Title: Selpercatinib for untreated RET fusion-positive advanced non-small-cell lung cancer [ID4056]
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). In 2018, 39,754 people were diagnosed with NSCLC in England & Wales, and around 61% had stage IIIB or stage IV disease[3] . Rearranged during transfection (RET) fusion-positive tumours occur in 1-2% of NSCLC and are more commonly found in people who are younger than 60 years, former light smokers or those who have never smoked[4] . _x000D_ _x000D_ Around a third of people with lung cancer survive for more than 1 year after diagnosis, however this is reduced to a fifth of people diagnosed at stage IV[3] . 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 mutations in epidermal growth factor receptor-tyrosine kinase [EGFR-TK], anaplastic-lymphoma-kinase [ALK] or PD-L1 status), 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. Testing for RET fusion status is not routinely carried out as standard of care in the UK. People with unconfirmed RET fusion-positive advanced NSCLC would therefore follow the standard NSCLC treatment pathway. _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. NICE technology appraisal 584 recommends atezolizumab plus bevacizumab, carboplatin, and paclitaxel. 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_ For previously untreated, metastatic, non-squamous NSCLC if the tumours express PD-L1 TPS =50%, NICE guideline 122 recommends pembrolizumab monotherapy (TA531), atezolizumab monotherapy (TA705), or pembrolizumab with pemetrexed and platinum chemotherapy (TA683). _x000D_ _x000D_ For previously untreated, metastatic, squamous NSCLC if the tumours express PDL1 with TPS between 0% and 49%, NICE guideline 122 recommends platinum-based chemotherapy (that is, gemcitabine or vinorelbine with carboplatin or cisplatin) or pembrolizumab with carboplatin and paclitaxel (TA770). _x000D_ _x000D_ People with metastatic, squamous NSCLC with PD-L1 TPS =50%, NICE technology appraisal 531 recommends pembrolizumab monotherapy, technology appraisal 705 recommends atezolizumab monotherapy, and technology appraisal 770 recommends pembrolizumab with carboplatin and paclitaxel. _x000D_ _x000D_ NICE technology appraisal 760 recommends selpercatinib for use within the Cancer Drugs Fund as an option for treating RET fusion-positive advanced NSCLC in adults who need systemic therapy after immunotherapy, platinum-based chemotherapy or both._x000D_ _x000D_ References_x000D_ 1 Lung cancer incidence by morphology. Cancer Research UK. Accessed March 2022_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 [Available from: https://seer.cancer.gov/csr/1975_2012/_x000D_ 3 National Lung Cancer Audit: Annual report 2021 (for the audit period 2018) (2021). Royal College of Physicians. Accessed March 2022_x000D_ 4 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

Lay abstract: To appraise the clinical and cost effectiveness of selpercatinib within its marketing authorisation for treating untreated RET fusion-positive advanced non-small-cell lung cancer.

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