Title: Tepotinib for treating advanced non-small-cell lung cancer with MET gene alterations [ID3761]
Funder: Department of Health and Social Care

Abstract: Lung cancer falls into two main histological categories: around 85–90% are nonsmall-cell lung cancers (NSCLC) and the remainder are small-cell lung cancers[1]. NSCLC can be further classified into squamous cell carcinoma and non-squamous cell carcinoma. Approximately 70% of NSCLC are of non-squamous histology and can be either large-cell undifferentiated carcinoma or adenocarcinoma[2]. Most lung cancers are diagnosed at an advanced stage, when the cancer has spread to lymph nodes and other organs in the chest (locally advanced disease; stage III) or to other parts of the body (metastatic disease; stage IV). Most people with mesenchymalepithelial transition (MET) exon 14 (METex14) skipping mutations are female and their cancer is usually of non-squamous histology[3],[4]._x000D_ _x000D_ In 2017, 39,205 people were diagnosed with NSCLC in England & Wales, and around 65% had stage IIIB or stage IV disease[5]. Around a third of people with lung cancer survive for more than 1 year after diagnosis[6], however this is reduced to a fifth of people diagnosed at stage IV[5]. METex14 skipping mutations occur in 3% to 4% of lung adenocarcinoma[7]._x000D_ _x000D_ At advanced stage (III and IV) NSCLC treatment aims to control the cancer for as long as possible and help with symptoms. Treatment generally includes chemotherapy, targeted drugs, radiotherapy and symptom control treatment. Treatment choices are influenced by the presence of biological markers (such as the checkpoint inhibitor programmed death-ligand 1 [PD-L1] and mutations in epidermal growth factor receptor-tyrosine kinase [EGFR-TK] or anaplastic-lymphoma-kinase [ALK], or), histology (squamous or non-squamous) and previous treatment experience. There are specific NICE treatment pathways for cancers positive for EGFR-TK, ALK or ROS-1 gene mutations but not for METex14 skipping mutations._x000D_ _x000D_ For previously untreated, metastatic, non-squamous NSCLC if the tumours express PD-L1 with a tumour proportion score (TPS) between 0% and 49%, NICE guideline 122 recommends platinum-based chemotherapy (that is, cisplatin or carboplatin and either docetaxel, gemcitabine, paclitaxel, or vinorelbine). NICE technology appraisal 683 recommends pembrolizumab with pemetrexed and platinum chemotherapy. Alternatively, people may receive pemetrexed in combination with cisplatin if the histology of the tumour has been confirmed as adenocarcinoma or large-cell carcinoma (NICE technology appraisal guidance 181)._x000D_ _x000D_ People with metastatic, non-squamous NSCLC with PD-L1 <50% whose disease progress after initial treatment with platinum-based chemotherapy can receive chemotherapy with docetaxel and the multikinase inhibitor nintedanib (TA347), atezolizumab (TA520), nivolumab (TA484), or pembrolizumab (TA428). People whose disease progress after treatment with pembrolizumab combination (TA683) can receive docetaxel with or without nintedanib (TA347). For previously untreated, metastatic, non-squamous NSCLC if the tumours express PD-L1 TPS =50%, NICE guideline 122 recommends pembrolizumab monotherapy (TA531) or pembrolizumab with pemetrexed and platinum chemotherapy (TA683). If the disease progresses following pembrolizumab monotherapy (TA531), NICE guideline 122 recommends platinum doublet (TA181) or pemetrexed with carboplatin. If the disease progresses following pembrolizumab combination (TA683), docetaxel_x000D_ with or without nintedanib (TA347) is recommended. For previously untreated, metastatic, squamous NSCLC if the tumours express PD-L1 with TPS between 0% and 49%, NICE guideline 122 recommends platinumbased chemotherapy (that is, gemcitabine or vinorelbine with carboplatin or cisplatin) or pembrolizumab with carboplatin and paclitaxel (TA600)a. If the disease progresses, people can be offered docetaxel, atezolizumab (TA520), nivolumab (TA655), or pembrolizumab (TA428)._x000D_ _x000D_ People with metastatic, squamous NSCLC with PD-L1 TPS =50%, NICE technology appraisal 531 recommends pembrolizumab monotherapy and technology appraisal 600a recommends pembrolizumab with carboplatin and paclitaxel. If disease progresses after pembrolizumab monotherapy, NICE guideline 122 recommends gemcitabine or vinorelbine with carboplatin or cisplatin. If disease progresses after pembrolizumab combination, NICE guideline 122 recommends docetaxel._x000D_ _x000D_ References_x000D_ 1 Lung cancer incidence by morphology. Cancer Research UK. Accessed April 2021_x000D_ 2 Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF,et al. SEER Cancer Statistics Review, 1975-2012. National Cancer Institute. 2015 Accessed April 2021_x000D_ 3 Awad, M et al. 2016. MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression. Journal of clinical Oncology: 34(7):721-30_x000D_ 4 Tong, J et al. 2016. MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non-Small Cell Lung Carcinoma with Poor Prognosis. Clinical cancer research: 22(12): 3048-56._x000D_ 5 National Lung Cancer Audit: Annual report 2018 (for the audit period 2017) (2019). Royal College of Physicians. Accessed April 2021_x000D_ 6 Falchook, G et al. 2016. Effect of the RET Inhibitor Vandetanib in a Patient With RET Fusion–Positive Metastatic Non–Small-Cell Lung Cancer. Journal of Clinical Oncology 34:15_x000D_ 7 Drilon, A et al. 2017. Targeting MET in Lung Cancer: Will Expectations Finally Be MET? Journal of Thoracic Oncology: 12:12-14

Lay abstract: To appraise the clinical and cost effectiveness of tepotinib within its marketing authorisation for treating adults with advanced non-small cell lung cancer (NSCLC) with mesenchymal–epithelial transition (MET) exon 14 (METex14) skipping mutations.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS