pan-canadian Oncology Drug Review Final Clinical Guidance Report Vemurafenib (Zelboraf) for Advanced Melanoma October 1, 2012

Transcription

1 pan-canadian Oncology Drug Review Final Clinical Guidance Report Vemurafenib (Zelboraf) for Advanced Melanoma October 1, 2012

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. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17, 2012 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: perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17, 2012 iii

4 TABLE OF CONTENTS DISCLAIMER & FUNDING... INQUIRIES... TABLE OF CONTENTS. ii iii 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 Summary of BRAF mutation testing Summary of BRIM ABOUT THIS DOCUMENT APPENDIX A: LITERATURE SEARCH STRATEGY REFERENCES perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17, 2012 iv

5 1 GUIDANCE IN BRIEF 1.1 Background The objective of this review is to evaluate the effect of vemurafenib 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. 1.2 Key Results and Interpretation Systematic Review Evidence One open-label randomized controlled trial (BRIM-3) met the inclusion criteria for the pcodr systematic review. 1-4 BRIM-3 randomized 675 adult patients with unresectable, previously untreated, BRAF V600E mutation-positive, stage IIIC or IV melanoma. Patients were randomized in a 1:1 ratio to one of two groups, either vemurafenib 960 mg twice daily orally (n=337) or dacarbazine 1000 mg/m 2 intravenously infused every three weeks (n=338). The co-primary outcomes of BRIM-3 were overall survival and progression-free survival. At the planned interim analysis, conducted at approximately six-months, patients treated with vemurafenib had a statistically significant improvement in overall survival and in progression-free survival compared with dacarbazine. Based on these results, the trial was terminated early and dacarbazine patients were permitted to cross-over to vemurafenib. Overall survival was defined as the time interval from randomization until death due to any cause. After the third and most recent overall survival analysis (Oct 2011 data cutoff), the median survival (with censoring) was estimated at 13.2 months for the vemurafenib group compared with 9.6 months for the dacarbazine group (HR=0.62; 95% CI: 0.49 to 0.77; p<0.001). 4 Progression-free survival was defined as the time from randomization to documented disease progression or death based on investigator assessment according to RECIST criteria. At the time of the pre-planned interim analysis (Dec 2010 data cut-off), progression-free survival was 5.3 months for the vemurafenib group versus 1.6 months for the dacarbazine group (HR: 0.26; 95% CI: 0.20 to 0.33; p<0.001). Quality of life was assessed using the Functional Assessment of Cancer Therapy-Melanoma v.4 (FACT-M) questionnaire. Analyses of FACT-M and its subscales suggested that there was no difference in quality of life measured over time on study treatment in patients treated with vemurafenib compared with patients treated with dacarbazine. Interpretation of data was limited because fewer patients completed FACT-M assessment at later cycles as per protocol. Nonfatal serious adverse events occurred in 42.9% of patients receiving vemurafenib and in 17.8% receiving dacarbazine. A total of 7.1% (24/336) of patients treated with vemurafenib and 4.2% (12/293) of patients treated with dacarbazine discontinued treatment due to adverse events. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

