Context and Policy Issues

Skin cancer is the most common cancer in Canada, with about 6,500 new cases of skin malignant melanoma reported in 2014, and 1250 Canadians expected to die from it in 2017.^1,2 Approximately 40-60% of melanomas contain a mutation in the gene that encodes BRAF, which leads to constitutive activation of downstream signaling in the MAP (mitogen-activated protein) kinase pathway. In 80-90% of these cases, the activating mutation consists of the substitution of glutamic acid for valine at amino acid 600 (V600E); the other less common BRAF mutations include V600D, K and R.^3,4 Approximately 20% of patients with BRAF-mutated advanced melanoma have brain metastases which are difficult to treat, and carry a poor prognosis.^5,6Targeted therapies with BRAF inhibitors (dabrafenib, vemurafenib), MEK inhibitors (trametinib, cobimetinib), or immunotherapy alone or in combination have been used with clinical benefits for patients with metastatic melanoma.^6-13 Oncologic patients’ performance status are often measured using the Eastern Cooperative Oncology Group (ECOG) Scale that describes a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical ability on a scale of 0 (fully active, able to carry on all pre-disease activities without restriction) to 5 (deceased).¹⁴

The pan-Canadian Oncologic Drug Review (pCODR) expert review committee (pERC) has recommended combination therapies of dabrafenib plus trametinib or cobimetinib plus vemurafenib, and monotherapies of dabrafenib, vemurafenib, or trametinib for previously untreated patients with BRAF mutation positive unresectable or metastatic melanoma^15-19 based on evidence that excluded patients with active or symptomatic brain metastases.^20-22 Brain metastases are considered active when tumour growth has been shown on sequential CT scans; active brain metastases can be symptomatic or asymptomatic. The effectiveness of these treatments in patients with active brain metastases remains unclear.

This Rapid Response report aims to review the clinical effectiveness and safety of dabrafenib plus trametinib and cobimetinib plus vemurafenib for patients with BRAF mutation positive metastatic melanoma with active brain metastasis.

Research Questions

1.

What is the clinical effectiveness of dabrafenib and trametinib for patients with BRAF mutation positive metastatic melanoma with active or symptomatic brain metastasis?

2.

What is the clinical effectiveness of cobimetinib and vemurafenib for patients with BRAF mutation positive metastatic melanoma with active or symptomatic brain metastasis?

Key Findings

Data from a non-randomized, no control, open-label phase 2 study suggested that the clinical benefit and tolerability of dabrafenib plus trametinib, as measured by intracranial response and adverse event rate, were found in patients with melanoma and active brain metastasis with BRAF V600E mutation after a median 8.5 months follow-up.

Methods

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1:

Selection Criteria

Summary of Evidence

Summary of Findings

The main findings of the included study are presented in Appendix 4 and summarized in Table 2.

Table 2:

Summary of Study Findings

What is the clinical effectiveness of dabrafenib and trametinib for patients with BRAF mutation positive metastatic melanoma with active or symptomatic brain metastasis?

Data from a multi-centre, multi-cohort, open-label, phase 2 trial on 125 patients with BRAF V600- mutation-positive melanoma with active brain metastasis²⁴ showed that after a median follow-up of 8.5 months, an intracranial response was found in 58% of patients (44/76 patients) in cohort A (BRAF V600E-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an ECOG performance status of 0 or 1) achieved an intracranial response (primary endpoint). Intracranial response was also achieved in 56% of patients (9/16 patients) in cohort B (BRAF V600E-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1), 44% of patients (7/16 patients) in cohort C (BRAF V600D/K/R-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1), and 59% of patients (10/17 patients) in cohort D (BRAF V600D/E/K/R-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2). The median duration of response was 6.5 months, 7.3 months, 8.3 months and 4.5 months, in cohorts A, B, C, and D, respectively.

Extracranial response (percentage of patients with a confirmed extracranial complete or partial response assessed by the investigator using modified RECIST version 1.1 criteria) was found in 55% of patients in cohort A with median duration of response of

10.2 months, 44% of patients in cohort B with median duration of response not estimable, 75% of patients in cohort C with median duration of response of 4.9 months, and 41% of patients in cohort D with median duration of response of 5.9 months.

