News
NICE guidance on axitinib for treating advanced renal cell carcinoma after failure of prior systemic treatment On Feb 25, 2015, the National Institute for Health and Care Excellence (NICE) published guidance recommending axitinib as an option for treating adults with renal cell carcinoma after failure of treatment with a first-line tyrosine kinase inhibitor (TKI) or a cytokine, as long as the manufacturer provides axitinib with the discount agreed in the patient access scheme.1 Axitinib was appraised under the Single Technology Appraisal process. Pfizer (Surrey, UK), the manufacturer of axitinib, submitted clinical evidence and a health economic model2 that was critiqued by an independent evidence review group (Kleijnen Systematic Reviews, York, UK).3 An independent appraisal committee met five times to consider the evidence and to develop the final guidance on axitinib, with clinical experts, patient experts, and company representatives present at the meetings. An appeal took place after the second meeting.4 Three key issues arose in this appraisal process: first, the decline in the use of cytokines following the emergence of targeted therapies (ie, sunitinib and pazopanib), meaning that best supportive care (BSC) was no longer an appropriate comparator; second, the marketing authorisation confining axitinib’s second-line use to after sunitinib when pazopanib is often the treatment of choice; and third, the modelling of axitinib benefit in patients previously treated with sunitinib population in which a high proportion of the gain related to the period after treatment discontinuation. The key clinical evidence came from the AXIS trial5 in which axitinib was compared with sorafenib for treating advanced renal cell carcinoma after failure of first-line systemic therapy. The appraisal was based on the subgroups of patients who were previously treated with sunitinib (54%) or a cytokine (35%), in line www.thelancet.com/oncology Vol 16 April 2015
with the marketing authorisation for axitinib. The results for both subgroups showed that median progression-free survival (PFS) improved with axitinib, whereas no difference was noted in overall survival between axitinib and sorafenib. Because the initial scope for this appraisal specified BSC as the comparator for axitinib, the company presented an indirect comparison of axitinib with BSC using data from the AXIS trial and TARGET trial (sorafenib compared with placebo) 6 for the population previously treated with a cytokine. The results of the indirect comparison found improvements in PFS (HR 0·25, 95% credible interval [CrI] 0·17–0·38) and overall survival (0·63, 0·41–0·99) with axitinib compared with BSC. The Committee, however, considered that the appropriate comparison for this population should be sunitinib or pazopanib, and following the appeal, the scope was updated to include these comparators. Based on the available evidence from AXIS and single-arm trials of sunitinib (RTKC 0511 0147 and A6181006/ NCT00077974 8), the company did naive comparisons of survival data for axitinib and sunitinib. The results showed that axitinib increased PFS by 3·3 months and overall survival by 5·5 months compared with sunitinib. For the comparison with pazopanib, it did an indirect comparison for PFS using data from AXIS, TARGET, and the VEG1051929 trial (pazopanib compared with placebo), and a naive comparison for overall survival as a result of crossover in the VEG105192 trial. The PFS comparison favoured axitinib (HR 0·47, 95% CrI 0·26–0·85) and the naive comparison suggested that axitinib increased overall survival by 6·7 months compared with pazopanib. In the absence of available evidence to provide a direct link between axitinib and BSC in patients previously treated
with sunitinib, the company presented a simulated treatment comparison (STC) to create an adjusted indirect comparison between the AXIS and RECORD-110 trials (everolimus compared with BSC). The STC analysis showed improvements in PFS (5·8 months for axitinib and 1·7 months for BSC) and overall survival (15·2 months for axitinib and 8·3 months for BSC); hazard ratios were not reported. The company submitted an economic model comparing axitinib with BSC in patients previously treated with a cytokine or those treated with sunitinib. The model consisted of a progression-free, progressed disease, and death state, with a lifetime horizon of 15 years consisting of 4 weekly cycles and a half-cycle correction. Utility values were derived directly from the AXIS trial using the EuroQol-5D (EQ-5D) questionnaire. The company and the UK Department of Health agreed a confidential patient access scheme discount to be applied to the list price of axitinib. The incremental cost-effectiveness ratios (ICERs) for the group previously treated with a cytokine was £55 300 and for those previously treated with sunitinib was £33 500 per quality-adjusted life-year (QALY) gained compared with BSC. The company also estimated an ICER of £52 900 per QALY gained for the population previously treated with sunitinib using the assumption of no QALY or survival gain after progression. For the comparison with sunitinib and pazopanib in the population previously treated with a cytokine, the company performed a naive economic analysis showing that BSC was more effective and less costly than were sunitinib and pazopanib as a result of a lower cost and higher median overall survival of 24 months with BSC. The review by the evidence review group raised concerns about the reliability of the overall survival indirect
Published Online February 25, 2015 http://dx.doi.org/10.1016/ S1470-2045(14)70484-X
367
News
comparison analysis because of crossover, and no clear evidence showed that any treatment for the group previously treated with a cytokine was superior. It also questioned the robustness and reliability of the STC method because it involved major assumptions, such as the comparability of patients between the trials and that the results of one trial would apply in the setting of the other. For the group previously treated with a cytokine, the Committee considered that the median survival of 24 months estimated from the indirect comparison for the BSC arm was implausible and that the true median survival was closer to the lower 95% CI of 17·46 months, with an ICER of £36 500 per QALY gained. Based on the comparable clinical-effectiveness evidence in patients previously treated with a cytokine and the differences in National Health Service costs, the Committee concluded that axitinib, sunitinib, and pazopanib could have comparable cost effectiveness. For the group previously treated with sunitinib, the Committee considered that the use of the STC method was uncertain and that the model results showed that an implausibly high proportion of the total QALY gains with axitinib occurred after disease progression when active treatment with axitinib had stopped. It considered the plausibility of a post-progression survival gain in the context of a PFS and overall survival relationship. It examined the evidence from Grunwald and colleagues,11 which suggests a plausible post-progression benefit with active targeted therapies because of tumour shrinkage, and concluded that this relationship was likely to lie midway between the company’s estimate of 1:1·6 (ratio of PFS to overall survival; ICER of £33 500 per QALY gained) and the evidence review group’s estimate of 1:1 (£52 900 per QALY gained). The Committee considered the ICERs in the context of NICE’s supplementary advice on appraising life-extending, 368
end-of-life treatments12 and concluded that axitinib met these criteria in the group previously treated with sunitinib and only for the BSC comparison of the group previously treated with a cytokine. It did not accept that axitinib was superior to sunitinib and pazopanib in patients previously treated with a cytokine, and therefore did not accept that the end-of-life criteria had been met for these comparisons, but it was aware that axitinib, sunitinib, and pazopanib are used interchangeably in clinical practice. The Committee concluded that it was comparable with the alternative treatments recommended by NICE that meet the end-of-life criteria, and that only a very small population is now included in the group previously treated with a cytokine and more uncertainty could be accepted. It therefore concluded that an ICER compared with best supportive care above but close to the upper limit of the normal range was acceptable for the group previously treated with a cytokine. The Committee was aware that the marketing authorisation of axitinib (and the remit referred to NICE by the Department of Health for this technology appraisal) specified sunitinib or a cytokine as prior treatments and not pazopanib. However, it did not consider it reasonable to limit its recommendation to people whose prior-TKI was sunitinib, because of the growing, if not majority use, of pazopanib as a first-line treatment. Such a restriction would leave an unmet need and would not reflect clinical practice. Therefore the Committee recommended axitinib after failure of a first-line TKI or a cytokine. However, the use of axitinib after treatment with TKI other than sunitinib is not subject to statutory funding.
*Nwamaka Umeweni, Boglarka Mikudina, Frances Sutcliffe, Andrew Stevens
The authors declare no competing interests. 1
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NICE. Axitinib for treating advanced renal cell carcinoma, 2015. http://www.nice.org.uk/ guidance/TA333 (accessed Feb 25, 2015). Pfizer. Axitinib for the treatment of advanced renal cell carcinoma after failure of prior systemic treatment, 2012. http://www.nice. org.uk/guidance/ta333/documents/renal-cellcarcinoma-advanced-axitinib-manufacturersubmission-pfizer2 (accessed Feb 9, 2015). Riemsma R, Al M, Corro Ramos I, et al. Axitinib for the treatment of advanced renal cell carcinoma after failure of prior systematic treatment: a Single Technology Appraisal. York: Kleijnen Systematic Reviews Ltd, 2012. http://www.nice.org.uk/guidance/ta333/ documents/renal-cell-carcinoma-advancedaxitinib-evidence-review-group-report2 (accessed Feb 9, 2015). NICE. Appeal hearing. Advice on the Single Technology Appraisal of Renal cell carcinoma for locally advanced and/or metastatic (2nd line)—axitinib, 2013. http://www.nice.org.uk/ guidance/ta333/documents/renal-cellcarcinoma-advanced-axitinib-appealdecision2 (accessed Feb 9, 2015). Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378: 1931–39. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009; 27: 3312–18. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 16–24. Motzer RJ, Michaelson MD, Rosenberg J, et al. Sunitinib efficacy against advanced renal cell carcinoma. J Urol 2007; 178: 1883–87. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010; 28: 1061–68. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010; 116: 4256–65. Grunwald V, Lin X, Kalanovic D, et al. Tumor response is an independent prognostic factor in patients (pts) treated for metastatic renal cell carcinoma (mRCC). European Cancer Congress; Amsterdam, Netherlands; Sept 27–Oct 1, 2013: abstr 2702. NICE. The appraisal of the evidence and structured decision-making: guide to the methods of technology appraisal 2013. http://publications.nice.org.uk/guide-to-themethods-of-technology-appraisal-2013pmg9 (accessed Feb 9, 2015).
