Current and future pharmacological therapies for extensive-stage small-cell lung cancer
- Open Access
- 28.04.2025
- short review
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Summary
Introduction
Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor subtype, accounting for 15% of lung cancers [1]. The median age at diagnosis is approximately 70 years, with smoking remaining the primary risk factor.
Prognosis largely depends on the clinical stage. In very limited stage (VLS; corresponding to T1–2 N0–1 in the World Health Organization classification) or limited stage (LS; T3–4 and/or N2–3), a platinum agent in combination with etoposide is administered concomitantly with radiotherapy resulting in a 5-year survival of 30–35% [2]. As recently published consolidation therapy with the programmed death-ligand 1 (PD-L1) checkpoint inhibitor durvalumab, given every 4 weeks for up to 24 months after radiochemotherapy for LS-SCLC, resulted in remarkable prolongation of median progression-free survival (PFS), with 16.6 (95% CI: 10.2–28.2) vs. 9.2 months (95% CI: 7.4–12.9) and median overall survival (OS) of 55.9 (95% CI: 37.3–not reached) vs. 33.4 months (95% CI: 25.5–39.9) for the investigational and the control arm, respectively, and can be considered a new standard of care [3]. Of note, in VLS, surgery followed by adjuvant platinum-based chemotherapy may be an alternative to radiochemotherapy. The individual approach should be discussed in a multidisciplinary tumor board.
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Unfortunately, the majority of patients (approximately 65%) are diagnosed with metastatic disease, i.e., extensive-stage SCLC (ES-SCLC) and long-term prognosis is poor. At this stage, SCLC is regarded as a systemic disease and local therapies play a subordinate role. Treatment primarily focuses on systemic pharmacological therapy. This review provides an overview of the current standard of care and aims to highlight potential new treatment options for ES-SCLC.
Standard of care and recent developments
First-line therapy
Standard first-line therapy for ES-SCLC in eligible patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 consists of a platinum doublet chemotherapy (i.e., cisplatin or carboplatin plus etoposide) in combination with a PD-L1 or PD‑1 checkpoint inhibitor (CPI) followed by CPI maintenance until progression or intolerable toxicity [4].
These regimens are based on three registrational phase 3 trials (see Table 1):
Table 1
Selected first-line study results of checkpoint inhibitors in extensive-stage small-cell lung cancer
Study name | Trial phase | Experimental agent (checkpoint inhibitor) vs. placebo | Additional chemotherapy backbone | Median OS (months) | HR (OS) (95% CI) | Median PFS (months) | HR (PFS) (95% CI) | Reference |
|---|---|---|---|---|---|---|---|---|
IMpower133 | Phase 3 | Atezolizumab | Carboplatin + etoposide | 12.3 vs. 10.3 | 0.70 (0.54–0.91) | 5.2 vs. 4.3 | 0.77 (0.62–0.96) | [5] |
CASPIAN | Phase 3 | Durvalumab | Platinum (cisplatin/carboplatin) + etoposide | 13.0 vs. 10.3 | 0.73 (0.59–0.91) | 5.1 vs. 5.4 | 0.78 (0.65–0.94) | [7] |
ASTRUM-005 | Phase 3 | Serplulimab | Carboplatin + etoposide | 15.4 vs. 10.9 | 0.63 (0.49–0.82) | 5.7 vs. 4.3 | 0.48 (0.38–0.59) | [10] |
RATIONALE-312 | Phase 3 | Tislelizumab | Platinum (cisplatin/carboplatin) + etoposide | 15.5 vs. 13.5 | 0.75 (0.61–0.93) | 4.7 vs. 4.3 | 0.64 (0.52–0.78) | [16] |
LBA93 EXTENTORCH | Phase 3 | Toripalimab | Platinum (cisplatin/carboplatin) + etoposide | 14.6 vs. 13.3 | 0.80 (0.65–0.98) | 5.8 vs. 5.6 | 0.67 (0.54–0.82) | [17] |
