pan-canadian Oncology Drug Review Final Clinical Guidance Report Trametinib (Mekinist) for Metastatic Melanoma October 22, 2013

Transcription

1 pan-canadian Oncology Drug Review Final Clinical Guidance Report Trametinib (Mekinist) for Metastatic Melanoma October 22, 2013

2 DISCLAIMER Not a Substitute for Professional Advice This report is primarily intended to help Canadian health systems leaders and policymakers make well-informed decisions and thereby improve the quality of health care services. While patients and others may use this report, they are made available for informational and educational purposes only. This report should not be used 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, or as a substitute for professional medical advice. Liability pcodr does not assume any legal liability or responsibility for the accuracy, completeness or usefulness of any information, drugs, therapies, treatments, products, processes, or services disclosed. The information is provided "as is" and you are urged to verify it for yourself and consult with medical experts before you rely on it. You shall not hold pcodr responsible for how you use any information provided in this report. Reports generated by pcodr are composed of interpretation, analysis, and opinion on the basis of information provided by pharmaceutical manufacturers, tumour groups, and other sources. pcodr is not responsible for the use of such interpretation, analysis, and opinion. Pursuant to the foundational documents of pcodr, any findings provided by pcodr are not binding on any organizations, including funding bodies. pcodr hereby disclaims any and all liability for the use of any reports generated by pcodr (for greater certainty, "use" includes but is not limited to a decision by a funding body or other organization to follow or ignore any interpretation, analysis, or opinion provided in a pcodr report). FUNDING The pan-canadian Oncology Drug Review is funded collectively by the provinces and territories, with the exception of Quebec, which does not participate in pcodr at this time pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW ii

3 INQUIRIES Inquiries and correspondence about the pan-canadian Oncology Drug Review (pcodr) should be directed to: pan-canadian Oncology Drug Review 1 University Avenue, suite 300 Toronto, ON M5J 2P1 Telephone: Fax: info@pcodr.ca Website: pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW iii

4 TABLE OF CONTENTS DISCLAIMER AND FUNDING... ii INQUIRIES... iii TABLE OF CONTENTS... iv 1 GUIDANCE IN BRIEF Background Key Results and Interpretation Conclusions CLINICAL GUIDANCE Context for the Clinical Guidance Interpretation and Guidance Conclusions BACKGROUND CLINICAL INFORMATION SUMMARY OF PATIENT ADVOCACY GROUP INPUT SUMMARY OF PROVINCIAL ADVISORY GROUP (PAG) INPUT SYSTEMATIC REVIEW Objectives Methods Results Ongoing Trials SUPPLEMENTAL QUESTIONS Critical Appraisal of an Indirect Comparison of Trametinib with Vemurafenib for Metastatic Melanoma Summary of BRAF Mutation Testing in Metastatic Melanoma ABOUT THIS DOCUMENT APPENDIX A: LITERATURE SEARCH STRATEGY REFERENCES pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW iv

5 1 GUIDANCE IN BRIEF 1.1 Background The purpose of this review is to evaluate the safety and efficacy of trametinib on patient outcomes compared with standard treatment, placebo, or best supportive care in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and activity. Trametinib has a Health Canada indication for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. The recommended dose is 2 mg administered orally once daily. 1.2 Key Results and Interpretation Systematic Review Evidence The pcodr systematic review assessed the efficacy and safety of trametinib, 2 mg orally once daily (n=214), compared with DTIC, 1000mg/m 2 every 3 weeks (n = 62), or paclitaxel, 175 mg/m 2 every 3 weeks (n = 37), in one international, multicentre, open-label, randomized controlled trial, METRIC % of all patients had V600E mutations, and 13% had V600K mutations. Patients could have received one previous chemotherapy regimen for advanced or metastatic melanoma, with the exclusion of BRAF and MEK inhibitors and ipilimumab. 33% of the trametinib group had previous chemotherapy compared to 35% in the chemotherapy group. Patients with stable brain metastases were allowed to enroll. 4% of the trametinib group had a history of brain metastasis compared to 2% in the chemotherapy group. METRIC included patients with ECOG status of 0 (64%) and 1 (36%). Patients were generally well balanced in demographics between the two arms. Patients in the chemotherapy group were allowed to cross over to receive trametinib after disease progression had been confirmed by an independent review. Treatment for all patients continued until disease progression, death, or withdrawal. Efficacy The primary end-point for the METRIC study was progression-free survival (PFS) in the primary efficacy population (patients with the V600E BRAF mutation who did not have brain metastases at baseline). Secondary outcomes included PFS and overall survival (OS) in the ITT population and in subgroups of the primary efficacy population (with and without prior chemotherapy; by BRAF mutation status (V600E and V600K)). For the primary outcome, median progression-free survival (PFS) in the primary efficacy population was 4.8 and 1.4 months in the trametinib and chemotherapy group, respectively (HR 0.44, 95% CI: 0.31 to 0.64 p<0.0001). Similar results were observed for PFS in the ITT population and in the subgroups except in patients with V600K mutation. For the secondary outcome of OS, the hazard ratio (HR) for OS was 0.54 (95% CI, 0.32 to 0.92; p=0.01), at the first data cut-off of October 2011 (median follow-up of 4.9 and 4.8 months in the trametinib and chemotherapy arms, respectively) and 0.78 (95% CI, 0.57 to 1.06; p=0.0912) at the second data cut-off of May 20, 2013( median follow up of 14.7 and 2013 pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 1

