Dabrafenib for treating unresectable or metastatic BRAF V600 mutationpositive melanoma

Evidence-based recommendations on dabrafenib (Tafinlar) for treating unresectable or metastatic melanoma in adults with a BRAF V600 mutation.

# Guidance
This guidance was developed using the Single Technology Appraisal (STA) process.
Dabrafenib is recommended, within its marketing authorisation, as an option for treating unresectable or metastatic BRAF V600 mutationpositive melanoma only if the company provides dabrafenib with the discount agreed in the patient access scheme.# The technology
Dabrafenib (Tafinlar, Novartis) is an inhibitor of the BRAF V600 protein kinase. When the activity of protein kinase is blocked, the cancer cells stop growing and die. Dabrafenib has a marketing authorisation in the UK in monotherapy for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
The summary of product characteristics lists the following very common adverse reactions for dabrafenib: papilloma, decreased appetite, headache, cough, nausea, vomiting, diarrhoea, hyperkeratosis, alopecia, rash, palmarplantar erythrodysaesthesia syndrome, arthralgia, myalgia, pain in extremity, pyrexia, fatigue, chills and asthenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The list price of dabrafenib is 1400 for a pack of 75mg capsules (28 capsules per pack) and 933.33 for a pack of 50mg capsules (28 capsules per pack) (excluding VAT; 'British national formulary'  edition 67). It is taken orally at a recommended dose of 150 mg twice daily. Novartis has agreed a patient access scheme with the Department of Health that makes dabrafenib available with a discount applied at the point of purchase or invoice. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The company's submission
The Appraisal Committee (section 7) considered evidence submitted by the company that manufactures dabrafenib and a review of this submission by the Evidence Review Group (ERG; section 8).

# Clinical effectiveness
The key clinical evidence came from the BREAK3 trial. This was an international, multicentre, randomised, openlabel, activecontrolled trial comparing dabrafenib with dacarbazine in people with previously untreated, unresectable, advanced or metastatic BRAF V600 mutationpositive melanoma. The company also provided supportive evidence from 4 other trials of dabrafenib, including 2 randomisedcontrolled trials (BRF113220 and Combid) and 2 single arm trials (BREAK2 and BREAKMB). However, none of these trials included comparators relevant to the decision problem; therefore they were not included in a quantitative analysis.
Patients in BREAK3 were randomly assigned in a 3:1 ratio to receive either 150 mg of dabrafenib twice daily orally (n=187) or 1000 mg/m2 of bodysurface area of dacarbazine by intravenous infusion every 3 weeks (n=63). Baseline patient characteristics were generally similar between the treatment groups. The mean age was 53.5 years in the dabrafenib arm of the trial and 51.6 years in the dacarbazine arm. Approximately 67% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. The company stated that most patients had undergone surgery previously, and adjuvant immunotherapy with interferon was the most common previous anticancer therapy.
The company conducted 2 separate analyses based on 2 different cutoff dates (December 2011 and June 2012) for the primary outcome of investigatorassessed progressionfree survival and all secondary outcomes. For the outcome of overall survival, the company conducted a third analysis based on a later cutoff date of December 2012. In response to a request for clarification from NICE, the company presented more recent overall survival data with a cutoff date of January 2014.
Results from the June 2012 analysis of BREAK3 showed that there was a 63% reduction in disease progression for patients receiving dabrafenib compared with patients receiving dacarbazine. The median progressionfree survival was 6.9 months for dabrafenib compared with 2.7 months for dacarbazine, a statistically significant difference of 4.2 months (hazard ratio  0.37, 95% confidence interval  0.24 to 0.58, p<0.0001). The company reported results from a range of prespecified subgroups including age, sex, ECOG performance status, disease stage, lactate dehydrogenase levels and number of disease sites. The results showed that the progressionfree survival benefit with dabrafenib treatment was generally maintained across each subgroup.
Results from the December 2012 analysis of BREAK3 showed an improvement of 2.6 months in the key secondary outcome of median overall survival, which was 18.2 months in the dabrafenib group compared with 15.6 months in the dacarbazine group. However, the difference between the treatments was not statistically significant (HR 0.76, 95% CI 0.48 to 1.21, p value not presented).The company explained that approximately 57% of patients assigned to receive dacarbazine had crossed over to the dabrafenib arm by the time the analysis was conducted in December 2012. Therefore, the company adjusted the overall survival results using the 'rank preserving structural failure time' (RPSFT) model. The RPSFTadjusted analysis resulted in a hazard ratio of 0.55 (95% CI 0.21 to 1.43). The analysis based on the January 2014 data was not adjusted for crossover, and the results were designated academic in confidence by the company. The company specified that a crossoveradjusted analysis of the final data from BREAK3 would be completed at a later date.