CAPSTONE‑1 | Phase 3 | Adebrelimab | Carboplatin + etoposide | 15.3 vs. 12.8 | 0.72 (0.58–0.90) | 5.8 vs. 5.6 | 0.67 (0.54–0.83) | [18] |
KEYNOTE-604 | Phase 3 | Pembrolizumab | Platinum (cisplatin/carboplatin) + etoposide | 10.8 vs. 9.7 | 0.80 (0.64–0.98) | 4.5 vs. 4.3 | 0.75 (0.61–0.91) | [14] |
ECOG-ACRIN EA5161 | Phase 2 | Nivolumab | Platinum (cisplatin/carboplatin) + etoposide | 11.3 vs. 8.5 | 0.67 (0.46–0.98) | 5.5 vs. 4.6 | 0.65 (0.46–0.91) | [15] |
ETER701 | Phase 3 | Benmelstobart + anlotinib (multi-target antiangiogenic molecule) | Carboplatin + etoposide | 19.3 vs. 11.9 | 0.61 (0.47–0.79) | 6.9 vs. 4.2 | 0.32 (0.26–0.41) | [56] |
The IMpower133 phase 3 trial evaluated the combination of carboplatin and etoposide with either atezolizumab or a placebo for four cycles, followed by maintenance treatment with atezolizumab or placebo until disease progression or unacceptable toxicity [5]. Prophylactic cranial irradiation therapy in the maintenance phase was allowed, with 11% of patients undergoing the radiation treatment in each arm [5].
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The median OS was superior in the experimental arm vs. the standard-of-care cohort (HR: 0.7; 95% CI: 0.54–0.91; 12.3 vs. 10.3 months) [3]. However, the 5‑year update of the IMbrella A extension trial reported a 5-year OS rate of only 12% [6]. No new safety signals were detected and the toxicity profile is consistent with that of the individual agents.
The randomized CASPIAN phase 3 study evaluated the efficacy and safety of a similar regimen (i.e., cisplatin or carboplatin plus etoposide) in combination with the PD-L1 inhibitor durvalumab with or without the cytotoxic T‑lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab, followed by durvalumab maintenance compared to the respective chemotherapy backbone [7].
Patients randomized to the chemotherapy plus durvalumab cohort achieved a longer median OS (13.0 months) compared to patients treated with chemotherapy only (10.3 months; HR: 0.73; 95% CI: 0.59–0.91). Longer follow-up demonstrated a 36-month OS rate of 17.6% in the durvalumab group, compared to 5.8% in the standard-of-care arm [8]. The subgroup analysis showed an advantage for the additional administration of durvalumab across all relevant subgroups and identified no predictive biomarker for this regimen, whereby the response was independent of PD-L1 status. Prophylactic cranial irradiation therapy was only permitted in the control arm (21/268 patients). Interestingly, the addition of tremelimumab to durvalumab and chemotherapy did not result in an additional survival benefit (OS: 10.4 months vs. 10.5 months; HR: 0.82; 95%: CI 0.68–1.00; [9]).
In the ASTRUM-005 phase 3 study, serplulimab, a PD‑1 inhibitor, was evaluated vs. placebo for efficacy and safety in combination with carboplatin and etoposide for up to four cycles, followed by serplulimab or placebo maintenance [10]. In the serplulimab arm, 67.4% of patients were of Asian descent and 32.6% were of non-Asian descent (all of whom were White).
Median OS was in favor of the serplulimab arm by reaching 15.4 months vs. 10.9 months in the placebo group (HR: 0.63; 95% CI: 0.49–0.82).
An extended follow-up subgroup analysis by race showed similar trends of a prolonged median OS in Asians (unstratified HR: 0.61; 95% CI: 0.48–0.77) and non-Asians (unstratified HR: 0.57; 95% CI: 0.39–0.83; [11]). The estimated OS rate at 3 years was 24.6% (95% CI: 19.5–30.1) and 9.8% (95% CI: 5.6–15.4) in the respective arms. In February 2025, serplulimab, in combination with carboplatin and etoposide, was approved by the European Medicines Agency.
