What Is On the Horizon for the Diagnosis and Treatment of SCLC and Large Cell Neuroendocrine Cancer?

Abstract

SCLC is a high-grade neuroendocrine malignancy associated with poor prognosis, comprising 15% of lung cancer cases globally. Advances in genetic profiling have revealed that SCLC is a molecularly heterogeneous disease, categorized into subtypes such as SCLC-A, SCLC-N, SCLC-P, and SCLC-I, on the basis of their neuroendocrine and immune-related characteristics. This heterogeneity underscores the need for tailored therapeutic strategies. Large cell neuroendocrine carcinoma (LCNEC) shares histologic and molecular similarities with SCLC but remains a distinct entity. LCNEC is categorized into two major subtypes: Type I, characterized by STK11 and KEAP1 mutations and a neuroendocrine phenotype, and Type II, defined by TP53 and RB1 alterations with higher proliferative indices. LCNEC's rarity and molecular diversity present challenges for standardized treatment, further highlighting the need for comparative research with SCLC. In this review, we highlight the genetic and clinicopathologic features of SCLC and LCNEC. Furthermore, we discuss emerging therapeutics and future directions in the treatment of SCLC and LCNEC.

Keywords: Diagnostics; Large cell neuroendocrine carcinoma; Novel therapies; Small cell lung cancer.

Figure 1

Molecular subtypes of SCLC and their immune microenvironment. A recent study proposed that SCLC is composed of four major molecular subtypes: SCLC-A (ASCL-1^high subtype), SCLC-N (NEUROD1^high subtype), and SCLC-I (inflamed; characterized by increased expression of immune-related genes) subsets, which can be further subdivided into SCLC-I-NE and SCLC-I–non-NE subtypes. These SCLC-I subtypes differ in their composition of transcription factor composition, tumor microenvironment, and responsiveness to ICI. The SCLC-I–non-NE subtype is characterized by increased POU2F3 expression and immunosuppressive TAM infiltration, which is associated with reduced efficacy of ICI. In contrast, the SCLC-I–NE subtype exhibits relatively lower immunosuppressive TAM infiltration, consequently, higher susceptibility to ICI. ICI, immune checkpoint inhibitor; NE, neuroendocrine; TAM, tumor-associated macrophage.

Figure 2

Subtypes of SCLC and LCNEC. NE carcinomas can be divided into two major categories: SCLC and LCNEC. LCNEC has two major molecular subtypes. Type I features STK11 and KEAP1 mutations, elevated ASCL1 and DLL3, and suppressed NOTCH signaling. The high DLL3 expression in this subtype may suggest potential responsiveness to DLL3-targeting bispecific engagers. Type II is defined by increased NOTCH signaling and cell cycle activity, reduced NE marker expression, and potential responsiveness to SCLC-like chemotherapy regimens such as etoposide-platinum chemotherapy. SCLC has four major molecular subtypes, each with distinctive genetic and therapeutic characteristics. The SCLC-I non-NE subtype has decreased NE marker expression but increased TAM infiltration. A known inhibitory macrophage subset reduces the efficacy of ICIs in this group. In contrast, the SCLC-I NE subtype exhibits higher expression of NE markers and decreased TAM infiltration, making it more susceptible to ICIs. The SCLC-A subtype is characterized by higher expression of the ASCL1 transcription factor, with preclinical studies reporting intrinsic susceptibility to BCL2 inhibitors. Finally, the SCLC-N subtype exhibits increased expression of NEUROD1 and reduced NOTCH signaling. This subtype has exhibited greater susceptibility to AURK inhibitors. ICI, immune checkpoint inhibitor; NE, neuroendocrine; TAM, tumor-associated macrophage; LCNEC, large cell NE carcinoma; STK11, serine threonine kinase 11.

Figure 3

Novel ADCs and DLL3-targeting agents in SCLC. B7-H3 (CD276), an immune checkpoint molecule, is overexpressed in a wide range of solid tumors. Ifinatamab deruxtecan (I-DXd, DS-7300a) is an anti–B7-H3 ADC conjugated to DXd, a topoisomerase I inhibitor. HS-20093 and MHB088C are additional anti–B7-H3 ADCs linked to topoisomerase I inhibitors. DLL3 is a NOTCH ligand selectively expressed on SCLC cells and largely absent from normal adult tissues. Rova-T is an ADC targeting DLL3, though its development has been halted because of negative results. FZ-AD005 is an ADC combining an anti-DLL3 antibody with a DXd payload by means of a valine-alanine linker. DB-1314 is an anti-DLL3 ADC conjugated with P1021, a topoisomerase I inhibitor. ZL-1310 is an ADC consisting of a humanized anti-DLL3 antibody, a protease-cleavable linker, and a novel camptothecin derivative. Tarlatamab is a BiTE that binds DLL3 on SCLC cells and CD3 on T-cells to facilitate T-cell–mediated tumor killing. SEZ6 is a transmembrane protein markedly up-regulated in ASCL1-driven SCLC and in platinum-resistant cells. ABBV-706 is an ADC targeting SEZ6 and conjugated with a topoisomerase I inhibitor. TROP2 is a transmembrane glycoprotein overexpressed in high-grade NE tumors, including SCLC. SG is an ADC composed of an anti-TROP2 antibody linked to SN-38, a topoisomerase I inhibitor. ESG-401 is an investigational ADC featuring an anti-TROP2 antibody with the same SN-38 payload, though its linker is undisclosed. ADC, antibody-drug conjugates; BiTE, bispecific T-cell engagers; SG, Sacituzumab govitecan; Rova-T, Rovalpituzumab tesirine; SN-38, active metabolite of irinotecan (topoisomerase I inhibitor); NE, neuroendocrine.