Current Therapeutic Landscape in NSq NSCLC

Poor prognosis, limited post-immunotherapy options in NSCLC

Despite advances, prognosis is poor after first-line treatment when resistance develops to immunotherapy. Most patients with NSCLC progress while on immunotherapy and, when they do, they also have a poor prognosis with current therapies.^1,2

Real-world outcomes with second-line therapies after failure of first-line immunotherapy or immunotherapy plus chemotherapy in advanced NSCLC²

2.4-5.5 months median progression-free survival

Compounding this problem, there are limited sequencing options once resistance develops to immunotherapy. Investigating novel targets and biomarkers could help address challenges in later-line treatment selection and represents an important area of clinical investigation in NSCLC. As more targeted therapies are approved, guideline recommendations on biomarker testing continue to be updated.^3,4

Comprehensive biomarker testing is recommended for eligible patients with advanced or metastatic NSq NSCLC.⁵

OS=overall survival; PFS=progression-free survival.

There are four major listed treatment classes currently available or under investigation for NSq NSCLC patients

Chemotherapy (Chemo)

Chemotherapies are non-specific anticancer drugs that work by targeting rapidly dividing cells.⁶

Can be recommended⁷:

Before surgery (neoadjuvant)
After surgery (adjuvant)

The chemotherapeutic agents recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) and ESMO guidelines are^5,8-11:

Alkylating agents
- Cytotoxic DNA damage
Anti-microtubule/anti-mitotic agents
- Cell cycle arrest and apoptosis
Topoisomerase inhibitors
- DNA damage and apoptosis
Anti-metabolites
- Inhibit nucleotide synthesis and DNA replication

Immunotherapy (IO)

Immunotherapies are monoclonal antibodies that facilitate the recognition and destruction of cancer cells by the host immune system.¹²

The National Comprehensive Cancer Network® (NCCN®) and ESMO Clinical Practice Guidelines recommend PD-L1 IHC testing in all patients with metastatic NSCLC as the following immunotherapy agents are available for this immune biomarker^5,13:

PD-1 receptor inhibitors
- PD-1 is expressed on T cells
PD-L1 inhibitors
- PD-L1 is expressed on cancer cells and antigen-presenting cells

Another recommended IO is a cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody that binds to CTLA-4; CTLA-4 inhibits T-cell activation.⁵

Targeted Therapy

Targeted therapies aim at specific targets that alter a particular signaling pathway.¹²

Small molecule inhibitors are the main group of targeted therapy in lung cancer. These therapies are directed against specific oncogenic driver mutations that are expressed on the cell. In NSCLC, small molecule inhibitors constitute most of the first-line and second-line treatment algorithm for NSCLC⁵

Immunotherapy (IO)

Immunotherapies are monoclonal antibodies that facilitate the recognition and destruction of cancer cells by the host immune system.¹²

PD-1 receptor inhibitors
- PD-1 is expressed on T cells
PD-L1 inhibitors
- PD-L1 is expressed on cancer cells and antigen-presenting cells

Another recommended IO is a cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody that binds to CTLA-4; CTLA-4 inhibits T-cell activation.⁵

Antibody-Drug Conjugates (ADCs)

Antibody-drug conjugates (ADCs) are a class of anticancer drugs that consist of a monoclonal antibody attached to a cytotoxic drug via a linker.¹⁴

ADCs are designed to target cancer cell surface proteins and intended to deliver the cytotoxic drug to the cancer cell, thereby potentially reducing systemic exposure and toxicity compared with conventional chemotherapy.¹⁴

DNA=deoxyribonucleic acid; ESMO=European Society for Medical Oncology; IHC=immunohistochemistry; NCCN=National Comprehensive Cancer Network^® (NCCN^®); PD-1=programmed cell death protein 1; PD-L1=programmed death-ligand 1.

ESMO Clinical Practice Guidelines for advanced or metastatic NSCLC^18,19

An emerging era of biomarker discovery to inform treatment selection

To determine treatment selection, ESMO Guidelines recommend comprehensive biomarker testing at diagnosis for all eligible patients with advanced NSCLC. Actionable driver mutations are identified in approximately 34%-54% of patients with NSCLC. When biomarker status is discovered during first-line systemic therapy, patients may complete planned systemic therapy or interrupt in favor of targeted therapy.^5,15-17

In pursuit of more efficacious and selective alternatives to chemotherapy, the scientific community has ushered in an era of biomarker discovery. In NSCLC, this has led to 10 actionable biomarkers—9 of which are oncogenic mutations—occurring in protein kinases of different signaling pathways.^20-22

There are a number of small molecule inhibitors currently indicated for the first-line treatment of advanced NSq NSCLC, with targeted therapies constituting the majority of available options.⁵

Immunotherapy has emerged as a breakthrough that significantly increases patient survival and has changed the standard of care in NSCLC. As a result, there is an urgent call in the oncology community for the development of novel therapies that can treat patients who progress, as well as those who are not positive for an actionable biomarker. However, for many patients, chemotherapy remains the only feasible option for first-line therapy and beyond.^5,23

Protein kinase inhibitors constitute most of the targeted therapies in the first- and second-line treatment algorithm for NSCLC, with only one antibody-drug conjugate in the second line, for HER2.⁵

As one of the fastest-growing treatment classes in oncology, antibody-drug conjugates combine the specificity of antigen-specific monoclonal antibodies with the cytotoxic effects of chemotherapy. At this time, there are several emerging biomarkers that are being investigated as targets for antibody-drug conjugates (ADCs) with potential relevance for the treatment of NSq NSCLC, including CEACAM5.^14,24

A Review of Clinical Practice Guidelines in NSCLC

WATCH NOW