Healthrelated quality of life (HRQoL) was assessed in BREAK3 using the EuroQoL (EQ5D) utility index. EQ5D data were collected for all the participants in the trial at screening, week 6, week 12, week 15, at disease progression, and approximately 30 days after disease progression. The mean change in EQ5D utility index score from baseline to week 15 was lower in the dabrafenib group (+0.053) than in the dacarbazine group (+0.128).
The data from December 2012 showed that the most commonly reported grade 3 adverse events with dabrafenib were pyrexia, back pain, squamous cell carcinoma and hyperglycaemia; whereas neutropenia, decreased appetite and leukopenia had a higher incidence in the dacarbazine arm. Treatmentrelated adverse events, adverse events leading to discontinuation of trial treatment, and adverse events leading to dose reduction or interruption were not reported for the December 2012 analysis. For the December 2011 analysis, treatmentrelated adverse events occurred with a higher frequency in the dabrafenib arm (88%) than in the dacarbazine arm (73%), whereas the incidence of adverse events leading to discontinuation of trial treatment or dose reduction was similar between the treatment arms.

## Indirect treatment comparison
To estimate the effectiveness of dabrafenib compared with vemurafenib, in the absence of headtohead trials comparing dabrafenib and vemurafenib, the company conducted an indirect treatment comparison using data from the BREAK3 and BRIM3 trials. BRIM3 was a multicentre, randomised, open label, activecontrolled trial that compared vemurafenib (960 mg twice daily orally; n=337) with dacarbazine (1000 mg/m2 of body surface area; n=338). The study population comprised adults with previously untreated advanced or metastatic BRAF V600 mutationpositive melanoma. Patients in BRIM3 were similar to those in BREAK3 in terms of age, sex, ECOG status and disease stage. However, the trials differed in the proportion of patients with elevated lactate dehydrogenase levels (BREAK3 = 34%; BRIM3 = 58%), sample size (BREAK3, n=250; BRIM3, n=675), ratio of randomisation (BREAK3, 3:1; BRIM3, 1:1) and median followup time at the latest cutoff points.
Overall survival and progressionfree survival were joint primary outcomes in BRIM3. The company explained that approximately 34% of patients assigned to receive dacarbazine had crossed over to the vemurafenib arm by the time the analysis was conducted at the latest cutoff date (February 2012). The RPSFT method was used to adjust for crossover. The results using the February 2012 data showed statistically significant differences between vemurafenib and dacarbazine for the primary outcomes of progressionfree survival (HR 0.38, 95% CI 0.32 to 0.46, p<0.001); unadjusted overall survival (HR 0.76, 95% CI 0.63 to 0.93, p value not presented) and RPSFTadjusted overall survival (HR 0.64, 95% CI 0.53 to 0.78, p value not presented).
The company conducted the indirect comparison using the method described by Bucher et al. based on the assumption that the patient characteristics between BREAK3 and BRIM3 were similar. Results of the indirect comparison found no difference between dabrafenib and vemurafenib in progressionfree survival (HR 0.97, 95% CI 0.59 to 1.60) or overall survival (unadjusted HR 1.00, 95% CI 0.62 to 1.62; crossoveradjusted HR 0.86, 95% CI 0.32 to 2.29).

# Cost effectiveness
The company submitted a de novo '3state partitioned survival' model comparing dabrafenib with dacarbazine and vemurafenib for previously untreated, unresectable or metastatic BRAF V600 mutationpositive melanoma. The company considered a partitioned survival model to be more appropriate than a Markov model because it uses distributions of progressionfree survival and overall survival as model inputs and therefore ensures that the model results match those observed in the trial. Patients were assumed to enter the model in the 'progressionfree' health state, and in each cycle could either remain in that state or progress to a worse state; that is, the 'postprogression' health state or 'death' state. The model had a lifetime horizon of 30 years, consisting of weekly cycles and no halfcycle correction. The company based the analysis on an NHS and personal social services perspective, and costs and benefits were discounted at an annual rate of 3.5%. The company explained that there were not enough clinical data available for it to estimate the cost effectiveness of dabrafenib in adults who had received previous treatment. No subgroup analyses were conducted by the company.
For the comparison with dacarbazine, the proportion of people in each health state in the company's model was estimated based on survival functions for investigatorassessed progressionfree survival and overall survival using the June 2012 and December 2012 data respectively from BREAK3. The company fitted independent lognormal distributions to individual patient data for progressionfree survival for both treatment arms from time 0, using accelerated failure time (AFT) regression. The fitted curves were then extrapolated beyond the trial period (defined as 53.1 weeks for dacarbazine and 71.1 weeks for dabrafenib based on the last censor or observed failure time for progressionfree survival) to 30 years. The company stated that the lognormal distribution provided the best fit to the data based on goodnessoffit statistics and comparisons of the area under the curve.
