NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Health Technology Evaluation

Selpercatinib for untreated RET fusion-positive advanced non-small-cell lung cancer

Final scope

Remit/evaluation objective

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.

Background

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] .

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.

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).

Final scope for the evaluation of selpercatinib for untreated RET fusion-positive advanced non-small-cell lung cancer Issue Date: July 2022 © National Institute for Health and Care Excellence 2022. All rights reserved.

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).

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).

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.

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.

The technology

Selpercatinib (Retsevmo, Eli Lilly) does not have a marketing authorisation in the UK for treating people with untreated RET fusion-positive advanced non-small-cell lung cancer. It is being studied in a randomised clinical trial comparing selpercatinib to platinum-based and pemetrexed therapy with or without pembrolizumab as initial treatment of advanced or metastatic RET fusion-positive NSCLC. The trial includes adults with advanced RET fusion-positive non-squamous NSCLC who have not had prior systemic therapy for metastatic disease.

Final scope for the evaluation of selpercatinib for untreated RET fusion-positive advanced non-small-cell lung cancer Issue Date: July 2022

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• Atezolizumab

For people with non-squamous NSCLC whose tumours express PD-L1 with a tumour proportion score below 50%:

• Pembrolizumab combination with pemetrexed and platinum chemotherapy

• Atezolizumab plus bevacizumab, carboplatin and paclitaxel

• Chemotherapy (docetaxel, gemcitabine, paclitaxel or vinorelbine) in combination with a platinum drug (carboplatin or cisplatin)

  • with or without pemetrexed maintenance treatment

For people with adenocarcinoma or large-cell carcinoma whose tumours express PD-L1 with a tumour proportion score below 50%:

• Pemetrexed in combination with a platinum drug (carboplatin or cisplatin)

  • with (following cisplatin-containing regimens only) or without pemetrexed maintenance treatment

For people with squamous NSCLC whose tumours express PD-L1 with at least a 50% tumour proportion score:

• Pembrolizumab monotherapy

• • Atezolizumab • Pembrolizumab with carboplatin and paclitaxel (who need urgent clinical intervention)

• For people with squamous NSCLC whose tumours express PD-L1 with a tumour proportion score below 50%:

  • Chemotherapy (gemcitabine or vinorelbine) in combination with a platinum drug (carboplatin or cisplatin)

  • • Pembrolizumab with carboplatin and paclitaxel

• Outcomes The outcome measures to be considered include: • overall survival • progression free survival • response rate

  - time to treatment discontinuation 
  
  - • adverse effects of treatment • health-related quality of life.
  

Final scope for the evaluation of selpercatinib for untreated RET fusion-positive advanced non-small-cell lung cancer Issue Date: July 2022 © National Institute for Health and Care Excellence 2022. All rights reserved.

Final scope for the evaluation of selpercatinib for untreated RET fusion-positive advanced non-small-cell lung cancer Issue Date: July 2022 © National Institute for Health and Care Excellence 2022. All rights reserved.

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• Atezolizumab monotherapy for untreated advanced non small-cell lung cancer. (2021) NICE technology appraisal 705. - Atezolizumab in combination for treating metastatic non squamous non-small-cell lung cancer. (2019) NICE technology appraisal guidance 584. Pembrolizumab for untreated PD-L1-positive metastatic nonsmall-cell lung cancer. (2018) NICE technology appraisals guidance 531. Pemetrexed for the maintenance treatment of non-small-cell lung cancer .(2017) NICE technology appraisal guidance 190 Pembrolizumab for treating PD-L1-positive non-small-cell lung cancer after chemotherapy. (2017) NICE technology appraisal guidance 428 Pemetrexed maintenance treatment for non-squamous nonsmall-cell lung cancer after pemetrexed and cisplatin. (2016) NICE technology appraisal guidance 402 Pemetrexed for the first-line treatment of non-small-cell lung cancer. (2009) NICE technology appraisal 181. Appraisals in development (including suspended appraisals): Pralsetinib for RET fusion-positive advanced non-small-cell lung cancer. NICE Technology Appraisal Guidance [ID3875]. In progress. Atezolizumab with carboplatin or cisplatin and pemetrexed for untreated advanced non-squamous non-small-cell lung cancer. NICE Technology Appraisal Guidance [ID1495] Suspended. Durvalumab with tremelimumab for untreated non-small-cell lung cancer with no EGFR- or ALK-positive mutations. NICE technology appraisal guidance [ID1143]. In progress. - Nivolumab in combination with ipilimumab for untreated PD L1-positive non-small-cell lung cancer. NICE technology appraisal guidance [ID1187]. Suspended. Nivolumab in combination with platinum-doublet chemotherapy for untreated PD-L1-negative non-small-cell lung cancer. NICE technology appraisal guidance [ID1135]. Suspended. Nivolumab monotherapy for non-small-cell lung cancer. NICE technology appraisal guidance [ID1088]. Suspended. Pembrolizumab for untreated PD-L1 positive non-small-cell lung cancer with at least 1% tumour proportion score. NICE technology appraisal guidance [ID1247]. Suspended.

Final scope for the evaluation of selpercatinib for untreated RET fusion-positive advanced non-small-cell lung cancer Issue Date: July 2022 © National Institute for Health and Care Excellence 2022. All rights reserved.

Final scope for the evaluation of selpercatinib for untreated RET fusion-positive advanced non-small-cell lung cancer Issue Date: July 2022 © National Institute for Health and Care Excellence 2022. All rights reserved.

References

1 Lung cancer incidence by morphology. Cancer Research UK. Accessed March 2022

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/

3 National Lung Cancer Audit: Annual report 2021 (for the audit period 2018) (2021). Royal College of Physicians. Accessed March 2022

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

Final scope for the evaluation of selpercatinib for untreated RET fusion-positive advanced non-small-cell lung cancer Issue Date: July 2022 © National Institute for Health and Care Excellence 2022. All rights reserved.