Current therapy and development of therapeutic agents for lung cancer

In the past decades, great progress has been made for the prevention and treatment of lung cancer. Yet, lung cancer remains as the leading cause of cancer death worldwide. In this manuscript, we describe the current genetic and molecular characterization of lung cancer subtypes, review up-to-date treatment options for lung cancer patients, summarize the antibodies and small molecule drugs under clinical development, and elaborate on the expression and characteristics of important RTK primary targets and representative preclinical agents which may provide new opportunities for lung cancer treatment. Since gefitinib was first introduced to non-small-cell lung carcinoma (NSCLC) patients in 2002, remarkable progress has been made in targeted therapy for NSCLC patients with the development of multiple generations of small molecule inhibitors targeting relevant driver mutations. However, very little achievement has been made in the development of targeted drugs for small-cell lung carcinoma (SCLC). The successful harness of immune checkpoint inhibitors against PD-1/PD-L1 has marked a major advancement in recent lung cancer treatment. Looking forward, therapeutic strategies that tackle brain metastasis are highly desirable, the combination of molecular testing and strategies tailored to tackle tumor heterogeneity and resistance mechanisms is the key direction for future development. READ ARTICLE

Cell Insight DOI:10.1016/j.cellin.2022.100015

Authors: Zilai Wang, Jiyeon Kim, Pin Zhang, Jazmin M. Galvan Achi, Yuwei Jiang, Lijun Rong

Management of Advanced Disease in NSCLC

Lung cancer remains the leading cause of cancer death world-wide. This is in part due patients presenting late with disseminated disease and despite recent advances, a limited therapeutic landscape... Despite these advances there remains a significant unmet clinical need with much research needed to elucidate the optimal treatment paradigm to improve response rates, mortality and quality of life for patients with advanced NSCLC. READ ARTICLE

Encyclopedia of Respiratory Medicine (Second Edition) DOI:10.1016/B978-0-08-102723-3.00265-1

Authors: Alice Davies, Martin Forster

Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma

Methods: We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles. Results:While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC = − 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC = − 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine–cytokine receptor signaling, were differentially expressed be..... READ ARTICLE

Cancer Immunology, Immunotherapy DOI:doi.org/10.1007/s00262-021-02981-w

Authors: Jan Budczies, Martina Kirchner, Klaus Kluck, Daniel Kazdal, Julia Glade, Michael Allgäuer, Mark Kriegsmann, Claus-Peter Heußel, Felix J. Herth, Hauke Winter, Michael Meister, Thomas Muley, Torsten Goldmann, Stefan Fröhling, Martin Wermke, Cornelius F. Waller, Amanda Tufman, Martin Reck, Solange Peters, Peter Schirmacher, Michael Thomas, Petros Christopoulos, & Albrecht Stenzinger

Strong ALK and PD-L1 positive IHC expression related ALK amplification in an advanced lung sarcomatoid carcinoma: A therapeutic trap?

We demonstrated that IHC positive test, in these cases, must be interpreted with caution. FISH analysis has to be recommended to confirm IHC results in case of unusual phenotype, such as smoker or lung cancer other than adenocarcinoma. Although lung carcinoma with ALK rearrangement seems to be not sensitive to ICI, further investigations should be conducted on other types of ALK molecular alterations. ALK amplifications, as observed in the present case, should not be an impediment to taking into account the PD-L1 marking for the initiation of treatment by immunotherapy. READ ARTICLE

Lung Cancer DOI: 10.1016/j.lungcan.2020.12.022.

Authors: Gendarme S, Matton L, Antoine M, Kerrou K, Ruppert AM, Epaud C, Cadranel J, Fallet V.