The company modelled overall survival in the dabrafenib arm in 3 phases:
Phase 1: The company fitted the lognormal distribution to individual patient data from the dabrafenib arm of BREAK3 for the trial period only (defined as 96 weeks based on maximum censor or failure time for overall survival) using AFT regression.
Phase 2: From the end of trial followup and up to 10 years, the company applied hazard rates obtained by fitting the loglogistic distribution to the overall survival data from the American Joint Committee on Cancer (AJCC) registry reported by Balch et al. (2009), which was weighted by the relative proportions of patients according to disease stage in BREAK3.
Phase 3: For the remaining duration of the model, the company modelled survival by applying mortality rates obtained from UK general population life tables.
The company stated that there are uncertainties associated with fitting parametric curves to the data from the RPSFT analysis for the dacarbazine arm because of the small number of patient in the analysis. Therefore, it modelled overall survival for the dacarbazine arm as proportional hazards compared with dabrafenib using the RPSFTadjusted hazard ratio from BREAK3. This hazard ratio was applied for the trial period of 96 weeks, after which no further treatment effect was assumed.
For the comparison with vemurafenib, the company applied the progressionfree survival and overall survival hazard ratios from the indirect treatment comparison to the parametric survival curves used to model the dabrafenib arm. Proportional hazards were assumed throughout the entire model timeframe for progressionfree survival, whereas for overall survival it was assumed for the trial period of 96 weeks only.
Treatmentspecific EQ5D utility data for preprogression and postprogression, derived directly from BREAK3, were used in the model for dabrafenib and dacarbazine. The utility values for the progressionfree health state were 0.77 for dabrafenib and 0.75 for dacarbazine. The value for the postprogression state was 0.68 for dabrafenib. The company did not calculate the decrement in postprogression utility for dacarbazine because of potential confounding from crossover in BREAK3. Given that there was no rationale to assume that healthrelated quality of life after progression would differ between treatments, the company assumed that the postprogression utility value for dacarbazine would be the same as that for dabrafenib. In the absence of comparable EQ5D utility data for vemurafenib, the company assumed that the vemurafenib utility values would be the same as those for dabrafenib. The company did not include disutilities associated with adverse events in the model because it considered the effect of adverse events on quality of life to be captured in the progressionfree and postprogression health state utility values. Health related quality of life was assumed to be constant over time in each health state.
Costs incorporated in the company's model included drug costs, dispensing costs for dabrafenib and vemurafenib, administration cost for dacarbazine, BRAF testing, anticancer therapy after the study, costs associated with health states and adverse events and oneoff costs for starting treatment and for death. The costs of dabrafenib and vemurafenib were estimated using the patient access schemes provided by the companies; the cost of dacarbazine was based on the list price. Estimates of the costs of treating adverse events were based on the results of a costofillness study commissioned by the company and the incidence of adverse events from BREAK3 and BRIM3. The anticancer therapy costs after the study were estimated to be 3013 for dabrafenib and vemurafenib and 6044 for dacarbazine.
The basecase incremental costeffectiveness ratio (ICER) was 49,019 per qualityadjusted life year (QALY) gained for dabrafenib compared with dacarbazine, and 11,028 per QALY gained for dabrafenib compared with vemurafenib.
The company's probabilistic analysis showed that at a maximum acceptable ICER of 30,000 per QALY, dabrafenib would have a 6% probability of being cost effective compared with dacarbazine and a 56% probability compared with vemurafenib. At a maximum acceptable ICER of 50,000 per QALY dabrafenib would have a 43.5% probability of being cost effective compared with dacarbazine.
The company conducted a series of deterministic sensitivity analyses. For the comparison with dacarbazine, overall survival was the key driver of the costeffectiveness results. When the RPSFTadjusted hazard ratio for overall survival was varied using the 95% confidence interval, the ICERs ranged from 26,470 per QALY gained to dacarbazine dominating dabrafenib (that is, dabrafenib was more expensive and less effective). The key driver of the costeffectiveness result for the comparison with vemurafenib was the progressionfree survival assumption; varying the hazard ratio using the 95% confidence interval resulted in ICERs ranging from 67,220 per QALY gained to a scenario where dabrafenib dominated vemurafenib. The cost effectiveness estimate for dabrafenib compared with vemurafenib was also sensitive to the overall survival hazard ratio used in the model, assuming a class effect between dabrafenib and vemurafenib and using alternative distributions to model survival. Changes to the time horizon, cost parameters and utility values did not have a large effect on the basecase ICER.

