EP. 1: Extensive-Stage Small Cell Lung Cancer Treatment Landscape

Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) is the most aggressive type of lung cancer, characterized by a rapid doubling time.¹ This form of lung cancer is most frequently diagnosed in patients who have a history of heavy smoking.² SCLC accounts for about 13% to 15% of all new lung cancer diagnoses, with over 200,000 new cases occurring each year worldwide.^1,2 With its rapid growth, SCLC tends to metastasize early in the disease course.^1,2

Based on the Veterans Administration Lung Study Group classification scheme, when SCLC is confined to one hemithorax that can be safely encompassed within a tolerable radiation field, the disease is described as limited-stage SCLC.^2,3 Limited-stage SCLC may present with regional lymph node involvement.² Treatment of limited-stage SCLC typically consists of chemotherapy, often combined with radiation therapy.³ Based on recommendations by the National Comprehensive Cancer Network (NCCN) guidelines, preferred regimens in this setting include cisplatin plus etoposide combinations.³

Approximately 60% to 70% of patients with SCLC are initially diagnosed with extensive-stage disease, which is defined as disease beyond the ipsilateral hemithorax that cannot be safely encompassed within a radiation field.^2,3 The presence of malignant pleural or pericardial effusion or hematogenous metastases would also constitute extensive-stage SCLC^.3 The recommended primary treatment for patients with extensive-stage SCLC is systemic therapy, with the addition of radiation therapy for patients with localized symptomatic sites or brain metastases.³ The standard systemic treatment for extensive-stage SCLC has recently evolved from platinum chemotherapy in combination with etoposide to regimens combining chemotherapy with immunotherapy.³

Although both limited-stage SCLC and extensive-stage SCLC are responsive to initial chemotherapy regimens, most patients eventually relapse, and recurrences are usually associated with resistance.¹ Topotecan is the standard second-line treatment for patients with SCLC who experience relapse within the first six months of first-line therapy.^1,3,4 Additional preferred regimens in this setting include lurbinectedin and clinical trial enrollment.³ Treatment with the original, first-line regimen is the preferred treatment for patients who experience relapse after 6 months of primary therapy.³

Treatment of Extensive-Stage SCLC

For decades, the standard of care for the first-line systemic treatment of patients with extensive-stage SCLC has consisted of platinum chemotherapy with carboplatin or cisplatin in combination with etoposide.^2,3 Regimens containing carboplatin have been preferred over those containing cisplatin given the more tolerable toxicity and equivalent efficacy of carboplatin compared with cisplatin.³ More recently, the standard of care has changed following the approvals of the immune checkpoint inhibitors atezolizumab and durvalumab in this setting.^3,5,6

In March 2019, the FDA approved the combination regimen of atezolizumab, an anti-programmed death ligand 1 (PD-L1) monoclonal antibody, with carboplatin and etoposide for the frontline treatment of patients with extensive-stage SCLC.^5,7 The approval was based on results from the phase 3 portion of the IMpower133 trial.^5,7 In this trial, patients with extensive-stage SCLC were randomized to receive frontline carboplatin plus etoposide with either atezolizumab or placebo in the induction phase, followed by maintenance atezolizumab or placebo, respectively.^5,7 Overall survival (OS) was significantly improved with atezolizumab compared with placebo, with a resulting median OS of 12.3 months and 10.3 months, respectively (HR, 0.70 [95% CI, 0.54-0.91]; P = .007).⁷ Additionally, treatment with atezolizumab resulted in longer median progression-free survival (PFS) compared with placebo (5.2 months versus 4.3 months, respectively; HR, 0.77 [95% CI, 0.62-0.96]; P = .02).⁷

Durvalumab, also an anti-PD–L1 agent, received FDA approval in March, 2020 for its use in combination with carboplatin or cisplatin, plus etoposide for the first-line treatment of extensive-stage SCLC.^6,8 The approval was based on the CASPIAN phase 3 trial results, and specifically on the comparison of patients who received durvalumab plus chemotherapy followed by durvalumab maintenance versus patients who received chemotherapy alone.^6,8 The chemotherapy regimen consisted of etoposide plus carboplatin or cisplatin.⁸ The addition of durvalumab resulted in significantly longer median OS compared with platinum–etoposide-only treatment (13.0 months versus 10.3 months, respectively; HR, 0.73 [95% CI, 0.59-0.91]; P = .0047).⁸ Although testing for statistical significance was not performed for PFS during the interim analysis, results favored durvalumab plus chemotherapy over chemotherapy only (HR, 0.78 [95% CI, 0.65-0.94]).⁸

Subsequent to these trials, preferred regimens by the NCCN guidelines for the primary treatment of extensive-stage SCLC now consist of carboplatin plus etoposide plus atezolizumab followed by maintenance atezolizumab, and etoposide plus carboplatin or cisplatin plus durvalumab followed by maintenance durvalumab.³ Chemotherapy only regimens, consisting of platinum plus etoposide, are now listed under other recommended regimens.³

