Scope — TA898

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Health Technology Evaluation

Dabrafenib in combination with trametinib for treating advanced, metastatic BRAF V600 mutation-positive non-small-cell lung cancer (review of technology appraisal 564)

Final scope

Remit/evaluation objective

To appraise the clinical and cost effectiveness of dabrafenib in combination with trametinib within its marketing authorisation for treating advanced, metastatic BRAF V600 mutation-positive non-small-cell lung cancer.

Background

Lung cancer falls into 2 main histological categories: around 80–85% are non-smallcell lung cancers (NSCLC) and the remainder are small cell lung cancers.[1] NSCLC can be further classified into 3 main histological sub-types of large-cell undifferentiated carcinoma, squamous cell carcinoma and adenocarcinoma.[1] 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 3) or to other parts of the body (metastatic disease; stage 4). BRAF is a protein which is part of the mitogen activated protein kinase signalling pathway, which helps to regulate cell proliferation, differentiation and death.[2]

In 2020 around 28,300 cases of non-small-cell lung cancer were diagnosed in England.[3] In the same year 19% of all lung cancer cases were stage 3 and 40% were stage 4.[3 ] Lung cancer survival rates are relatively low, between 2013 and 2017 40% of people with lung cancer survived for one year and 16% survived for 5 years or longer. BRAF mutations are found in approximately 1-4% of NSCLCs, and of these mutations about 50% are BRAF V600E mutations.[4 ]

Current clinical management for advanced or metastatic (stage 3 or 4) NSCLC typically aims to control the cancer for as long as possible and help with symptoms. Treatment generally includes surgery, chemotherapy, radiotherapy, chemoradiation or targeted small molecule and immunotherapy drugs. Treatment choices are influenced by the histology of the condition (squamous, or non-squamous) and by previous treatments. Choices are also influenced by the presence of certain biomarkers such as the programmed cell death-ligand 1 (PD-L1) or mutations affecting proteins such as epidermal growth factor receptor (EGFR), anaplasticlymphoma kinase (ALK) or the ROS-1 and KRAS receptors. There are specific NICE treatment pathways for cancers which have EGFR, ALK, ROS-1 or KRAS gene mutations but not currently for BRAF mutations.

Final scope for the evaluation of dabrafenib in combination with trametinib for treating advanced, metastatic BRAF V600E mutation-positive non-small-cell lung cancer Issue Date: June 2022

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Disease with no biomarkers

For untreated non-squamous metastatic NSCLC with no ALK or EGFR mutations, pembrolizumab with pemetrexed and platinum chemotherapy is recommended (TA683). Pemetrexed is also recommended as maintenance therapy for nonsquamous NSCLC which is locally advanced or metastatic and which has not progressed after other chemotherapies (TA190 & TA402). For those who have adenocarcinoma or large cell carcinoma (subsets of non-squamous NSCLC) pemetrexed is recommended as first line chemotherapy (TA181) and nintedanib with docetaxel is recommended for adenocarcinoma that has progressed after first line chemotherapy (TA347).

For those with locally advanced or metastatic NSCLC who have previously had chemotherapy (or targeted EGFR or ALK treatment) atezolizumab is recommended (TA520). For those who have squamous NSCLC which is locally advanced or metastatic and which has been previously treated with chemotherapy, nivolumab is recommended (TA655).

Disease with PD-L1 biomarker

For those with untreated metastatic NSCLC disease with no EGFR or ALK mutations, where tumour PD-L1 expression is 50% or more, NICE recommends pembrolizumab monotherapy (TA531) or atezolizumab monotherapy [which can also be given if 10% or more of tumour infiltrating immune cells express PD-L1] (TA705). For untreated metastatic NSCLC where targeted EGFR or ALK therapy has failed and which has tumour PD-L1 expression of 0 to 49%, atezolizumab with bevacizumab, carboplatin and paclitaxel is recommended (TA584). For untreated metastatic squamous NSCLC which expresses PD-L1 on 0 to 49% of cells (or 50% or more if urgent treatment is required) pembrolizumab with carboplatin and paclitaxel is recommended (TA770).