6 1.2.2 Additional Evidence pcodr received input on vemurafenib from one patient advocacy group, Melanoma Network of Canada. Provincial Advisory Group input was obtained from eight of the nine provinces (Ministries of Health and/or cancer agencies) participating in pcodr. In addition, two supplemental questions were identified during development of the review protocol as relevant to the pcodr review of vemurafenib and are discussed as supporting information: Summary of BRAF mutation testing in metastatic melanoma Summary of BRIM-2: a single-arm, non-randomized study evaluating the efficacy and safety of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma who had received prior treatment for their disease. The primary endpoint of BRIM-2 was best overall response rate, with a target of 30%, and of the 132 patients who received treatment with vemurafenib, 53% achieved the primary outcome of best overall response rate after a median follow-up of 12.9 months. In addition, median progression-free survival was seven months and median overall survival was 16 months. In general, the efficacy and safety effects of vemurafenib observed in BRIM-2 are similar to those observed in the randomized, controlled phase III trial, BRIM-3. 1 However, given the noncomparative, unblinded design and limited robustness of the data, caution should be used when drawing conclusions from these results Interpretation and Guidance 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 have not changed and have remained within the range of six to twelve months. Metastatic melanoma is the eighth most common cancer in Canada, accounting for approximately 950 deaths in Canada per year. There is limited evidence that conventional treatments such as dacarbazine improve either quality of life or overall survival, therefore, effective new treatments are needed in both the first and second line setting. There were several potential limitations identified with the BRIM-3 study in untreated patients including a lack of blinding and a short follow-up time for overall survival, which could mean that differences in median overall survival between groups was not as robust. In addition, following the planned interim analyses, patients in the dacarbazine group were permitted to crossover to receive vemurafenib, which could have resulted in inflated overall survival hazard ratios at subsequent analyses. Despite these limitations, BRIM-3 represents the first randomized trial in first-line treatment of metastatic melanoma to show improved overall survival and the magnitude of observed benefit was such that these limitations do not decrease confidence in the trial results. The use of vemurafenib is also dependent upon the accuracy and availability of BRAF mutation testing of each prospective patient s primary or metastatic tumour. BRIM-2 was a single-arm non-randomized study of vemurafenib in previously treated patients with metastatic melanoma. Despite the limitations of relying on nonrandomized evidence, BRIM-2 was completed at a time when there were no accepted second-line treatment options. The median survival of approximately 16 months seen in BRIM-2 was far greater than expected, as was the percentage of patients alive at one year (58%), both of which help to demonstrate the efficacy of vemurafenib in the second-line setting. The response rate of 53% was much higher than response typically perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

7 observed with second-line treatments for metastatic melanoma (e.g.10-12% for taxol or carboplatin/taxol). In addition, an expanded access program used to treat first and second line patients has provided further experience in the second-line setting and there is no evidence to suggest that vemurafenib is less efficacious than other therapies that are currently used in this setting. In general, adverse events reported for vemurafenib appeared to be well-tolerated and manageable. Patients in the vemurafenib group experienced a greater incidence of grade three and four adverse events, including arthralgia, rash, elevated liver enzymes, photosensitivity reaction, and squamous cell carcinoma of skin. Approximately one-quarter of patients in the vemurafenib group experienced cutaneous squamous cell carcinomas (including both squamous cell carcinomas of skin and keratoacanthoma) and new primary malignant melanomas compared to less than one percent of dacarbazine patients. 1.3 Conclusions The pcodr Melanoma Clinical Guidance Panel concluded that there is a net overall clinical benefit to vemurafenib based on one randomized controlled trial, BRIM-3, which demonstrated an improvement in overall survival with vemurafenib when compared to dacarbazine in previously untreated patients with BRAF V600 mutationpositive unresectable or metastatic melanoma. In addition, the Panel considered that vemurafenib is effective in the second line setting based on better than anticipated survival observed in the BRIM-2 study, and response rates similar to those seen in BRIM- 3. The Clinical Guidance Panel also considered that from a clinical perspective: Vemurafenib has an acceptable tolerability profile with predictable and manageable toxicities. Metastatic melanoma is the eighth most common cancer in Canada, accounting for approximately 950 deaths in Canada per year. There is limited evidence that conventional treatments such as dacarbazine improve either quality of life or overall survival, therefore, new treatments are much needed. This trial represents the first randomized trial in first-line treatment of metastatic melanoma to show improved overall survival and the magnitude of observed benefit is considerable. Vemurafenib in the second line setting also led to better than expected survival in a group of patients with a poor prognosis. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

8 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 vemurafenib. 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 vemurafenib 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 vemurafenib and a summary of submitted Provincial Advisory Group Input on vemurafenib are provided in Sections 3, 4 and 5 respectively. 2.1 Context for the Clinical Guidance Introduction The manufacturer of vemurafenib has a Health Canada approved indication for the treatment patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The recommended dose is 960 mg administered orally twice daily. Vemurafenib is a BRAF inhibitor that selectively targets the mutated BRAF V600E isoform. BRAF is part of the RAS/mitogen activated protein (MAP) kinase signalling pathway, which helps regulate the proliferation, differentiation, and apoptosis of cells. BRAF V600E, is present in approximately 50% of malignant melanomas. 1 A companion diagnostic test, the cobas 4800 BRAF V600 Mutation Test, has been developed by the manufacturer of vemurafenib (Hoffmann-La Roche) to test whether a patient s melanoma is BRAF V600E-positive Objectives and Scope of pcodr Review The objective of this review is to evaluate the effect of vemurafenib 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 vemurafenib 960 mg orally twice daily (n=337) were compared with dacarbazine 1000 mg/m 2 intravenously every three weeks perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

