Your resource for the latest research into the MET alteration. CRUSADER NEWSLETTER Q2 2020 RESEARCH EDITION MET Crusaders is a community of Lung Cancer patients and care givers collaborating with advocates and medical professionals collectively dedicated to helping patients with a MET alteration live normal lives. Come Join Us! [email protected] In this edition Top-level MET gene copy number gain defines .................... 2 Molecular Mechanisms of Acquired Resistance ................... 5 a subtype of poorly differentiated pulmonary to MET Tyrosine Kinase Inhibitors in Patients adenocarcinomas with poor prognosis with MET Exon 14-Mutant NSCLC EDITOR Characteristics and Clinical Outcomes of ............................. 2 MET Alterations Are a Recurring and Actionable .................. 6 Jessica McKernan, PharmD Non-Small Cell Lung Cancer Patients in Korea Resistance Mechanism in ALK-Positive Lung Cancer with MET Exon 14 Skipping Atrium Health Tepotinib in Non-Small-Cell Lung Cancer with ...................... 6 Charlotte, NC Clinical and molecular correlates of PD-L1 ........................... 2 MET Exon 14 Skipping Mutations (VISION Trial) expression in patients with lung adenocarcinomas Therapeutic Efficacy of ABN401, a Highly ............................. 7 CONTRIBUTING EDITORS Efficacy and Safety of Anti-PD-1 Immunotherapy ................. 3 Potent and Selective MET Inhibitor, Based on Julia Stevens, PharmD in Patients With Advanced NSCLC With BRAF, HER2, Diagnostic Biomarker Test in MET-Addicted Cancer or MET Mutations or RET Translocation: GFPC 01-2018 Beth Israel Deaconess Erlotinib plus tivantinib versus erlotinib alone ..................... 7 Medical Center Alterations in the PI3K Pathway Drive Resistance ................ 3 in patients with previously treated stage IIIb/IV Boston, MA to MET Inhibitors in NSCLC Harboring MET non-small-cell lung cancer: A meta-analysis based Exon 14 Skipping Mutations on randomized controlled trials Laura Schmidt, PharmD Incidence and PD-L1 Expression of MET 14 .......................... 4 Tepotinib plus gefitinib in patients with ................................. 8 Northwestern Memorial Skipping in Chinese Population: A Non-Selective EGFR-mutant non-small-cell lung cancer with Hospital NSCLC Cohort Study Using RNA-Based Sequencing MET overexpression or MET amplification and Chicago, IL acquired resistance to previous EGFR inhibitor High-level gain of mesenchymal-epithelial ............................ 4 (INSIGHT study): an open-label, phase 1b/2, transition factor (MET) copy number using CONTENT ADVISOR multicentre, randomised trial next-generation sequencing as a predictive Laura Greco biomarker for MET inhibitor efficacy Response to Checkpoint Inhibition in .................................... 8 Non-Small Cell Lung Cancer with Molecular MET Crusaders Management of NSCLC Patients with ..................................... 5 Driver Alterations MET Exon 14 Skipping Mutations CRUSADER EWSLETTER Q2 2020 RESEARCH EDITION Top-level MET gene copy number gain defines a subtype of poorly differentiated pulmonary adenocarcinomas with poor prognosis Journal: Translational Lung Cancer Research A variety of MET alterations can occur in non-small cell lung cancer (NSCLC), including MET amplification. This study aimed to quantify and define what it means to be MET amplified. A total of 373 patients with NSCLC were tested for their MET gene copy number (GCN). The data led to defining the top-level category for MET amplification as greater than the 90th percentile of the average GCN, or at least 10 MET gene copies per tumor cell on average. Data from trials with MET inhibitors have suggested that these inhibitors may have a “gene dose effect,” suggesting that the GCN may play a role in response to inhibitors and survival outcomes. The authors of this study suggest it may be reasonable to give patients with MET top-level amplification earlier access to MET inhibitors by using it in the first line setting given the aggressive nature of MET top-level amplified NSCLC, though much further research is needed through prospective clinical trials to support this. LINK TO ARTICLE Characteristics and Clinical Outcomes of Non-Small Cell Lung Cancer Patients in Korea with MET Exon 14 Skipping Journal: In Vivo This study assessed Korean patients with NSCLC and MET exon 14 skipping. A total of 1,020 patients were analyzed via next-generation sequencing, 20 of which were found to have MET exon 14 skipping (all negative for EGFR, ALK, ROS1, BRAF, and RET alterations). The median overall survival (OS) in patients who received first-line traditional platinum-based chemotherapy was 9.5 months, and progression-free survival (PFS) was 4 months. This illustrates poor clinical