Small-Cell Lung Cancer—An Update on Targeted and Immunotherapies
Abstract
1. Introduction
2. Pathological and Genomic Profiles of SCLC
3. Current Standard Treatment
3.1. Limited Stage SCLC
3.2. Extensive Stage SCLC
Study | Year | Agents | Phase; Line (n) | Key Results |
---|---|---|---|---|
First Line Treatment | ||||
IMpower133 [5] | 2018 | EP +/− atezolizumab | III; 1 (403) | EP + atezolizumab: mOS 12.3 mo EP + placebo: mOS 10.3 mo (p = 0.0154) |
CASPIAN [22] | 2019 | EP + durvalumab + tremelimumab or EP + durvalumab or EP alone | III; 1 (805) | EP + durva + trem: mOS 10.4 mo EP + durva: mOS 12.9 mo EP alone: mOS 10.5 mo |
KEYNOTE-604 [23] | 2020 | EP +/− pembrolizumab | III; 1 (453) | EP + pembrolizumab: mOS 10.8 mo EP + placebo: 9.7 mo (p = 0.0164 1) |
CheckMate 451 [24] | 2021 | EP -> ipilimumab + nivolumab followed by nivolumab, or EP -> nivolumab, or EP -> placebo | III; 1 (849) | EP -> ipi/nivo: mOS 9.2 mo EP -> nivo: mOS 10.4 mo EP -> placebo: 9.6 mo |
CAPSTONE-1 [25] | 2022 | EP +/− adebrelimab | III; 1 (462) | EP + adebrelimab: mOS 15.3 mo EP + placebo: mOS 12.8 mo (p = 0.0017) |
ASTRUM-005 [26] | 2022 | EP +/− serplulimab | III; 1 (585) | EP + serplulimab: mOS 15.4 mo EP + placebo: mOS 10.9 mo (p < 0.001) |
Recurrent Disease | ||||
CheckMate 032 [28] | 2016 | Nivolumab 2 | I/II; ≥3 (109) | mPFS 1.4 mo; mOS 5.6 mo |
KEYNOTE-028, KEYNOTE-158 [29] | 2020 3 | Pembrolizumab (10 mg/kg q2 weeks, n = 19, 200 mg q3 weeks n = 64) | Ib/II; ≥2 (83) | mPFS 2.0 mo, mOS 7.7 mo (mOS 14.6 mo for PD-L1 CPS ≥ 1) |
4. Recurrent Disease
4.1. Chemotherapy
4.2. Immunotherapy
4.3. Alkylating Agent—Lurbinectedin
5. Emerging Therapies
5.1. Antibody–Drug Conjugates (ADCs)
5.1.1. DLL-3 Targeting ADCs
5.1.2. TROP-2 Directed ADCs
5.2. PARP Inhibitors
Agents | Study Design | Key Results |
---|---|---|
Veliparib + temozolomide [58] | Phase II, randomized, placebo-controlled N = 104 | TMZ/veliparib mOS 8.2 mo; ORR 39% TMZ/placebo mOS 7.0 mo; ORR 14% SLFN11 predicted improved PARPi response |
Olaparib + temozolomide [59] | Phase I/II, single-arm N = 48 | mOS 6.7 mo; ORR 41% * |
Fuzuloparib + SHR-1316 (PD-L1 inhibitor) [63] | Phase Ib, multi-stage N = 23 | mOS 5.6 mo; ORR 6.3% * |
Olaparib + durvalumab [62] | Phase II, single-arm N = 20 | mOS 4.1 mo; ORR 10.5% 1 CR in BRCA-mutant disease |
5.3. Anti-Angiogenesis
5.4. Tyrosine Kinase Inhibitors
5.5. Bispecific T-Cell Engagers
6. Discussion
7. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Subtype (Key Gene; % of Sample 1) | Key Characteristics | Potential Therapeutic Vulnerabilities |
---|---|---|
SCLC-A (ASCL1; 51%) | Neuroendocrine, epithelial subtype; TTF1 expression | BCL2 inhibitors |
SCLC-N (NEUROD1; 23%) | Neuroendocrine, lacks TTF1 expression, cMYC expression | Aurora kinase inhibitors (AURKi) |
SCLC-P (POU2F3; 7%) | Less neuroendocrine (NE) expression | PARP inhibitors, antimetabolites, AURKi |
SCLC-I (inflamed; 17%) 2 | Less NE expression, mesenchymal type | Immune checkpoint inhibitors |
First line | Carboplatin or cisplatin, etoposide + atezolizumab or durvalumab |
Second line | CAV (cyclophosphamide, doxorubicin, vincristine) Topotecan Lurbinectedin * Nivolumab + Pembrolizumab |
Agents | Study Design | Key Results |
---|---|---|
Cediranib [69] | Phase II, single-arm N = 25 | mPFS 2 mo; mOS 6 mo; No confirmed objective responses |
Sorafenib [70] | Phase II, single-arm N = 89 | Platinum-sensitive: mOS 6.7 mo; ORR 11% Platinum-resistant: mOS 5.3 mo; ORR 2% |
Apatinib [71] | Phase II, single-arm N = 57 | mOS 11.2 mo; ORR 14.3% |
Anlotinib [72] | Retrospective N = 40 | mOS 7.8 mo; ORR 10% |
Pazopanib [73] | Phase II, single-arm N = 58 | Platinum-sensitive: mOS 8.0 mo; ORR 17.9% Platinum-resistant: mOS 4.0 mo; ORR 5.3% |
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McNamee, N.; da Silva, I.P.; Nagrial, A.; Gao, B. Small-Cell Lung Cancer—An Update on Targeted and Immunotherapies. Int. J. Mol. Sci. 2023, 24, 8129. https://doi.org/10.3390/ijms24098129
McNamee N, da Silva IP, Nagrial A, Gao B. Small-Cell Lung Cancer—An Update on Targeted and Immunotherapies. International Journal of Molecular Sciences. 2023; 24(9):8129. https://doi.org/10.3390/ijms24098129
Chicago/Turabian StyleMcNamee, Nicholas, Ines Pires da Silva, Adnan Nagrial, and Bo Gao. 2023. "Small-Cell Lung Cancer—An Update on Targeted and Immunotherapies" International Journal of Molecular Sciences 24, no. 9: 8129. https://doi.org/10.3390/ijms24098129
APA StyleMcNamee, N., da Silva, I. P., Nagrial, A., & Gao, B. (2023). Small-Cell Lung Cancer—An Update on Targeted and Immunotherapies. International Journal of Molecular Sciences, 24(9), 8129. https://doi.org/10.3390/ijms24098129