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NICE guidance on dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma
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NICE guidance on dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma On Oct 22, 2014, the National Institute for Health and Care Excellence (NICE) published guidance1 recommending the use of dabrafenib as an option for treating unresectable or metastatic BRAF V600 mutation-positive melanoma, but only if companies provide the drug with the discount agreed in the patient access scheme. Dabrafenib was appraised under the Single Technology Appraisal process. The company that markets dabrafenib (GlaxoSmithKline [GSK], Uxbridge, UK) submitted evidence about the clinical and cost-effectiveness of this drug2 that was reviewed by an independent evidence review group, the Liverpool reviews, and the implementation group.3,4 An independent appraisal committee met once to develop guidance for the use of dabrafenib and clinical specialists, patient experts, and manufacturer representatives also attended. Key clinical evidence in the appraisal was from the BREAK-3 trial5 that compared effects of dabrafenib with those of dacarbazine in people with previously untreated, unresectable advanced or metastatic BRAF V600 mutation-positive melanoma. Results from the June, 2012 company analysis (the first of which was presented in December, 2011) for progressionfree survival showed that the median length of progression-free survival was 6·9 months for dabrafenib and 2·7 months for dacarbazine (hazard ratio [HR] 0·37, 95% CI 0·24–0·58, p<0·0001). A third analysis (submitted by the company with a cutoff date in December, 2012) for overall survival reported the median overall survival time for patients of 18·2 months in the dabrafenib group and 15·6 months in the dacarbazine group. This difference between overall survival time was not significant (HR 0·76, 95% CI 0·48–1·21). However, when the third analysis was done in
December, 2012, 57% of patients who were previously assigned to receive dacarbazine had switched to receive treatment with dabrafenib. Since December 2012, vemurafenib was recommended by NICE for the treatment of BRAF V600 positive unresectable or metastatic melanoma, the use of dacarbazine as the comparator in the BREAK-3 trial5 no longer represents the standard of care for patients with this cancer. GSK’s submitted evidence therefore included an indirect comparison with vemurafenib because data was used from the BREAK-3 trial5 and the BRIM-3 trial.6 The BRIM-3 trial6 compared use of vemurafenib in patients with use of dacarbazine. Results from this indirect comparison showed no differences between dabrafenib and vemurafenib in progression-free survival (HR 0·97, 95% CI 0·59–1·60) or overall survival (0·86, 0·32–2·29). An economic assessment that compared dabrafenib against both dacarbazine and vemurafenib was submitted for untreated, unresectable, or metastatic BRAF V600 mutationpositive melanoma. The company’s model consisted of a so-called progression-free and a postprogression state of health and a death state. Their model had a time horizon of 30 years. Survival in the dabrafenib group was mathematically modelled by fitting the log-normal curve to data from the BREAK-3 trial5 only for the trial period, followed by the loglogistic curve fitted to the American Joint committee on Cancer registry data for up to 10 years, and then mortality rates from UK life tables for the remaining 20 years of the model. To model survival in the comparator groups the company used the hazard ratios from the BREAK-3 trial5 (for the comparison with dacarbazine) or from the indirect comparisons between the treatments (for the comparison
www.thelancet.com/oncology Vol 15 December 2014
with vemurafenib) to the parametric survival curves derived for the dabrafenib group. Utility values for the health states on treatment were based on assessments of quality of life using the EuroQol (EQ-5D) questionnaire in the BREAK-3 trial.5 Treatment with vemurafenib was assumed to be associated with the same quality of life as treatment with dabrafenib. The analysis used a UK National Health Service (NHS) and personal social services perspective on costs. GSK and the Department of Health for England agreed to a confidential discount to the list price of dabrafenib as part of a patient access scheme. The company’s base–case analysis resulted in an incremental costeffectiveness ratio of £49 019 per quality adjusted life year (QALY) gained compared with dacarbazine, and £11 028 per QALY gained for dabrafenib compared with vemurafenib; the patient access schemes for both dabrafenib and vemurafenib were included in the analysis. The evidence review group indicated that the company’s approach to model overall survival could have overestimated survival in the dabrafenib group. A different approach was used by the evidence review group to model overall patient survival; this method increased the incremental cost-effectiveness ratio for dabrafenib compared with dacarbazine to £99 560 per QALY gained. The evidence review group questioned the validity of the company’s indirect comparisons between dabrafenib and vemurafenib because the assumption of proportional hazards ratio was not valid in the BREAK-3 or BRIM-3 trials,5,6 or between the dacarbazine groups of both trials. Additionally, concerns were raised that concentrations of lactate dehydrogenase differed between the two trials, suggesting that patients in BRIM-3 trial6 had worse prognoses
