection for fit patients has shown favorable outcomes in several studies. For medically inoperable patients, or for those who refuse surgery, definitive radiotherapy is the preferred local treatment modality.

Role of surgery

Historically, surgery alone has played a limited role in the treatment of LS-SCLC, as it was associated with an overall 5-year survival close to 0%. In 1969, the British Medical Research Council Trial randomized 144 operable SCLC patients to either surgical resection or radiotherapy (RT) showing a survival benefit for RT over surgery (300 days for RT vs. 199 days for surgery, P=0.04; 10-year survival: ~4% vs. 0%) (9-11).

However, in recent years, the role of surgery has been re-evaluated, particularly for highly selected early-stage SCLC patients without mediastinal involvement (12). Several studies have shown that surgical resection can offer a significant survival benefit in patients with stage I to IIA (T1–2N0M0), especially when combined with adjuvant platinum-etoposide chemotherapy (ChT) (13-15). When surgery is undertaken, lobectomy with systematic mediastinal lymph node dissection is the preferred approach, as it provides better local control (LC) and accurate pathologic staging. There is no supporting evidence for sublobar resection in SCLC (16,17). Although some studies have reported improved survival in surgically treated patients with N1–N2 disease (18), the current evidence supports the use of surgery only in patients without mediastinal nodal involvement. Despite there being no evidence to support the use of neoadjuvant therapy in SCLC, surgery has also been evaluated for residual disease following a good response to ChT. Salvage surgery for SCLC may be a reasonable treatment in very highly selected patients (19).

In patients who have undergone surgery, postoperative radiotherapy is recommended for incomplete resection or positive margins, either sequentially or concurrent with ChT. It may also be considered for incidental pN2 involvement, though it is not advised for N0–1 disease.

In summary (Table 2), although SCLC remains a disease primarily managed with systemic therapies, surgery can play a potentially curative role in a small subset of patients with highly selected early-stage SCLC and no mediastinal nodal involvement. Decision-making should be multidisciplinary, individualized, and based on precise staging.

Role of stereotactic body radiotherapy (SBRT)

SBRT is emerging as a promising treatment option for T1–2N0M0 SCLC, particularly for patients who are medically inoperable or refuse surgery as an alternative to systemic therapy concurrent with RT, building upon the favorable outcomes observed in the treatment of medically inoperable early NSCLC (19,20).

However, several limitations must be considered: most available data come from retrospective studies or database analyses, and patients who undergo SBRT are usually unfit or have comorbidities that contraindicate adjuvant systemic treatment. Additionally, mediastinal staging is frequently suboptimal. Experience from early-stage NSCLC illustrates how imaging alone can underestimate nodal disease: in clinical stage IA3 NSCLC, up to one fifth of patients are upstaged to N1–N2 at surgery. By analogy, inadequate invasive staging in very limited-stage SCLC likely contributes to inferior survival outcomes reported in some SBRT series, underscoring the need for rigorous mediastinal assessment before definitive SBRT (21).

In consequence, outcomes from SBRT are not comparable to those obtained with surgery in terms of LC and overall survival (OS). Considering these limitations, SBRT achieves a 2-year LC rate of 70–95% and a 2-year OS rate of 35–60% (22,23).

Toxicity is generally low, with grade ≥3 toxicity uncommon in most series, although risks increase for central or ultracentral tumors. Insufficient mediastinal and distant staging and aggressiveness of the disease may explain the low OS reported. The addition of ChT after SBRT in LS-SCLC leads to a significant increase in OS, especially in tumors >2 cm and it is highly recommended (24).

Regarding the SBRT technique, the optimal fractionation schedule depends on tumor size, location, and patient health. The most recommended fractionation schedules range from 3 to 8 fractions, with a total dose between 54 and 60 Gy, achieving a biologically effective dose (BED) >100 Gy.

Limited stage IIB–IIIC (T3–4N0M0; T1–4N1–3M0)

Approximately one-quarter to one-third of patients with SCLC are diagnosed with LS-SCLC (25). Although this stage is potentially curable, the median OS remains modest, ranging from 25 to 30 months, with a 5-year OS rate around 30% (26,27).