Overall response was found in 58% of patients in cohort A with median duration of response of 6.5 months, 56% of patients in cohort B with median duration of response of 12.5 months, 44% of patients in cohort C with median duration of response of 6.6 months, and 65% of patients in cohort D with median duration of response of 4.5 months.

Progression-free survival (the median interval between the first dose of study treatment and the earliest date of disease progression or death from any cause) was 5.6 months, 7.2 months, 4.2 months and 5.5 months, in cohorts A, B, C, and D, respectively. Overall survival (the median time from first dose until death due to any cause) was 10.8 months, 24.3 months, 10.1 months and 11.5 months, in cohorts A, B, C, and D, respectively.

The most common serious adverse events related to study treatment were pyrexia for dabrafenib (8/125 patients [6%]) and decreased ejection fraction (5/125 patients [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (3/125 patients [3%]) and headache (3/125 patients [2%]).

The authors recognized the non-randomized design with small sample size and no control group was a limitation of the study but suggested that the clinical benefit and tolerability of dabrafenib plus trametinib was achieved in patients with melanoma and active brain metastases.

What is the clinical effectiveness of cobimetinib and vemurafenib for patients with BRAF mutation positive metastatic melanoma with active or symptomatic brain metastasis?

There was no evidence found on the clinical effectiveness of cobimetinib and vemurafenib for patients with BRAF mutation positive metastatic melanoma with active or symptomatic brain metastasis.

Conclusions and Implications for Decision or Policy Making

Data from a phase 2 study suggested that the clinical benefit and manageable tolerability of dabrafenib plus trametinib were found in patients with melanoma and active brain metastasis with BRAF V600E mutation, as measured by intracranial response and adverse event rate after a median 8.5 months follow-up. There was no evidence found on the clinical effectiveness of cobimetinib and vemurafenib for patients with BRAF mutation positive metastatic melanoma with active brain metastasis.

References

1.

Canadian cancer statistics. Special topic: skin cancers [Internet]. Canadian Cancer Society: Toronto; 2014 May. [cited 2017 Sep 28]. Available from: http://www.cancer.ca/~/media/cancer.ca/CW/cancer%20information/cancer%20101/ Canadian%20cancer%20statistics/Canadian-Cancer-Statistics-2014--EN.pdf?la=en.

2.

Melanoma [Internet]. Canadian Cancer Society: Toronto; 2017. [cited 2017 Sep 28]. Available from: http://www.cancer.ca/en/cancer-information/cancer-type/skin- melanoma/statistics/?region=on.

3.

Vora NL. Intracorporeal lithotripsy. In: Medscape [Internet]. New York (NY): Medscape LLC; 2016 Feb 10 [cited 2017 Oct 2]. Available from: http://emedicine.medscape.com/article/2045059-overview.

4.

Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, et al. The role of BRAF V600 mutation in melanoma. J Transl Med [Internet]. 2012 [cited 2017 Oct 2];10(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391993/pdf/1479- 5876-10-85.pdf.

5.

Long GV, Margolin KA. Multidisciplinary approach to brain metastasis from melanoma: the emerging role of systemic therapies. Am Soc Clin Oncol Educ Book. 2013;•••:393–398. [PubMed: 23714558]

6.

Papadatos-Pastos D, Soultati A, Harries M. Targeting brain metastases in patients with melanoma. BioMed Res Int. 2013;•••:186563. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884779/pdf/BMRI2013-186563.pdf [Internet]. Available from. [PMC free article: PMC3884779] [PubMed: 24455677]

7.

Wood K, Luke JJ. Optimal use of BRAF targeting therapy in the immunotherapy era. Curr Oncol Rep. 2016;18(11) [PubMed: 27613168]

8.

Simeone E, Grimaldi AM, Festino L, Vanella V, Palla M, Ascierto PA. Combination treatment of patients with BRAF-mutant melanoma: a new standard of care. BioDrugs. 2017;31(1):51–61. [PubMed: 28058658]

9.