9 (n=338) in one international, multicentre, open-label, randomized controlled trial, BRIM The study enrolled patients with unresectable, previously untreated, BRAF V600E mutation-positive (identified using the cobas 4800 BRAF V600 Mutation Test), stage IIIC or IV melanoma. Patients were also included if they had a life expectancy of greater than three months, an Eastern Cooperation Oncology Group (ECOG) performance status of zero or one, no brain metastases, and adequate hematologic, hepatic, and renal functions. Median age was 56 years in the vemurafenib group and 52 years in the dacarbazine group. Patients were equally distributed between groups regarding ECOG performance status (zero=68%, one=32% in both groups). Approximately two-thirds of patients in the vemurafenib and dacarbazine groups had M1c stage metastases (66% and 65%, respectively). The co-primary outcomes of BRIM-3 were overall survival and progression-free survival. The final analysis for overall survival was planned after 196 deaths, with an interim analysis after 50% of the projected deaths had occurred. In total, three survival analyses were conducted: first, a pre-planned interim analysis conducted at the cut-off date of December 30, 2010; second, an unplanned interim analyses with a data cut-off date of March 31, 2011; and a third (and most recent) unplanned interim analysis with a data cut-off date of October 3, The final analysis for progression-free survival, as well as the secondary outcomes related to tumour response, quality of life, and adverse events,was conducted at the time of the interim analysis for overall survival. 1-4 Patients treated with vemurafenib had a statistically significant improvement in overall survival compared with dacarbazine at the six month interim analysis (hazard ratio=0.37; 95% CI: 0.26 to 0.55), as well as in progression-free survival (hazard ratio=0.26; 95% CI: 0.20 to 0.33). Based on these results, the Independent Data and Safety Monitoring Board recommended a protocol amendment to close accrual and allow cross-over, so that patients treated with dacarbazine could crossover to receive vemurafenib. One potential limitation of ending a study early is that it reduces the ability to assess long term safety with the study drug, as well as limiting the ability to determine the durability of response. 1-3 Because the median overall survival had not been reached at the time of the planned (first) interim analysis, two subsequent unplanned (exploratory) analyses of overall survival were conducted at three and 10 months after the first interim analysis. Median overall survival was not achieved until the third analysis, at which point a total of 81 dacarbazine patients had crossed over to receive vemurafenib. The median survivals were estimated at 13.2 and 9.6 months for the vemurafenib and dacarbazine groups, respectively (hazard ratio=0.62; 95% CI: 0.49 to 0.77). 4 Quality of life was assessed using the Functional Assessment of Cancer Therapy- Melanoma v.4 (FACT-M) questionnaire. Analyses of FACT-M and its subscales suggested that there was no difference in quality of life measured over time on study treatment in patients treated with vemurafenib compared with patients treated with dacarbazine. Interpretation of data was limited because fewer patients completed FACT-M assessment at later cycles as per protocol. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

