Current and Emerging Therapeutic Strategies for Limited- and Extensive-Stage Small-Cell Lung Cancer
Abstract
1. Introduction
2. Pathobiology: From Histology to Molecular Subtypes
2.1. Histopathology and Immunohistochemistry
2.2. Genomic Landscape and Molecular Drivers
2.3. Molecular Subtyping
2.3.1. SCLC-A (ASCL1)
2.3.2. SCLC-N (NEUROD1)
2.3.3. SCLC-P (POU2F3)
2.3.4. SCLC-I (Inflamed)
3. Staging Paradigms
3.1. The Veterans Administration Lung Study Group (VALSG) Two-Stage System
3.1.1. Limited-Stage SCLC (LS-SCLC)
3.1.2. Extensive-Stage SCLC (ES-SCLC)
4. Staging Workup
5. Management of Limited-Stage SCLC (LS-SCLC): A Curative-Intent Paradigm
5.1. The Cornerstone of Concurrent Chemoradiotherapy (cCRT): Evidence and Regimens
5.1.1. Chemotherapy Backbone
5.1.2. Cisplatin vs. Carboplatin
5.1.3. Alternative Regimens
5.1.4. Timing of cCRT
5.2. Optimizing Thoracic Radiotherapy: Dose, Fractionation, and Technology
5.2.1. Dose and Fractionation
5.2.2. Standard Regimen
5.2.3. Alternative Regimen
5.2.4. Prophylactic Cranial Irradiation (PCI)
Efficacy in LS-SCLC
PCI Dose
5.3. The MRI-Era Controversy and Neurotoxicity
5.3.1. Impact of MRI
5.3.2. Neurotoxicity
5.3.3. Hippocampal Avoidance (HA-PCI):
5.4. Current Treatment Options for Limited-Stage SCLC
5.5. Current Ongoing Clinical Trials for Limited-Stage SCLC (Table 2)
6. Extensive-Stage SCLC
6.1. Management of First Line of Therapy for Extensive-Stage SCLC
6.1.1. IMpower133 Trial (Atezolizumab)
6.1.2. CASPIAN Trial (Durvalumab)
6.1.3. RATIONALE-312 Trial (Tislelizumab)
6.1.4. ASTRUM-005 Trial (Serplulimab)
6.1.5. IMforte Trial (New Strategy for Induction Phase: Atezolizumab Monotherapy or a Combination of Atezolizumab and Lurbinectedin)
Feature | IMpower133 [53,54] | CASPIAN [55] | RATIONALE-312 [56] | ASTRUM-005 [57] | IMforte [58] |
---|---|---|---|---|---|
Study Design | First-line induction | First-line induction | First-line induction | First-line induction | First-line maintenance (after chemoimmunotherapy induction) |
Study Drug(s) | Atezolizumab + carboplatin + etoposide | Durvalumab + platinum + etoposide (± tremelimumab) | Tislelizumab + platinum (carboplatin or cisplatin) + etoposide | Serplulimab + carboplatin + etoposide | Lurbinectedin + atezolizumab vs. atezolizumab alone (maintenance after platinum–etoposide–atezo) |
Primary Endpoint | OS and PFS (co-primary) | OS | OS | OS | OS and IRF-assessed PFS (co-primary, from randomization into maintenance) |
OS (Median) | 12.3 months (vs. 10.3 months for chemo alone) | 13.0 months (vs. 10.3 months for chemo alone) (durvalumab + EP arm) | 15.5 months (vs. 13.5 months for chemo alone) | 15.4 months (vs. 10.9 months for chemo alone) | 13.2 months (lurbinectedin + atezo) vs. 10.6 months (atezo alone) |
PFS (Median) | 5.2 months (vs. 4.3 months for chemo alone) | 5.1 months (durvalumab + EP arm; vs. 5.4 months chemo alone) | 6.9 months (vs. 4.2 months for chemo alone) | 5.7 months (vs. 4.3 months for chemo alone) | 5.4 months (lurbinectedin + atezo) vs. 2.1 months (atezo alone) |
Patients Enrolled | 403 | 805 (randomized to 3 arms) | 457 | 585 | 483 (maintenance phase; 660 patients initially enrolled in induction phase) |