# Evidence Review Group comments
The ERG was satisfied that all relevant studies with the appropriate comparisons were included in the company's analysis. In general, it concluded that BREAK3 was a good quality trial. The ERG agreed that evidence from the BREAK3 trial shows that treatment with dabrafenib was associated with progressionfree survival benefits compared with dacarbazine. However, it did not agree with the company that crossover in BREAK3 explained the lack of an overall survival benefit with dabrafenib, because an analysis of the survival data showed that patients in the dacarbazine arm who crossed over did not gain any significant benefit over patients that did not cross over.
The ERG did not consider the RPSFT method used to adjust for crossover in BREAK3 to be appropriate for the following reasons:
survival data was not based on the final trial data, but on an interim analysis with few deaths
the assumption in the RPSFT method of a 'common treatment effect' (that is, that the effect of dabrafenib is the same whether treatment starts at diagnosis or after the disease has progressed) is questionable
patients in the dabrafenib arm and dacarbazine arm did not receive similar treatments at the time of disease progression, and some received treatments that are not used in routine clinical practice in the UK.The ERG stated that it might have been more appropriate to use the 'inverse probability of censoring weighting' (IPCW) method to adjust for crossover. However, it acknowledged that the lack of complete overall survival data and the small number of deaths to date may invalidate the use of the IPCW method at present.
Regarding the company's indirect treatment comparison, the ERG was satisfied that the BREAK3 and BRIM3 trials were broadly similar in terms of patient population and eligibility criteria. However, it noted that a greater proportion of patients in BRIM3 had lactate dehydrogenase levels above the upper limit of the normal range than patients in BREAK3. The ERG commented that this may have a negative effect on the prognosis of patients in BRIM3 compared with that for patients in BREAK3. The ERG questioned the validity of the approach used to conduct the indirect comparison because the assumption about constant hazard ratios for progressionfree survival and overall survival within BREAK3 and the assumption about constant proportional hazards for dacarbazine overall survival between the 2 trials were not met. The ERG also commented that because of the problem of adjusting for crossover in the individual trials it is more appropriate to use the unadjusted hazard ratios in the indirect treatment comparison. The ERG also noted that the most recent overall survival data from BREAK3 trial (January 2014 data) had not been used in the company's indirect treatment comparison. In view of these issues, the ERG stated that the evidence from the company's indirect treatment comparison was not robust. It was therefore unable to comment on the clinical effectiveness of dabrafenib compared with vemurafenib.
The ERG stated that the assumptions about the clinical effectiveness model inputs were the main drivers of the company's cost effectiveness estimate. The ERG noted that the company censored progressionfree and overall survival data at the date of last observation, which could misrepresent survival projections when used to calibrate parametric survival functions. It considered that, to remove any bias, censoring survival data at the date of datacut would have been more appropriate.
The ERG noted that the company modelled overall survival in 3 phases and it considered this approach to be complex and associated with several limitations, as follows:
Phase 1 from randomisation until 96 weeks (1.8 years): The ERG stated that the log normal distribution used to represent the whole period of the trial followup was questionable because the lognormal distribution is known to have a long tail, and therefore overestimates overall survival gain. The ERG also considered that it would have been more appropriate to use the most recent overall survival data available from BREAK3 (January 2014).
Phase 2 data from 1.8 to 10 years: The ERG noted that the company did not present evidence to support the clinical or biological plausibility of the loglogistic distribution fitted to the AJCC registry data used in this phase. It also noted that the registry data are based on a North American population and therefore may not be representative of the UK population.
Phase 3 data from 10 to 30 years: The ERG noted that this approach assumes, without any supporting evidence, that longterm survivors are effectively cured of metastatic disease.
The ERG noted that the dabrafenib parametric model was used as a basis for modelling survival for the first 10 years in the dacarbazine and vemurafenib arms and was concerned that the company's assumption of proportional hazards across the 3 treatments may not be valid. The ERG indicated that the reliability of this approach was strongly affected by the assumptions about the RPSFTadjusted hazard ratio from BREAK3 used to model the dacarbazine arm.
The ERG noted that the majority of the estimated QALY gain in the company's model arises from the estimated lifeyears after disease progression (62% for the comparison with dacarbazine and 93% for the comparison with vemurafenib). It also noted that the estimated mean survival in the company's model is much larger than is normally observed in clinical trials or in registry data. The ERG explained that 2 aspects of the model contributed to these results:
the use of the RPSFTadjusted survival data from BREAK3 resulted in a large survival difference between dabrafenib and dacarbazine after 96 months
the structure of the model in 3 phases involves applying mortality rates from different sources that are not compatible, and that seriously underestimate death rates, so extending estimated survival times over many years. The ERG drew attention to the sudden changes in mortality rates at 96 months and 10 years in the company's model, which lack any clinical or epidemiological justification.These 2 features of the model serve to establish a large early survival advantage for dabrafenib at 96 months, which is then extended over 3 decades by the overoptimistic modelling of mortality.