6 8.7 months in the trametinib and chemotherapy arms, respectively). However, OS may however have been confounded by crossover as, 47% of patients randomized to chemotherapy had crossed over to receive trametinib at the time of the first data cut off. Health related quality of life (HRQOL) assessments were performed using EORTC QLQ-C30 and EQ-5D questionnaires. In general, trametinib treatment was associated with smaller functional impairment, smaller declines in health status, and less symptoms exacerbation over the course of treatment as compared to chemotherapy. For patients who experienced disease progression, trametinib was associated with improvement in scores for pain, insomnia, appetite loss and constipation, while chemotherapy was associated with no change or minimal to modest worsening of symptoms. Statistical significance was not assessed. Harms Serious adverse events (SAEs) occurred at a similar rate in the trametinib (18%) and chemotherapy (20%) arms, with cellulitis (2%) being the most common in the trametinib arm, and pyrexia (4%) in the chemotherapy arm (treated with DTIC). One death occurred in the trametinib arm due to renal failure that may be related to trametinib. 4 AEs led to dose interruption in 35% and to dose reductions in 27% of patients overall. A higher proportion of patients in the trametinib group experienced AEs that led to dose interruption or dose reduction than in the chemotherapy group. In the trametinib group, the most common AEs were rash, diarrhea, peripheral edema, fatigue, hypertension and dermatitis acneiform. A decreased ejection fraction occurred in 14 patients (7%) and serious grade 3 cardiac events occurred in 2 patients (0.01%). Ocular events occurred in 19 patients (9%) Additional Evidence pcodr received input on trametinib for metastatic melanoma from one patient advocacy group, (Melanoma Network of Canada). Provincial Advisory group input was obtained from nine of the nine provinces participating in pcodr. In addition, two supplemental questions were identified during development of the review protocol as relevant to the pcodr review of dabrafenib and are discussed as supporting information: Summary of Indirect comparison to vemurafenib An adjusted indirect treatment comparison was performed between trametinib and vemurafenib based on the METRIC (October 2011 data cut-off) and BRIM-3 studies. Conclusions drawn from such indirect comparisons are not as robust as those from direct, head-to-head trial data. Summary of BRAF Mutation Testing in Metastatic Melanoma Interpretation and Guidance Burden of Illness and Need In Canada, 5500 new cases of primary melanoma are expected in 2011 and approximately 950 patients will die from melanoma pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 2

7 Unresectable Stage III and IV melanoma is an incurable malignancy with approximately 6% of patients surviving 5 years, and 75% percent of patients dying within one year of diagnosis. Brain metastases are relatively common in advanced melanoma and occur in up to 75% of patients with overt metastatic disease. They often prove to be relatively refractory to radiotherapy and systemic treatment and are associated with a particularly dismal prognosis. Select patients with metastatic disease would benefit from surgery or radiotherapy alone. Systemic treatment is most commonly offered. Over the past 30 years, the standard first line systemic therapy has been dacarbazine but complete responses are rare and have never been shown to improve survival in metastatic melanoma A very wide spectrum of chemotherapeutic and immunological treatments approaches have been explored in metastatic melanoma with limited to no success. Vemurafenib and dabrafenib are BRAF inhibitors that selectively target the mutated BRAF V600. Although vemurafenib is currently the standard first line treatment in this patient population, dabrafenib is currently under review for treatment of patients with unresectable stage III or Stage IV melanoma that harbours the BRAF V600E or V600K mutation. Patient advocacy group input indicates that patients experience serious and severe side effects with currently available therapies and seek an alternative treatment option. Effectiveness Trametinib demonstrated a statistically significant improvement in its primary endpoint of PFS. The median PFS in the intention-to treat population was 4.8 months and 1.5 months for trametinib and dacarbazine arms, respectively. There was a slightly greater PFS when assessed by the independent review committee; however the results were similar in the primary efficacy population. Overall survival was significantly longer in the trametinib arm but may have been confounded by crossover of patients from the placebo group to trametinib. In general, at weeks 6 and 12 trametinib treatment was associated with smaller functional impairment, smaller declines in health status, and less symptoms exacerbation over the course of treatment as compared to chemotherapy. Although there are no randomized clinical trials comparing trametinib to a BRAF inhibitor, an indirect comparison of trametinib and vemurafenib demonstrated that there was a greater likelihood of better PFS and OS rates with vemurafenib therapy than with trametinib while the use of longer follow up data from the BRIM-3 trial demonstrated a greater likelihood of better OS rates with trametinib therapy than with vemurafenib. Conclusions drawn from such indirect comparisons are however not as robust as those from direct head-to-head trial data and therefore must be taken in context. In addition, the indirect comparison used trametinib data from the October 2011 data cut-off and did not incorporate data from the May 2013 cut-off, which demonstrated a potential waning of the trametinib effect over time. Without a head-to-head trial, the relative effectiveness of these two drugs is uncertain, the mechanisms of action differ and results from the BRIM-3 and METRIC studies suggest there could be differences. Trametinib could therefore be considered in patients who are unable to tolerate a BRAF inhibitor. Therefore the eligibility criteria for trametinib could include patients with metastatic and /or unresectable melanoma whose tumours harbours the V600E or V600K mutation and have not received prior BRAF inhibitor therapy. Patients should have an 2013 pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 3

