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pCODR Reimbursement Decision




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  Zelboraf
Generic Name Vemurafenib
Manufacturer Hoffmann-La Roche Ltd.
pCODR Indication Advanced Melanoma
pCODR Tumour Type Melanoma
Funding Request Treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma (second-line).
Submission Date 2011-12-06
Submission Type New Drug
Review Status Notification to Implement Issued
Recommendation Date 2012-06-01
Notification to Implement Date 2012-06-18
RD Interpretation of pERC Recommendation Not recommended - clinical benefit insufficient/unclear and cost-effectiveness insufficient/unclear.
pERC Recommendation

Patient Population

Second-line: Patients with BRAF V600 mutation-positive unresectable stage IIIC or IV melanoma or with metastatic disease. Patients should have good performance status (ECOG <= 1), and, if brain metastases are present, the metastases must have been previously treated and be stable. Treatment may be continued until disease progression.

RD Interpretation of Patient Population Requested vs Actual

Same

Summary of pERC Deliberations - Clinical

pERC noted that the BRIM-3 study only included untreated patients and that there is no randomized controlled trial evidence evaluating vemurafenib in previously treated patients. pERC considered feedback from the manufacturer on evidence for the use of vemurafenib in the second-line setting and further deliberated upon the results of BRIM-2, a single-arm study conducted in previously treated patients. pERC discussed the limitations of non-randomized studies and considered that the quality of evidence supporting vemurafenib in the second-line setting was not robust and that stronger study designs could have been used. pERC considered that, given the absence of a comparator arm in BRIM-2, the magnitude of vemurafenib response is uncertain and likely overestimates the magnitude of clinical benefit associated with vemurafenib in previously treated patients. Despite the limitations in evidence, pERC discussed whether or not there is a need for vemurafenib in the second-line setting in patients who are BRAF V600 mutation positive. pERC considered feedback from the Provincial Advisory Group that there may be BRAF V600 mutation positive patients who had received an alternative agent in the first-line setting prior to vemurafenib being made available. These patients, therefore, would not be eligible for vemurafenib funding in the first-line setting and would not be able to access vemurafenib unless it were available as a second-line treatment. pERC considered that prior to the availability of vemurafenib, there were limited treatment options in the first-line setting and that for a time-limited period it would be clinically reasonable for patients who are BRAF V600 positive and who progressed after first-line therapy (e.g. dacarbazine, treatment in a clinical trial) to have access to vemurafenib in the second-line setting. pERC noted that the Provincial Advisory Group considered this to be a potential implementation issue that would need to be addressed at a jurisdictional level, while recognizing that pERC did not consider vemurafenib cost-effective. {From pERC Final Recommendation Report. Evidence in Brief: Overall Clinical Benefit} pERC considered feedback from the manufacturer on evidence for the use of vemurafenib in the second- line setting and further deliberated upon the results of BRIM-2, a single-arm study involving previously treated patients. pERC discussed the limitations of non-randomized studies and considered that the quality of evidence supporting vemurafenib in the second-line setting was not robust and that stronger study designs could have been used such as a comparison with best supportive care or the use of a historical control group. pERC noted that a 53% best overall response rate (95% confidence interval: 44% to 62%) was achieved, of which 6% of patients had a complete response. pERC considered that, given the lack of comparator arm, the magnitude of vemurafenib response is uncertain and likely overestimates the magnitude of clinical benefit associated with vemurafenib in previously treated patients.

Summary of pERC Deliberations - Safety

pERC discussed the toxicity profile of vemurafenib based on the serious adverse events observed in the BRIM-3 study. pERC noted that nonfatal serious adverse events occurred in a greater proportion of vemurafenib patients compared with dacarbazine patients. pERC also noted that over one-quarter of patients in the vemurafenib group experienced cutaneous squamous cell carcinomas, new primary malignant melanomas and other cutaneous lesions, compared with less than 1% of dacarbazine patients. pERC noted that these adverse events were manageable through excision or the use of local therapies; however, the Committee expressed concern over possible long-term effects of vemurafenib. pERC determined that because of the short trial follow-up (approximately 7 months) the long-term safety of vemurafenib is unknown and long-term survivors should be monitored for adverse events that may appear after continuous, long-term administration of vemurafenib.

Summary of pERC Deliberations - Cost-effectiveness

pERC noted that a cost minimization analysis had also been attempted by the manufacturer that evaluated the cost-effectiveness of vemurafenib in previously treated patients. However, pERC considered that this approach was not appropriate since there is no evidence to suggest that the efficacy of vemurafenib is similar to other second-line therapies. In addition, pERC noted that because the magnitude of clinical benefit of vemurafenib is uncertain in previously treated patients, it was challenging to estimate cost-effectiveness. Therefore, pERC considered that these estimates of cost-effectiveness in previously treated patients were not robust.

Provincial Funding Report: pCODR Provincial Funding Summary Report  pCODR Provincial Funding Summary report
https://www.cadth.ca/sites/default/files/pcodr/pcodr-provfund_zelboraf-advmel.pdf
Final Recommendation Report: pCODR-pERC Final Recommendation report  pCODR-pERC Final Recommendation report
https://www.cadth.ca/sites/default/files/pcodr/pcodr-zelboraf-adv-mel-fn-rec.pdf
Final Clinical Guidance Report: pCODR Final Clinical Guidance Report  pCODR Final Clinical Guidance report
https://www.cadth.ca/sites/default/files/pcodr/pcodr-zelboraf-unredact-fn-cgr.pdf
Final Economic Guidance Report: pCODR Final Economic Guidance report  pCODR Final Economic Guidance report
https://www.cadth.ca/sites/default/files/pcodr/pcodr-zelboraf-adv-mel-fn-egr.pdf

†The information referenced on this page is compiled from publicly available documents published by pCODR and is available through the embedded links.


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