Most Common AEs (Grade 3/4) | Neutropenia, anemia, thrombocytopenia, febrile neutropenia, fatigue | Neutropenia, anemia, thrombocytopenia, leukopenia | Neutropenia, ↓ WBC count, anemia, thrombocytopenia, alopecia, nausea | Neutropenia, ↓ WBC count, anemia, thrombocytopenia | Higher AE incidence in combo arm (83.5% vs. 40%); Grade 3/4 AEs: 25.6% (combo) vs. 5.8% (atezo alone). Specific AEs not detailed. |
6.2. Therapeutic Approaches Following Disease Progression in Extensive-Stage SCLC
6.2.1. Platinum-Sensitive Relapse (TFI > 6 Months)
6.2.2. Platinum-Resistant/-Refractory Relapse (TFI < 6 Months)
6.2.3. Lurbinectedin
6.2.4. Topotecan
6.2.5. Tarlatamab
6.2.6. Clinical Trials
6.3. The Role of Consolidative Thoracic Radiotherapy in the Immunotherapy Era
6.4. Management of Brain Metastases
6.4.1. The Evolving Role of PCI and MRI Surveillance in ES-SCLC
6.4.2. Indication for Surgical Intervention
Management of Hemorrhagic Metastases
Diagnostic Uncertainty
6.5. Current Ongoing Clinical Trials for Extensive-Stage SCLC (Table 4)
7. Discussion
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Abbreviation | Full Term |
LS-SCLC | Limited-stage small-cell lung cancer |
SCLC | Small-cell lung cancer |
ES-SCLC | Extensive-stage small-cell lung cancer |
PCI | Prophylactic cranial irradiation |
cCRT | Concurrent chemoradiotherapy |
ICIs | Immune checkpoint inhibitors |
NCCN | National Comprehensive Cancer Network |
ESMO | European Society for Medical Oncology |
BiTEs | Bi-specific T-cell engagers |
IHC | Immunohistochemical |
NSCLC | Non-small-cell lung cancer |
TTF-1 | Thyroid transcription factor-1 |
RB1 | Retinoblastoma 1 |
TP53 | Tumor suppressor protein 53 |
MYC | Myelocytomatosis |
FHIT | Fragile Histidine Triad Diadenosine Triphosphatase |
ASCL1 | Achaete-scute homolog 1 |
NEUROD | Neurogenic Differentiation Factor 1 |
POU2F3 | POU Class 2 Homeobox 3 |
HPF | High-pass filter |
MRI | Magnetic resonance imaging |
CT | Contrast-enhanced computed tomography |
PET-CT | Positron emission tomography–contrast-enhanced computed tomography |
EP | Platinum agent and etoposide |
OS | Overall survival |
PFS | Progression-free survival |
TRT | Thoracic radiotherapy |
AEs | Adverse events |
ORR | Overall response rate |
DOR | Duration of response |
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Feature Category | Specific Marker/Feature | Typical Finding/Prevalence | Clinical/Biological Significance |
---|---|---|---|
Cell Size | Small (<3x lymphocyte diameter) | Diagnostic criterion | |
Cytoplasm | Scant | Diagnostic criterion | |
Chromatin | Finely granular (“salt and pepper”) | Diagnostic criterion, distinguishes from NSCLC | |
Histology | Nucleoli | Absent or inconspicuous | Key distinguishing feature from NSCLC |
Mitotic Rate | High (>10 per 10 HPF) | Reflects rapid proliferation | |
Nuclear Molding | Present | Diagnostic feature of cellular crowding | |
Ki-67 Index | High (>80%) | Hallmark of high-grade proliferation | |
Immunohistochemistry | Synaptophysin, Chromogranin, CD56 | Positive | Confirms neuroendocrine differentiation |
TTF-1 | Positive (~90%) | Confirms pulmonary origin | |
p-RB | Negative/absent | Reflects universal RB1 gene inactivation | |
TP53 Inactivation | >90% | Loss of key tumor suppressor and apoptosis regulator | |
Key genetic alterations | RB1 Inactivation | >95% | Loss of key cell cycle gatekeeper |