Published Online October 22, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71033-2
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than did patients in BREAK-3 trial.5 The ERG stated that any estimated incremental cost-effectiveness ratios generated by this indirect comparison would be unreliable and likely to be misleading. The appraisal committee accepted the views of the clinical specialists that in patients for whom dabrafenib is suitable, the relevant comparator is the alternative BRAF targeted therapy vemurafenib, in view of that dacarbazine is no longer widely used in this setting. The Committee discussed the evidence of clinical effectiveness for dabrafenib compared with vemurafenib. Concerns were noted from the evidence review group about differing concentrations of lactate dehydrogenase between the two trials; however, the clinical specialists explained to the Committee that lactate dehydrogenase is not a reliable marker for disease progression in isolation. Therefore, the Committee was satisfied that patients were otherwise well matched in the two trials. Clinical specialists also stated that the clinical effectiveness of dabrafenib and vemurafenib were not deemed to differ in clinical practice and that choice between the two treatments would be mostly based on the drug adverse reaction profiles. The Committee considered sizes of the trials: BRIM-3 was a large trial and could show an overall survival benefit with use of vemurafenib, whereas BREAK-3 was a smaller trial and thus difficult to report a significant benefit of overall survival with
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use of dabrafenib. The Committee noted that gains for progression free survival in both trials were very similar, and concluded that no evidence clearly showed that dabrafenib and vemurafenib differed in clinical effectiveness and that it would not be unreasonable to assume that both have similar effect. The Committee noted the evidence review group’s comments about the restrictions of the company’s model, but was aware that the ERG did not do exploratory analyses because of concerns that any estimated incremental cost-effectiveness ratios generated from the results of the company’s indirect comparison would be unreliable. However, because of the little evidence for differences in clinical effectiveness between the treatments, and no differences in overall costs were shown in the economic analysis, the Committee concluded that any difference in the cost-effectiveness would be small and be in the range regarded to be a cost effective use of NHS resources. As a result, dabrafenib should be recommended as an option for treating unresectable or metastatic BRAF V600 mutation-positive melanoma. NICE issued a final appraisal determination7 stating the Committee’s decision. Stakeholders were given the opportunity to request corrections of factual inaccuracies or to appeal against the Committee’s recommendations but none were received. We declare no competing interests.
*Helen Tucker, Nwamaka Umeweni, Janet Robertson, Jane Adam National Institute for Health and Care Excellence, London SW1A 2BU, UK [email protected] 1
2
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NICE. Dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma, 2014. http://www.nice.org.uk/ guidance/TA321 (accessed Oct 6, 2014). GlaxoSmithKline. Manufacturer’s submission: melanoma (unresectable/metastatic BRAFV600 mutation-positive)—dabrafenib, 2014. http://www.nice.org.uk/guidance/ TA321/documents/melanoma-braf-v600unresectablemetastatic-dabrafenib-id605evaluation-report2 (accessed Oct 6, 2014). Fleeman N, Bagust A, Beale S, et al. Dabrafenib for the treatment of unresectable, advanced or metastatic BRAFv600 mutation-positive melanoma [ID605]: a single technology appraisal. Liverpool reviews and implementation group, 2014. http://www. nice.org.uk/guidance/TA321/documents/ melanoma-braf-v600-unresectablemetastaticdabrafenib-id605-evaluation-report2 (accessed Oct 6, 2014). Fleeman N, Bagust A, Beale S, et al. Dabrafenib for the treatment of unresectable, advanced or metastatic BRAFv600 mutation-positive melanoma [ID605]: a single technology appraisal—updated replacement pages. Liverpool reviews and implementation group, 2014. http://www.nice.org.uk/guidance/ TA321/documents/melanoma-braf-v600unresectablemetastatic-dabrafenib-id605evaluation-report2 (accessed Oct 6, 2014). Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380: 358–65. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutationpositive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, openlabel study. Lancet Oncol 2014; 15: 323–32. National Institute for Health and Care Excellence. Melanoma (BRAF V600, unresectable, metastatic)—dabrafenib [ID605]: final appraisal determination, 2014. http://www.nice.org.uk/guidance/TA321/ documents /melanoma-braf-v600unresectable-metastatic-dabrafenib-id605final-appraisal-determination-document2 (accessed Oct 6, 2014).