8 ECOG performance of 0 or 1, if present, have stable brain metastases and have an adequate renal, hematologic and liver function. As patients who received prior BRAF Inhibitor therapy were excluded from this trial, there is no evidence to support the use of trametinib after progression on a BRAF Inhibitor, despite evidence that several pathways of resistance are upstream from MEK and lead to increased activation and phosphorylation of MEK. Similarly, only 9 patients with a history of brain metastases were on the trametinib arm and 2 in the chemotherapy arm. Therefore the true efficacy of trametinib in patients with brain metastases is not assessable. Safety Trametinib was well tolerated with an acceptable safety profile. Trametinib can safely be administered to patients with metastatic melanoma. 1.3 Conclusions The pcodr Melanoma Clinical Guidance Panel concluded that there is a net overall clinical benefit to trametinib compared with chemotherapy based on one randomized controlled trial, METRIC, which demonstrated an improvement in progression free survival with trametinib when compared to dacarbazine or paclitaxel in patients who are BRAF treatment naive and have BRAF V600 (E and K) mutation positive unresectable melanoma. The Clinical Guidance Panel also considered that from a clinical perspective: Trametinib has an acceptable tolerability profile with predictable and manageable toxicities. There are no randomized clinical trials comparing trametinib to the BRAF inhibitor, vemurafenib, and the results of an indirect comparison to vemurafenib were not as robust as those from direct, head-to-head trial data, and therefore must be taken in context. For those patients in whom a BRAF inhibitor is not tolerated or contraindicated, trametinib would be an effective alternative to BRAF inhibitor monotherapy. There is no evidence to support the use of a MEK Inhibitor after progression on a BRAF Inhibitor or in patients with brain metastasis Currently trials are ongoing comparing the combination of a MEK inhibitor plus a BRAF inhibitor versus a BRAF inhibitor, which could result in a broader role for MEK inhibitors, like trametinib, in clinical practice pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 4

9 2 CLINICAL GUIDANCE This Clinical Guidance Report was prepared to assist the pcodr Expert Review Committee (perc) in making recommendations to guide funding decisions made by the provincial and territorial Ministries of Health and provincial cancer agencies regarding trametinib (Mekinist) for metastatic melanoma. The Clinical Guidance Report is one source of information that is considered in the perc Deliberative Framework. The perc Deliberative Framework is available on the pcodr website, This Clinical Guidance is based on: a systematic review of the literature regarding trametinib conducted by the pcodr Melanoma Clinical Guidance Panel and the pcodr Methods Team; input from patient advocacy groups; input from the Provincial Advisory Group; and supplemental issues relevant to the implementation of a funding decision. The systematic review and supplemental issues are fully reported in Sections 6 and 7. Background Clinical Information provided by the Clinical Guidance Panel, a summary of submitted Patient Advocacy Group Input on trametinib and a summary of submitted Provincial Advisory Group Input on trametinib are provided in Sections 3, 4 and 5 respectively. 2.1 Context for the Clinical Guidance Introduction Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and activity. Trametinib has been developed specifically to address known oncogenic mutations in the upstream mitogen activated protein kinase (MAPK) pathway proteins BRAF and RAS, which signal through MEK1 and MEK2. The FDA approved trametinib on May 29, 2013 for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. Trametinib was submitted to Health Canada and a Notice of Compliance was received in July 2013 with an indication for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. The recommended dose is 2 mg administered orally once daily Objectives and Scope of pcodr Review The objective of this review is to evaluate the effect of trametinib on patient outcomes including overall survival, progression free survival, quality of life, and adverse events compared with standard treatment, placebo, or best supportive care in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma Highlights of Evidence in the Systematic Review This section describes highlights of evidence in the systematic review. Refer to section 2.2 for the clinical interpretation of this evidence and section 6 for more details of the systematic review. The efficacy and safety of trametinib 2 mg orally once daily (n=214) were compared with DTIC 1000mg/m2 every 3 weeks (n = 62) or paclitaxel 175 mg/m2 every 3 weeks (n = 37) in one international, multicentre, open-label, randomized controlled trial, METRIC. 1-3 The study enrolled 322 patients who had histologically confirmed unresectable stage IIIC or IV cutaneous melanoma with a V600E or V600K BRAF mutation. 87% of all patients had 2013 pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 5