For those who have locally advanced or metastatic NSCLC whose tumours express PD-L1 on 1% or more of cells and which have been previously treated with chemotherapy, NICE recommends pembrolizumab [also given after treatment with an EGFR or ALK inhibitor if appropriate] (TA428) and nivolumab when the NSCLC is non-squamous (TA713).

The technology

Dabrafenib (Tafinlar[®] , Novartis Pharmaceuticals) is a selective inhibitor of BRAF V600E kinase activity. Trametinib (Mekinist[®] , Novartis pharmaceuticals) is an inhibitor of MEK1 and MEK2 activity. BRAF V600E and MEK proteins work in a chain to send signals to encourage cell growth, by blocking these proteins these drugs cause cancer cells to stop growing and die. Both treatments are administered orally.

Dabrefanib with trametinib is indicated for the treatment of adult patients with advanced non-small-cell lung cancer with a BRAF V600E mutation.

Intervention(s)	Dabrafenib with trametinib
Population(s)	Adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation

Final scope for the evaluation of dabrafenib in combination with trametinib for treating advanced, metastatic BRAF V600E mutation-positive non-small-cell lung cancer Issue Date: June 2022

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Subgroups If the evidence allows the following subgroups will be
considered:
•
previous therapy (treated or untreated)
•
tumour histology (squamous or non-squamous)
•
Level of PD-L1 expression (strong positive or weak
positive)

Comparators Untreated NSCLC disease:
For people with non-squamous NSCLC whose tumours
express PD-L1 with at least a 50% tumour proportion score:
•
Pembrolizumab monotherapy
•
Atezolizumab monotherapy (Tumour PD-L1
expression of 50% or more or of 10% or more on
tumour infiltrating immune cells)
•
Pembrolizumab combination with pemetrexed and
platinum chemotherapy
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
•
Chemotherapy (docetaxel, gemcitabine, paclitaxel or
vinorelbine) in combination with a platinum drug
(carboplatin or cisplatin)
owith or without pemetrexed maintenance
treatment
For people with adenocarcinoma or large-cell carcinoma
•
Pemetrexed in combination with a platinum drug
(carboplatin or cisplatin)
owith (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
•
Pembrolizumab with carboplatin and paclitaxel (only if
urgent clinical intervention is needed)
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

Subgroups	If the evidence allows the following subgroups will be considered: • previous therapy (treated or untreated) • tumour histology (squamous or non-squamous) • Level of PD-L1 expression (strong positive or weak positive)
Comparators	Untreated NSCLC disease: For people with non-squamous NSCLC whose tumours express PD-L1 with at least a 50% tumour proportion score: • Pembrolizumab monotherapy • Atezolizumab monotherapy (Tumour PD-L1 expression of 50% or more or of 10% or more on tumour infiltrating immune cells) • Pembrolizumab combination with pemetrexed and platinum chemotherapy 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 • Chemotherapy (docetaxel, gemcitabine, paclitaxel or vinorelbine) in combination with a platinum drug (carboplatin or cisplatin) `o`with or without pemetrexed maintenance treatment For people with adenocarcinoma or large-cell carcinoma • Pemetrexed in combination with a platinum drug (carboplatin or cisplatin) `o`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 • Pembrolizumab with carboplatin and paclitaxel (only if urgent clinical intervention is needed) 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

Final scope for the evaluation of dabrafenib in combination with trametinib for treating advanced, metastatic BRAF V600E mutation-positive non-small-cell lung cancer Issue Date: June 2022

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	For previously treated disease: For people with non-squamous NSCLC PD-L1 ≥50%: • Platinum doublet • Pemetrexed • Docetaxel, with (for adenocarcinoma histology) or without nintedanib • Best supportive care For people with non-squamous NSCLC PD-L1 <50%: • Atezolizumab monotherapy • Docetaxel, with (for adenocarcinoma histology) or without nintedanib • Best supportive care For people with non-squamous NSCLC which is PD-L1 1% or more: • Pembrolizumab monotherapy • Nivolumab monotherapy For people with squamous NSCLC PD-L1 >50%: • Gemcitabine with carboplatin or cisplatin • Vinorelbine with carboplatin or cisplatin • Docetaxel • Best supportive care For people with squamous NSCLC PD-L1 <50%: • Atezolizumab monotherapy • Docetaxel • Best supportive care For people with squamous NSCLC which is PD-L1 1% or more: • Pembrolizumab monotherapy • Nivolumab ( no PD-L1 status requirement)
Outcomes	The outcome measures to be considered include: • overall survival • progression-free survival • response rate • adverse effects of treatment • health-related quality of life.

