Molecular Biology, Classification, and Clinical Features

SCLC is highly responsive to initial chemotherapy and radiotherapy, but relapse is extremely common. The 5-year survival rate ranges from 3% to 8% overall and from 10% to 13% in patients with limited-stage disease.

Although the tumor mutational burden is very high in SCLC,¹ a major challenge in SCLC compared with non–small cell lung cancer has been the lack of targetable driver mutations. TP53 and RB1 alterations are nearly ubiquitous in SCLC, noted Dr. Ganti. However, other mutations like CREBBP, TP73, and NOTCH1 occur in only a small minority of cases.

SCLC is now classified into 4 molecular subtypes: SCLC-A (70%), SCLC-N (11%), SCLC-P (11%), and SCLC-Y (8%). Although these subtypes do not yet have treatment implications or approvals, according to Dr. Ganti there are preliminary data suggesting differential responses to certain targeted therapies.

Staging has traditionally used the Veterans’ Administration Lung Study Group 2-stage classification system of limited-stage (all disease is able to be encompassed within one radiation field) versus extensive-stage SCLC. However, the AJCC TNM staging system is now recommended, because it identifies the 5% of patients with T1–2,N0,M0 disease who may benefit from surgical resection.²

Treatment of Limited-Stage SCLC

Despite the short median time to relapse, the primary goal of treating limited-stage SCLC remains cure. The standard treatment approach combines chemotherapy with thoracic radiotherapy.

Platinum (cisplatin or carboplatin) with etoposide is the typical chemotherapy regimen. A randomized phase III trial in the late 1980s compared cisplatin/etoposide (EP) with cyclophosphamide/doxorubicin/vincristine (CAV) and alternating CAV/EP.³ EP showed slightly higher response rates and faster time to best response, leading to it becoming the standard of care. Carboplatin/etoposide gained popularity in 1999 due to a more favorable side-effect profile.

Studies in the 1980s and 1990s demonstrated that adding thoracic radiotherapy to chemotherapy improved survival in limited-stage SCLC. A study in the 1990s compared 45 Gy of concurrent thoracic radiotherapy given twice daily for 3 weeks versus daily for 5 weeks. Twice-daily radiation was superior, but the study was criticized for comparing unequal biologically effective doses.⁴

The CALGB 30610/RTOG 0538 study compared 45 Gy twice daily over 3 weeks, 70 Gy once daily over 7 weeks, and 61.2 Gy with a concomitant boost over 5 weeks.⁵ The 61.2-Gy arm was discontinued because of inferiority. The final comparison showed no significant difference in overall survival (OS) or progression-free survival (PFS) between 45 Gy twice daily and 70 Gy once daily. However, 45 Gy twice daily remains the standard of care, because the study could not demonstrate superiority of 70 Gy once daily.

After discussing the pros and cons with a radiation oncologist, patients with a complete response (<10% of original mass on CT) may also consider PCI. According to Dr. Ganti, a small group of patients with very-early-stage SCLC (T1–2,N0) may benefit from surgery followed by adjuvant treatment, although prospective data comparing surgery to chemoradiation are lacking.

Treatment of Extensive-Stage SCLC

For extensive-stage SCLC, contemporary studies have investigated the addition of PD-L1 inhibitors to platinum/etoposide chemotherapy. The IMpower133 trial of atezolizumab and the CASPIAN trial of durvalumab showed nearly identical survival curves, suggesting the superiority of adding an immune checkpoint inhibitor to chemotherapy.^6,7

“PD-L1 expression does not appear to affect the response to checkpoint inhibitors in SCLC, unlike in non–small cell lung cancer,” commented Dr. Ganti. He noted that a meta-analysis of 4 studies (IMpower133, CASPIAN, KEYNOTE-604 with pembrolizumab, and ECOG-ACRIN 5161 with nivolumab) confirmed the benefit of adding PD-1/PD-L1 inhibitors to chemotherapy.⁸

Currently, only atezolizumab and durvalumab are approved by the FDA for the first-line treatment of extensive-stage SCLC in combination with chemotherapy. An ongoing NRG trial is evaluating the role of thoracic radiotherapy for extensive-stage SCLC in the immunotherapy era (ClinicalTrials.gov identifier: NCT03811002).

Prophylactic Cranial Irradiation

The role of PCI in SCLC has been a topic of discussion, given the high incidence and morbidity associated with central nervous system metastases. The risk of developing clinically significant metastases at 2 years is between 50% and 80%.⁹ Once patients develop brain metastases, the median survival is <4 months. PCI has been proposed as a preventive measure to address this issue.

Two recent studies, one by the EORTC and another from Japan, have investigated the role of PCI in extensive-stage SCLC. The EORTC study randomly assigned patients after any response to chemotherapy, without requiring an MRI after treatment, and the primary endpoint was the development of symptomatic brain metastases.¹⁰ The Japanese study, although smaller, required a prerandomization MRI showing no brain metastases and mandated periodic MRIs during follow-up, with OS as the primary endpoint.¹¹ Both studies showed that PCI decreased the incidence of brain metastases. However, the EORTC study demonstrated a significant improvement in OS, whereas the Japanese study showed no such difference, with the observation group having a numerically superior OS.