10 V600E mutations, and 13% had V600K mutations. Patients could have received one previous chemotherapy regimen for advanced or metastatic melanoma, with the exclusion of BRAF and MEK inhibitors and ipilimumab. Patients with stable brain metastases were allowed to enroll. Median age was 55 years in the trametinib group and 54 in the chemotherapy group. METRIC included patients with ECOG status of 0 (64%) and 1 (36%). There was no substantial imbalance between treatment groups with respect to demographic or disease characteristics. 4% of the trametinib group had a history of brain metastasis compared to 2% in the chemotherapy group. 33% of the trametinib group had previous chemotherapy compared to 35% in the chemotherapy group. In the chemotherapy group, 62 patients received DTIC, and 37 patients received paclitaxel. Patients in the chemotherapy group were allowed to cross over to receive trametinib after disease progression had been confirmed by an independent review. Treatment for all patients continued until disease progression, death, or withdrawal. The primary efficacy endpoint was progression-free survival (PFS) defined as the time from randomization until the earliest date of disease progression documented by the investigator or death due to any cause. The primary efficacy analysis was restricted to patients who had V600E BRAF mutation and who did not have brain metastases at baseline. The secondary endpoints were PFS, overall survival (OS), overall response rate (ORR), duration of response, adverse event rate and quality of life. Secondary outcomes were restricted to the Intent to Treat (ITT) population. At the time of the first data cut off (October 2011), the hazard ratio (HR) for overall survival rate (OS) in the ITT population was 0.54 (95% CI, 0.32 to 0.92; p=0.01), representing a 46% reduction in the risk of death for patients treated with trametinib compared to those treated with chemotherapy. At the second data cut-off (May 2013), the hazard ratio (HR) for OS was 0.78 (95% CI, 0.57 to 1.06; p=0.0912). Median progression-free survival (PFS) in the ITT population was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group. HR was 0.45 [95% CI: 0.33, 0.63]; p<0.0001, representing a 55% reduction in the risk of tumor progression in trametinib arm compared to chemotherapy. Similar results were observed in the primary efficacy population. Subgroup analyses in the primary efficacy population revealed statistically significant 53% reduction in risk of tumour progression in patients with V600E mutation (PFS HR 0.47 (95% CI: 0.33, 0.67)), while risk reduction in a small number of patients with V600K mutation (n = 40) was not statistically significant (PFS HR 0.50 (95% CI: 0.18, 1.35). Also, for the subset of patients with no prior treatment, the tumour progression HR was 0.44 (95% CI, 0.28 to 0.69); for patients with prior treatment, the HR was 0.52 (95% CI, 0.29 to 0.93). Health related quality of life (HRQOL) assessments were performed at baseline and throughout active therapy using EPRTC QLQ-C30 and EQ-5D questionnaires. In general, at weeks 6 and 12, trametinib treatment was associated with smaller functional impairment, smaller declines in health status, and less symptoms exacerbation over the course of treatment as compared to chemotherapy. Statistical analysis was not assessed. There was a statistically significant improvement in overall response rate (ORR) 22% of the patients (n = 47) in the trametinib arm as compared to 8% (n = 9) in the chemotherapy arm (p=0.01). The median duration of response for the 47 patients in the trametinib group was 5.5 months and was not reached for the 9 patients in the chemotherapy group pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 6

11 The majority of adverse events (AEs) in the trametinib group was mild to moderate in severity and occurred in a greater proportion of patients in the trametinib group than in the chemotherapy group, except fatigue. A higher proportion of patients in the trametinib group experienced AEs that led to dose interruption or dose reduction than in the chemotherapy group even though the proportion of patients reporting permanent discontinuation of study drug due to AEs was similar between the treatment arms (9%). In the trametinib group, the most common AEs were rash, diarrhea, peripheral edema, fatigue, hypertension and dermatitis acneiform. AEs led to dose interruption in 35% and to dose reductions in 27% of patients. In the chemotherapy group, the most common AEs were fatigue, nausea, constipation, vomiting, and alopecia. AEs led to dose interruption in 22% and to dose reduction in 10% of patients. Severe adverse events (SAEs) occurred at a similar rate in the trametinib (18%) and chemotherapy (20%) arms, with cellulitis (2%) being the most common in the trametinib arm, and pyrexia (4%) in the chemotherapy arm (treated with DTIC). One death occurred in the trametinib arm due to renal failure that may be related to trametinib. 4 Limitations of the METRIC trial included the lack of blinding which may have resulted in observer bias for the progression-free survival outcome. The short follow-up period for overall survival likely limits the robustness of differences in median overall survival between groups. The small number of patients with V600K mutation may contribute to the lack of statistical significance in subgroup analyses. The confounding effect of the crossover of dacarbazine-treated patients to receive trametinib also influences the determination of the absolute outcome impact of trametinib Comparison with Other Literature The pcodr Clinical Guidance Panel and the pcodr Methods Team did not identify other relevant literature providing supporting information for this review Summary of Supplemental Questions Critical appraisal of an Indirect Comparison of Trametinib with Vemurafenib for Metastatic Melanoma An adjusted indirect treatment comparison was performed between trametinib and vemurafenib that employed the Bucher method to assess efficacy. This analysis found that there was a greater likelihood of better PFS and OS rates with vemurafenib therapy than with trametinib therapy in patients with BRAF V600E mutation positive unresectable or metastatic melanoma. However, there was a greater likelihood of better OS rates with trametinib therapy than with vemurafenib therapy when longer follow-up data from the BRIM-3 trial was used. Conclusions drawn from such indirect comparisons are not as robust as those from direct, head-to-head trial data. In addition, the indirect comparison used trametinib data from the October 2011 data cut-off and did not incorporate data from the more recent May 2013 cut off, which demonstrated a potential waning of the trametinib effect over time. Summary of BRAF Mutation Testing in Metastatic Melanoma The cobas 4800 BRAF V600 Mutation Test, developed by Roche Diagnostics Canada, has received regulatory approval The cobas test is a fully automated in vitro diagnostic device intended for the qualitative detection of the BRAF V600E mutation in DNA extracted from formalin-fixed, paraffin-embedded human melanoma tissue; one 5-micron specimen is sufficient to conduct the analysis. The cobas test is able to detect V600E mutations 2013 pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 7