Taken together, the aforementioned trials demonstrated a moderate but statistically significant OS benefit for chemo-immunotherapy over chemotherapy alone, establishing these regimens as the standard of care in this setting.
Of note, patients with an ECOG performance status of ≥ 2 due to SCLC (and not due to comorbidities) should be offered systemic doublet chemotherapy as well [4]. Due to its high initial activity in this setting, rapid tumor shrinkage and improvement of the general condition can be expected. However, for this patient group the role of adding a CPI is less clear, since CASPIAN, IMpower 133, and ASTRUM-005 excluded this patient population. Specifically, the addition of a CPI in this setting is recommended by the National Comprehensive Cancer Network (NCCN) but not the European Society for Medical Oncology (ESMO) guidelines [4, 12].
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Likewise, the role of thoracic radiation remains a matter of debate in the immunotherapy era, as this procedure was not permitted in the pivotal phase 3 studies. In the pre-immunotherapy era, Slotman et al. demonstrated an OS benefit for thoracic radiotherapy in patients with complete responses to systemic therapy and residual disease limited to the chest compared to no radiotherapy (2-year OS: 13% [95% CI: 9–19] for thoracic radiotherapy vs. 3% [95% CI: 2–8] for no radiotherapy; p = 0.004; [13]). Therefore, this procedure may be considered following a shared decision-making process for selected patients according to the ESMO guidelines [4].
Most notably, CPI trials employing the PD‑1 inhibitors nivolumab or pembrolizumab in predominantly Western ES-SCLC populations included smaller sample sizes or failed to show superiority over chemotherapy alone.
In the randomized KEYNOTE-604 phase 3 study, pembrolizumab plus chemotherapy resulted in a numerically improved OS, although the statistical significance threshold was not met (24-month OS rates were 23% vs. 11%, respectively; HR: 0.80; 95% CI: 0.64–0.98; [14]). In the ECOG-ACRIN EA5161 phase 2 study, nivolumab plus chemotherapy was compared with platinum-doublet therapy [15]. Although this study met its endpoints and OS was improved with nivolumab plus chemotherapy vs. chemotherapy alone (HR: 0.67; 95% CI: 0.46–0.98; OS: 11.3 vs. 8.5 months), no phase 3 data are available for nivolumab in the first-line ES-SCLC setting.
In contrast to the aforementioned studies, clinical phase 3 trials primarily conducted with Asian populations evaluating both PD‑1 and PD-L1 inhibitors in combination with chemotherapy such as tislelizumab, toripalimab, and adebrelimab met their primary endpoints resulting in regulatory approval in this region [16‐18].
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While cross-trial comparisons should be interpreted with caution, it is notable that the OS appears to be longer in the trials conducted in Asia. This phenomenon reflects a different tumor biology rather than an improved efficacy of those compounds and warrants further research.
An alternative chemotherapy regimen for patients with contraindications for CPI is combining a platinum agent with irinotecan (instead of etoposide). This approach is based on the findings of a Japanese phase 3 study published in 2002, assessing cisplatin with irinotecan or etoposide, respectively [17], with a median OS of 12.8 vs. 9.4 months in favor of the irinotecan arm [19]. However, trials conducted in Western populations could not replicate this benefit. While a similar efficacy could be demonstrated, partially different toxicity profiles (more gastrointestinal adverse events for irinotecan, more hematological adverse events for etoposide) should be considered [20‐22].
Molecular subtypes of SCLC
Based on the expression of key transcription regulators, four molecular subtypes have been defined for SCLC: SCLC‑A, SCLC‑N, SCLC‑P, and SCLC‑Y [23]. In a more recent publication, omitting the SCLC‑Y subgroup and replacing it with an SCLC‑I (“inflamed”) subtype was proposed [24]. In a retrospective analysis, the SCLC‑I subtype appeared to benefit more from CPI therapy. While research on the therapeutic implications of those molecular subtypes is ongoing, these investigations have no therapeutic consequences for standard clinical practice as of yet.