In ES-SCLC, an analysis of 21 phase III clinical trials and data from the SEER database from 1972 to 1994 demonstrated a 2-month OS improvement in patients treated with cisplatin-based chemotherapy compared to those who did not receive such chemotherapy (28). Subsequently, a meta-analysis of 19 randomized clinical trials including 4,054 patients with both LS-SCLC and ES-SCLC reported a 1-year OS increase of 4.4% with platinum-based chemotherapy (29). These findings established platinum-etoposide as the standard systemic treatment for both LS and ES-SCLC.

Concurrent ChT with cisplatin and etoposide and RT is considered the treatment of choice (30,31). The COCIS meta-analysis, which evaluated individual patient data from four clinical trials involving 663 patients (including 210 with LS-SCLC), found no significant differences in progression-free survival (PFS) or OS according to the platinum agent used (32). Similarly, a recent cohort study of 1,756 patients with LS-SCLC failed to demonstrate differences in OS between cisplatin and carboplatin-based chemotherapy (33).

Thoracic radiotherapy

The addition of thoracic RT to ChT has demonstrated a 5% improvement in OS in the management of LS-SCLC (34,35), albeit with an increase in treatment-related toxicity. However, the optimal sequencing and timing of RT in relation to ChT has remained a topic of debate. Several studies have investigated the impact of early versus delayed initiation of RT on clinical outcomes in patients with LS-SCLC, suggesting a survival benefit for concurrent treatment in multivariate analysis (31). Two meta-analyses assessed different timing strategies and suggested a survival benefit with an “earlier or shorter” RT regimen [hazard ratio (HR) 0.79, 95% confidence interval (CI): 0.69–0.91], including when RT was started within 30 days of chemotherapy onset (36,37).

RT fractionation is another important topic. The role of accelerated hyperfractionation RT has been investigated to counteract the rapid repopulation characteristic of SCLC tumors. Initial trials evaluating hyperfractionation RT in LS-SCLC showed a significant increase in severe esophageal toxicity (30). Later, two phase III trials compared high-dose once-daily RT versus hyperfractionated twice-daily RT [45 Gy in 1.5 Gy fractions twice daily (BID)], both concurrent with platinum-etoposide. The CONVERT trial (26) evaluated 66 Gy in 33 once-daily fractions, while the CALGB 30610/RTOG 0538 (27) tested 70 Gy in 35 once-daily fractions against the same 45 Gy BID control arm. No significant differences were observed in terms of OS, and toxicity profiles were comparable between the two arms. While the results may initially appear similar, it is important to note that the CONVERT trial was designed as a superiority study. Based on these results, the investigators concluded that hyperfractionation RT should remain the standard of care (SOC). Nevertheless, its adoption in clinical practice remains limited due to logistical challenges or patient inconvenience for twice-daily treatment (38), and normofractionation RT continues to be the most used regimen in clinical practice.

The ASTRO guidelines (39) recommend concurrent chemoradiotherapy (CRT) for the treatment of LS-SCLC and RT should be started earlier. The optimal fractionation regimen is 45 Gy in 30 twice-daily fractions; however, normofractionated RT between 60–70 Gy is considered an acceptable alternative. The recommended thoracic RT field for LS-SCLC should include the involved field. In cases of tumor shrinkage, it is recommended to treat the nodal regions involved at baseline, while adjusting the contours of the primary tumor to reflect its post-ChT size.

Recently, dose-intensified RT schedules have been studied, including 60 Gy in 40 twice-daily fractions and high-dose hyperfractionated/SIB approaches, with reported OS benefit and no significant increase in toxicity compared with standard 45 Gy in 30 twice-daily fractions (40-42).

Prophylactic cranial irradiation (PCI)

The brain is one of the most frequent sites of metastasis in SCLC. Between 10–20% of patients present with brain metastases at diagnosis, and 60–70% will develop them over the course of the disease (43,44). International guidelines recommend the use of PCI for patients with LS-SCLC who have achieved locoregional control following CRT, with a schedule of 25 Gy in 10 fractions over 2 weeks. This recommendation is based on its benefit in OS and a reduction in the incidence of brain metastases. A meta-analysis in patients with LS-SCLC who achieved complete response after CRT showed that PCI was associated with a significant reduction in the 3-year incidence of brain metastases by 25.3% and significant improvement in 3-year OS of 5.4% compared to the control group (45). In a recent meta-analysis including 18,575 LS-SCLC patients, PCI was also associated with an OS benefit (pooled adjusted HR 0.62, 95% CI: 0.57–0.69) (46).