12 with a higher sensitivity than the reference method of Sanger sequencing, but it is not as specific The test showed cross-reactivity with non-v600e mutants, predominantly V600E2 ( 65%), V600K ( 35%), and V600D ( 10%). Canadian testing centres may utilize their own (non-commercial) validated BRAF tests. As a result, there is variability in mutation reporting, with some centres reporting specific mutations (V600E and/or V600K) and other not specifying the specific mutation. See section 7.1 and 7.2 for more information Other Considerations See Section 4 and Section 5 for a complete summary of patient advocacy group input and Provincial Advisory Group (PAG) Input, respectively. Patient Advocacy Group Input From a patient perspective, there is a critical need to provide more treatment options and alternatives to treat metastatic melanoma. While there are therapies approved for metastatic melanoma patients that have shown a positive impact on overall survival rates; however, it is reported that these drugs do not work effectively for all advanced stage patients. In addition, there have been reports of severe side effects with the existing therapies. When asked about potential side effects, respondents noted that they were willing to accept side effects and the serious risks associated with a future new drug if they knew those side effects can be effectively managed. With respect to trametinib, it was noted that the side effects were reported to be well tolerated more so than other current therapies. The respondents on trametinib also noted that their melanoma has been stabilized with no progression. Because metastatic melanoma has few treatment options, 71% of the respondents ranked the importance of quality of life while on treatment as either important or very important. PAG Input Input on trametinib (Mekinist) for metastatic melanoma was obtained from the nine provinces (Ministries of Health and/or cancer agencies) participating in pcodr. From the PAG perspective, trametinib has enablers that include being an oral therapy that can be easily delivered in the community setting and BRAF testing being in place in many jurisdictions. However, potential barriers include PAG s concerns with sequential therapy of trametinib, vemurafenib and other treatments and the lack of direct comparison trials of trametinib with other targeted therapies in the treatment of BRAF mutated metastatic melanoma. 2.2 Interpretation and Guidance Burden of Illness and Therapeutic Options for Advanced Melanoma Unresectable stage III and IV melanoma is an incurable malignancy with approximately six percent of all patients surviving at five years. Until recently the median survival rates with both single and multiple drug combinations had not changed and had remained within the 2013 pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 8

13 range of six to twelve months. It is a challenging cancer for both patients and oncologists, as until recently no effective treatment options existed. Treatment options have included dacarbazine, temozolomide, and carboplatin plus paclitaxel. The objective response rates to systemic agents are low and have generally been less than 15%. There is no evidence that standard chemotherapy regimens used either as single agents or as combinations, improve either the quality of life or overall survival. More recently vemurafenib, a selective BRAF inhibitor of melanoma with the activating mutation V600, was shown to improve overall survival and progression free survival when compared to single agent dacarbazine and was subsequently approved. BRAF mutations exist in about 50% of all patients with metastatic melanoma, particularly in younger patients and in those areas of the skin intermittently exposed to the sun. For those patients who are BRAF mutation negative the standard treatment at most academic centers has been to enroll patients into clinical trials of new agents. Ipilimumab, a CTLA-4 inhibitor, was also recently approved by Health Canada in a second line indication of unresectable melanoma. Ipilimumab improved overall survival when compared to a comparator gp100 vaccine. Still only about 20% of unresectable melanoma patients have long term survival and for those patients who do not have a V600 activating mutation and do not respond to ipilimumab the prognosis is poor. Thus, effective new treatments are needed for patients with metastatic melanoma. Effectiveness and Safety of Trametinib Trametinib is a small molecule inhibitor of MEK1 and MEK2. The METRIC study met its primary endpoint of an improvement in progression free survival. The median PFS in the intention-to treat population was 4.8 months and 1.5 months for trametinib and chemotherapy respectively (H.R. for progression 0.45; 95% C.I ; p<0.001), as assessed by site investigators. There was a slightly greater PFS when assessed by the independent review committee, and the results were similar in the primary efficacy population. A total of 195 patients (61%) had disease progression or had died at the time of the preliminary analysis. The 6 month overall survival in the intention-to-treat population was 81% for trametinib and 67% in the chemotherapy group (findings were identical in the primary efficacy population).the hazard ratio for death in the trametinib was 0.54 (95% C.I., p=0.01), despite 51 of 108 patients in the chemotherapy group crossing over to receive trametinib. Based on a subsequent data cut in May 2013, after a median follow up of follow-up of 14.7 (trametinib) and 8.7 (chemotherapy) months, the median OS was 15.6 and 11.3 months for the trametinib and chemotherapy arms, respectively (HR = 0.78; 95% CI, 0.57 to 1.06; p=0.0912). Patients in the chemotherapy group were allowed to cross over to receive trametinib after disease progression had been confirmed by an independent review. The confounding effect of the crossover of dacarbazine-treated patients to receive trametinib also influences the determination of the absolute outcome impact of trametinib. The response rate for trametinib was 22% and 8% for the chemotherapy group as assessed by RECIST criteria in the intention-to-treat population, and the median duration of response was 5.5 months for trametinib (95% C.I., ) and had not been reached for the chemotherapy arm (9 patients). Health related quality of life (HRQOL) assessments were performed at baseline and throughout active therapy using EORTC QLQ-C30 and EQ-5D questionnaires. In general, at weeks 6 and 12 trametinib treatment was associated with smaller functional impairment, smaller declines in health status, and less symptoms exacerbation over the course of treatment as compared to chemotherapy. Trametinib was well tolerated with an acceptable safety profile. Adverse events occurred in at least 15% of the 310 patients evaluable for toxicity. The most common adverse events were rash, diarrhea, peripheral 2013 pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 9