For previously treated disease:
For people with non-squamous NSCLC PD-L1 ≥50%:
•
Platinum doublet
•
Pemetrexed
•
Docetaxel, with (for adenocarcinoma histology) or
without nintedanib
•
Best supportive care
For people with non-squamous NSCLC PD-L1 <50%:
•
Atezolizumab monotherapy
•
Docetaxel, with (for adenocarcinoma histology) or
without nintedanib
•
Best supportive care
For people with non-squamous NSCLC which is PD-L1 1% or
more:
•
Pembrolizumab monotherapy
•
Nivolumab monotherapy
For people with squamous NSCLC PD-L1 >50%:
•
Gemcitabine with carboplatin or cisplatin
•
Vinorelbine with carboplatin or cisplatin
•
Docetaxel
•
Best supportive care
For people with squamous NSCLC PD-L1 <50%:
•
Atezolizumab monotherapy
•
Docetaxel
•
Best supportive care
For people with squamous NSCLC which is PD-L1 1% or
more*:
•
Pembrolizumab monotherapy
•
Nivolumab (* no PD-L1 status requirement)

Outcomes

The outcome measures to be considered include:
•
overall survival
•
progression-free survival
•
response rate
•
adverse effects of treatment
•
health-related quality of life.

Final scope for the evaluation of dabrafenib in combination with trametinib for treating advanced, metastatic BRAF V600E mutation-positive non-small-cell lung cancer Issue Date: June 2022

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Economic analysis	The reference case stipulates that the cost effectiveness of treatments should be expressed in terms of incremental cost per quality-adjusted life year. The reference case stipulates that the time horizon for estimating clinical and cost effectiveness should be sufficiently long to reflect any differences in costs or outcomes between the technologies being compared. Costs will be considered from an NHS and Personal Social Services perspective. The availability of any commercial arrangements for the interventions, comparator and subsequent treatment technologies will be taken into account. The availability and cost of biosimilar and generic products should be taken into account. The use of dabrafenib in combination with trametinib is conditional on the presence of the BRAF V600E The economic modelling should include the costs associated with diagnostic testing for BRAF V600 in people with NSCLC who would not otherwise have been tested. A sensitivity analysis should be provided without the cost of the diagnostic test. See section 4.8 of the guidance development manual (available here: https://www.nice.org.uk/process/pmg36/chapter/introduction- to-health-technology-evaluation).
Other considerations	Guidance will only be issued in accordance with the marketing authorisation. Where the wording of the therapeutic indication does not include specific treatment combinations, guidance will be issued only in the context of the evidence that has underpinned the marketing authorisation granted by the regulator.
Related NICE recommendations	Related Technology Appraisals: Pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous non-small-cell lung cancer (2022) NICE technology appraisal guidance 770. Review date 2025 Nivolumab with ipilimumab and chemotherapy for untreated metastaticnon-small-celllung cancer (2021) NICE technology appraisal guidance 724. Review date 2024 Nivolumab for advancednon-squamousnon-small-celllung cancer after chemotherapy (2021) NICE technology guidance 713 Review date 2024 Atezolizumab monotherapy for untreated advancednon- small-celllung cancer (2021) NICE technology guidance 705 Review date 2024 Pembrolizumab with pemetrexed and platinum chemotherapy for untreated, metastatic,non-squamousnon-small-celllung

Economic analysis

The reference case stipulates that the cost effectiveness of
treatments should be expressed in terms of incremental cost
per quality-adjusted life year.
The reference case stipulates that the time horizon for
estimating clinical and cost effectiveness should be
sufficiently long to reflect any differences in costs or
outcomes between the technologies being compared.
Costs will be considered from an NHS and Personal Social
Services perspective.
The availability of any commercial arrangements for the
interventions, comparator and subsequent treatment
technologies will be taken into account.
The availability and cost of biosimilar and generic products
should be taken into account.
The use of dabrafenib in combination with trametinib is
conditional on the presence of the BRAF V600E The
economic modelling should include the costs associated with
diagnostic testing for BRAF V600 in people with NSCLC who
would not otherwise have been tested. A sensitivity analysis
should be provided without the cost of the diagnostic test.
See section 4.8 of the guidance development manual
(available here:
https://www.nice.org.uk/process/pmg36/chapter/introduction-
to-health-technology-evaluation).

