New immunotherapeutic drugs in advanced non-small cell lung cancer (NSCLC): from preclinical to phase I clinical trials

ABSTRACT

Introduction

The development of immune checkpoint inhibitors (ICI) has represented a revolution in the treatment of non-small cell lung cancer (NSCLC) and has established a new standard of care for different settings. However, through adaptive changes, cancer cells can develop resistance mechanisms to these drugs, hence the necessity for novel immunotherapeutic agents.

Areas covered

This paper explores the immunotherapeutics currently under investigation in phase I clinical trials for the treatment of NSCLC as monotherapies and combination therapies. It provides two comprehensive tables of phase I agents which are listed according to target, drug, drug class, mechanism of action, setting, trial identifier, and trial status. A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed and ClinicalTrials.gov.

Expert opinion

A key hurdle to success in this field is our limited understanding of the synergic interactions of the immune targets in the context of the TME. While we can recognize the links between inhibitors and some particularly promising new targets such as TIM-3 and LAG3, we continue to develop approaches to exploit their interactions to enhance the immune response of the patient to tumor cells.

KEYWORDS:

• NSCLC
• non-small cell lung cancer
• immune modulators
• immune checkpoint inhibitors
• IDO
• TIM-3
• LAG3
• OX40
• CAR T
• TIGIT
• GITR
• VISTA

Article highlights

• Limitations of immune checkpoint inhibitor (ICI) treatment include resistance mechanisms and disease progression, hence, new immunotherapeutics are being developed to overcome these issues.

• Our limited understanding of the synergic interactions between the various immune targets in the context of the tumor microenvironment (TME) represents one of the main hurdles to overcome in order to fully exploit these agents.

• These new immunotherapeutic agents are still in early phases of development/investigation and therefore we should be careful in drawing conclusions.

• However, according to the available data, anti-TIM-3, anti-LAG-3 and anti-OX40 mAbs seem to represent the most advanced and promising agents.

• These agents seem to grant better results when administered in an immune combination setting (two or more immunotherapeutics combined).

• We believe that five years from the publication of this review, several new immunotherapeutic drugs (anti-TIM-3, anti-LAG-3, and anti-OX40 mAbs first and foremost) will have entered our daily clinical practice.

This box summarizes key points contained in the article.

Declaration of interest

C Gridelli has received honoria as a speaker’s bureau and advisory ard member from AstraZeneca, BMS, MSD and Roche. The authors have no other 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 paper was not funded.