Despite these benefits, PCI is not without toxicity. Between 30–50% of patients may experience any neurological adverse event within six months after PCI, including neurocognitive decline such as memory loss and functional deterioration, especially in older patients and/or with cardiovascular morbidities. In a randomized trial of patients with brain metastases receiving whole-brain radiotherapy (WBRT), the addition of hippocampal avoidance (HA) to WBRT plus memantine significantly reduced the risk of cognitive function failure compared with WBRT plus memantine alone (HR 0.74; 95% CI: 0.58–0.95; P=0.02) (47). In patients with SCLC, the phase III PREMER trial demonstrated that HA during PCI significantly lowered the rate of cognitive decline at 3 months compared with standard PCI (5.8% vs. 23.5%; P=0.003) (48).

Retrospective series of completely resected early-stage SCLC have reported a relatively low risk of brain metastases in p-stage I disease (3-year risk 9.7%) (49). As a result, the role and potential survival benefit of PCI in this setting may be limited. In selected patients—particularly those with early-stage LS-SCLC, those at higher risk for neurocognitive decline, or those who decline PCI—active surveillance with brain MRI may represent a reasonable alternative to PCI. In summary, PCI remains an integral component of the therapeutic strategy for LS-SCLC in clinically fit patients who achieve a good response to CRT.

Consolidation therapy in LS-SCLC

The introduction of ICIs as consolidation therapy after CRT has set a new standard for LS-SCLC patients based on the results of the ADRIATIC trial.

The ADRIATIC trial showed a significant benefit with durvalumab, given for up to 24 months, in terms of PFS (16.6 vs. 9.2 months; HR 0.76) and OS (55.9 vs. 33.4 months; HR 0.73) compared with placebo. Benefits were observed across subgroups defined by platinum agent, thoracic RT fractionation schedule (twice-daily vs. once-daily), and PCI use, although the trial was not powered for subgroup comparisons (50). In an ADRIATIC progression-pattern analysis, time to brain/CNS progression or death was prolonged with durvalumab versus placebo (HR 0.64; 95% CI, 0.40-1.01), and first brain/CNS progression rates were lower with durvalumab regardless of PCI use (51).

Prior to the positive results of the ADRIATIC trial, two previous studies evaluating ICIs in the consolidation setting for LS-SCLC had failed to demonstrate clinical benefit. The phase II ETOP/IFCT 4-12 STIMULI clinical trial evaluated consolidation treatment with four cycles of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every three weeks, followed by nivolumab 240 mg every two weeks for up to 12 months vs. observation with no benefit in terms of PFS (median PFS 10.7 vs. 14.5 months in the observation arm; HR 1.02, 95% CI: 0.66–1.58; P=0.93), probably related to a higher rate of toxicity in the experimental arm (52). Similarly, the phase II/III NRG Oncology/Alliance LU005 trial assessed the addition of atezolizumab during concurrent CRT, followed by maintenance for 1 year, with no significant differences in terms of PFS or OS (53). More recently, a phase II trial comparing atezolizumab or placebo as consolidation therapy until disease progression or unacceptable toxicity also failed to demonstrate significant benefit in PFS or OS (54). Currently, new drugs that have demonstrated efficacy in ES-SCLC, such as tarlatamab, are also under evaluation as consolidation therapy after CRT in clinical trials in patients with LS-SCLC (55).

