Immune Checkpoint Inhibitors in Lung Cancer: Role of Biomarkers and Combination Therapies.

Tun Zan Maung,Mehwish Javed,Safeera Khan,Evelyn E Inga,Huseyin Ekin Ergin

doi:10.7759/cureus.8095

Abstract

Lung cancer is the leading cause of cancer-related death worldwide, with a poor prognosis. Despite aggressive treatment, progression-free survival (PFS) and overall survival are limited. Recently, various kinds of immune checkpoint inhibitors (ICIs) have emerged for several cancers, targeting PD1, PDL1, and CTLA-4. ICIs have made a significant breakthrough in cancer and revolutionized the management of cancer including lung cancer. However, there are a lot of controversies regarding which group of patients is most suitable to be treated with ICIs in terms of monotherapy, combination, and predictive biomarkers. We reviewed various kinds of studies, such as meta-analysis, randomized control trials, multi-center cohort studies, and case-control studies from PubMed written in English from the last five years. ICIs have significant benefits in the overall survival compared with traditional chemotherapy. Patients with a higher level of PDL1 expression and high tumor mutational burden (TMB) have a higher response rate, and those with EGFR-/ALK- were better than those with EGFR+/ALK+. The patient who responded to immunotherapy completely can still maintain the efficacy after two years of treatment. Neoadjuvant immunotherapy in patients with resectable non-small cell lung cancer resulted in a 45% major pathology response (MPR) and 40% downstaging. Combined therapy (ICIs + chemotherapy) was better than chemotherapy alone, irrespective of PD‐L1 expression. A combination of ICIs such as CTLA‐4 and PD‐1/PD‐L1 improved PFS as well. Radiochemotherapy ahead of ICIs is promising as well. However, ICIs combined with EGFR/ALK‐TKI (tyrosine kinase inhibitor) are not suggested for the time being. PDL1 expression, TMB, and EGFR/ALK mutations are promising predictive biomarkers. Gut microbiota, galectin-3, and intensity of CD8 cell infiltration are other potential predictive biomarkers. These are very important in the future management of lung cancers as they can prevent unnecessary toxicities and cost of treatment.

Highlights

BackgroundLung cancer is at the top of the list for cancer-related death worldwide [1]
Galectin-3, and intensity of CD8 cell infiltration are other potential predictive biomarkers. These are very important in the future management of lung cancers as they can prevent unnecessary toxicities and cost of treatment
Which patient group is most beneficial from this kind of treatment, such as histology types, programmed death 1 (PD1), or PDL1 expression? Is it worth checking predictive biomarkers that indicate a good response? Do combination therapies such as immune checkpoint inhibitors (ICIs) and chemotherapy, ICIs and tyrosine kinase inhibitors (TKIs), ICIs and radiotherapy, and a combination of ICIs bring better outcomes? Should ICIs be rechallenged in relapse cases? In this traditional review, we are going to look into the impact of PD1, PDL1 expression, predictive biomarkers, and combination therapy on disease-free survival (DFS) and overall survival (OS) of lung cancer

Summary

Introduction

BackgroundLung cancer is at the top of the list for cancer-related death worldwide [1]. First-line chemotherapy provides reasonable response rates in advanced disease, but progression-free survival (PFS) and overall survival (OS) are limited. New drugs such as some targeted therapies and immune therapies are promising in SCLC. Pembrolizumab was already approved as the first-line agent in lung cancer with PDL1 expression of more than 50%. Checkpoint inhibitors have become first-line therapy for most of the patients with metastatic disease, but there are a lot of controversies regarding ICIs [10]. We are going to look into the impact of PD1, PDL1 expression, predictive biomarkers, and combination therapy on DFS and OS of lung cancer Which patient group is most beneficial from this kind of treatment, such as histology types, PD1, or PDL1 expression? Is it worth checking predictive biomarkers that indicate a good response? Do combination therapies such as ICIs and chemotherapy, ICIs and TKIs, ICIs and radiotherapy, and a combination of ICIs bring better outcomes? Should ICIs be rechallenged in relapse cases? In this traditional review, we are going to look into the impact of PD1, PDL1 expression, predictive biomarkers, and combination therapy on DFS and OS of lung cancer

Methods

Discussion

Conclusion