The ERG noted that a comparison of the cost effectiveness of dabrafenib and vemurafenib depends on an indirect treatment comparison between the BREAK3 and BRIM3 trials, in order to generate progressionfree survival and overall survival hazard ratios. The ERG examined the trial results and found that the proportional hazards ratio assumption was not valid within each trial or between the dacarbazine arms of the trials. Therefore, robust hazard ratios for dabrafenib compared with dacarbazine could not be obtained. The ERG concluded that any estimated ICERs generated by this indirect comparison would be unreliable and likely to be misleading. The ERG therefore restricted any detailed numerical comparisons to the direct evidence from the BREAK3 trial for dabrafenib compared with dacarbazine.
For the comparison with dacarbazine, the ERG used alternative methods to derive the clinical effectiveness model inputs. The ERG revised the censoring of progressionfree survival data for some patients still at risk at the end of the trial to reflect the date of datacut rather than the date of last observation. It then used the area under the curve approach to model progressionfree survival in the early variable segment and an exponential projective function for the latter period. This change increased the ICER from 49,019 to 52,035 per QALY gained.
The ERG analysed the latest overall survival data from the January 2014 data and concluded that the risk of bias introduced by the choice of censoring method is small, and could only possibly affect the last few recorded events in each trial arm. Therefore the analysis was carried out without any posthoc adjustments. The ERG was aware that the latest overall survival data were unadjusted for cross over. However, it noted its earlier analysis, which showed no statistically significant survival difference between the patients in the dacarbazine group who crossed over and those who did not cross over (see section 3.21). The ERG then modelled overall survival using the area under the curve survival data until a long term trend was established and then applying the longterm exponential function throughout the rest of the trial period, that is, 1.8 years. It continued to apply the longterm exponential projection derived from BREAK3 data throughout the company's phase 2 time period, that is, up to 10 years. The ERG noted that all patients had died at the end of 10 years; therefore it restricted the modelling to 10 years rather than the 30 years assumed by the company. The ERG's analysis resulted in a considerably lower overall survival gain than the company's base case, and the resulting ICER was 99,560 per QALY gained.
The ERG made several amendments to the dacarbazine acquisition and administration cost estimates, which increased the ICER for dabrafenib compared with dacarbazine by 87 per QALY gained. The ERG applied equal costs for anticancer treatment after the study to the dabrafenib and dacarbazine groups because the difference between the poststudy treatments received in BREAK3 were not statistically significant. This amendment increased the ICER by 3047 per QALY gained for dabrafenib compared with dacarbazine. Combining all the ERG's exploratory analyses and model amendments resulted in an ICER of 112,727 per QALY gained for the comparison with dacarbazine.
Full details of all the evidence are in the committee papers.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dabrafenib, having considered evidence on the nature of unresectable or metastatic BRAF V600 mutationpositive melanoma and the value placed on the benefits of dabrafenib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered the clinical need for treatment in people with unresectable or metastatic BRAF V600 mutationpositive melanoma. The Committee heard from the patient expert that metastatic melanoma can be associated with severe and debilitating symptoms. Dabrafenib may sometimes have very rapid therapeutic effects such as improving poor performance status and slowing down the progression of high volume disease, even in those who are severely ill or bedridden. In some cases, this enables people to resume everyday tasks and activities. The patient expert also stated that people may experience very few side effects with dabrafenib. The clinical specialist explained that the sideeffect profile of dabrafenib differed from that of vemurafenib in that there were much lower rates of photosensitivity with dabrafenib, but higher rates of nonspecific fever. The Committee concluded that an alternative BRAFtargeted treatment with a manageable adverse reaction profile, such as dabrafenib, was a potentially valuable additional treatment option for people with unresectable or metastatic melanoma.