Taken together, these trials underscore that both the timing and the mode of immunotherapy delivery in LS-SCLC are critical determinants of clinical benefit. The ADRIATIC trial evaluated single-agent PD-L1 blockade administered after completion of CRT and demonstrated a clear, clinically meaningful OS benefit with an acceptable toxicity profile. In contrast, the STIMULI trial combined nivolumab with ipilimumab, leading to high rates of grade ≥3 toxicity and very limited median treatment exposure, which likely attenuated any potential efficacy signal. The LU005 trial explored the concurrent administration of atezolizumab with CRT and failed to improve survival, raising the possibility that overlapping pulmonary and hematologic toxicities may offset potential benefit, and that the post-CRT period may represent a more favorable window for immune priming. Although differences in trial phase, sample size and patient selection complicate direct comparisons, the available evidence currently supports consolidation durvalumab following CRT as the preferred immunotherapy strategy in LS-SCLC, whereas dual-checkpoint or concurrent chemoradiation-immunotherapy approaches should remain investigational.

ES-SCLC

First-line systemic treatment (Table 3)

For more than three decades, platinum-etoposide was the only evidence-based treatment for newly diagnosed ES-SCLC, eliciting rapid responses in most patients but translating to a median OS of barely 10 months and a 2-year survival rate below 10% (64). Numerous attempts to intensify or maintain cytotoxic therapy failed, underscoring the need for biology-driven strategies.

With the arrival of PD-(L)1 blockade agents, a significant benefit in OS has been achieved. The IMpower133 trial randomized 403 patients to receive induction treatment with carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles, followed by maintenance treatment with either atezolizumab or placebo. The addition of atezolizumab significantly prolonged median OS from 10.3 to 12.3 months (HR 0.70, 95% CI: 0.54–0.91), without compromising chemotherapy delivery or markedly increasing grade ≥3 toxicity (56). This benefit was consistent across prespecified subgroups, including patients with liver or brain metastases. Emerging real-world data suggest that host factors may also influence outcomes with chemoimmunotherapy: in a recent retrospective analysis, metabolic phenotype and sex appeared to correlate with survival in patients receiving atezolizumab plus carboplatin-etoposide, hinting that patient-level characteristics could refine risk stratification beyond traditional clinical variables (65). The CASPIAN trial subsequently confirmed the class effect of PD-L1 inhibition: durvalumab combined with investigator’s choice of cisplatin or carboplatin-etoposide, followed by maintenance durvalumab, significantly increased OS from 10.3 to 13.0 months (HR 0.73, 95% CI: 0.59–0.91) (57). Of note, the trial allowed up to 6 cycles of ChT in the control arm, yet the survival advantage persisted, arguing that the immune component and not additional cytotoxic cycles drives the improvement. Together, these trials established platinum-etoposide plus PD-(L)1 blockade as the cornerstone of first-line treatment for ES-SCLC and it is recommended in current guidelines (66).

Carboplatin is often preferred due to its more favorable toxicity profile; in CASPIAN, outcomes were broadly consistent regardless of whether cisplatin or carboplatin was selected (57). Four cycles mirror the randomized evidence, while extending ChT up to six has not improved OS and adds myelosuppression. Maintenance atezolizumab every three weeks or durvalumab every four weeks is recommended until progression or unacceptable toxicity. Immune-related adverse events are generally manageable, with endocrinopathies among the most frequent (56,57).

It is important to note that several other combinations of chemotherapy and immunotherapy have been evaluated with negative or inconclusive results, including ipilimumab (with increased toxicity), the addition of tremelimumab to durvalumab, or pembrolizumab. In the phase III KEYNOTE-604 trial, pembrolizumab combined with platinum-etoposide significantly improved PFS, but the primary endpoint of OS was not met (HR 0.80; 95% CI: 0.64–0.98), narrowly missing its prespecified significance boundary (P=0.0164 vs. a boundary of 0.0128). This may illustrate statistical design constraints rather than a complete absence of biological activity, given that the observed OS HR is very similar to those seen with atezolizumab and durvalumab (58). In contrast, other phase III trials have reported larger absolute OS gains with PD-(L)1 inhibitors. The ASTRUM-005 trial that combined ChT with serplulimab and the CAPSTONE-1 trial with adebrelimab showed median OS of around 15 months (59,60). Differences in eligibility criteria (for example, a lower proportion of patients with liver metastases), duration of ChT, or a younger median age may partly explain these absolute differences; however, taken together, these studies confirm that the benefit of PD-(L)1 inhibitors is reproducible across platforms and ethnicities. Some real-world cohorts have also mirrored the results of pivotal trials. A Korean multicenter prospective cohort reported median PFS of 6.0 months, median OS of 13.5 months, and a 1-year OS rate of 62.2% with first-line atezolizumab plus chemotherapy, broadly consistent with IMpower133 (67). Elderly patients and those with limited organ reserve appeared to derive similar relative benefit, provided Eastern Cooperative Oncology Group (ECOG) performance status was preserved.