14 edema, fatigue and dermatitis acneiform. A decreased ejection fraction occurred in 7 % of patients leading to permanent discontinuation of the drug. Ocular events occurred in 9% of patients (mostly Grade 1 or 2) in the trametinib group with blurred vision (4%) the most common; reversible chorioretinopathy (grade 3) occurred in 1 patient (<1%). At the time that the study was undertaken BRAF inhibitors were not approved for clinical use; however, they were widely available through clinical trials. Although there are no randomized clinical trials comparing trametinib to a BRAF inhibitor, the pcodr review assessed an indirect comparison of trametinib and vemurafenib submitted by the manufacturer. The IDC demonstrated that there was a greater likelihood of better PFS and OS rates with vemurafenib therapy than with trametinib therapy in patients with BRAF V600E mutation positive unresectable or metastatic melanoma when data with shorter but similar follow-up time on trametinib and vemurafenib was used. However, there was a greater likelihood of better OS rates with trametinib therapy than with vemurafenib therapy when longer follow-up data from the BRIM-3 trial was used. Conclusions drawn from such indirect comparisons are not as robust as those from direct, head-to-head trial data, and therefore must be taken in context. Without a head-to-head trial, the relative effectiveness of these two drugs is uncertain, the mechanisms of action differ and results from the BRIM-3 and METRIC studies suggest there could be differences. Trametinib could therefore be considered in patients who are unable to tolerate a BRAF inhibitor. Therefore the eligibility criteria for trametinib use should include patients with metastatic and /or unresectable melanoma whose tumours harbours the V600E or V600K mutation and have not received prior BRAF inhibitor therapy. Patients should have an ECOG performance of 0 or 1, if present, have stable brain metastases and have an adequate renal, hematologic and liver function. As patients who received prior BRAF Inhibitor therapy were excluded from the this trial, there is no evidence to support the use of trametinib after progression on a BRAF Inhibitor, despite evidence that several pathways of resistance are upstream from MEK and lead to increased activation and phosphorylation of MEK. Similarly, only 9 patients with a history of brain metastases were on the trametinib arm and 2 in the chemotherapy arm. Therefore the true efficacy of trametinib in patients with brain metastases is not assessable. Need With the approval of vemurafenib and dabrafenib for the treatment of unresectable, BRAF V600 mutation positive tumors it is likely that the majority of patients will receive such therapy. For those patients in whom a BRAF inhibitor is not tolerated or contraindicated, trametinib would be an effective alternative to BRAF inhibitor therapy. There is no evidence to support the use of trametinib in patients who have demonstrated resistance to BRAF inhibitor therapy. Currently trials are ongoing comparing the combinations of a MEK inhibitor plus a BRAF inhibitor versus a BRAF inhibitor. 2.3 Conclusions The pcodr Melanoma Clinical Guidance Panel concluded that there is a net overall clinical benefit to trametinib compared with chemotherapy, based on one randomized controlled trial, METRIC, which demonstrated an improvement in progression free survival with trametinib when compared 2013 pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 10

15 to dacarbazine or paclitaxel in patients who are BRAF treatment naive and have BRAF V600 (E and K) mutation positive unresectable melanoma. The Clinical Guidance Panel also considered that from a clinical perspective: Trametinib has an acceptable tolerability profile with predictable and manageable toxicities. There are no randomized clinical trials comparing trametinib to the BRAF inhibitor, vemurafenib, and the results of an indirect comparison to vemurafenib were not as robust as those from direct, head-to-head trial data, and therefore must be taken in context. For those patients in whom a BRAF inhibitor is not tolerated or contraindicated, trametinib would be an effective alternative to BRAF inhibitor monotherapy. There is no evidence to support the use of a MEK Inhibitor after progression on a BRAF Inhibitor or in patients with brain metastasis Currently trials are ongoing comparing the combination of a MEK inhibitor plus a BRAF inhibitor versus a BRAF inhibitor, which could result in a broader role for MEK inhibitors, like trametinib, in clinical practice pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 11

16 3 BACKGROUND CLINICAL INFORMATION This section was prepared by the pcodr Melanoma Clinical Guidance Panel. It is not based on a systematic review of the relevant literature. 3.1 Description of the Condition Melanoma is a malignancy of melanocytes which are distributed throughout the body including skin, eyes, and gastrointestinal tract. Although primary melanomas can occur in a variety of anatomical sites, the skin is the most common, comprising 95% of cases. In Canada, 5500 new cases of primary melanoma are expected in 2011 and approximately 950 patients will die from melanoma. 5 The incidence of melanoma has been steadily increasing over the past 50 years. At present, the lifetime probability of developing a melanoma for women is 1 in 85 and for men is 1 in Staging of melanoma is based on the current AJCC 7th Edition Classification. 16 The tumour characteristics principally involve the Breslow height, mitotic rate and the presence or absence of ulceration in the primary. The detection of microscopic and macroscopic lymph node involvement, serum lactate dehydrogenase and the sites of metastatic disease are integral components to the staging classification. All of these factors have been shown to be important prognostic variables which influence patient outcomes and which help to guide management decisions. 3.2 Accepted Clinical Practice In early stage melanoma, cures are commonly achieved with surgery alone. The primary tumour is excised with appropriate margins. Depending upon the Breslow height, mitotic rate, presence of ulceration and location of the primary, a sentinel node biopsy may be performed to assess nodal status. If the sentinel node is positive then a completion node dissection of the surrounding nodal basin is often performed in order to reduce the risk of a regional recurrence. 17 Although only 5% of patients actually present with metastatic disease, the majority of patients who die from melanoma, will have developed recurrent and/or distant disease. Approximately one-third of patients with early stage melanoma will develop metastasis whereas half of patients with nodal disease will recur and likely die from the development of metastatic disease. 18 Brain metastases are relatively common in advanced melanoma and occur in up to 75% of patients with overt metastatic disease. 19 They often prove to be relatively refractory to radiotherapy and systemic treatment and are associated with a particularly dismal prognosis. Highly selected patients with Stage IV disease may benefit from surgical resection of the metastases and 5 year survival in these patients ranges from 15 to 25%. For those patients who were not candidates for surgical resection systemic treatment with chemotherapy was most commonly offered. Unfortunately, the prognosis for these patients has remained poor. The median survival is six to nine months and the five-year survival is approximately 6%. 20 In spite of multiple phase II and III trials with systemic therapy, the objective response to systemic chemotherapy agents remains low and has generally been less than 15%. Until recently, the median survival rates with both single and multiple drug combinations have not changed and have remained within the range of six to twelve months. Over the past 30 years, the standard first line systemic therapy has been dacarbazine. 17,21 Although this intravenous alkylating agent is generally well tolerated, complete responses are rare. 11 In comparative studies, it has never been shown to improve survival in 2013 pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 12