10 Data regarding adverse events were extracted from the U.S. FDA medical review of vemurafenib. 5 Up to the first interim analysis, approximately 20% of patients in the vemurafenib group had died, compared with almost 34% of those treated with dacarbazine. All of the deaths among the vemurafenib group were attributed to underlying medical conditions and interventions, or to advanced melanoma progression. 5 Serious non-fatal adverse events occurred in 43% of patients receiving vemurafenib (predominantly due to squamous cell carcinomas of skin) versus 18% of dacarbazine patients. Non-serious adverse events commonly seen in this trial (occurring 20% of patients) included arthralgia, alopecia, fatigue, rash, elevated liver enzymes, nausea, photosensitivity reaction, diarrhea, hyperkeratosis, headache, pruritus, and skin papilloma; all occurred more frequently with vemurafenib compared with dacarbazine. Patients in the vemurafenib group also experienced a greater incidence of grades three and four adverse events, including arthralgia, rash, elevated liver enzymes, photosensitivity reaction, and squamous cell carcinoma of skin. Adverse events leading to treatment discontinuation included arthralgia, dysphagia, and pneumonia. 5 An important limitation of the BRIM-3 trial was the lack of blinding and the absence of an independent radiological committee to assess progression free survival, which may have resulted in observer bias and contributed to a high dropout rate for the dacarbazine group. Additionally, the short follow-up period for overall survival (approximately seven months) likely limits the robustness of differences in median overall survival between groups. Furthermore, the confounding effect of the crossover of dacarbazine-treated patients to receive vemurafenib influences the determination of the absolute outcome impact of vemurafenib 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 Summary of BRAF Mutation Testing in Metastatic Melanoma The cobas 4800 BRAF V600 Mutation Test, developed by Roche Diagnostics Canada, has received regulatory approval and is currently the only approved test available for use in Canada to detect BRAF V600E genetic mutations, and thereby identifying patients eligible to receive vemurafenib for advanced melanoma. 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. It is a validated, real-time polymerase chain reaction test that was applied in BRIM-2 and BRIM- 3. 6,7 The cobas test is able to detect V600E mutations with a higher sensitivity than the reference method of Sanger sequencing, but it is not as specific. 5,8,9 The test showed cross-reactivity with non-v600e mutants, predominantly V600E2 ( 65%), V600K ( 35%), and V600D ( 10%). See section 7.1 for more information. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

11 Summary of BRIM-2: a Single-Arm, Non-Randomized Study Evaluating Vemurafenib in Previously Treated Patients This supplemental issue summarized data from BRIM-2, 6,10 a single-arm, nonrandomized phase II trial examining the efficacy and safety of vemurafenib among patients with BRAF V600E mutation-positive metastatic melanoma who had received prior treatment for their disease. The primary endpoint of the study was best overall response rate, with a target of 30%, as determined by a blinded independent radiologic committee. Over half of patients had an ECOG performance status of one, 61% had M1c disease, and 49% had elevated lactate dehydrogenase levels. Fifty-one percent of patients had one prior systemic therapy and 27% received two prior systemic therapies. Of the 132 patients who received treatment, 53% achieved the primary outcome of best overall response rate after a median follow-up of 12.9 months. Median progressionfree survival was seven months and median overall survival was 16 months. However, the absence of a control group is an important limitation of the BRIM- 2 results. It is uncertain whether equipoise would exist in the second-line setting between vemurafenib and other available systemic therapeutics to conduct a randomized controlled trial. Nonetheless, randomized controlled trials have been conducted in similar circumstances, such as one evaluating ipilimumab for the second-line treatment of metastatic melanoma. Furthermore, other options to include a comparison group, such as an historical control group, could have been used by the investigators to potentially address concerns of equipoise. Given the non-comparative, unblinded design and limited robustness of the data, caution should be used when drawing conclusions from these results. Almost all patients experienced an adverse event, 64% of which were rated as grade three or more. The most frequent (>30%) adverse events related to the study drug were arthralgia, rash, photosensitivity reaction, alopecia, pruritis, skin papilloma and squamous cell carcinoma of the skin. Squamous cell carcinoma of the skin was the most common grade 3 or higher adverse event (26%). In general, the efficacy and safety effects of vemurafenib observed in BRIM-2 are similar to those observed in the randomized, controlled phase III trial, BRIM-3. 1 See section 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, extending life expectancy to allow more time with family is an important aspect when consideration is given to treatment. There are currently very few effective treatments available in Canada for advanced melanoma and many of the available therapies have severe side effects associated with them. Patients indicated that they are willing to tolerate certain side effects of a new treatment, particularly if those side effects can be effectively managed and the treatment they are receiving could extend their life expectancy. Patients are also looking for a therapy that will help to improve their quality of life. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