Maintenance treatment (Table 3)

Prior to recent advances, no cytotoxic or targeted maintenance strategy has shown an improvement in OS in ES-SCLC. For example, the MERU trial with rovalpituzumab tesirine was stopped for futility, with OS numerically worse than placebo (68). Recently, the phase III IMforte trial randomized 483 patients without progression after four cycles of induction atezolizumab-carboplatin-etoposide to receive maintenance lurbinectedin plus atezolizumab or atezolizumab alone every three weeks (61). IMforte showed a significant benefit in median PFS (5.4 vs. 2.1 months; HR 0.54, 95% CI: 0.43–0.67) and median OS (13.2 vs. 10.6 months; HR 0.73, 95% CI: 0.57–0.95). All-cause grade 3-4 adverse events were more frequent with lurbinectedin plus atezolizumab (38.0% vs. 22.1%); febrile neutropenia was uncommon (2% vs. 0%), and adverse events leading to discontinuation of any study drug occurred in 6% vs. 3% (61). These results highlight the potential of lurbinectedin plus atezolizumab as a new first-line maintenance treatment option for patients with ES-SCLC.

Currently, several drugs are being studied in first-line treatment either as maintenance therapy or from the induction treatment. Atigotatug (BMS-986012), an afucosylated IgG1 targeting the tumor-associated ganglioside fucosyl-GM1, has shown promising activity combined with carboplatin-etoposide and nivolumab in early-phase studies (69). The ongoing phase III TIGOS trial compares this combination with atezolizumab plus carboplatin and etoposide (70). The addition of the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib to cisplatin-etoposide produced only a modest median PFS benefit in the phase II ECOG-ACRIN 2511, and an exploratory analysis suggested the signal was restricted to SLFN11-high (Schlafen 11) tumors (71). That biomarker hypothesis has not translated into a survival improvement with the addition of talazoparib to atezolizumab in the maintenance treatment in patients with SLFN11-positive ES-SCLC (72). The combination with an antiangiogenic agent has also been tested in the phase III ETER-701 trial with benmelstobart (PD-L1 inhibitor) and anlotinib plus carboplatin-etoposide. The combination achieved a median OS 19.3 versus 11.9 months in the ChT arm (HR 0.61; P=0.0002), albeit with more hypertension and proteinuria. Confirmation in non-Asian populations is awaited (63). By contrast, the addition of the TIGIT antibody tiragolumab to atezolizumab-ChT failed to improve survival outcomes in the phase III SKYSCRAPER-02 trial, reinforcing that not all ICI combinations have a synergistic effect (62). Tarlatamab is also being evaluated either as maintenance therapy or from the induction treatment (DeLLphi-305, NCT06211036).

Efforts to refine patient selection have shifted from single markers to broader transcriptional archetypes. Integrative analyses segregate SCLC into ASCL1-, NEUROD1- and POU2F3-driven neuroendocrine lineages and an “inflamed” SCLC-I subtype that is rich in interferon-γ signatures and CD8-cell infiltration (73,74). Retrospective series suggest that SCLC-I tumors achieve the longest PFS with chemoimmunotherapy, suggesting a biologically tractable enrichment strategy that is now being explored in prospective trials.