It should be noted that in SCLC, despite being considered a highly mutated tumor type, no common druggable mutations have been identified to date, in contrast to non-small-cell lung adenocarcinoma.
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Second-line therapy
Although initial response rates for standard first-line therapy are high, these responses are not durable, and the vast majority of patients experience disease relapse.
The recommended approach for second-line therapy depends on the response to first-line therapy and the treatment-free intervals (TFI; [4, 12]).
The outcomes for platinum-sensitive patients (TFI ≥ 3 months) are superior compared to platinum-resistant (TFI ≤ 3 months) patients [4]. Notably, there is no consensus between the European ESMO and the American NCCN guidelines regarding the definition of platinum sensitivity. The NCCN guidelines are more stringent requiring a TFI of ≥ 6 months to define platinum sensitivity [12].
For platinum-sensitive patients, re-challenge with first-line platinum-etoposide appears to be a valid option.
However, it should be noted that this recommendation was initially based on smaller studies, whereas more recent data did not demonstrate an OS benefit over topotecan, a topoisomerase 1 inhibitor available for second-line therapy [24]: A phase 3 study comparing carboplatin/etoposide re-challenge with topotecan in platinum-sensitive patients showed a median PFS for carboplatin plus etoposide of 4.7 months vs. 2.7 months for topotecan, while median OS was similar (7.5 months for carboplatin plus etoposide, and 7.4 months for topotecan; [25]).
For platinum-sensitive and platinum-resistant patients, topotecan is a valuable option and the only approved compound in this setting in Europe.
In a phase 3 study, topotecan exhibited significant improvement in OS vs. best supportive care, 25.9 weeks vs. 13.9 weeks, respectively [26]. In another phase 3 study, oral vs. IV formulations of topotecan yielded comparable results [27]. An additional study assessed topotecan vs. cyclophosphamide, doxorubicin, and vincristine (CAV). Topotecan was at least as effective as CAV, while providing symptom improvement [28]. Importantly, topotecan demonstrated intracranial activity [29].
Other possible therapies include CAV, temozolomide, irinotecan, etoposide, or paclitaxel [4].
Investigational agents
The investigational agents presented in this section represent a curated selection by the authors and should not be considered a comprehensive overview of the subject matter.
Lurbinectedin
Lurbinectedin inhibits oncogenic transcription, ultimately inducing apoptosis in tumor cells [30]. A phase 2 basket trial, investigating lurbinectedin monotherapy (3.2 mg/m2) in a variety of cancers, demonstrated encouraging results for SCLC with an overall response rate (ORR) of 35% (22.2% in platinum-resistant and 45% in platinum-sensitive patients), a median PFS of 3.5 (95% CI: 2.6–4.3) months, and an OS of 9.3 (95% CI: 6.3–11.8) months ([31]; see Table 2).
Table 2
Selected second-line study results in extensive-stage small-cell lung cancer
Investigational agent | Comparator arm | Study phase | Overall response rate | Median OS (months) | HR (OS) (95% CI) | Median PFS (months) | HR (PFS) (95% CI) | Reference |
|---|---|---|---|---|---|---|---|---|
Topotecan | Best supportive care | 3 | 7% (5/71) vs. NR | 6.0 vs. 3.2 | 0.64 (0.45 to 0.90) | NR | NR | [26] |
Carboplatin etoposide re-challenge | Topotecan | 3 | 49% (39/81) vs. 25% (19/81) | 7.5 vs. 7.4 | 1.03 (0.87–1.19) | 5.7 vs. 3.6 | 0.50 (0.37–0.68) | [25] |
Lurbinectedin (3.2 mg/m2 dose) | – | 2 | 35.2% (37/105) | 9.3 | – | 3.5 | – | [31] |
Lurbinectedin (2.0 mg/m2 dose) + doxorubicin | Topotecan, irinotecan, CAV | 3 | 32% (97/307) vs. 30% (91/306) | 8.6 vs. 7.6 | 0.97 (0.82–1.15) | 4.0 vs. 4.0 | 0.83 (0.69–1.00) | [32] |
Tarlatamab (10 mg dose) (AMG 757) | – | 2 | 40% (40/100) | 15.2 | – | 4.9 | – | [38] |
However, the subsequent phase 3 ATLANTIS trial, investigating lurbinectedin plus doxorubicin as second-line therapy vs. topotecan, irinotecan, or CAV failed to demonstrate a significant advantage in the primary endpoint OS [32].
