First-line immunotherapy in non-small cell lung cancer: how to select and where to go

ABSTRACT

Introduction

Immunotherapy (IO) has established a new milestone in lung cancer treatment. Several registrational studies have approved immune checkpoint inhibitors (ICIs) in different settings, including the metastatic nonsmall cell lung cancer (NSCLC). As well known, responders are just a certain proportion of patients; therefore, their selection by using predictive factors has stood out as a crucial issue to address in tailoring a patient-centered care.

Areas covered

In our review we propose a detailed yet handy cross section on ICIs as first-line treatment in metastatic NSCLC, regarding indications, histological, clinical, and blood-based biomarkers, other than their mechanisms of resistance and new immunological actionable targets. We performed a literature search through PubMed entering keywords complying with crucial features of immunotherapy.

Expert opinion

IO represents the backbone of lung cancer treatment. Trials are currently testing novel immune blockade agents assessing combinatorial approaches with standard ICIs, or antibody drug conjugates (ADC), harboring immunological targets. Perfecting patients’ selection is an ongoing challenge and a more and more urgent need in order to best predict responders who will consistently benefit from it.

KEYWORDS:

• NSCLC
• ICIS
• predictive factors
• oncogene addicted
• primary resistance
• acquired resistance
• LAG3
• TIGIT

Article highlights

• Immunotherapy (ICIs) is the new milestone for non-small cell lung cancer (NSCLC) treatment, specifically for the non-oncogene addicted subtype.

• The role of ICIs in oncogene addicted NSCLC, alone or combined with targeted therapy, in still under investigation with promising results.

• Some clinical (BMI, concomitant medications, gender, smoking etc.…) and blood factors (NRL, SII, LDH value) should be evaluated before starting ICIs to define patients who would benefit the most.

• New molecular tools (likes TMB and genetic signature) and progressive knowledge of micro-environment tumour cell (TILs, TAMs, TANs, MDSCs etc.) composition will help clinicians to better characterize lung cancer and its predictive factors.

• Outlining the mechanisms behind resistance to immunotherapy (microbiome alterations, mutational burden, epigenetics etc.) could improve the personalized approach to treatment.

• Identifying new immunological targets (as LAG-3, TIM-3, TIGIT etc.) might strengthen the role of PD1/PD-L1 inhibitors and lead to novel immunological blockade agents to exploit against acquired mutation.

Declaration of interest

G.L. Banna received grant consultancies from AstraZeneca and Astellas Pharma. A. Addeo received consulting fees from BMS, AstraZeneca, Boehringer-Ingelheim, Roche, MSD, Pfizer, Eli Lilly and Astellas; speakers fees from Eli Lilly and AstraZeneca. Giannis Mountzios reports honorary lectures, consulting fees, expert testimony and travel/congress fees from Roche, MSD, BMS, Amgen, AstraZeneca, Sanofi, Novartis, Takeda, Pfizer, Amgen, and Janssen. A. Friedlaender reports consulting fees from Amgen, AstraZeneca, Roche, Astellas, Takeda, Bristol-Myers-Squibb, Merck Sharpe Dohme, Pfizer, Merck, Novartis and Janssen. R. Kanesvaran reported receiving personal fees from Merck, Bristol Myers Squibb, Astellas, Johnson & Johnson, Eisai, Ipsen and Novartis. S. Novello has received consulting fees from Sanofi and Novartis, honoraria from AstraZeneca, Amgen, MSD, Takeda, Roche, Pfizer, Thermofisher, Novartis, and Sanofi, and is an advisory board member for AstraZeneca, Roche, Pfizer and MSD. 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.