Title: Pralsetinib for RET fusion-positive advanced non-small cell lung cancer [ID3875]
Funder: Department of Health and Social Care

Abstract: Lung cancer falls into two main histological categories: around 85 – 90% are non-small-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 2017, 39,201 people were diagnosed with NSCLC in England & Wales, and around 57% 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[5]. 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 but not currently for RET-fusions/mutations (subject to ongoing appraisal ID3743). Testing for RET fusion/mutations 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, NICE guideline 122 recommends platinum-based chemotherapy (that is, cisplatin or carboplatin and either docetaxel, gemcitabine, paclitaxel, or vinorelbine). NICE technology appraisal guidance 683 recommends pembrolizumab combination therapy as an option for metastatic untreated non-squamous NSCLC if the tumour has no EGFR- or ALK-positive mutations. NICE technology appraisal guidance 584 recommends atezolizumab with bevacizumab, carboplatin and paclitaxel as an option for untreated non-squamous NSCLC if the tumour expresses PD-L1 with less than 50% tumour proportion score and has no EGFR- or ALK-positive mutations. Alternatively, people may receive pemetrexed in combination with cisplatin if the histology of the tumourhas 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 progresses after initial treatment with platinum-based chemotherapy can receive chemotherapy with docetaxel and the multikinase inhibitor nintedanib (TA347), atezolizumab (TA520), nivolumab (TA484)a, or pembrolizumab (TA428). People whose disease progress after treatment with pembrolizumab combination (TA683) or atezolizumab combination (TA584) can receive docetaxel with or without nintedanib (TA347)._x000D_ _x000D_ 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 with or without nintedanib (TA347) is recommended._x000D_ _x000D_ For previously untreated, metastatic, squamous NSCLC if the tumours express PD-L1 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 (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 December 2020_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 2018 (for the audit period 2017) (2019). Royal College of Physicians. Accessed December 2020_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_x000D_ 5 Royal College of Physicians (2017) National Lung Cancer Audit annual report 2016 (for the audit period 2015). Accessed December 2020.

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

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