While less hematologic toxicity occurred in the experimental arm, it has to be emphasized that lurbinectedin was administered at a dose of 2.0 mg/m2, which might have contributed to the negative outcome of this study.
After yielding promising results for the combination of lurbinectedin and irinotecan in a phase 2 trial [33], the phase 3 LAGOON trial, investigating two experimental arms, lurbinectedin monotherapy or lurbinectedin plus irinotecan, respectively, vs. the control arm, topotecan or irinotecan, has recently completed accrual [34].
More importantly, a recent press release revealed that the phase 3 Imforte trial evaluating the efficacy of lurbinectedin plus atezolizumab maintenance therapy after platinum, etoposide, plus atezolizumab induction therapy in first-line ES-SCLC met its primary endpoint, improving both OS and PFS vs. atezolizumab alone [35].
Lurbinectedin monotherapy is currently approved for second-line therapy of ES-SCLC by the U.S. Food and Drug Administration (FDA) and recommended by the ESMO as an investigational option in Europe.
Surface-protein targeting agents
DLL3-targeting-agents
Delta-like ligand 3 (DLL3) is a protein involved in NOTCH signaling inhibition. While DLL3 is frequently overexpressed on the cell surface of SCLC cells, it appears to be minimally or not expressed on normal cells, rendering it an interesting therapeutic target [36]. In a real-world analysis, the overexpression of DLL3 (defined as ≥ 25% of tumor cells) was identified in 895/1050 (85%) of SCLC specimens, with 719/1050 (68%) displaying a high DLL3 expression (defined as ≥ 75% of tumor cells; [37]).
Tarlatamab (known as AMG 757) and obrixtamig (BI 764532) are bispecific antibodies, coupling DLL3 with the T‑cell protein CD3, inducing T‑cell-mitigated cell lysis. Furthermore, HPN328 also links DLL3 with CD3, with an additional domain binding to albumin for half-life extension, rendering it a trispecific antibody.
Tarlatamab is the most advanced compound in clinical development. In the phase 2 DeLLphi-301 study, 10 mg or 100 mg of tarlatamab was administered intravenously in previously treated SCLC patients (median number of prior therapies = 2), regardless of DLL3 expression. The 10-mg dose of tarlatamab resulted in an encouraging ORR of 40% and a duration of response of at least 6 months in 59% of the patients [38].
The most common adverse event was cytokine release syndrome (CRS), detected in 51% of patients in the 10-mg dose group. Overall, 1% of patients experienced a CRS grade 3 event, and no grade 4 or 5 events were reported; CRS occurred primarily during cycle 1.
Another adverse event of interest, immune effector cell-associated neurotoxicity syndrome (ICANS), was observed in 8% of patients, with no grade 3 or higher events reported.
In an updated analysis of the 10-mg dosage subgroup with a median follow-up of 12.1 months, a minor but relevant portion of patients of 29.4% (5 of 17) experienced durable disease control [39].
Biomarker studies, including DLL3 expression analysis for the DeLLphi-301 study, are pending. In preclinical studies, a low expression of DLL3 was sufficient for high-efficacy killing of SCLC cells [40]. Likewise, an exploratory analysis of a phase 1 study, suggested a higher magnitude of clinical benefit with increased DLL3 expression [41].