www.thelancet.com/oncology Vol 15 December 2014
NICE guidance on dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma On Oct 22, 2014, the National Institute for Health and Care Excellence (NICE) published guidance1 recommending the use of dabrafenib as an option for treating unresectable or metastatic BRAF V600 mutation-positive melanoma, but only if companies provide the drug with the discount agreed in the patient access scheme. Dabrafenib was appraised under the Single Technology Appraisal process. The company that markets dabrafenib (GlaxoSmithKline [GSK], Uxbridge, UK) submitted evidence about the clinical and cost-effectiveness of this drug2 that was reviewed by an independent evidence review group, the Liverpool reviews, and the implementation group.3,4 An independent appraisal committee met once to develop guidance for the use of dabrafenib and clinical specialists, patient experts, and manufacturer representatives also attended. Key clinical evidence in the appraisal was from the BREAK-3 trial5 that compared effects of dabrafenib with those of dacarbazine in people with previously untreated, unresectable advanced or metastatic BRAF V600 mutation-positive melanoma. Results from the June, 2012 company analysis (the first of which was presented in December, 2011) for progressionfree survival showed that the median length of progression-free survival was 6·9 months for dabrafenib and 2·7 months for dacarbazine (hazard ratio [HR] 0·37, 95% CI 0·24–0·58, p<0·0001). A third analysis (submitted by the company with a cutoff date in December, 2012) for overall survival reported the median overall survival time for patients of 18·2 months in the dabrafenib group and 15·6 months in the dacarbazine group. This difference between overall survival time was not significant (HR 0·76, 95% CI 0·48–1·21). However, when the third analysis was done in
December, 2012, 57% of patients who were previously assigned to receive dacarbazine had switched to receive treatment with dabrafenib. Since December 2012, vemurafenib was recommended by NICE for the treatment of BRAF V600 positive unresectable or metastatic melanoma, the use of dacarbazine as the comparator in the BREAK-3 trial5 no longer represents the standard of care for patients with this cancer. GSK’s submitted evidence therefore included an indirect comparison with vemurafenib because data was used from the BREAK-3 trial5 and the BRIM-3 trial.6 The BRIM-3 trial6 compared use of vemurafenib in patients with use of dacarbazine. Results from this indirect comparison showed no differences between dabrafenib and vemurafenib in progression-free survival (HR 0·97, 95% CI 0·59–1·60) or overall survival (0·86, 0·32–2·29). An economic assessment that compared dabrafenib against both dacarbazine and vemurafenib was submitted for untreated, unresectable, or metastatic BRAF V600 mutationpositive melanoma. The company’s model consisted of a so-called progression-free and a postprogression state of health and a death state. Their model had a time horizon of 30 years. Survival in the dabrafenib group was mathematically modelled by fitting the log-normal curve to data from the BREAK-3 trial5 only for the trial period, followed by the loglogistic curve fitted to the American Joint committee on Cancer registry data for up to 10 years, and then mortality rates from UK life tables for the remaining 20 years of the model. To model survival in the comparator groups the company used the hazard ratios from the BREAK-3 trial5 (for the comparison with dacarbazine) or from the indirect comparisons between the treatments (for the comparison
www.thelancet.com/oncology Vol 15 December 2014
with vemurafenib) to the parametric survival curves derived for the dabrafenib group. Utility values for the health states on treatment were based on assessments of quality of life using the EuroQol (EQ-5D) questionnaire in the BREAK-3 trial.5 Treatment with vemurafenib was assumed to be associated with the same quality of life as treatment with dabrafenib. The analysis used a UK National Health Service (NHS) and personal social services perspective on costs. GSK and the Department of Health for England agreed to a confidential discount to the list price of dabrafenib as part of a patient access scheme. The company’s base–case analysis resulted in an incremental costeffectiveness ratio of £49 019 per quality adjusted life year (QALY) gained compared with dacarbazine, and £11 028 per QALY gained for dabrafenib compared with vemurafenib; the patient access schemes for both dabrafenib and vemurafenib were included in the analysis. The evidence review group indicated that the company’s approach to model overall survival could have overestimated survival in the dabrafenib group. A different approach was used by the evidence review group to model overall patient survival; this method increased the incremental cost-effectiveness ratio for dabrafenib compared with dacarbazine to £99 560 per QALY gained. The evidence review group questioned the validity of the company’s indirect comparisons between dabrafenib and vemurafenib because the assumption of proportional hazards ratio was not valid in the BREAK-3 or BRIM-3 trials,5,6 or between the dacarbazine groups of both trials. Additionally, concerns were raised that concentrations of lactate dehydrogenase differed between the two trials, suggesting that patients in BRIM-3 trial6 had worse prognoses
