Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology

Context.— In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular P...

Purpose: The third-generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat patients with EGFR T790M-positive non-small cell lung cancer (NSCLC) who have developed resistance to earlier-generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown.Experimental Design: We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients. In vitro experiments were conducted to functionally study the secondary EGFR mutations identified.Results:EGFR G796/C797, L792, and L718/G719 mutations were identified in 24.7%, 10.8%, and 9.7% of the cases, respectively, with certain mutations coexisting in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC50) of osimertinib in vitro, among which the L718Q mutation conferred the greatest resistance to osimertinib, as well as gefitinib resistance when not coexisting with T790M. Further analysis of the 12 matched pretreatment samples confirmed that these EGFR mutations were acquired during osimertinib treatment. Alterations in parallel or downstream oncogenes such as MET, KRAS, and PIK3CA were also discovered, potentially contributing to the osimertinib-resistance in patients without EGFR secondary mutations.Conclusions: We present comprehensive mutation profiles of a large cohort of osimertinib-resistance lung cancer patients using mainly cfDNA. Besides C797 mutations, novel secondary mutations of EGFR L718 and L792 residues confer osimertinib resistance, both in vitro and in vivo, and are of great clinical and pharmaceutical relevance. Clin Cancer Res; 24(13); 3097-107. ©2018 AACR.

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Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non–Small Cell Lung Cancer Patients

Crizotinib in Patients With MET-Amplified NSCLC

Purpose of review In this article, we summarize the current knowledge on molecular alterations in lung cancer that are targets for therapy, and provide an outlook on the future development of molecular pathology in precision oncology. Recent findings Lung cancer has become a paradigm for the success of molecular targeted therapies in solid tumors. Tyrosine kinase inhibitors are effective treatment options in adenocarcinoma patients with an EGFR, ALK, ROS1 or B-Raf Proto-Oncogene, Serine/Threonine kinase mutation. Additional molecular targets that are addressed in clinical trials include ERBB2, MET, RET, NTRK1 and FGFR. Therapies with antibodies that block the interaction of PD-L1 with PD-1 and thereby liberate an antitumor immune response have introduced a new era in cancer therapy with impressive therapeutic benefits. The high financial burden, treatment failures and therapeutic side effects of immunotherapies have prompted a search for biomarkers beyond PD-L1 expression, for example, tumor mutation load or immune cell profiling, that might more reliably identify patients that are likely to respond. Summary The discoveries of cancer research have been translated into the clinical management of lung cancer patients. So far, the approach of targeted therapy that is directed towards certain molecular alterations in a given tumor has been successful for adenocarcinomas, but not yet for squamous or small cell carcinomas. Further clinical progress will require a better understanding of the molecular interactions within cancer cells that will subsequently enable innovative drug designs. Diagnostic molecular pathology will be a provider of information on a tumor's features and thus, navigate precision cancer therapy.

Molecular pathology of lung cancer: current status and perspectives.

Responses to Crizotinib Can Occur in High-Level MET-Amplified Non-Small Cell Lung Cancer Independent of MET Exon 14 Alterations.

In March 2016, this patient presented with symptoms of cough, weight loss, hyporexia, and dyspnea. Initial work-up demonstrated a 3.13 2.3–cm posterior left upper lobe mass, multiple bilateral lung micronodules, as well as several enlarged lymph nodes (ipsilateral hilum, bilateral upper paratracheal, and para-aortic sites). Pulmonary transbronchial biopsy revealed an adenocarcinoma(Fig1). F-labeled fluorodeoxyglucosepositron emission tomography showed increased uptake in primary mass, enlarged lymph nodes, and lymphangitic carcinomatosis (T2aN3M1a).

Metastatic Lung Adenocarcinoma Harboring an EGFR-Activating Mutation in a Heart Transplant Recipient.

Phase IV trials, studies conducted in the post-marketing scenario, are usually performed with a large number of patients and heterogeneous populations. They can be used to increase the generalizability of findings from phase III trials, to evaluate uncommon adverse events, and sometimes to assess cost-effectiveness. In oncology, phase IV trials also encompass the concept of “compassionate use”, where patients are given access to new therapies when enrollment in clinical trials is not feasible. Recently, regulatory agencies have started requesting phase IV studies for approved drugs; however, only 25% of marketed drugs go beyond mandatory phase III trials. Several study designs have been described for phase IV trials, but this is still a sparsely regulated area.

Phase IV Trials: Interventional and Non-interventional Studies

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Responses to Crizotinib Can Occur in High-Level MET-Amplified Non-Small Cell Lung Cancer Independent of MET Exon 14 Alterations.

Metastatic Lung Adenocarcinoma Harboring an EGFR-Activating Mutation in a Heart Transplant Recipient.

Phase IV Trials: Interventional and Non-interventional Studies