17 metastatic melanoma Temozolomide, an oral imidazazole tetrazene derivative of DTIC which is activated to the active metabolite of dacarbazine (MTIC), has also been commonly used. However, in a phase III trials which compared temozolomide directly with dacarbazine, equivalent progression free and overall survival were observed, although the temozolomide tended to be better tolerated In the 1990 s the FDA approved the use of high dose interleukin-2 based on phase II data showing an overall response rate of 16% but also a durable complete response rate of 5%, extending beyond five years. 25,26 Unfortunately, high dose interleukin-2 is accompanied with significant toxicity and requires intense cardiac monitoring and hemodynamic support. Interleukin-2 has been used in a few selective centres but is largely unavailable throughout Canada. A very wide spectrum of chemotherapeutic and immunological treatments approaches have been explored in metastatic melanoma with until recent limited to no success. Patient outcomes have not changed significantly over the past three decades. 11 Nevertheless, what has become apparent is that melanoma represents a heterogeneous group of diseases which appear to have varying genetic abnormalities which drive cellular proliferation and metastases The MAP kinase signalling pathway appears to be a key regulatory mechanism for cell growth, and differentiation in melanoma. 30 Mutations in the BRAF protein in this pathway can alter the activity of BRAF and result in uncontrolled cellular proliferation and increased potential for metastatic spread. 31 Approximately 50% of human melanomas appear to have an activated mutation in BRAF and has consequently become a potential key target for inhibition and potential therapeutic site. 32 Vemurafenib is a BRAF inhibitor that selectively targets the mutated BRAF V600 and was approved in August 2011 by the FDA as a treatment of late stage or unresectable melanoma in patients harbouring a V600E mutation, and subsequently approved by Health Canada in February Just fewer than 50% of all melanoma patients will harbour a V600 mutation, with the majority being V600E. In the randomized Phase III study (BRIM3) there was a relative reduction of 63% in the risk of death and a 74% relative reduction in the risk of tumor progression. The overall response rate was 48%. 36 This is now a standard first line treatment of advanced, unresectable melanoma in patients harbouring a V600 mutation. Likewise the immune checkpoint inhibitor of CTLA-4, ipilimumab was approved by Health Canada in February 2012 in a second line indication in pre-treated patients with advanced melanoma. 37 Dabrafenib is a BRAF inhibitor that selectively targets the mutated BRAF V600 and has been under clinical trials since In 2012, a multicentre non-blinded phase III study of dabrafenib in comparison to dacarbazine in the first line treatment of 250 patients with unresectable or metastatic melanoma with a BRAF V600E mutation was reported. Patients were randomized 3 to 1 to receive either dabrafenib (187) or DTIC (63) respectively. Those patients who received DTIC could cross-over to receive dabrafenib at disease progression. The primary endpoint was Progression Free Survival as determined by the Investigator. The key inclusion criterion was the presence of V600 mutation. The use of dabrafenib is dependent upon the accuracy and availability of BRAF mutation testing of each prospective patient s primary or metastatic tumour (See Section 7.1). Dabrafenib was approved by Health Canada in July 2012 for unresectable stage III or Stage IV melanoma that harbours the BRAF V600E or V600K mutation pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 13