Furthermore, 62.5% (10 of 16) of patients with baseline CNS metastases experienced tumor shrinkage. While previous intracranial radiotherapy was obligatory, those numbers suggest potential intracranial activity of tarlatamab.
Tarlatamab is currently being assessed in a variety of studies, including in the first-line setting as a single agent or in combination with other drugs including CPI.
In May 2024, FDA accelerated approval was granted for tarlatamab for patients experiencing relapse on or after platinum-based chemotherapy. A potential EMA approval is awaited and a confirmatory phase 3 study in SCLC is underway [42].
Another DLL3/CD3 T‑cell engager, obrixtamig (BI 764532), demonstrated efficacy in a phase 1 trial with a reported ORR of 33% (8/24) for pretreated SCLC ([43]; see Table 3). Notably, in this study, the tumor had to be positive for DLL3 expression.
Table 3
Selected phase 1 and phase 2 study results in extensive-stage small-cell lung cancer
Investigational agent | Median prior lines of therapy (range) | Study phase | Overall response rate | Reference |
|---|---|---|---|---|
Obrixtamig (BI 764532) | ≥ 2 prior lines of therapy: 69% | 1 | 33% (8/24) | [43] |
HPN 328 | 3 (1–7) | 1 | 50% (12/24) | [44] |
Ifinatamab deruxtecan (DS-7300) | 2.0 (1–3) | 2 | 54.8% (23/42) | [46] |
ABBV-706 | 2.5 (1–6) | 1 | 40% (6/15) | [51] |
In an updated analysis of a phase 1/2 study, the confirmed ORR for HPN328 was 50% (12/24; [44]).
Agents targeting other molecules
Ifinatamab deruxtecan (I-DXd), formerly known as DS-7300, is an antibody–drug conjugate (ADC) targeting B7 homolog 3 (B7-H3). B7-H3 possesses an immune checkpoint function, but has also been linked to cell proliferation and metastasis [45]. In the IDeate-Lung01 phase 2 trial, a dose of 12 mg/kg I‑DXd resulted in a response rate of 54.8% (23/42), a PFS of 5.5 months, and an OS of 11.8 months in pretreated ES-SCLC patients (median 2 prior lines of therapy), as presented at the 2024 World Conference on Lung Cancer (WCLC; [46]). I‑DXd demonstrated intracranial activity with an ORR of 38% (14/38) in patients with baseline brain metastases [47]. The phase 3 trial IDeate-Lung02 recently started recruiting [48].
Sacituzumab govitecan is a trophoblast cell-surface antigen 2 (TROP2)-directed ADC. In an updated analysis of a phase 2 study evaluating this drug in relapsed ES-SCLC, the investigator-assessed ORR was 41.9% among 43 patients, and median PFS and OS were 4.4 and 13.6 months, respectively [49]. A following phase 3 trial is planned.
Another potential target in SCLC is seizure-related homolog 6 (SEZ6). Two SEZ-6-targeting ADCs elicited in their respective phase 1 studies in relapsed ES-SCLC a response rate of 25% (10/40) for 1 mg/kg of ABBV-011 and a confirmed response rate of 40% (6/15) as well as an unconfirmed response rate of 76% (11/15) for ABBV-706 [50, 51]. ABBV-011 was discontinued from further clinical development.
In a randomized two-arm phase 2 study, BMS-986012, binding fucosyl-GM1 (fuc-GM1), is being evaluated in the first-line setting for ES-SCLC in combination with four induction cycles of carboplatin/etoposide/nivolumab, followed by BMS-986012/nivolumab maintenance therapy for up to 2 years, vs. induction therapy of carboplatin/etoposide/nivolumab, and maintenance therapy of nivolumab only. In a planned interim analysis, the safety profiles between the arms were similar. While the median PFS was also similar (5.8 vs. 5.1 months), there was an encouraging signal for a median OS improvement in the experimental arm (15.6 vs. 11.4 months; [52]).