outcomes and low responses to therapy in these patients in the setting of many advancements and recent approvals of several MET inhibitors, emphasizing the need for screening for MET exon 14 skipping alterations in patients with NSCLC. LINK TO ARTICLE Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas Journal: Annals of Oncology Programmed death-ligand 1 (PD-L1) is an FDA-approved biomarker that can help determine the body’s response to antibody drugs like immune checkpoint inhibitors (ICIs). This article took a deeper dive into the molecular and clinical features of PD-L1 expression and how these features may help predict a patient’s response to ICIs. A total of 1,586 patients with lung adenocarcinoma had undergone PD-L1 testing. PD-L1 expression was significantly lower in primary tissue than metastatic tissue but did not significantly differ based on smoker status. PD-L1 was expressed at different levels depending on organ type. Among metastatic sites, PD-L1 expression was highest in lymph nodes and lowest in bone. KRAS, TP53, and MET alterations were associated with high PD-L1 expression, while EGFR, STK11, and WNT alterations were associated with negative PD-L1 expression. Among the frequent gene alterations in lung adenocarcinomas, patients with MET alterations had the greatest proportion of PD-L1 high expression. These results demonstrate that there may be a correlation between levels of PD-L1 expression and existence of other molecular markers. LINK TO ARTICLE 2 CRUSADER EWSLETTER Q2 2020 RESEARCH EDITION Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients With Advanced NSCLC With BRAF, HER2, or MET Mutations or RET Translocation: GFPC 01-2018 Journal of Thoracic Oncology The objective of this study was to determine the efficacy of immune-checkpoint inhibitors (ICIs) in 107 patients with metastatic NSCLC harboring BRAF, HER2, MET, or RET alterations. A total of 44 patients had a BRAF mutation, 23 had a HER2 mutation, 30 had a MET exon 14 skipping mutation, and 9 had a RET mutation. Programmed cell death ligand 1 (PD-L1) status was known in 70 patients, 34 of which were greater than or equal to 1% expression. These patients had received a median of one treatment prior to ICI. Median duration of response was 15.4 months, progression-free survival (PFS) was 4.7 months, and overall survival (OS) was 16.2 months. Response rates varied based on alteration (BRAF: 26 to 35%, HER2: 27%, MET: 36%, RET: 38%). Of note, patients with MET exon 14 skipping were treated with either pembrolizumab or nivolumab, with a response rate of 35.7%, a median duration of treatment of 3.3 months, a median duration of response of 10.4 months, median PFS of 4.9 months, and median OS of 13.4 months. Overall, this study demonstrated higher response rates in patients with MET exon 14 skipping compared to previous studies. This study concluded that ICI efficacy in patients with metastatic NSCLC and BRAF, HER2, MET, or RET alterations was similar to patients who did not harbor these alterations as shown in previous studies, but further studies are needed to confirm these findings. LINK TO ARTICLE Alterations in the PI3K Pathway Drive Resistance to MET Inhibitors in NSCLC Harboring MET Exon 14 Skipping Mutations Journal of Thoracic Oncology This article emphasizes the prevalence of resistance to tyrosine kinase inhibitors (TKIs) for patients with NSCLC and MET exon 14 skipping mutations. Previous studies suggest response rates to targeted therapies like TKIs may be lower in patients with MET exon 14 skipping compared to other alterations, potentially due to this resistance. As a result, this study looked at the phosphoinositide 3-kinase (PI3K) pathway, which is known to be connected to MET. They hypothesized that patients with PI3K pathway alterations and MET exon 14 skipping may have resistance to MET TKIs. They analyzed 65 patients with MET exon 14 skipping and assessed if they had any PI3K pathway alterations. They then used a cell line derived from a patient with known MET TKI resistance and cell lines from patients who had MET exon 14 skipping and a PI3K pathway alteration to assess sensitivity to a MET TKI (capmatinib, tepotinib, crizotinib, or foretinib) with or without a PI3K inhibitor (GDC0941). The researchers found a phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutation in 2 of 65 samples (3%) and loss of phosphatase and tensin homolog (PTEN, which helps regulate PI3K pathway signaling) in 6 of 26 samples (23%). All 3 patients who were treated with a MET TKI (specific inhibitor not listed as patients were receiving through clinical trials) and had progression at their first clinical assessment after starting the MET TKI also had a PI3K alteration. Additionally, MET TKIs had no effect on