Second and subsequent lines

Despite the addition of immunotherapy to first-line treatment, disease control remains short for many patients, with median PFS in pivotal chemoimmunotherapy trials on the order of ~5 months (56,57). These poor outcomes after relapse are not only a function of advanced stage but also reflect fundamental biological features of SCLC. SCLC is characterized by profound transcriptional plasticity and intratumoral heterogeneity: tumors contain mixtures of ASCL1-, NEUROD1-, POU2F3-driven and “inflamed” subpopulations, and can dynamically shift between neuroendocrine and non-neuroendocrine states under therapeutic pressure (73-76). This evolutionary flexibility allows resistant clones to emerge rapidly after initial treatment, making durable disease control with a single mechanism of action unlikely. Prognosis after relapse remains poor, as only 45–50% of patients receive subsequent therapy (56,77), and tumor plasticity contributes to chemoresistance mechanisms to conventional chemotherapy (75,76). Relapsed disease is categorized as platinum-sensitive or platinum-resistant according to the platinum-free interval (PFI), most commonly using a cutoff of 3 or 6 months (8,78). Topotecan has historically been the standard of care in this setting, with median OS typically around ~5 months for platinum-refractory disease and ~7 months for platinum-sensitive relapse (78). In platinum-sensitive relapse, rechallenge with carboplatin-etoposide provides higher objective response rate (ORR) (49% versus 25%) and longer PFS compared with topotecan (4.7 versus 2.7 months), with similar OS and lower rates of neutropenia and febrile neutropenia (79). In a recent large real-world series, doxorubicin plus paclitaxel achieved an ORR of approximately 22% with a median OS of about 5 months in heavily pretreated SCLC, including platinum-resistant disease, at the cost of frequent dose reductions due to hematologic toxicity and neuropathy (80).

Lurbinectedin is a marine-derived drug that both inhibits transcription in the tumor cells and reverses pro-tumor microenvironment induced by tumor-associated macrophages (81,82). In a phase II trial, lurbinectedin presented an ORR of 35% (45% in PFI ≥3 months) and median OS of 9.3 months (11.9 months in PFI ≥3 months), with neutropenia as the most frequent grade 3 or 4 adverse event, warranting primary prophylaxis with G-CSF (83). The combination with doxorubicin failed to improve survival in a phase III clinical trial, which may be attributed to the use of a lower dose of lurbinectedin (84), while lurbinectedin plus irinotecan yielded an ORR of 44%, median PFS of 4.7 months and median OS of 9.6 months (14 months for PFI ≥3 months), but with high rates of grade 3–4 diarrhea and fatigue (85). The combination of lurbinectedin and irinotecan is being studied in the phase III LAGOON trial (NCT05153239).

Lurbinectedin has also been evaluated in combination with ICIs (81). In combination with pembrolizumab, lurbinectedin has demonstrated an ORR of 46%, median PFS of 4.6 months and median OS of ~10.5 months, with no synergistic toxicity (86). Lurbinectedin combined with atezolizumab has shown ORR of 40.4%, median PFS of 4.6 months and median OS of 10.1 months (87). Delta-like ligand 3 (DLL3) is a transmembrane protein expressed in around 90% of SCLC cases, predominantly on neuroendocrine, ASCL1-high and NEUROD1-high SCLC cells, and is largely absent from normal adult tissues, making it an attractive therapeutic target (88,89). By contrast, emergent non-neuroendocrine (non-NE) or “variant” populations that arise under treatment may express other surface proteins such as TROP-2 or B7-H3, which are being exploited by antibody-drug conjugates (74,90-93). This biological heterogeneity provides a rationale for sequencing or combining DLL3-directed agents with ADCs to address the full spectrum of intratumoral diversity.

Tarlatamab is a bispecific T-cell engager (BiTE) that promotes immune synapsis with its domains against T-cell protein CD3 and delta-like ligand 3 (DLL3), a transmembrane protein expressed in a high proportion of SCLC cases (often reported in the ~80–90% range, depending on assay and positivity threshold) (88,94). In a phase III trial, tarlatamab significantly improved OS compared with chemotherapy (13.6 vs. 8.3 months, HR 0.6) as well as PFS, ORR and respiratory symptoms. Of note, tarlatamab showed fewer grade ≥3 treatment-related adverse events (27% vs. 62%) (95). This trial is consistent with findings from earlier phase I-II studies in previously treated ES-SCLC patients evaluating different tarlatamab doses. At the 10-mg dose, tarlatamab achieved an ORR of 35–40% and median PFS of approximately 4–5 months. Notably, due to a prolonged duration of response, median OS was approximately 14–15 months, with no consistent differences according to platinum sensitivity (96-99). The most frequent adverse events are cytokine release syndrome (CRS) (any grade 49–56%, grade 3–4 ≤3%) and immune effector cell-associated neurotoxicity syndrome (ICANS), both occurring predominantly in early cycles (95,98,99). As previously mentioned, lurbinectedin and tarlatamab are currently under evaluation in the maintenance setting.

