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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 (first-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 Recommended - conditional on improved cost-effectiveness.
pERC Recommendation

The pCODR pERC recommends funding vemurafenib (Zelboraf) conditional on the cost-effectiveness of vemurafenib being improved to an acceptable level. Funding should be as a first-line therapy for patients presenting with BRAF V600 mutation-positive unresectable stage IIIC or IV melanoma or for patients who develop metastatic disease. Patients should have good performance status (ECOG ≤ 1), and, if brain metastasis are present, the metastases must have been previously treated and be stable. Treatment may be continued until disease progression. The Committee made this recommendation because they were satisfied that, despite some limitations in the clinical trial design, there is an overall clinical benefit of vemurafenib compared with dacarbazine. However, at the submitted price and the Economic Guidance Panel's best estimates of the incremental cost-effectiveness ratio, vemurafenib could not be considered cost-effective compared with dacarbazine.

Patient Population

First-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 deliberated upon the results of the BRIM-3 study, which evaluated the oral administration of vemurafenib in a dose of 960 mg twice daily (8 tablets per day) as a first-line therapy for metastatic melanoma. pERC concluded that there is a net clinical benefit associated with vemurafenib, despite some limitations observed in the BRIM-3 study. pERC noted that there was a statistically significant improvement in the hazard ratios for overall survival at the planned interim analysis conducted at approximately six months and at exploratory analyses of overall survival conducted at three months and 10 months after the planned interim analysis. pERC also considered the median overall survival results that were obtained at the third analysis and considered that these were clinically significant. However, pERC noted that the trial was not blinded, which may have affected the integrity of the trial results and the magnitude of the observed benefit. pERC discussed that while overall survival may not be directly affected in an unblinded trial, the supportive care management of patients in the trial may have been affected and biased the overall trial results. In addition, it was noted that a larger proportion of patients in the dacarbazine group withdrew from the trial compared with the vemurafenib group. It was recognized that blinding of the BRIM-3 study would have been challenging because an orally administered drug (vemurafenib) was compared with a drug that is administered intravenously (dacarbazine), however, the Committee noted that randomized double-blind trials are considered the gold standard and should be attempted whenever possible; double dummies may be used when oral and IV treatments are compared.

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 deliberated upon the cost-effectiveness of vemurafenib in untreated patients. It was concluded that vemurafenib is not cost-effective based on the Economic Guidance Panel’s best estimates, which were consistent with the manufacturer’s estimates. In order for it to be cost-effective, pERC considered that the price of vemurafenib would need to be reduced substantially. pERC expressed concern that the manufacturer would not publicly disclose their estimates of cost-effectiveness; however, pERC noted that because it was known that the manufacturer’s estimates were within the range of the Economic Guidance Panel’s best estimates, this reduced the challenges pERC had in interpreting the redacted cost-effectiveness information. pERC noted that the time horizon used in the submitted economic evaluation and in the Economic Guidance Panel’s best estimates was five years. pERC discussed this in light of the short follow-up period for the BRIM-3 study and the uncertainty of long-term outcomes. As a result, pERC noted that the incremental cost utility ratios associated with vemurafenib could potentially be even higher than what was estimated by the Economic Guidance Panel.

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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