12 Provincial Advisory Group (PAG) Input Input on the vemurafenib review was obtained from eight of the nine provinces (Ministries of Health and/or cancer agencies) participating in pcodr. From a PAG perspective, issues surrounding the implementation and additional costs of BRAF mutational testing would be of great importance. PAG also identified that ipilimumab would likely enter the Canadian market at a similar time as vemurafenib and therefore, any comparative data between the two agents would be beneficial to help PAG determine which patient populations would be best suited for each treatment and potential funding criteria for each agent. PAG would also appreciate any evidence on vemurafenib in the adjuvant treatment of melanoma and whether vemurafenib should be used in the first or second-line treatment of advanced melanoma. Other One of the more frequent and serious adverse events observed with vemurafenib in BRIM-3 was squamous cell carcinoma of the skin. 1 There is molecular evidence that BRAF inhibitors, such as vemurafenib, induce hyperactivation of the MAP kinase pathway in BRAF wild-type cells. This upregulation of the MAP-kinase system may help activate mutations in RAS, which has been linked with the development of squamous cell carcinoma of the skin. Thus, treating one form of skin cancer may put patients at risk for another form of skin cancer. A manufacturer-sponsored molecular analysis of squamous cell carcinoma of the skin lesions taken from patients who participated in the vemurafenib phase I to phase III trials was recently published. 11 Among the tumour samples, 60% harbored RAS mutations and increased proliferation of mutant cell lines, via the MAP-kinase signaling pathway, occurred when exposed to vemurafenib. 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 have not changed and have remained within the range of six to twelve months. It is a challenging cancer for both patients and oncologists as no effective treatment options exist. 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 quality of life or overall survival. As such the standard treatment at most academic centers has been to enroll patients into clinical trials of new agents. Thus, effective new treatments are needed for patients with metastatic melanoma. Vemurafenib is a small molecule inhibitor of the activating mutation of the BRAF protein. 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. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

13 BRIM-3 Clinical Trial Only one randomized study of vemurafenib compared to a suitable control was identified in this pcodr systematic review. In the Phase III study by Chapman et al (BRIM-3), 675 patients with BRAF V600 mutation positive, untreated melanoma were enrolled from 104 centers in 12 countries. Patients were randomized to either dacarbazine (1000 mg/m 2 ) or to vemurafenib (960 mg twice daily). The study was not blinded and 14% of patients randomized to dacarbazine never received treatment but were included in the intention-to-treat analysis. The co-primary endpoints of the study were to assess overall survival and progression free survival. Secondary outcomes included best overall response rates, duration of response, time to overall response and adverse events. Patients were well balanced for age, sex and other demographics. The final survival analysis was planned after 196 deaths had occurred, with an interim analysis planned after 50% of the deaths had occurred. The Data and Safety Monitoring Board recommended a protocol amendment to close accrual after the planned interim analysis and patients randomized to dacarbazine be allowed to cross over to vemurafenib after progression on dacarbazine. Effectiveness of Vemurafenib: First-Line Setting The Data and Safety Monitoring Board recommended a protocol amendment to close accrual of the study after 118 patients had died because the a priori criteria for statistical significance had been met showing a difference in overall survival and progression free survival in favour of vemurafenib. As of the third analysis in October 2011, the median overall survival estimate was 13.2 months for vemurafenib versus 9.6 months for dacarbazine. This analysis includes several patients who had crossed over to vemurafenib from dacarbazine. The evidence shows that vemurafenib improves both overall survival and progression free survival with a tolerable safety profile. Quality of life was assessed using the Functional Assessment of Cancer Therapy- Melanoma v.4 (FACT-M) questionnaire. Analyses of FACT-M and its subscales suggested that there was no difference in quality of life measured over time on study treatment in patients treated with vemurafenib compared with patients treated with dacarbazine. Interpretation of data was limited because fewer patients completed FACT-M assessment at later cycles as per protocol. The best overall response rate of 48% for the vemurafenib arm was considered very high relative to response rates observed in previous phase III trials in metastatic melanoma. The lack of blinding and the absence of an independent radiological committee to assess progression free survival may have resulted in observer bias. Lack of blinding likely also led to a high dropout rate on the dacarbazine arm, as dacarbazine is felt to be an ineffective treatment. Thus, one of the reasons the response rate to dacarbazine was only 5.5%. Despite the limitations, the progression free survival of 1.6 months with dacarbazine is in keeping with other randomized studies where dacarbazine was the control arm. Likewise an additional 11 patients randomized to dacarbazine did not receive treatment due to progressive disease leading to a decline in performance status or discovery of brain metastases. Only two patients in the vemurafenib arm were withdrawn for similar reasons. The lower withdrawal in the vemurafenib arm may be due to investigator bias as phase I trials had shown that such patients could still respond to vemurafenib. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