Published Online October 22, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71033-2
1425
News
than did patients in BREAK-3 trial.5 The ERG stated that any estimated incremental cost-effectiveness ratios generated by this indirect comparison would be unreliable and likely to be misleading. The appraisal committee accepted the views of the clinical specialists that in patients for whom dabrafenib is suitable, the relevant comparator is the alternative BRAF targeted therapy vemurafenib, in view of that dacarbazine is no longer widely used in this setting. The Committee discussed the evidence of clinical effectiveness for dabrafenib compared with vemurafenib. Concerns were noted from the evidence review group about differing concentrations of lactate dehydrogenase between the two trials; however, the clinical specialists explained to the Committee that lactate dehydrogenase is not a reliable marker for disease progression in isolation. Therefore, the Committee was satisfied that patients were otherwise well matched in the two trials. Clinical specialists also stated that the clinical effectiveness of dabrafenib and vemurafenib were not deemed to differ in clinical practice and that choice between the two treatments would be mostly based on the drug adverse reaction profiles. The Committee considered sizes of the trials: BRIM-3 was a large trial and could show an overall survival benefit with use of vemurafenib, whereas BREAK-3 was a smaller trial and thus difficult to report a significant benefit of overall survival with
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use of dabrafenib. The Committee noted that gains for progression free survival in both trials were very similar, and concluded that no evidence clearly showed that dabrafenib and vemurafenib differed in clinical effectiveness and that it would not be unreasonable to assume that both have similar effect. The Committee noted the evidence review group’s comments about the restrictions of the company’s model, but was aware that the ERG did not do exploratory analyses because of concerns that any estimated incremental cost-effectiveness ratios generated from the results of the company’s indirect comparison would be unreliable. However, because of the little evidence for differences in clinical effectiveness between the treatments, and no differences in overall costs were shown in the economic analysis, the Committee concluded that any difference in the cost-effectiveness would be small and be in the range regarded to be a cost effective use of NHS resources. As a result, dabrafenib should be recommended as an option for treating unresectable or metastatic BRAF V600 mutation-positive melanoma. NICE issued a final appraisal determination7 stating the Committee’s decision. Stakeholders were given the opportunity to request corrections of factual inaccuracies or to appeal against the Committee’s recommendations but none were received. We declare no competing interests.
*Helen Tucker, Nwamaka Umeweni, Janet Robertson, Jane Adam National Institute for Health and Care Excellence, London SW1A 2BU, UK [email protected] 1
2
3
4
5
6
7
NICE. Dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma, 2014. http://www.nice.org.uk/ guidance/TA321 (accessed Oct 6, 2014). GlaxoSmithKline. Manufacturer’s submission: melanoma (unresectable/metastatic BRAFV600 mutation-positive)—dabrafenib, 2014. http://www.nice.org.uk/guidance/ TA321/documents/melanoma-braf-v600unresectablemetastatic-dabrafenib-id605evaluation-report2 (accessed Oct 6, 2014). Fleeman N, Bagust A, Beale S, et al. Dabrafenib for the treatment of unresectable, advanced or metastatic BRAFv600 mutation-positive melanoma [ID605]: a single technology appraisal. Liverpool reviews and implementation group, 2014. http://www. nice.org.uk/guidance/TA321/documents/ melanoma-braf-v600-unresectablemetastaticdabrafenib-id605-evaluation-report2 (accessed Oct 6, 2014). Fleeman N, Bagust A, Beale S, et al. Dabrafenib for the treatment of unresectable, advanced or metastatic BRAFv600 mutation-positive melanoma [ID605]: a single technology appraisal—updated replacement pages. Liverpool reviews and implementation group, 2014. http://www.nice.org.uk/guidance/ TA321/documents/melanoma-braf-v600unresectablemetastatic-dabrafenib-id605evaluation-report2 (accessed Oct 6, 2014). Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380: 358–65. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutationpositive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, openlabel study. Lancet Oncol 2014; 15: 323–32. National Institute for Health and Care Excellence. Melanoma (BRAF V600, unresectable, metastatic)—dabrafenib [ID605]: final appraisal determination, 2014. http://www.nice.org.uk/guidance/TA321/ documents /melanoma-braf-v600unresectable-metastatic-dabrafenib-id605final-appraisal-determination-document2 (accessed Oct 6, 2014).
www.thelancet.com/oncology Vol 15 December 2014