Case StudyKirk SmithFebruary 15, 2021ALK, Amplification, Immunotherapy, Lung cancer, Sarcomatoid

Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement

Objectives: Treatment options for malignant pleural mesothelioma (MPM) are limited but some studies on immune checkpoint inhibitors (ICIs) in MPM have reported antitumor activity. Very little is known about immune-related predictive factors. Conclusions: Our findings indicate that the use of immunotherapy in MPM warrants further investigation. Furthermore, the impressive clinical response obtained by our patient suggests that immune checkpoint inhibitors could help in the management of the disease after the failure of other treatments. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.02.006

Authors: Giuseppe Bronte, Angelo Delmonte, Marco Angelo Burgio, Alberto Verlicchi, Maurizio Puccetti, Sara Bravaccini, Paola Cravero, Maria MaddalenaTumedei, Danila Diano, Giulio Rossi, Paola Ulivi, Giovanni Martinelli, Lucio Crinòa

Case StudyKirk SmithApril 1, 2020Mesothelioma, PD-L1, Immunotherapy, Immune checkpoint inhibitors, EML4-ALK

Targeted Therapy and Checkpoint Immunotherapy in Lung Cancer

Lung cancer is the leading cause of cancer
mortality. It is classified into different histologic subtypes, including adenocarcinoma, squamous carcinoma, and large cell carcinoma (commonly referred as non–small cell lung cancer) and small cell lung cancer. Comprehensive molecular characterization of lung cancer has expanded our understanding of the cellular origins and molecular pathways affected in each of these subtypes. Many of these genetic alterations represent potential therapeutic targets for which drugs are constantly under development. This article discusses the molecular characteristics of the main lung cancer subtypes and discusses the current guidelines and novel targeted therapies, including checkpoint immunotherapy. READ ARTICLE

Surgical Pathology Clinics DOI:10.1016/j.path.2019.11.002

Authors: Roberto Ruiz-Cordero, Walter Patrick Devine

Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models

Background: With the advance of immunotherapy, treatment of non-small-cell lung cancer (NSCLC) has revolutionized by having anti-PD-1 therapy in front-line setting. In this era of cancer immunotherapy, humanized mouse models which recapitulate human immune system, are needed for predicting immunotherapy response in patients. We established a Hu-PBL-NSG mouse model which can be used as a preclinical testing platform for assessing efficacy of different immunotherapeutic agents. Conclusion: Hu-PBL-NSG mouse model which highly resembles human immune system was successfully established. This model could be a strong preclinical model for testing efficacy of immunotherapeutic agents, and also for pursuing novel immunotherapy treatment strategies in advanced NSCLC. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2018.11.035

Authors: Kyoung Ho Pyo, Jae Hwan Kim, Ji-Min Lee, Sung Eun Kim, Jae Seok Cho, Sun Min Lim, Byoung Chul Cho

Pre-ClinicalKirk SmithJanuary 1, 2019Humanized mouse, Hu-PBL-NSG, Immunotherapy, EML4-ALK

Clinical utility of tumor mutational burden in patients with non-small cell lung cancer treated with immunotherapy

Anti-programmed death (ligand)-1 [anti-PD-(L)1] therapies such as pembrolizumab, nivolumab or atezolizumab have become standard of care for non-small cell lung cancer (NSCLC) patients either in first line or beyond. PD-L1 expression level allows enriching the treated population with responders, but it is still not an optimal biomarker. Even in patients with PD-L1 tumor proportion score (TPS) levels of ≥50% treated with first line pembrolizumab overall response rate (ORR) is only 44.8% and overall survival at one year is 70%. Moreover, in combination trials with chemotherapy and anti-PD-(L)1 therapy, a significant proportion of patients does not respond (ORR ranges from 45.3% to 64.0%), regardless of PD-L1 expression. Furthermore, PD-L1 expression level is not associated with improved benefit in patients treated with combinations of anti-PD-(L)1 and anti-cytotoxic T-lymphocyte-associated antigen (anti-CTLA4) therapy. One of the new promising biomarkers is tumor mutational burden (TMB). ..... READ ARTICLE

Translational Lung Cancer Research DOI:10.21037/tlcr.2018.09.22

Authors: Lizza E. Hendriks, Etienne Rouleau and Benjamin Besse