14 Because of the emergent improvement in survival, the Data and Safety Monitoring Board recommended a protocol amendment to close accrual early and allow patient patients to cross over from the dacarbazine to the vemurafenib arm. However, subsequent analyses conducted three months and ten months after the planned interim analysis affirmed the consistency of the survival benefit conferred by the vemurafenib. The short follow up for overall survival (approximately seven months) was also a potential concern, limiting the robustness of differences in median overall survival between groups. Furthermore, the confounding effect of the crossover will influence the determination of the absolute outcome impact of vemurafenib. However, such studies are difficult to perform when it is known among clinicians and patients that there is a promising drug that has demonstrated marked improvements and it is evaluated against an ineffective, although standard, therapy such as dacarbazine. Equipoise did not exist for this trial as mentioned in an editorial in the New England Journal of Medicine. 12 Nevertheless, the magnitude of the benefit observed in the trial is unique in the treatment of metastatic melanoma and will likely help define a new standard of care in select patients. Effectiveness of Vemurafenib: Second-Line Setting BRIM-3 only included first line untreated melanoma patients but a prior phase II study (see summary of BRIM-2, section 7.2) and phase I study in previously treated melanoma patients also showed high response rates. 13 In the phase I study previously reported in the New England Journal of Medicine, once the recommended phase II dose of vemurafenib was reached, an expanded cohort of 32 V600E patients were treated with vemurafenib 960 mg/m The response rate was 81%. This lead to a multicenter phase II trial done in the USA and Australia at 13 centers (BRIM-2). In the original design, 90 patients were to be enrolled and treated to demonstrate a response rate of 30% or greater. There were 132 patients enrolled and treated at a dose of 960 mg/m 2. Many of these patients were already in screening when the target accrual was met, leading to a larger than planned sample size. The overall response rate in BRIM-2 based on independent review committee assessment was 53% with a complete response rate of 6%. The median overall survival was 15.9 months, and the median progression free survival was 6.8 months. Primary progression was observed in only 14% of patients. Toxicities were similar to that seen in BRIM-3 and the rate of squamous cell carcinomas was 26% with the majority being keratoancanthoma like malignancies. Patients had good performance status (ECOG 0 or 1), 61% had M1c disease, and 49% of patients had an elevated LDH, the latter two are prognostic factors typically associated with a poor survival. Despite the limitations of relying on non-randomized evidence, at the time of BRIM-2 there was no accepted second line treatment in metastatic melanoma, and no randomized evidence existed that any currently available treatments improved survival. Although taxol or carboplatin/taxol have been used as second line treatment options, the response rates are low (approximately 10-12%), and there is no improvement in overall survival. From a clinical perspective, to have conducted a trial in the second line setting using a taxol regimen would have been difficult, and possibly unethical, as clinical equipoise may not have existed. In addition, the BRAF V600E mutation is associated with a worse prognosis in melanoma patients and treatment options are required for this population. In BRIM-2 the median survival of 15.9 months perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