Antiangiogenic therapy
Prior to the era of CPI therapy in first-line ES-SCLC, adding antiangiogenic compounds such as the vascular endothelial growth factor (VEGF)–antibody bevacizumab to standard first-line chemotherapy did not result in improved OS [53, 54]. Consistently, the addition of bevacizumab to the current first-line standard-of-care platinum plus etoposide in combination with atezolizumab showed a prolonged PFS but a worse OS for the experimental arm [55].
From this perspective, the results of a placebo-controlled, three-arm, Chinese phase 3 trial stand out, assessing the PD-L1-inhibitor benmelstobart, the multikinase-inhibitor anlotinib, and chemotherapy (platinum agent plus etoposide; arm A) vs. anlotinib and chemotherapy (arm B) and chemotherapy only in first-line ES-SCLC (arm C; [56]). In an interim report, the co-primary endpoint, median OS, was prolonged in arm A compared to arm C (19.3 vs. 11.9 months) and also showed a trend in favor of arm B compared to arm C (13.3 vs. 11.9 months). The main limitation of this study is the absence of a CPI in the (chemotherapy) control arm, rendering implications for standard clinical practice difficult.
Conclusion
In the first-line treatment of ES-SCLC, the addition of a checkpoint inhibitor (such as atezolizumab, durvalumab, or serplulimab) to a chemotherapy regimen of a platinum agent and etoposide represents the standard of care for eligible patients. While these regimens achieve high response rates, the vast majority of patients ultimately relapse.
For second-line therapy of ES-SCLC, topotecan remains the only approved agent in Europe, although several alternative therapies are recommended as options by ESMO or NCCN. The long-term prognosis remains poor for most patients.
Nevertheless, several promising investigational drugs are on the horizon, offering hope for improved treatment options. The furthest along in clinical development are lurbinectedin, a selective inhibitor of oncogenic transcription, and tarlatamab, a bispecific antibody targeting DLL3 and CD3. Both agents have already been approved by the FDA for relapsed ES-SCLC in the United States, with authorization in Europe still pending.
Take-home message
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For ES-SCLC, the recommended first-line therapy is the combination of a platinum agent, etoposide, and an approved PD‑1 or PD-L1 checkpoint inhibitor.
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Topotecan remains the only EMA-approved second-line therapy.
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Lurbinectedin, a selective inhibitor of oncogenic transcription, is currently approved by the FDA but not the EMA.
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Several DLL3-targeting agents yielded encouraging results. The bispecific tarlatamab is furthest in clinical development and is approved by the FDA.
Conflict of interest
J. Schöche received honoraria for lectures or advisory board participation from the following for-profit companies (all outside of the submitted work): from Amgen, AOP, Beigene, BMS, GSK, Johnson & Johnson, Miltenyi Biomedicine, Servier; and travel grants from Johnson & Johnson and Roche. A. Steindl received a travel grant from Pierre Fabre. T. Fuereder declares honoraria (MSD; BMS, Astra Zeneca, Roche, Sanofi; Merck; BI, Janssen, Eli Lilly, Invios, Takeda, Amgen, GSK, Astra Zeneca, Pfizer, Pierre Fabre); consulting or advisory roles (MSD; BMS, Astra Zeneca, Roche, Sanofi; Merck; BI, Janssen, Eli Lilly, Invios, Takeda, Amgen, GSK, Beigene, Daiichi, PharmaMar); research funding (MSD; Merck); and travel, accommodation and expenses (MSD, Merck, Roche). B. Kiesewetter received honoraria for lectures or advisory board participation from the following for-profit companies (all outside of the submitted work): from AAA, AstraZeneca, BMS, Beigene, Daichii Sankyo, Boehringer Ingelheim, Ipsen, MSD, Novartis, Eli Lilly, Roche, and Janssen Cilag.
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