The Committee considered the clinical management of unresectable or metastatic BRAF V600 melanoma and discussed the relevant comparators for this appraisal. It was aware that in its evidence submission the company compared dabrafenib with dacarbazine and vemurafenib, and not with any other comparators specified in the scope (including temozolomide in people with brain metastases and ipilimumab in previously treated people). The Committee noted the consultees' statement, confirmed by the clinical specialist, that the management of metastatic melanoma is rapidly evolving, with several ongoing clinical trials, and there is uncertainty about how these treatments would be sequenced in future. The Committee heard from the clinical specialist that vemurafenib is the current standard of care for people with BRAF V600 mutationpositive melanoma because it is a targeted therapy. The Committee heard from the clinical specialist and noted the statements from consultees that ipilimumab, which is now available for first and secondline use, is more commonly used in a subgroup of patients with good performance status and in whom the disease is not progressing rapidly. The Committee also heard that dacarbazine is no longer routinely used as a firstline treatment in clinical practice and would now be used only further down the treatment pathway, probably as a thirdline option. The clinical specialist also stated that temozolomide is not a standard drug used in people with brain metastases and that there was no evidence that it results in a better outcome than the targeted therapies. The Committee accepted the views of the clinical specialists that in those patients being considered for dabrafenib treatment, the relevant comparator is the alternative BRAFtargeted therapy vemurafenib.

# Clinical effectiveness
The Committee considered the clinical effectiveness of dabrafenib and noted that the key clinical evidence in the company's submission came from the BREAK3 trial, which compared dabrafenib with dacarbazine. It discussed the relevance of the BREAK3 trial, given that dacarbazine is no longer considered established clinical practice in the UK. It heard from the clinical specialist that dabrafenib and vemurafenib were developed at around the same time and that dacarbazine was the standard of care when the BREAK3 trial was conducted. It also noted the comment in the company's submission that although dacarbazine is no longer widely used in this setting, results from BREAK3 allow an indirect comparison of dabrafenib with vemurafenib. The Committee concluded that the BREAK3 trial was relevant for this appraisal.
The Committee examined the results of BREAK3 presented by the company. It noted that dabrafenib reduces the risk of progression compared with dacarbazine, with a statistically significant difference of 4.2 months in median time to progression. The Committee was aware that for overall survival, the point estimate for the hazard ratio suggested that dabrafenib results in an overall survival benefit, but that the difference did not reach statistical significance. The Committee noted the high level of crossover (57%) in the trial and was aware that even after adjusting for crossover using the RPSFT method (see section 3.22) the company's estimate of overall survival gain did not reach statistical significance. The Committee was aware of the ERG's concerns about the appropriateness of the RPSFT method (see section 3.22); however, it did not think it was necessary to discuss the issue further because it considered vemurafenib to be the relevant comparator for this appraisal. The Committee noted that the relatively low numbers in the dacarbazine arm of the trial (3:1 randomisation) and the high rates of crossover made it very difficult to draw a firm conclusion about the precise effect on overall survival. The Committee concluded that compared with dacarbazine, dabrafenib significantly improved progressionfree survival and probably improved overall survival, but it was unable to draw firm conclusions about the magnitude of overall survival benefit.
The Committee went on to discuss the clinical effectiveness evidence for dabrafenib compared with vemurafenib, which is based on an indirect comparison using data from the BREAK3 and BRIM3 trials. The Committee understood the ERG's concern that the proportional hazards assumption that this analysis relied upon was not supported by the trial data. It noted the ERG's comment that lactate dehydrogenase levels differed between BREAK3 and BRIM3, which suggests that patients in BRIM3 had worse prognoses than patients in BREAK3 (see section 3.23), and that the median overall survival in the dacarbazine arm in BREAK3 was better than in BRIM3 (15.6 months compared with 9.6 months).The Committee heard from the clinical specialist that although lactate dehydrogenase level is one of many measures of disease severity used in clinical practice, it was not a marker of disease prognosis that could be relied on in isolation. The Committee noted that patients were otherwise well matched in the BREAK3 and BRIM3 trials, including for the stage of disease. The clinical specialist highlighted that BRIM3 was conducted in the UK, where there may be a more conservative approach to treatment initiation than outside the UK where BREAK3 was conducted, and that the crossover criteria differed in the 2 trials. The Committee noted the statement from consultees that 'the BREAK3 trial convincingly shows that dabrafenib is as active as vemurafenib, in terms of response rate and progressionfree and overall survival hazard ratios compared with the standard arm, dacarbazine'. The Committee also heard from the clinical specialist that the clinical effectiveness of dabrafenib and vemurafenib were not considered to differ in clinical practice and that the choice between the 2 treatments would be largely based on their adverse reaction profiles. The Committee considered that BRIM3 was a large trial and could show an overall survival benefit with vemurafenib, whereas BREAK3 was a smaller trial and it would be more difficult to demonstrate a statistically significant overall survival benefit with dabrafenib. The Committee also noted that the progressionfree survival gains in the 2 trials were very similar, and concluded that there was no clear evidence that dabrafenib and vemurafenib differed in clinical effectiveness and that it would not be unreasonable to assume that they have similar effect.