Other
considerations

Guidance will only be issued in accordance with the
marketing authorisation. Where the wording of the therapeutic
indication does not include specific treatment combinations,
guidance will be issued only in the context of the evidence
that has underpinned the marketing authorisation granted by
the regulator.

Related NICE
recommendations

Related Technology Appraisals:
Pembrolizumab with carboplatin and paclitaxel for untreated
metastatic squamous non-small-cell lung cancer (2022) NICE
technology appraisal guidance 770. Review date 2025
Nivolumab with ipilimumab and chemotherapy for untreated
metastaticnon-small-celllung cancer (2021) NICE
technology appraisal guidance 724. Review date 2024
Nivolumab for advancednon-squamousnon-small-celllung
cancer after chemotherapy (2021) NICE technology guidance
713 Review date 2024
Atezolizumab monotherapy for untreated advancednon-
small-celllung cancer (2021) NICE technology guidance 705
Review date 2024
Pembrolizumab with pemetrexed and platinum chemotherapy
for untreated, metastatic,non-squamousnon-small-celllung

Final scope for the evaluation of dabrafenib in combination with trametinib for treating advanced, metastatic BRAF V600E mutation-positive non-small-cell lung cancer Issue Date: June 2022

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cancer (2021) NICE technology guidance 683 Review date 2024 Nivolumab for advanced squamous non-small-cell lung cancer after chemotherapy (2020) NICE technology guidance 655 Review date 2023 Atezolizumab in combination for treating metastatic non - squamous non-small-cell lung cancer (2019) NICE technology guidance 584 Review date 2022 Pembrolizumab for untreated PD-L1-positive metastatic nonsmall-cell lung cancer (2018) NICE technology guidance 531 Review date 2021 Atezolizumab for treating locally advanced or metastatic nonsmall-cell lung cancer after chemotherapy (2018) NICE technology guidance 520 Review date 2021 Pembrolizumab for treating PD-L1-positive non-smallcell lung cancer after chemotherapy (2017) NICE technology guidance 428 Review date 2021 Pemetrexed for the maintenance treatment of non-smallcell lung cancer (2010) NICE technology guidance 190 Review date to be confirmed Necitumumab for untreated advanced or metastatic squamous non-small-cell lung cancer (2016, reviewed 2020) NICE technology guidance 411 Review date to be confirmed Pemetrexed maintenance treatment for non -squamous nonsmall-cell lung cancer after pemetrexed and cisplatin (2016) NICE technology guidance 402 Review date 2019 Ramucirumab for previously treated locally advanced or metastatic non-small-cell lung cancer (2016, reviewed 2019) NICE technology guidance 403 Review date to be confirmed Nintedanib for previously treated locally advanced, metastatic, or locally recurrent non-small-cell lung cancer (2015) NICE technology guidance 347 Erlotinib monotherapy for maintenance treatment of nonsmall-cell lung cancer (2011) NICE technology guidance 227 Pemetrexed for the first-line treatment of non-small-cell lung cancer (2009) NICE technology guidance 181 Pemetrexed for the treatment of non-small-cell lung cancer (2007) NICE technology guidance 124 Related appraisals in development (including suspended appraisals) Atezolizumab with carboplatin or cisplatin and pemetrexed for untreated advanced non-squamous non-small-cell lung cancer NICE technology appraisal guidance [ID1495] Publication date to be confirmed.