15 was far greater than expected, as was the percentage of patients alive at one year (58%). The results from the phase I expanded cohort of 32 patients and from BRIM-2 attest to the efficacy of vemurafenib in the second line setting. In addition, an expanded access program used to treat first and second line patients has provided additional experience in the second line setting. None of the evidence available from these studies suggests that vemurafenib is less efficacious in the second-line setting than any other available treatments. Safety of Vemurafenib Adverse events were reported and demonstrated that the drug was well tolerated. Approximately, one quarter of patients receiving vemurafenib developed 25% of patients developed a secondary skin malignancy or new primary malignant melanoma compared with less than one percent of dacarbazine patients. However, this did not result in discontinuation of treatment by any patients. Other literature has reported that combinations of BRAF inhibitors and a MEK inhibitor appear to significantly lower the incidence of secondary skin cancers without an increase in toxicity, or a loss of efficacy. BRAF Mutation Testing and Clinical Practice Because the clinical effect of vemurafenib is limited to those patients with the V600 BRAF mutation, diagnostic testing prior to initiating treatment is essential. Currently, routine testing for BRAF mutations or other potential therapeutic targets in melanoma are not being performed. The use of vemurafenib is dependent upon the accuracy and availability of BRAF mutation testing of each prospective patient s primary or metastatic tumour (See Section 7.1). The Roche cobas 4800 BRAF V600 Mutation Test has been approved by Health Canada and the US FDA. However alternate methodologies, such as the Sanger sequencing process for determining mutation status can be utilized. All methods require meticulous quality controls and should only be performed in laboratories with the appropriate infrastructure and trained personnel. The laboratories must also be able to communicate the findings in a timely manner to the clinicians. Patients with BRAF positive metastatic melanoma often follow an aggressive clinical course and therefore, the ability to provide life extending treatment, should not be significantly hampered by excessive delays in testing. Nineteen patients with a V600K mutation were identified (rather than the V600E mutation) and an exploratory analysis was performed that suggested improvements in overall survival and progression free survival were observed. 2.3 Conclusions The pcodr Melanoma Clinical Guidance Panel concluded that there is a net overall clinical benefit to vemurafenib based on one randomized controlled trial, BRIM-3, which demonstrated an improvement in overall survival with vemurafenib when compared to dacarbazine in previously untreated patients with BRAF V600 mutationpositive unresectable or metastatic melanoma. In addition, the Panel considered that vemurafenib is effective in the second line setting based on better than anticipated survival observed in the BRIM-2 study, and response rates similar to those seen in BRIM- 3. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

16 The Clinical Guidance Panel also considered that from a clinical perspective: Vemurafenib has an acceptable tolerability profile with predictable and manageable toxicities. Metastatic melanoma is the eighth most common cancer in Canada, accounting for approximately 950 deaths in Canada per year. There is limited evidence that conventional treatments such as dacarbazine improve either quality of life or overall survival, therefore, new treatments are much needed. This trial represents the first randomized trial in first-line treatment of metastatic melanoma to show improved overall survival and the magnitude of observed benefit is considerable. Vemurafenib in the second line setting also led to better than expected survival in a group of patients with a poor prognosis. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

17 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 the 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. 14 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 American Joint Committee on Cancer 7th Edition Classification. 16 The tumour characteristics principally involve the Breslow height, mitotic rate and the presence of ulceration in the primary tumour. 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 tumour, the sentinel node biopsy is 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 onethird 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 15% to 20% of patients with overt metastatic disease. 13 They often prove to be relatively refractory to radiotherapy and systemic treatment and are associated with a particularly dismal prognosis. Few patients with metastatic disease would benefit from surgery or radiotherapy alone. Systemic treatment is most commonly offered. Unfortunately, the prognosis has remained poor. The median survival is six to nine months and the five-year survival rate is approximately six percent. 19 In spite of multiple phase II and III trials with systemic therapy, the objective response to systemic 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. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