Queirolo P, Spagnolo F. BRAF plus MEK-targeted drugs: a new standard of treatment for BRAF-mutant advanced melanoma. Cancer Metastasis Rev. 2017;36(1):35–42. [PubMed: 28299583]

10.

Zhu Z, Liu W, Gotlieb V. The rapidly evolving therapies for advanced melanoma-towards immunotherapy, molecular targeted therapy, and beyond. Crit Rev Oncol Hematol. 2016;99:91–99. [PubMed: 26708040]

11.

Eroglu Z, Ribas A. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. Ther Adv Med Oncol [Internet]. 2016 [cited 2017 Sep 20];8(1):48-56. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699264/pdf/10.1177_175883401561 6934.pdf. [PMC free article: PMC4699264] [PubMed: 26753005]

12.

Srivastava N, McDermott D. Update on benefit of immunotherapy and targeted therapy in melanoma: The changing landscape. Cancer Manag Res. 2014;6(1):279–289. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073973/pdf/cmar-6- 279.pdf [Internet]. Available from. and. [PMC free article: PMC4073973] [PubMed: 25018651]

13.

Fonkem E, Uhlmann EJ, Floyd SR, Mahadevan A, Kasper E, Eton O, et al. Melanoma brain metastasis: overview of current management and emerging targeted therapies. Expert Rev Neurother. 2012;12(10):1207–1215. [PubMed: 23082737]

14.

ECOG performance status [Internet]. Philadelphia (PA): ECOG-ACRIN Cancer Research Group; 2017. [cited 2017 Oct 2]. Available from: http://ecog-acrin.org/resources/ecog- performance-status.

15.

Tafinlar & mekinist in combo for metastatic melanoma - details [Internet]. Ottawa: CADTH; 2017. [cited 2017 Sep 26]. Available from: https://www.cadth.ca/tafinlar-mekinist- combo-metastatic-melanoma-details.

16.

Cotellic for metastatic melanoma – details [Internet]. Ottawa: CADTH; 2017. [cited 2017 Sep 26]. Available from: https://www.cadth.ca/cotellic-metastatic-melanoma-details.

17.

Tafinlar for metastatic melanoma - details [Internet]. Ottawa: CADTH; 2017. [cited 2017 Sep 26]. Available from: https://www.cadth.ca/tafinlar-metastatic-melanoma-detail.

18.

Zelboraf for advanced melanoma - details [Internet]. Ottawa: CADTH; 2017. [cited 2017 Sep 26]. Available from: https://www.cadth.ca/zelboraf-advanced-melanoma-details.

19.

Mekinist for metastatic melanoma - details [Internet]. Ottawa: CADTH; 2017. [cited 2017 Sep 26]. Available from: https://www.cadth.ca/mekinist-metastatic-melanoma-details.

20.

Long GV, Stroyakovskiy D, Gogas H, Levchenko E. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877–1888. de BF, Larkin J, et al. [PubMed: 25265492]

21.

Long GV, Stroyakovskiy D, Gogas H, Levchenko E. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444–451. de BF, Larkin J, et al. [PubMed: 26037941]

22.

Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–39. [PubMed: 25399551]

23.

Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377–384. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdf [Internet]. Available from. [PMC free article: PMC1756728] [PubMed: 9764259]

24.

Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18(7):863–873. [PMC free article: PMC5991615] [PubMed: 28592387]

Appendix 1. Selection of Included Studies

Appendix 2. Characteristics of Included Publications

Table 3:

Characteristics of Included Clinical Studies

Appendix 3. Critical Appraisal of Included Publications

Table 4:

Summary of Critical Appraisal of Included Studies

Appendix 4. Main Study Findings and Author’s Conclusions

Table 5:

Main Study Findings and Authors’ Conclusions

Suggested citation:

BRAF targeted therapy for patients with melanoma and active brain metastases: a review of clinical effectiveness. Ottawa: CADTH; 2017 Oct.(CADTH rapid response report: summary with critical appraisal).

Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.

While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.

CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.

This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.

Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third party supplier of information.

This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.

This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.