Final scope for the evaluation of dabrafenib in combination with trametinib for treating advanced, metastatic BRAF V600E mutation-positive non-small-cell lung cancer Issue Date: June 2022

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	Avelumab for untreated PD-L1 positive non-small-cell lung cancer.NICE technology appraisal guidance [ID1261]. Publication date to be confirmed. Durvalumab with tremelimumab for untreated non-small-cell lung cancer with no EGFR-or ALK-positive mutations.NICE technology appraisal guidance [ID1143]. Suspended. 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 with ipilimumab and chemotherapy for untreated advanced non-small-cell lung cancer NICE technology guidance [ID1566] Expected publication date June 2021 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. Veliparib with carboplatin and paclitaxel for untreated non- squamous non-small-cell lung cancer.NICE technology appraisal guidance [ID1277]. Publication date to be confirmed. Related Guidelines: EGFR-TK mutation testing in adults with locally advanced or metastaticnon-small-celllung cancer (2013). NICE diagnostic guideline 9. Lung cancer: diagnosis and management (2019) NICE guideline 122 Related Interventional Procedures: Microwave ablation for primary or metastatic cancer in the lung (2022) Interventional procedures guidance 716. Review date 2025 Irreversible electroporation for treating primary lung cancer and metastases in the lung (2013) Interventional procedures guidance 441. Review date to be confirmed Related Quality Standards: Lung cancer in adults (2012). NICE quality standard 17
Related National Policy	The NHS Long Term Plan, 2019.NHS Long Term Plan NHS England (2018/2019)NHS manual for prescribed specialist services (2018/2019) Department of Health,NHS Outcomes Framework 2016-2017

Avelumab for untreated PD-L1 positive non-small-cell lung
cancer.NICE technology appraisal guidance [ID1261].
Publication date to be confirmed.
Durvalumab with tremelimumab for untreated non-small-cell
lung cancer with no EGFR-or ALK-positive mutations.NICE
technology appraisal guidance [ID1143]. Suspended.
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 with ipilimumab and chemotherapy for untreated
advanced non-small-cell lung cancer NICE technology
guidance [ID1566] Expected publication date June 2021
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.
Veliparib with carboplatin and paclitaxel for untreated non-
squamous non-small-cell lung cancer.NICE technology
appraisal guidance [ID1277]. Publication date to be
confirmed.
Related Guidelines:
EGFR-TK mutation testing in adults with locally advanced or
metastaticnon-small-celllung cancer (2013). NICE
diagnostic guideline 9.
Lung cancer: diagnosis and management (2019) NICE
guideline 122
Related Interventional Procedures:
Microwave ablation for primary or metastatic cancer in the
lung (2022) Interventional procedures guidance 716. Review
date 2025
Irreversible electroporation for treating primary lung cancer
and metastases in the lung (2013) Interventional procedures
guidance 441. Review date to be confirmed
Related Quality Standards:
Lung cancer in adults (2012). NICE quality standard 17

Related National
Policy

The NHS Long Term Plan, 2019.NHS Long Term Plan
NHS England (2018/2019)NHS manual for prescribed
specialist services (2018/2019)
Department of Health,NHS Outcomes Framework 2016-2017

Final scope for the evaluation of dabrafenib in combination with trametinib for treating advanced, metastatic BRAF V600E mutation-positive non-small-cell lung cancer Issue Date: June 2022

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----- Start of picture text -----
Department of Health (2014) The national cancer strategy: 4 [th]
annual report
Department of Health (2011) Improving outcomes: a strategy
for cancer
Department of Health (2009) Cancer commissioning
guidance
Department of Health (2007) Cancer reform strategy
Department of Health and Social Care, NHS Outcomes
Framework 2016-2017 (published 2016): Domains 1, 2, 4, 5.
https://www.gov.uk/government/publications/nhs-outcomes-
framework-2016-to-2017
Other policies
Independent Cancer Taskforce (2015) Achieving world-class
cancer outcomes: a strategy for England 2015-2020
----- End of picture text -----

References

Cancer Research UK (2020) Types of lung cancer. Accessed April 2022
Chan, X. Y. et al (2017) Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma
National Lung Cancer Audit (2022) Annual Report (2019/2020 data) Accessed April 2022
Shiau, C.J. Tsao, M. -S. (2017). Diagnostic Molecular Pathology. Chapter 23: Molecular testing in lung cancer Accessed April 2022

Final scope for the evaluation of dabrafenib in combination with trametinib for treating advanced, metastatic BRAF V600E mutation-positive non-small-cell lung cancer Issue Date: June 2022