Chromosome 3p Deletion | >90% | Loss of tumor suppressor genes (e.g., FHIT) | |
MYC Family Amplification | ~30% | Drives proliferation | |
SCLC-A | ASCL1-high | Most common subtype, classic neuroendocrine features | |
Molecular subtypes (inflamed signature with absence of ASCL-1, NEUROD1, POU2F3) | SCLC-N | NEUROD1-high | Associated with metastasis and combined histology |
SCLC-P | POU2F3-high | Non-neuroendocrine variant, distinct biology | |
SCLC-I | Inflamed signature | Immune-infiltrated, potential for immunotherapy response |
Study Title (NCT Number) | Main Therapeutic Strategy | Simplified Patient Participants | Common Primary Endpoints (Highly Likely) | Reference |
---|---|---|---|---|
Phase 3 Study of Toripalimab Alone or in Combination With Tifcemalimab as Consolidation Therapy | Immunotherapy (Toripalimab ± Tifcemalimab) as consolidation after cCRT | Adults with LS-SCLC, ECOG 0–1, achieved CR/PR/SD after platinum-based cCRT | OS, PFS, Safety | [7,48] |
General Research Direction | Immunotherapy (concurrent or consolidation) with chemoradiotherapy; PCI vs. surveillance | LS-SCLC patients post-treatment or in combination with standard therapy | OS, PFS, Brain Metastasis Rate, QoL | [25,49] |
Study Title (NCT Number) | Main Therapeutic Strategy | Simplified Patient Participants | Common Primary Endpoints | REF |
---|---|---|---|---|
RAPTOR Trial: Testing Radiation with Atezolizumab (NCT04402788) | Addition of Thoracic Radiation to Atezolizumab | ES-SCLC patients on atezolizumab | OS, PFS, Local Control, Safety | [66] |
Iadademstat + Atezolizumab/Durvalumab (NCT06287775) | LSD1 Inhibitor (Iadademstat) + Immunotherapy | SCLC patients (mostly ES-SCLC) | ORR, DOR, PFS, OS, Safety | [73] |
Ifinatamab Deruxtecan vs. Physician’s Choice (NCT06203210) | Antibody-Drug Conjugate (ADC) vs. Standard Therapy | Relapsed SCLC patients (ES-SCLC or relapsed LS-SCLC) | OS, PFS, ORR, Safety | [74] |
IDeate-Lung03: I-DXd + Atezolizumab ± Carboplatin (NCT06362252) | ADC (I-DXd) + Atezolizumab ± Carboplatin (1L Induction/Maintenance) | ES-SCLC patients in the first-line setting | PFS, OS, ORR, Safety | [75] |
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Shalata, W.; Naamneh, R.; Najjar, W.; Asla, M.; Abu Gameh, A.; Abu Amna, M.; Saiegh, L.; Agbarya, A. Current and Emerging Therapeutic Strategies for Limited- and Extensive-Stage Small-Cell Lung Cancer. Med. Sci. 2025, 13, 142. https://doi.org/10.3390/medsci13030142
Shalata W, Naamneh R, Najjar W, Asla M, Abu Gameh A, Abu Amna M, Saiegh L, Agbarya A. Current and Emerging Therapeutic Strategies for Limited- and Extensive-Stage Small-Cell Lung Cancer. Medical Sciences. 2025; 13(3):142. https://doi.org/10.3390/medsci13030142
Chicago/Turabian StyleShalata, Walid, Rashad Naamneh, Wenad Najjar, Mohnnad Asla, Adam Abu Gameh, Mahmoud Abu Amna, Leonard Saiegh, and Abed Agbarya. 2025. "Current and Emerging Therapeutic Strategies for Limited- and Extensive-Stage Small-Cell Lung Cancer" Medical Sciences 13, no. 3: 142. https://doi.org/10.3390/medsci13030142
APA StyleShalata, W., Naamneh, R., Najjar, W., Asla, M., Abu Gameh, A., Abu Amna, M., Saiegh, L., & Agbarya, A. (2025). Current and Emerging Therapeutic Strategies for Limited- and Extensive-Stage Small-Cell Lung Cancer. Medical Sciences, 13(3), 142. https://doi.org/10.3390/medsci13030142