Other DLL3-directed T-cell engagers are being investigated in early-phase trials. Obrixtamig (BI 764532) has shown an ORR of 26% with prolonged duration of response (100). HPN328 (MK6070), a trispecific T-cell activating protein construct (Tri-Tac) containing CD3, DLL3 and albumin targeting domains, has shown an ORR of 50%, with no grade 3–4 CRS or ICANS (101). Lastly, alveltamig (ZG006), a trispecific T-cell engager targeting two different DLL3 epitopes and CD3, has achieved an overall ORR 66.7% (53.8% at 10 mg; 78.6% at 30 mg), with one grade 3 CRS event and no grade 4 CRS (102).

Given the coexistence of multiple transcriptional states within the same tumor, antibody-drug conjugates (ADCs) targeting broadly expressed antigens such as B7-H3 or TROP-2 offer a complementary approach to attack SCLC clones that may have lost DLL3 or neuroendocrine features under therapeutic pressure (74,90-93).

ADCs targeting B7-H3 (e.g., ifinatamab deruxtecan, HS-20093) have shown objective response rates in the ~50–60% range in early reports, and the phase III Ideate-Lung02 trial (NCT06203210) is ongoing (90,91). TROP-2 ADCs (e.g., sacituzumab govitecan, SHR-A1921) have reported ORRs of ~33–40% in early-phase trials (92,93), and ABBV-011 (a SEZ6-targeting ADC) has also shown preliminary activity (103). Gastrointestinal and hematologic toxicity are common, and interstitial lung disease has been observed with deruxtecan-based ADCs (90-93).

Radiotherapy in extensive-stage SCLC

Consolidative thoracic radiotherapy

Consolidative thoracic RT is used to address residual or persistent intrathoracic disease in patients with ES-SCLC with response to initial systemic therapy. This strategy aims to improve LC and OS by targeting remaining cancer cells within the thoracic region. The phase III CREST trial showed a reduced risk of intrathoracic recurrence and improved 2-year OS in patients who had a response to systemic treatment with consolidative thoracic RT (30 Gy in 10 fractions) (13% compared to 3% in the control group) (104). It is important to note that the primary endpoint (1-year OS) was not met, and the 2-year OS improvement was a secondary endpoint. A secondary analysis also demonstrated OS and PFS benefit in patients with <3 metastatic lesions. In contrast, the presence of liver and/or bone metastases were associated with significantly worse OS (105).

Prospective evidence on the role of consolidative thoracic RT following chemoimmunotherapy in ES-SCLC remains limited. A recent meta-analysis of 15 studies including 1,033 patients showed that the addition of thoracic RT to chemoimmunotherapy improved OS (HR =0.52, 95% CI: 0.39, 0.68) with manageable adverse events (106). In the absence of more robust data, consolidative thoracic RT may be considered for patients with residual or persistent disease following chemoimmunotherapy, in line with current international clinical guidelines.

PCI

The role of PCI in ES-SCLC remains controversial due to conflicting results from two pivotal phase III trials. In the EORTC trial, 286 patients with ES-SCLC who responded to chemotherapy were randomized to PCI (dose/fractionation at investigator discretion) versus observation. PCI significantly reduced the 1-year incidence of symptomatic brain metastases (14.6% vs. 40.4%; HR 0.27; P<0.001) and improved OS (median OS 6.7 vs. 5.4 months; HR 0.68; P=0.003), with a higher 1-year survival rate (27.1% vs. 13.3%) (107). However, baseline brain MRI was not mandated, raising the possibility that some patients harbored occult CNS disease at enrollment.

These findings were challenged by a Japanese phase III trial that required baseline brain MRI to exclude pre-existing metastases and used MRI surveillance every 3 months in the observation arm (43). Although PCI reduced the cumulative incidence of brain metastases (40.1% vs. 63.8% at 18 months), it did not improve OS (median OS 11.6 vs. 13.7 months; HR 1.27; P=0.094), and the trial was terminated early for futility.