The Committee considered the adverse reactions associated with dabrafenib. It noted that pyrexia, cutaneous squamous cell carcinoma and back pain were the most commonly reported grade3 adverse reactions with dabrafenib. It heard from the clinical specialist that cutaneous squamous cell carcinoma was also an issue with vemurafenib. The clinical specialist stated that these targeted therapies are not given to people with serious medical conditions and are administered only in specialist centres with the ability to manage the skin malignancies that may occur. The Committee heard from the clinical specialist that some clinicians may prefer dabrafenib to vemurafenib because of lower rates of photosensitivity, which may be a major problem for some patients. The clinical specialist indicated that photosensitivity could also occur with dabrafenib, but in their experience the incidence was much lower than with vemurafenib. The Committee concluded that the current evidence suggests that adverse reactions from dabrafenib treatment were not a major concern when compared with those from alternative treatments and that the relative adverse reaction profile would be taken into account in discussions between patients and oncologists on the choice of the most appropriate therapy.

# Cost effectiveness
The Committee discussed the company's costeffectiveness analysis. The Committee had previously heard from the clinical specialist that dacarbazine was not an appropriate comparator and that people eligible for treatment with a BRAF inhibitor would not be given dacarbazine in clinical practice. Therefore it did not consider the cost effectiveness of dabrafenib compared with dacarbazine any further; it restricted its costeffectiveness discussion to the comparison with vemurafenib.
The Committee considered the company's economic model and the ERG's critique of the model. It noted the ERG's concerns regarding the structure of the model; in particular, the way the company modelled the clinical effectiveness estimates using a 3stage approach, resulting in survival curves that did not appear clinically plausible. The Committee also noted the ERG's concerns with the company's indirect comparison (see section 3.23) and noted that the ERG had not carried out exploratory analyses of the clinical or cost effectiveness of dabrafenib compared with vemurafenib.
The Committee considered whether dabrafenib was a costeffective use of NHS resources. It noted that the company's base case ICER was 11,000 per QALY gained for dabrafenib compared with vemurafenib, but was much lower than this if a class effect was assumed for dabrafenib and vemurafenib (see section 3.20). The Committee noted the ERG's comments on the limitations of the company's model but was aware that the ERG did not conduct exploratory analyses because of its concerns that any estimated ICERs generated from the results of the company's indirect comparison would be unreliable. In the absence of any further numerical analysis by the ERG, the Committee could not give an estimate of the most plausible ICER for the comparison of dabrafenib with vemurafenib. However, having considered the lack of evidence of difference in clinical effectiveness between the treatments, and that the overall costs were not different in the economic analysis, the Committee concluded that any difference in the cost effectiveness would be small and would fall within the range considered 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 mutationpositive melanoma.

# Summary of Appraisal Committee's key conclusions
TA321
Appraisal title: Dabrafenib for treating unresectable or metastatic BRAF V600 mutationpositive melanoma
Section
Key conclusion
Dabrafenib is recommended, within its marketing authorisation, as an option for treating unresectable or metastatic BRAF V600 mutationpositive melanoma only if the company provides dabrafenib with the discount agreed in the patient access scheme.
The Committee concluded that compared with dacarbazine, dabrafenib improved progressionfree survival and probably improved overall survival, but it was unable to draw firm conclusions about the magnitude of overall survival benefit.
The Committee concluded that it was likely that dabrafenib and vemurafenib did not differ in clinical effectiveness and that it would not be unreasonable to assume that they have similar effect.
The Committee concluded that vemurafenib was the most appropriate comparator, and therefore restricted its costeffectiveness discussions to the comparison with vemurafenib.
Having considered the lack of evidence of difference in clinical effectiveness between dabrafenib and vemurafenib, and that the overall costs were not different in the economic analysis, the Committee concluded that any difference in the cost effectiveness would be small and, would fall within the range considered to be a cost effective use of NHS resources.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from the patient expert that metastatic melanoma can be associated with severe and debilitating symptoms. It heard from the clinical specialist that vemurafenib is the current standard of care for people with BRAF V600 mutationpositive melanoma because it is a targeted therapy.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on healthrelated benefits?
The Committee heard that dabrafenib may sometimes have very rapid therapeutic effects such as improving poor performance status and slowing down the progression of high volume disease, even in those who are severely ill or bedridden, in some cases enabling them to resume everyday tasks and activities. The patient expert also stated that people may experience very few side effects with dabrafenib. The clinical specialist explained that the sideeffect profile of dabrafenib differed from that of vemurafenib in that there were much lower rates of photosensitivity with dabrafenib, but higher rates of nonspecific fever. The Committee concluded that an alternative BRAFtargeted treatment with a manageable adverse reaction profile, such as dabrafenib, was a potentially valuable additional treatment option for people with unresectable or metastatic melanoma.
