Therapeutic modalities in small cell lung cancer: a paradigm shift after decades of quiescence

ABSTRACT

Introduction

Small cell lung cancer (SCLC) is known to be the most aggressive of all thoracic malignancies, notoriously known for its very poor prognosis. Platinum-based chemotherapy has been the standard of care for decades. Despite years of research, no treatment novelties with significant impact on survival have been achieved until recently. The last few years have witnessed light at the end of the tunnel with immunotherapy proving to improve survival. Nevertheless, responses were not homogeneous in all subgroups, and finding who would best benefit from treatment remains unanswered. Multiple limitations exist, and the quest for optimal biomarkers seemed unfruitful until the discovery of different SCLC phenotypes.

Areas covered

In this review, the authors briefly discuss SCLC phenotypes and biomarker assays. Then, the authors continue with the main trials of SCLC treatment using chemotherapy, immunotherapy, and targeted treatment in the frontline or subsequent line settings.

Expert opinion

Research has been extensively implemented to better understand the biology of SCLC and test for the optimal use of immunotherapy in patients with SCLC, as well as to enhance responses via possible combinations. Targeted mechanisms of action have also been attempted; yet no solid proof of efficacy has been established.

KEYWORDS:

• Small cell lung cancer
• novel chemotherapy
• immunotherapy
• targeted treatment
• biomarkers

Article highlights

• Small cell lung cancer (SCLC) is an aggressive disease with limited approved treatment options.

• Four major sub-types of SCLC have been recently identified with implications on therapeutic approaches: SCLC-A, SCLC-P, SCLC-N, and SCLC-I.

• Different molecular and epigenetic variables are identified in SCLC.

• Different immune biomarkers of SCLC have failed to be predictive of response.

• Only IMpower 133 and CASPIAN trials including anti-PD-L1 inhibitors proved clinically significant improvement in response in the first-line setting when combined with chemotherapy.

• In the second-line setting, Lurbinectedin showed promising results.

• Multiple targeted as well as alternative immunotherapeutic approaches are being attempted in SCLC.

This box summarizes key points contained in the article.

Abbreviations

SCLC: Small cell lung cancer

EP: etoposide-platinum chemotherapy

CAV: Cyclophosphamide, Adriamycin, and Vincristine

NSCLC: non-small cell lung cancer

RB1: retinoblastoma 1

DDR: DNA damage response

CHK1: checkpoint kinase 1

ATR: ataxia telangiectasia and RAD3-related protein

ATM: ataxia telangiectasia mutated

AURK: aurora kinase

EZH2: enhancer of zeste homology 2

LSD1: lysine-specific demethylase 1A

PD-L1: Programmed death ligand-1

TMB: tumor mutational burden

MSI: microsatellite instability

MMR: mismatch-repair

TILs: tumor infiltrating lymphocytes

ES: extensive stage

CTLA-4: cytotoxic T lymphocyte antigen-4

ORR: overall response rate

mPFS: median progression-free survival

mOS: median overall survival

irBORR: best immune-related ORR

HR: hazard ratio

CI: confidence interval

BSC: best supportive case

DCR: disease control rate

VEGF: vascular endothelial growth factor

TLR9: Toll-like receptor 9

PARP: Poly ADP-ribose polymerases

ITT: intention to treat

DOR: duration of response

PRC2: polycomb repressor complex 2

DLL3: Delta-like ligand 3

Rova-T: Rovalpituzumab tesirine

VEGFR: VEGF-receptor

PDGFR: platelet-derived growth factor receptor

FGFR: fibroblast growth factor receptor

CDK: Cyclin-dependent kinases

IL-2: Interleukin-2

KLH: keyhole limpet hemocyanin

PolySA: polysialic acid

ADCC: antibody-dependent cellular cytotoxicity

D: Dinutuximab

I: irinotecan

T: topotecan

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.