SCLC: Treatment Advancing One Small, but Quickening, Step at a Time

Herbert L. Duvivier, MD, JD

Herbert L. Duvivier, MD, JD, is a board-certified and fellowship-trained Hematologist and Medical Oncologist at Cancer Treatment Centers of America (CTCA) Atlanta.

Lung cancer is the second most diagnosed cancer behind only breast cancer. It is subdivided into small cell (SCLC) and non–small cell lung (NSCLC) cancers with NSCLC occurring approximately 85% of the time and SCLC the remainder.

In 2019, there were approximately 30,000 new cases of SCLC diagnosed in the United States and nearly all cases are attributable to cigarette smoking. The incidence of this disease is decreasing overall, but for women it is increasing, with a male:female ratio of 1:1.

The staging system for SCLC is divided into limited stage (stages I to III; LS-SCLC) and extensive stage (IV; ES-SCLC). Appropriate staging studies include history and physical, CT scans of chest/abdomen, and MRI of the brain. LS-SCLC occurs approximately one third of the time with ES-SCLC occurring the remainder of the time.

SCLC is characterized by a rapid doubling time and aggressive nature leading to early development of metastasis. However, even though the disease is aggressive it is highly sensitive to both chemotherapy and radiation therapy. Unfortunately, despite this sensitivity, relapse rates are high and overall survival (OS) remains low.

In general, unless the disease is stage I, or possibly II, where surgery may play a role, treatment is non-surgical with the goal of treatment for LS-SCLC being curative, while the goal in ES-SCLC is disease control.

All patients with SCLC require systemic treatment with chemotherapy, plus or minus immunotherapy, to reduce the risk of relapse. Even if the tumor has been removed by surgery, use of adjuvant chemotherapy helps reduce the risk of relapse. In those who cannot undergo surgical resection either due to medical reasons, patient refusal, or more locally advanced disease, chemotherapy with concurrent radiation therapy has been shown to improve survival and more recently concurrent chemotherapy with twice daily radiation therapy has been shown to be preferred over chemotherapy with once daily radiation therapy. For those with metastatic disease (ES-SCLC) the use of chemotherapy plus immunotherapy has been shown to significantly improve OS over standard chemotherapy alone.

Newer Treatment Approaches Introduced

Although there have been significant advances over the last decade in the treatment of metastatic NSCLC, these advances have not been as successfully translated to the treatment of ES-SCLC.

However, both the European Lung Cancer Virtual Congress 2021 (ELCC 2021) and the 2021 American Society of Clinical Oncology Annual Meeting (2021 ASCO) gave hints that SCLC treatment may be changing over the next 3 to 5 years.

ELCC 2021 had exciting news about continued advancements in the field of SCLC. In the field of epigenetics, development of epigenetic erasers, enzymes capable of removing epigenetic marks with reversal of their influence on gene expression, is being utilized in the possible treatment of SCLC.

In first-line extensive-stage disease, Ponce Aix S et al, discussed a phase 1b study (NCT03850067) of CC-90011 plus etoposide and cisplatin or carboplatin (EP).¹ CC-90011 is an epigenetic eraser of lysine-specific demethylase 1A (LSD1). Inhibition leads to decreased expression of tumor-promoting genes and increased expression of tumor-suppressing genes. Dose-limiting toxicities were hematologic with neutropenia and thrombocytopenia. Of 24 treated patients, 19 were evaluable; all of whom achieved a partial response. The recommended phase 2 dose of CC-90011 plus EP was established as 40 mg. The study is ongoing.

Technologic advances have brought about the increasing use of genomic DNA testing in multiple tumor types which help direct therapy; increasing use of functional genomic RNA testing (looking at transcriptional proteins) and increasing attention to circulating tumor cells (CTCs) is beginning to show results.

In SCLC, circulating tumor cells (CTCs) are becoming recognized as having prognostic significance. In 2012, Hou et al found that change of CTC number, after one cycle of treatment, from pre-treatment baseline was an independent prognostic factor for SCLC.² At a cutoff of 50 CTCs, there was a significant difference in outcomes related to both progression-free survival (PFS) and OS. Individuals with less than 50 CTCs/7.5 mL of blood had a median PFS of 8.8 months with a median OS of 11.5 months. Those with more than 50 CTCs had PFS of 4.6 months and OS of 5.4 months.

More recently, additional analysis of the CONVERT study (NCT00433563), an open-label, phase 3, randomized, superiority trial with the aim of establishing a standard chemoradiotherapy treatment regimen in LS-SCLC, found a prognostic value to CTC with a cutoff of 15.³ Those with less than 15 CTCs had a median PFS of 19 months and a median OS of 26.7 months. Those with more than 15 CTCs had a median PFS of 5.5 months with a median OS of 5.9 months.⁴

Within the field of functional genomics, there have been advances in further defining SCLC into subtypes. Although these subtypes still require clinical validation, they lay the foundation for continued advancement in the development of both targeted therapies and prognostic markers and will aid in more appropriate treatment selection.

Continuing the development of defining subtypes of SCLC, there was an abstract presented by Puri et al at ASCO 2021.⁵ The results further the characterization of SCLC into several distinct subtypes: SCLC-A/N/Y/P, with emerging evidence that the Y subtype is associated with a T-cell inflamed phenotype. The group examined the expression of clinically relevant biomarkers across SCLC subtypes using next-generation DNA and RNA sequencing, and immunohistochemistry. They found that the subtypes A/N/Y/P were expressed at rates of 36%, 18%, 21%, and 6%, respectively, with 19% being mixed. The Y subtype was expressed significantly more in primary tumors as compared with metastatic sites and was associated with the highest expression of T-cell inflamed, NK cell, and STING pathway signatures. N was the most common subtype expressed from central nervous system tumors.⁵

Gay et al examined data using SCLC transcriptional subtypes.⁶ It was shown that of the 4 subtypes, only the SCLC-Y subgroup showed benefit from the addition of immunotherapy.