The divergent OS results likely reflect differences in baseline CNS staging, surveillance intensity, and access to salvage treatment for detected brain metastases.

In the era of chemoimmunotherapy, the incremental value of PCI is even less clear. In a multicenter retrospective cohort, atezolizumab plus chemotherapy was associated with longer time to intracranial progression compared with chemotherapy alone (median 24.4 vs. 14.3 months; P=0.038), suggesting that chemoimmunotherapy may delay CNS progression in ES-SCLC (108).

In this context, MRI surveillance may be considered for patients receiving chemoimmunotherapy, reserving PCI for selected patients who are not receiving immunotherapy and/or for whom close MRI follow-up is not feasible.

Conclusions

SCLC remains an aggressive malignancy with poor long-term survival despite incremental therapeutic advances. In LS-SCLC, multimodal approaches combining optimal CRT, PCI in selected patients, and consolidation durvalumab have produced median survival exceeding four years, although cure remains elusive for the majority of patients. In ES-SCLC, ChT with PD-(L)1 inhibitors provides a modest but reproducible survival gain and has established a new standard backbone onto which additional agents can be layered. The next phase of progress could depend on embracing SCLC’s biological diversity. Prospective trials should incorporate molecular subtyping (ASCL1, NEUROD1, POU2F3 and inflamed SCLC-I) as a stratification factor or eligibility criterion or be powered to detect subtype-specific signals of benefit. Longitudinal tissue and liquid-biopsy studies may also be useful to map subtype switching and clonal evolution under therapy, informing rational sequencing of DLL3-targeted bispecifics, ADCs, PARP or epigenetic agents and novel IO combinations.

Overcoming the prototypically “cold” SCLC tumor microenvironment will also be critical. Strategies under evaluation include pairing checkpoint inhibitors with T-cell engagers or ADCs, targeting immunosuppressive myeloid populations, or using epigenetic or metabolic modulators to increase antigen presentation and T-cell infiltration.

Ultimately, integrating molecular classification, real-time biomarkers of resistance and innovative agents offers a realistic path to move SCLC treatment from a single-shot, cytotoxic paradigm toward adaptive, biology-driven therapy. Until then, enrollment in clinical trials should be strongly encouraged at every line of treatment, as it remains the fastest way to translate emerging scientific insights into improved outcomes for patients with this recalcitrant disease.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-104/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-104/coif). A.B. reports grants from Bristol-Myers Squibb (Clinical trial CA224-1044), Dizal (Nos. DZ2022E0005, DZ2019E0001), and Pfizer (Clinical trial C4221016); consulting fees from AstraZeneca, Roche, and Sanofi; advisory board participation in AstraZeneca, Roche, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus from AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Novartis, Pfizer, Pierre Fabre, Regeneron, Roche, Sanofi; payment for expert testimony from Bristol-Myers Squibb; and support for attending meetings and/or travel from Janssen, Pfizer, Pierre Fabre. S.M.R. reports the payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, AstraZeneca, Pierre Fabre, Sanofi, Bristol-Myers Squibb, Takeda, Novartis, Lilly, Regeneron; and support for attending meetings and/or travel from Roche, Lilly, Merck, Pfizer, Bristol-Myers Squibb, Novartis, MSD, Pierre Fabre, Janssen. M.P. reports the payment or honoraria for lectures, presentations from Merck, and support for attending meetings and/or travel from Pfizer, Roche, and Janssen. M.M. reports grants from Bristol-Myers Squibb, AstraZeneca, F. Hoffmann-La Roche Ltd.; travel and accommodation support from AstraZeneca, F. Hoffmann-La Roche Ltd., Pfizer, MSD; consulting fees, payment or honoraria as invited speaker/lecturer and educational events, as well as advisory board participation, from Amgen, AstraZeneca, Boehringer Ingelheim, BeOne, Bristol-Myers Squibb, Helsinn Therapeutics, Johnson & Johnson, MSD, Novartis, Pfizer, Pharmamar, F. Hoffmann-La Roche Ltd., Takeda, Sanofi, Regeneron, Casen Recordati, Immedica. The other authors have no conflicts of interest to declare.

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