Xiuning Le

Correlation between Classic Driver Oncogene Mutations in EGFR, ALK, or ROS1 and 22C3–PD-L1 ≥50% Expression in Lung Adenocarcinoma

Introduction: Targeted somatic genomic analysis (EGFR, anaplastic lymphoma receptor tyrosine kinase gene [ALK], and ROS1) and programmed death ligand 1 (PD‐L1) tumor proportion score (TPS) determined by immunohistochemistry (IHC) are used for selection of first‐line therapies in advanced lung cancer; however, the frequency of overlap of these biomarkers in routine clinical practice is poorly reported. Methods: We retrospectively probed the first 71 pairs of patients with lung adenocarcinoma from our institution. They were analyzed for PD‐L1 by IHC using the clone 22C3 pharmDx kit (Agilent Technologies, Santa Clara, CA) and evaluated for co‐occurrence of genomic aberrations and clinicopathologic characteristics. Results: Surgical resection specimens, small biopsy (transbronchial or core needle) samples, and cytologic cell blocks (needle aspirates or pleural fluid) were tested. A PD‐L1 TPS of at least ≥50% was seen in 29.6% of tumors. Of 19 tumors with EGFR mutations, ALK fluorescence in situ hybridization positivity, or ROS1 fluorescence in situ hybridization positivity, 18 had a PD‐L1 TPS less than 50% versus only one tumor with a PD‐L1 TPS of at least 50% (p = 0.0073). Tumors with a PD‐L1 TPS of at least 50% were significantly associated with smoking status compared with tumors with a PD‐L1 TPS less than 50% but were not associated with patient sex, ethnicity, tumor stage, biopsy site, or biopsy type/preparation. Conclusions: PD‐L1 IHC can be performed on routine clinical lung cancer specimens. A TPS of at least 50% seldom overlaps with presence of driver oncogenes with approved targeted therapies. Three biomarker‐specified groups of advanced lung adenocarcinomas can now be defined, each paired with a specific palliative first‐line systemic therapy of proven clinical benefit: (1) EGFR/ALK/ROS1‐affected adenocarcinoma paired with a matched tyrosine kinase inhibitor (˜20% of cases), (2) PD‐L1–enriched adenocarcinoma (TPS ≥50%) paired with anti–PD‐1 pembrolizumab (˜30% of cases), and (3) biomarker‐negative (i.e., EGFR/ALK/ROS1/PD‐L1–negative) adenocarcinoma paired with platinum doublet chemotherapy with or without bevacizumab (˜50% of cases).

The safety and efficacy of osimertinib for the treatment of EGFR T790M mutation positive non-small-cell lung cancer

ABSTRACT First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for metastatic non-small-cell lung cancers (NSCLCs) that harbor sensitizing EGFR mutations (i.e. exon 19 deletions or L858R). However, acquired resistance to EGFR TKI monotherapy occurs invariably within a median time frame of one year. The most common form of biological resistance is through the selection of tumor clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. The presence of the EGFR T790M mutation negates the inhibitory activity of gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs has been identified by probing a series of covalent pyrimidine EGFR inhibitors that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant forms of EGFR versus the wild-type receptor. We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M.

De novo pulmonary small cell carcinomas and large cell neuroendocrine carcinomas harboring EGFR mutations: Lack of response to EGFR inhibitors

INTRODUCTION Epidermal growth factor receptor (EGFR) mutations are present in 10-20% of all non-small-cell lung cancers and predict for response to EGFR tyrosine kinase inhibitors (TKIs). However, the incidence of these mutations and their ability to predict response to TKIs in high-grade pulmonary neuroendocrine carcinomas [i.e. small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC)] is unknown. METHODS The presence of EGFR mutations, clinicopathologic and anti-cancer therapy response data were retrospectively compiled and analyzed from a cohort of 608 patients-lung tumors to identify EGFR mutated high-grade pulmonary neuroendocrine carcinomas. We identified 126 EGFR-mutated (21.8% of 578 successful genotyped cases) lung cancers and only 2 (1.6%) were high-grade neuroendocrine carcinomas. RESULTS Case one was of a 63 year-old white never smoker woman with extensive stage SCLC harboring EGFR-delL747_P753insS but without EGFR protein expression. After progression on carboplatin/etoposide, the patient was treated with erlotinib and developed progressive disease with a survival <3 months from start of erlotinib. Case two was of a 73 year-old Asian 30 pack-year smoker man with metastatic LCNEC harboring EGFR-delL747_P753insQS and also lacking EGFR protein expression. The patient received first line therapy with erlotinib and had progressive disease with a survival of 4 months. CONCLUSIONS The lack of response to EGFR TKIs in EGFR mutated de novo SCLC and LCNEC reported here may indicate that tumor differentiation affects tumor dependency on EGFR as a driver oncogene.

Detection of Crizotinib-Sensitive Lung Adenocarcinomas With MET, ALK, and ROS1 Genomic Alterations via Comprehensive Genomic Profiling.

Introduction Crizotinib is an oral multitargeted tyrosine kinase inhibitor (TKI) with activity against lung cancers driven by ALK-rearrangements, ROS1-rearrangements and MET-amplification. Comprehensive genomic profiling (CGP) based on clinical next generation sequencing (NGS) can detect crizotinib-sensitive genomic changes. We describe use of CGP to identify tumors responsive to crizotinib. Methods Retrospective review of representative lung adenocarcinomas treated with crizotinib and assayed with a clinical NGS assay. Results We report 3 cases of lung adenocarcinoma; one each identified to harbor an ALK-rearrangement (EML4-ALK), ROS1-rearrangement (SDC4-ROS1) and MET-amplification by genomic profiling. Notably, the MET-amplification was only detected by CGP as subsequent FISH testing did not show amplification. CGP also revealed other common genomic changes (somatic mutations [TP53 in 2 cases], deletions [CDKN2A in 1 case], amplifications [MCL1 in 1 case] and variants of unknown significance) in these cases. All patients received crizotinib 250 mg twice daily and achieved radiographic tumor reduction for months. The case harboring MET amplification of 10 copies achieved partial response and is one of the first MET-amplified lung cancer responsive to crizotinib in which the sole detection method was CGP. Conclusions CGP holds the promise of detecting predictive genomic alterations (somatic mutations, copy number changes and rearrangements) that may underlie tumor dependency in an oncogene and govern response to clinically-available TKIs for lung adenocarcinomas.

Moving more potent and less toxic options to the frontline in the management of advanced lung cancer

The most common primary lung cancers can be divided into small cell lung cancer and non-small cell lung cancer (NSCLC)—the latter compromised predominantly of adenocarcinoma and squamous cell carcinoma histologies.

Fishing for Precision in ALK-Rearranged Non-Small-Cell Lung Cancers

Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) represent the current standard for identification of therapeutically relevant anaplastic lymphoma kinase (ALK) rearrangements in advanced non-small-cell lung cancers (NSCLCs). Use of tyrosine kinase inhibitors (TKIs) targeting the oncogenic ALK fusion protein is approved for use in advanced ALK-rearranged NSCLCs and with benefits both with regards to clinical outcomes and quality of life when compared with traditional palliative cytotoxic therapies. We report here 2 cases in which initial standard of care ALK testing by FISH yielded false positive results, leading to delays in determination of optimal systemic therapy.