18 3.3 Evidence-Based Considerations for a Funding Population Trametinib is an orally available selective inhibitor of MEK1 and MEK2. In pre-clinical trials trametinib inhibited melanoma growth in tumours that harboured a V600E or V600K mutation when they were transplanted into mice. In phase I and Phase II trials trametinib led to regressions and stabilization of tumours in patients with metastatic melanoma with V600E or V600K mutation. The pivotal Phase III trial was an open label, randomized trial of trametinib (2 mg orally daily) versus Dacarbazine (1000 mg/kg q 3weeks) or paclitaxel (175 mg/m 2 q 3weekly) with a 2:1 randomization. 1 Patients in the chemotherapy arm who had progression could cross over and receive trametinib. The primary endpoint was Progression Free Survival (PFS), and secondary endpoints of overall survival, overall response rate, duration of response, and safety. Progression Free Survival was chosen as the primary endpoint as although vemurafenib and ipilimumab were not commercially available when this study was undertaken it was felt that access to these treatments could confound a survival benefit. The primary efficacy analysis was restricted to the patients who had the V600E mutation and no evidence of brain metastases, although since no significant differences were observed between the primary efficacy population and the intention-totreat population, the data from the intention-to-treat population were presented. From December 2010 to July patients with unresectable Stage IIIC or IV melanoma with either a BRAF V600E or V600K mutation were enrolled from 103 centres worldwide. Patients could have received one prior chemotherapy regimen but could not have received a prior BRAF inhibitor or MEK inhibitor. Patients were well balanced in demographics between the two arms with only slightly more patients with M1C disease in the trametinib arm. Of the 322 patients 273 (85%) were in the primary efficacy population. Trametinib was well tolerated as assessed in the 310 patients who had received at least 1 dose of study drug. Adverse events were reported in at least 15% of patients in either group and the most common adverse events in the trametinib arm were rash, diarrhea, peripheral edema, fatigue, and dermatitis acneiform. Only 8% of patients with a rash had a Grade 3 or 4 rating. Decreased ejection fraction was seen in 14 patients (7%) in the trametinib group and 2 patients in the trametinib group had Grade 3 cardiac-related event. Ocular events occurred in 9% of the trametinib group with blurred vision in 4%, reversible chorioretinopathy in 1, and no cases of retinal vein occlusion. Trametinib can safely be administered to patients with metastatic melanoma. Patients who received prior BRAF Inhibitor therapy were excluded from the this trial and therefore there is no evidence to support the use of a MEK Inhibitor after progression on a BRAF Inhibitor, despite evidence that several pathways of resistance are upstream from MEK and lead to increased activation and phosphorylation of MEK. Only 9 patients with a history of brain metastases were on the trametinib arm and 2 in the chemotherapy arm. Therefore the true efficacy of trametinib in patients with brain metastases is not assessable. Therefore the following eligibility criteria could be applied for Trametinib: 1. Metastatic and /or unresectable melanoma patients whose tumours harbours the V600E or V600K mutation and have not received prior BRAF inhibitor therapy. 2. ECOG performance of 0 or If present, stable brain metastases. 4. Adequate renal, hematologic and liver function 2013 pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 14

19 3.4 Other Patient Populations in Whom the Drug May Be Used Trametinib may be potentially used in patients with high risk melanoma in an adjuvant setting. It could also be used after progression on BRAF inhibitor therapy either as a single agent, or in combination with a BRAF inhibitor albeit the evidence does not support this use. Trametinib could also be used in combination with a BRAF inhibitor as initial therapy in patients whose tumours have a BRAF mutation. Phase II trials consistently show higher response rates and longer progression free survival. The results of Phase III trials comparing single agent BRAF inhibitors versus a MEK inhibitor and a BRAF Inhibitor are pending. Trametinib could be considered in patients who are unable to tolerate a BRAF inhibitor pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 15

20 4 SUMMARY OF PATIENT ADVOCACY GROUP INPUT A patient advocacy group, Melanoma Network of Canada, provided input on trametinib (Mekinist) for use as a monotherapy for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600, and their input is summarized below. The Melanoma Network of Canada conducted an anonymous online survey to gather information about the patient and caregiver experience with advanced melanoma and the therapies, in particular with trametinib. The survey was promoted through cancer centres in Canada that treat melanoma and on the Melanoma Network Canada website. 24 respondents responded to questions about their experience with advanced melanoma and their consideration about any future drug therapy; one respondent responded to questions regarding their direct experience with trametinib; and one respondent provided input from a caregiver experience. From a patient perspective, there is a critical need to provide more treatment options and alternatives to treat metastatic melanoma. While there are therapies approved for metastatic melanoma patients that have shown a positive impact on overall survival rates; however, it is reported that these drugs do not work effectively for all advanced stage patients. In addition, there have been reports of severe side effects with the existing therapies. When asked about potential side effects, respondents noted that they were willing to accept side effects and the serious risks associated with a future new drug if they knew those side effects can be effectively managed. With respect to trametinib, it was noted that the side effects were reported to be well tolerated more so than other current therapies. The respondent on trametinib also noted that their melanoma has been stabilized with no progression. Because metastatic melanoma has few treatment options, 71% of the respondents ranked the importance of quality of life while on treatment as either important or very important. Please see below for a summary of specific input received from the patient advocacy groups. 4.1 Condition and Current Therapy Information Experiences Patients have with Metastatic Melanoma Generally, patients with metastatic melanoma face the certainty of disease progression including worsening of symptoms such as increasing shortness of breath, severe pain, fatigue, memory loss, loss of coordination, cognitive impairment from brain metastases or radiation, loss of sight, lymphedema, weight loss and death without treatment. Depending upon the site of metastases and type of treatment, many patients suffer from additional effects of treatment and of the current treatment therapies including headaches, neuropathy, bone fractures, blindness, hair loss, depression, anxiety, memory loss, decreased mobility, colitis, and disfiguring surgeries. Many patients have had extensive surgery to remove lymph nodes and/or tumours, which has caused decreased mobility, loss of functioning or capacity of certain organs, scarring and body image issues. Some of the comments from the respondents include: The limitations I have are my energy level has not returned to what it was and I have developed lymphedema in my leg, which requires regular lymphatic drainage therapy. The psychological impact is probably the greatest issue in that I have a wife and two young children. Knowing the severity and prognosis of Stage 4 metastatic melanoma continues to affect our lives and causes a lot of stress pcodr PAN-CANADIAN ONCOLOGY DRUG REVIEW 16