18 Over the past 30 years, the standard first line systemic therapy has been dacarbazine. 17,20 Although this intravenous alkylating agent is generally well tolerated, complete responses are rare. 21 In comparative studies, it has never been shown to improve survival in metastatic melanoma Temozolomide, an oral nitrosurea which is activated to the active metabolite of dacarbazine, has also been commonly used. However, in phase III trials which compare temozolomide directly with dacarbazine, similar progression free survival and overall survival were observed, although 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 response rate of 5%, extending beyond five years. 30,30 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 limited to no success. Patient outcomes have not changed significantly over the past three decades. 21 Nevertheless, what has become apparent is that melanoma represents a heterogeneous group of diseases which appear to have varying genetic abnormalities that drive cellular proliferation and metastases The MAP kinase signalling pathway appears to be a key regulatory mechanism for cell growth, and differentiation in melanoma. 34 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. 35 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 Evidence-Based Considerations for a Funding Population Vemurafenib is a BRAF inhibitor that selectively targets the mutated BRAF V600 and has been under clinical development for the past three years In 2011, a multicentre non-blinded phase III study of vemurafenib in comparison to dacarbazine in the first line treatment of 675 patients with unresectable or metastatic melanoma was reported. 1 (The details of this trial are provided in Section 6.3.) The key inclusion criterion was the presence of V600 mutation. Although other isoforms were included, 97% of patients had the V600E isoform. The use of vemurafenib is dependent upon the accuracy and availability of BRAF mutation testing of each prospective patient s primary or metastatic tumour (See Section 7.1). The efficacy of vemurafenib in patients with brain metastases is uncertain. In the BRIM-3 trial, patients who had previously treated brain metastases and in whom the central nervous system disease was stable for more than three months were included. In the reports of the interim multivariate analyses, brain metastases has not appeared to affect disease-free or overall survival. Furthermore, patients with ECOG performance of two or more were specifically excluded and therefore it is unknown the impact that vemurafenib would have on patients with a particularly grave prognosis. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

19 Therefore, the following eligibility criteria could be applied for vemurafenib: 1. Metastatic and/or unresectable melanoma; 2. BRAF V600 mutation present in primary or secondary tumour; 3. ECOG performance status of zero or one; 4. If present, stable brain metastases; 5. Adequate haematological, renal and liver function. 3.4 Other Patient Populations in Whom the Drug May Be Used Vemurafenib may be potentially used in patients with high risk melanoma. Adjuvant clinical trials are being developed to address whether vemurafenib will reduce the risk of developing recurrence; however, it is expected to be several years before these trials will have been reported. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,

20 4 SUMMARY OF PATIENT ADVOCACY GROUP INPUT The following patient advocacy group provided input on vemurafenib for advanced melanoma and their input is summarized below: Melanoma Network of Canada. The Melanoma Network of Canada conducted an anonymous online survey to gather information about the patient and caregiver experience related to the medical condition and drug under review. The survey consisted of multiple choice questions, ranking questions and free-form commentary. Response to the survey was solicited via cancer centers in Canada and on the Melanoma Network of Canada website. There were a total of 21 respondents to Part I of the survey regarding patients experience with advanced melanoma, two respondents to Part II of the survey regarding information from caregivers and four respondents to Part III of the survey regarding feedback from patients with direct experience with vemurafenib. From a patient perspective, extending life expectancy to allow more time with family is an important aspect when consideration is given to treatment. There are currently very few effective treatments available in Canada for advanced melanoma and many of the available therapies have severe side effects associated with them. Patients indicated that they are willing to tolerate certain side effects of a new treatment, particularly if those side effects can be effectively managed and the treatment they are receiving could extend their life expectancy. Patients are also looking for a therapy that will help to improve their quality of life. Please see below for a summary of specific input received from the patient advocacy group(s). 4.1 Condition and Current Therapy Information Experiences Patients have with Advanced Melanoma Patients with advanced melanoma may experience of number of debilitating symptoms as a result of their cancer, which typically worsen as their disease progresses and can have a negative impact on their quality of life. Some of these symptoms include shortness of breath, severe pain, fatigue, loss of coordination, loss of sight, lymphedema and weight loss. In addition, patients with metastatic disease may experience further symptoms depending upon the site of the metastases and type of treatment they receive, including headaches, numbness in the extremities, bone fractures, hair loss, depression, anxiety, memory loss, decreased mobility and constipation. As there are relatively few effective treatment options for advanced stage melanoma, patients are conscious of the fact that their disease will ultimately progress. Patients may also experience severe side effects from the medical treatments that they receive. Patients who have no further treatment options for their melanoma indicated that they experience feelings of fear, anxiety and hopelessness. Input from the patient advocacy group indicated that a patient s physical appearance can be severely affected by advanced melanoma. Surgeries performed on patients to remove tumours can lead to scarring which can further impact the physical appearance of the patient and cause body image issues. Furthermore, surgeries to remove tumours or lymph nodes can lead to decreased mobility and a loss of functioning or capacity of certain organs. perc Meeting: March 15, 2012; perc Reconsideration Meeting: May 17,