“One possible explanation [for these discrepancies] is that the EORTC study might have included patients with undetected brain metastases, and treating these patients led to improved survival,” said Dr. Ganti. “Additionally, the periodic MRIs in the Japanese study might have allowed for earlier intervention in patients who developed brain metastases during follow-up.”

Although PCI decreases the incidence of brain metastases, it is associated with toxicities. Acute toxicities include scalp edema, fatigue, alopecia, nausea, and vomiting; long-term toxicities such as neurologic and intellectual disabilities become more problematic as patients live longer. Strategies to mitigate these toxicities include decreasing the radiation dose, avoiding concurrent chemotherapy, using lower radiation fractions, opting for twice-daily dosing, and using hippocampal sparing.

“Without a clear survival advantage in the prophylactic setting, the use of PCI is under debate,” said Dr. Ganti. He noted that the ongoing MAVERICK study (SWOG S1827) should provide further insights into the role of PCI in the contemporary management of SCLC (ClinicalTrials.gov identifier: NCT04155034).

Relapsed SCLC

The treatment approach for relapsed SCLC depends on the type of relapse and the duration of the chemotherapy-free interval, according to Dr. Ganti. Although there are no approved agents for refractory disease, topotecan or lurbinectedin are commonly used due to the lack of better options.

For sensitive relapse (beyond 3 months), the approach is further stratified based on the chemotherapy-free interval. If the interval is <6 months, topotecan and lurbinectedin are approved options. For intervals >6 months, platinum-doublet reinduction with the same regimen used initially is preferred (Figure 1).

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Treatment algorithm for relapsed SCLC.

Abbreviation: SCLC, small cell lung cancer.

Citation: Journal of the National Comprehensive Cancer Network 22, Supplement; 10.6004/jnccn.2024.5021

Topotecan was approved for relapsed SCLC based on a study showing improved median OS compared with best supportive care (25.9 vs 13.9 weeks; P=.01).¹² The partial response rate was 7%, with 44% of patients achieving stable disease. Topotecan also slowed the deterioration of quality of life and provided better symptom control. A subsequent phase III study demonstrated equivalent efficacy between oral and intravenous topotecan, leading to the widespread use of oral topotecan for its convenience.¹³

More recently, lurbinectedin was approved based on a single-arm, open-label, phase II basket trial of 105 patients, showing an overall response rate of 35%, PFS of 3.5 months (95% CI, 2.6–4.3 months), and OS of 9.3 months (95% CI, 6.3–11.8 months).¹⁴ The main toxicity was hematologic, with 5% of patients experiencing neutropenia.

A review of various cytotoxic agents studied worldwide for relapsed SCLC revealed that combination carboplatin, ifosfamide, and etoposide (CIE) yielded the highest response rate at 84% and an OS of 18.2 months in a Japanese study,¹⁵ according to Dr. Ganti. However, this regimen was considered highly toxic and is not used in the United States. Other agents resulted in response rates between 20% and 35%, PFS of 1.5 to 4 months, and median OS of 5 to 9 months.

Immunotherapy and targeted therapies have also been studied in relapsed SCLC. However, according to Dr. Ganti, the response rates, PFS, and OS have been disappointing, and none of these agents are currently approved in the United States for this indication.

Newer Targets

Finally, Dr. Ganti presented several experimental targets and agents under investigation in SCLC. They include the following agents:

• • PARP inhibitors: Studies investigating the combination of temozolomide with PARP inhibitors (talazoparib, olaparib, veliparib) in relapsed SCLC have shown response rates around 40%, with median PFS of approximately 4.3 months, and median OS of 8 to 12 months in small studies, according to Dr. Ganti.^16–18 Potential predictive biomarkers such as SLFN11 are also being explored.

• • Tarlatamab (a DLL3/CD3-bispecific antibody): In a phase II study of 220 patients with DLL3-expressing SCLC, tarlatamab demonstrated a response rate of 40%, a median PFS of 4.9 months (95% CI, 2.9–6.7 months), and a median OS of 14.3 months.¹⁹ Cytokine-release syndrome was the most common adverse event. Other DLL3-targeting agents, such as rovalpituzumab tesirine and HPN328, are also under investigation.

• • Liposomal irinotecan: In the single-arm RESILIENT study of 30 patients with relapsed SCLC, liposomal irinotecan yielded response rates of approximately 40%, a median duration of response of approximately 3 months, and a median OS of 8.08 months.²⁰

• • Anlotinib: This multitargeted tyrosine kinase inhibitor demonstrated a median PFS of 4.1 months (vs 0.7 months), OS of 7.3 months (vs 4.9 months), and 1-year survival of 31% (vs 13%), which was superior to placebo.²¹

“Although these agents show promise, they are still considered experimental and are not yet approved for clinical use in SCLC,” said Dr. Ganti.