Lastly, systemic therapy advancements cannot be excluded from discussion. For years, the only treatment option was EP. However, this changed with the approval in 2018 of the triplet combination of carboplatin/etoposide/atezolizumab (Tecentriq). Since then, there has been an additional approval of cisplatin/etoposide/durvalumab (Imfinzi). These studies, which led to the approvals, laid the foundation for a paradigm shift by showing that the addition of immunotherapy to chemotherapy improved survival. These combinations are a first step and there continues to be progress in the field of systemic therapy.

In the lab, Del Rev-Vergara et al showed in a mouse model that the addition of savolitinib (a MET inhibitor) in combination with durvalumab provides a significantly improved anti-tumor effect over each agent alone.⁷ Although not yet ready for use in patients, it does show that “adding on” may prove beneficial.

In addition, there is continued progress in the immunotherapy field. In the arena of checkpoint inhibitors, TIGIT (T cell immunoglobulin and ITIM domain) is an inhibitory receptor expressed on lymphocytes. It interacts with CD155, which is expressed on antigen-presenting cells or tumor cells to down-regulate T cell and NK cell functions.⁸ Tiragolumab is an anti-TIGIT IgG1/kappa antibody which was shown to be effective in a NSCLC study. In CITYSCAPE (NCT03563716), the antibody was found to improve objective response rate and PFS in the intention-to-treat population when combined with atezolizumab, over atezolizumab and placebo.⁹ This agent is now being studied in the SKYSCRAPER 02 trial (NCT04256421), a phase 3 trial of carboplatin, etoposide, and atezolizumab with or without tiragolumab.

Adoptive cellular therapy is also making its mark in the field of SCLC. Bispecific T-cell engager (BiTE) cells are entering trials. Tarlatamab (AMG 557) is a half-life extended BiTE therapy that targets DLL3, an inhibitory Notch ligand. Initial results were presented in abstract form at 2021 ASCO.¹⁰ In the study, 83% of patients experienced treatment-related adverse events with 33% being grades 3 to 5. Although response rates were low at 13% (confirmed), the unconfirmed rate was 63% at the final dose level and duration of response was significant with a median duration of response of 8.7 months.

In summary, treatment advances are occurring along multiple fronts in the battle against SCLC. Adoptive immunotherapy, tumor subtyping, combinatorial immunotherapies, emerging risk stratification clues, and new checkpoint inhibitor medications are under active investigation. There is hope for SCLC; we should not forget that NSCLC started in the same fashion and treatment was stagnant until the 2010s with the development of PD-1 and PD-L1 inhibitors. SCLC is at the beginning of its road of discovery and clinical trials and human endeavor will push development along. Our success has already begun with the introduction of immunotherapy to chemotherapy showing an improvement in OS.

As always, clinical trials will lead the way toward a more successful treatment approach for SCLC. Currently, there are 112 actively recruiting trials in the United States.

_References:

_{1. Ponce Aix S, Juan-Vidal O, Carcereny E, et al. 50P A phase Ib study of CC-90011, a potent, reversible, oral LSD1 inhibitor, plus etoposide and cisplatin (EP) or carboplatin (EC) in patients (Pts) with first-line (1L) extensive-stage (ES) small cell lung cancer (SCLC): Updated results. J Thorac Oncol. 2021;16(4):S722-S723. doi:10.1016/S1556-0864(21)01892-X}

_{2. Hou JM, Krebs MG, Lancashire L, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012;30(5):525-532. doi:10.1200/JCO.2010.33.3716}

_{3. Faivre-Finn C, Snee M, Ashcroft L, et al; CONVERT Study Team. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT); an open-label, phase 3, randomized, superiority trial. Lancet Oncol. 2017;18(8):1116-1125. doi:10.1016/S1470-2045(17)30318-2}

_{4. Tay RY, Fernández-Gutiérrez F, Foy V, et al. Prognostic value of circulating tumour cells in limited-stage small-cell lung cancer: analysis of the concurrent once-daily versus twice-daily radiotherapy (CONVERT) randomised controlled trial. Ann Oncol. 2019;30(7):1114-1120. doi:10.1093/annonc/mdz122}

_{5. Puri S, Naqash AR, Elliott A, et al. Real-world multiomic characterization of small cell lung caner subtypes to reveal differential expression of clinically relevant biomarkers. J Clin Oncol. 2021;39(suppl 15):8508. doi:10.1200/JCO.2021.39.15_suppl.8508}

_{6. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39(3):346-360.e7. doi:10.1016/j.ccell.2020.12.014 Del}

_{7. Del Rev-Vergara R, Galindo-Campos MA, Hardy-Werbin M, et al. 53P Antitumoral effects of the Met inhibitor savolitinib in combination with durvalumab in a syngeneic small cell lung cancer mouse model. J Thorac Oncol. 2021;16(4):S724-S725. doi:10.1016/S1556-0864(21)01895-5}

_{8. Harjunpää H, Guillerey C. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 2020;200(2):108-119. doi:10.1111/cei.13407}

_{9. Rodriguez-Abreu, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected SCLC (CITYSCAPE). J Clin Oncol. 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503}

_{10. Owonikoko TK, Champiat S, Johnson ML, et al. Updated results from a phase 1 study of AMG 757, a half-life extended bispecific T-cell engager (BiTE) immune-oncology therapy against delta-like ligand 3 (DLL3), in small cell lung cancer (SCLC). J Clin Oncol. 2021;39(suppl 15):8510. doi:10.1200/JCO.2021.39.15_suppl.8510}