What is the position of the treatment in the pathway of care for the condition?
The Committee noted the consultees' statement, confirmed by the clinical specialist, that the management of metastatic melanoma is rapidly evolving, with several ongoing clinical trials, and there is uncertainty about how these treatments would be sequenced in future. The Committee accepted the views of the clinical specialists that in those patients being considered for dabrafenib treatment, the relevant comparator is the alternative BRAF targeted therapy vemurafenib.
Adverse reactions
The Committee concluded that the current evidence suggests that adverse reactions from dabrafenib treatment were not a major concern when compared with those from alternative treatments and that the relative adverse reaction profile would be taken into account in discussions between patients and oncologists on the choice of the most appropriate therapy.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee noted that the key clinical evidence in the company's submission came from the BREAK3 trial, which compared dabrafenib with dacarbazine.
The Committee discussed the clinical effectiveness evidence for dabrafenib compared with vemurafenib; which is based on an indirect comparison using data from the BREAK3 and BRIM3 trials.
Relevance to general clinical practice in the NHS
The Committee noted that dacarbazine was the standard of care when the BREAK3 trial was conducted and that the results of the BREAK3 trial allow an indirect comparison of dabrafenib with vemurafenib. The Committee concluded that the BREAK3 trial was relevant for this appraisal.
Uncertainties generated by the evidence
The Committee noted the high level of crossover in the BREAK3 trial and was aware that even after adjusting for crossover using the rank preserving structural failure time (RPSFT) method, the company's estimate of overall survival gain did not reach statistical significance.The Committee understood the ERG's concern that the proportional hazards assumption that the indirect comparison relied upon was not supported by the trial data.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
None.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that, compared with dacarbazine, dabrafenib significantly improved progressionfree survival by 4.2 months and probably improved overall survival, but it was unable to draw firm conclusions about the magnitude of overall survival benefit.In light of the available evidence, the Committee concluded that it was likely that dabrafenib and vemurafenib did not differ in clinical effectiveness and that it would not be unreasonable to assume that they have similar effect.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee did not consider the cost effectiveness of dabrafenib compared with dacarbazine, having noted that dacarbazine was not an appropriate comparator as it was no longer used in clinical practice. It restricted its costeffectiveness discussion to the comparison with vemurafenib.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted the ERG's concerns regarding the structure of the model; in particular, the way the company modelled the clinical effectiveness estimates using a 3stage approach, resulting in survival curves that did not appear clinically plausible.The Committee also noted the ERG's concerns with the company's indirect comparison and noted that the ERG had not carried out exploratory analyses of the clinical or cost effectiveness of dabrafenib compared with vemurafenib.
Incorporation of healthrelated qualityoflife benefits and utility values
Have any potential significant and substantial healthrelated benefits been identified that were not included in the economic model, and how have they been considered?
Treatmentspecific EQ5D utility data for preprogression and postprogression, derived directly from BREAK3, were used in the model for dabrafenib and dacarbazine. In the absence of comparable EQ5D utility data for vemurafenib, the company assumed that the vemurafenib utility values would be the same as those for dabrafenib.
Are there specific groups of people for whom the technology is particularly cost effective?
Not applicable
What are the key drivers of cost effectiveness?
The company conducted a series of deterministic sensitivity analyses. For the comparison of dabrafenib with dacarbazine, overall survival was the key driver of the costeffectiveness results.The key driver of the costeffectiveness result for the comparison of dabrafenib with vemurafenib was the progressionfree survival assumption.
Most likely costeffectiveness estimate (given as an ICER)
The Committee noted that the company's base case ICER was 11,000 per QALY gained for dabrafenib compared with vemurafenib, but was much lower than this if a class effect was assumed for dabrafenib and vemurafenib. In the absence of any further numerical analysis by the ERG, the Committee could not give an estimate of the most plausible ICER for the comparison of dabrafenib with vemurafenib.
Additional factors taken into account
Patient access schemes (PPRS)
Novartis has agreed a patient access scheme with the Department of Health that makes dabrafenib available with a discount applied at the point of purchase or invoice. The size of the discount is commercial in confidence.
Endoflife considerations
Not applicable.
Equalities considerations and social value judgements
No equality issues relevant to the Committee's recommendations were raised.

# Review of guidance
The guidance on this technology will be considered for review 3 years after publication. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveOctober 2014# Changes after publication
April 2017: The company changed from GlaxoSmithKline to Novartis. Contact details for the patient access scheme updated.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS.
This guidance was developed using the NICE single technology appraisal process.
It has been incorporated into the NICE pathway on melanoma along with other related guidance and products.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.
ISBN: 978-1-4731-0805-9