Chemotherapy-Induced Myelosuppression

Chemotherapy regimens, including those with platinum-containing agents, frequently cause myelotoxicity as a consequence of their antineoplastic effects.⁹ These agents may cause chemotherapy-induced myelosuppression by disrupting the complex processes involved in maintaining a functional hematopoietic system, including the cell cycle and the differentiation of stem cells and progenitor cells into blood cells.⁹ Thus, chemotherapy-induced myelosuppression may lead to a decrease in the production of neutrophils, hemoglobin, and/or platelets, resulting in neutropenia, anemia, and/or thrombocytopenia, respectively.⁹

Patients aged 65 years or older, who frequently have other comorbidities, are particularly vulnerable to the clinical effects of chemotherapy-induced myelosuppression.^10-12 The use of dose-dense regimens and the presence of comorbidities such as liver or renal dysfunction, cardiovascular disease, or pulmonary conditions increase the risk for the development of the serious clinical consequences of myelotoxicity from chemotherapy.^10,12 More than half of the patients with SCLC are aged 65 years or older and frequently have a smoking history with multiple comorbidities, and thus, most are susceptible to the effects of myelosuppression.¹²

Chemotherapy-induced myelosuppression can lead to serious clinical consequences for patients.^13-15 Severe neutropenia increases the risk for infection and febrile neutropenia, a life-threatening complication.¹³ Anemia may lead to a suboptimal response to chemotherapy as well as fatigue, which negatively impacts activities of daily living and the quality of life of patients.^9,14 The decrease in platelet production increases the risk for life-threatening spontaneous bleeding.⁹

Many patients report that chemotherapy-induced myelosuppression has a moderate or major negative impact on their quality of life.¹⁵ Additionally, chemotherapy regimen modifications such as dose delays or reductions are often implemented due to myelosuppression, which may impact treatment efficacy and compromise long-term outcomes.¹⁵ Thus, chemotherapy-induced myelosuppression is an important dose-limiting toxicity that can lead to serious clinical consequences and negative effects in the quality of life of patients.^13-15

References

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2. Wang S, Zimmermann S, Parikh K, Mansfield AS, Adjei AA. Current diagnosis and management of small-cell lung cancer. Mayo Clin Proc. 2019;94(8):1599-1622. doi:10.1016/j.mayocp.2019.01.034
3. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 1.2022. Accessed September 9, 2021. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf
4. Yang S, Zhang Z, Wang Q. Emerging therapies for small cell lung cancer. J Hematol Oncol. 2019;12(1):47. doi:10.1186/s13045-019-0736-3
5. FDA approves atezolizumab for extensive-stage small cell lung cancer. News release. FDA; March 18, 2019. Accessed September 9, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-extensive-stage-small-cell-lung-cancer
6. FDA approves durvalumab for extensive-stage small cell lung cancer. News release. FDA; March 27, 2020. Accessed September 9, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-extensive-stage-small-cell-lung-cancer
7. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064
8. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6
9. Barreto JN, McCullough KB, Ice LL, Smith JA. Antineoplastic agents and the associated myelosuppressive effects: a review. J Pharm Pract. 2014;27(5):440-446. doi:10.1177/0897190014546108
10. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic growth factors, version 4.2021. Accessed September 9, 2021. https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf
11. NCCN. Clinical Practice Guidelines in Oncology. Older adult oncology, version 1.2021. Accessed September 9, 2021. https://www.nccn.org/professionals/physician_gls/pdf/senior.pdf
12. Hussein M, Maglakelidze M, Richards DA, et al. Myeloprotective effects of trilaciclib among patients with small cell lung cancer at increased risk of chemotherapy-induced myelosuppression: pooled results from three phase 2, randomized, double-blind, placebo-controlled studies. Cancer Manag Res. 2021;13:6207-6218. doi:10.2147/CMAR.S313045
13. Li Y, Klippel Z, Shih X, Reiner M, Wang H, Page JH. Relationship between severity and duration of chemotherapy-induced neutropenia and risk of infection among patients with nonmyeloid malignancies. Support Care Cancer. 2016;24(10):4377-4383. doi:10.1007/s00520-016-3277-0
14. Bryer E, Henry D. Chemotherapy-induced anemia: etiology, pathophysiology, and implications for contemporary practice. Int J Clin Transfus Med. 2018;6:21-31. https://doi.org/10.2147/IJCTM.S187569
15. Epstein RS, Aapro MS, Basu Roy UK, et al. Patient burden and real-world management of chemotherapy-induced myelosuppression: results from an online survey of patients with solid tumors. Adv Ther. 2020;37(8):3606-3618. doi:10.1007/s12325-020-