National Institute for Health and Care Excellence, Level 1A City Tower, Piccadilly Plaza, Manchester M1 4BT, UK [email protected] www.thelancet.com/oncology Vol 16 April 2015
NICE guidance on axitinib for treating advanced renal cell carcinoma after failure of prior systemic treatment On Feb 25, 2015, the National Institute for Health and Care Excellence (NICE) published guidance recommending axitinib as an option for treating adults with renal cell carcinoma after failure of treatment with a first-line tyrosine kinase inhibitor (TKI) or a cytokine, as long as the manufacturer provides axitinib with the discount agreed in the patient access scheme.1 Axitinib was appraised under the Single Technology Appraisal process. Pfizer (Surrey, UK), the manufacturer of axitinib, submitted clinical evidence and a health economic model2 that was critiqued by an independent evidence review group (Kleijnen Systematic Reviews, York, UK).3 An independent appraisal committee met five times to consider the evidence and to develop the final guidance on axitinib, with clinical experts, patient experts, and company representatives present at the meetings. An appeal took place after the second meeting.4 Three key issues arose in this appraisal process: first, the decline in the use of cytokines following the emergence of targeted therapies (ie, sunitinib and pazopanib), meaning that best supportive care (BSC) was no longer an appropriate comparator; second, the marketing authorisation confining axitinib’s second-line use to after sunitinib when pazopanib is often the treatment of choice; and third, the modelling of axitinib benefit in patients previously treated with sunitinib population in which a high proportion of the gain related to the period after treatment discontinuation. The key clinical evidence came from the AXIS trial5 in which axitinib was compared with sorafenib for treating advanced renal cell carcinoma after failure of first-line systemic therapy. The appraisal was based on the subgroups of patients who were previously treated with sunitinib (54%) or a cytokine (35%), in line www.thelancet.com/oncology Vol 16 April 2015
with the marketing authorisation for axitinib. The results for both subgroups showed that median progression-free survival (PFS) improved with axitinib, whereas no difference was noted in overall survival between axitinib and sorafenib. Because the initial scope for this appraisal specified BSC as the comparator for axitinib, the company presented an indirect comparison of axitinib with BSC using data from the AXIS trial and TARGET trial (sorafenib compared with placebo) 6 for the population previously treated with a cytokine. The results of the indirect comparison found improvements in PFS (HR 0·25, 95% credible interval [CrI] 0·17–0·38) and overall survival (0·63, 0·41–0·99) with axitinib compared with BSC. The Committee, however, considered that the appropriate comparison for this population should be sunitinib or pazopanib, and following the appeal, the scope was updated to include these comparators. Based on the available evidence from AXIS and single-arm trials of sunitinib (RTKC 0511 0147 and A6181006/ NCT00077974 8), the company did naive comparisons of survival data for axitinib and sunitinib. The results showed that axitinib increased PFS by 3·3 months and overall survival by 5·5 months compared with sunitinib. For the comparison with pazopanib, it did an indirect comparison for PFS using data from AXIS, TARGET, and the VEG1051929 trial (pazopanib compared with placebo), and a naive comparison for overall survival as a result of crossover in the VEG105192 trial. The PFS comparison favoured axitinib (HR 0·47, 95% CrI 0·26–0·85) and the naive comparison suggested that axitinib increased overall survival by 6·7 months compared with pazopanib. In the absence of available evidence to provide a direct link between axitinib and BSC in patients previously treated
with sunitinib, the company presented a simulated treatment comparison (STC) to create an adjusted indirect comparison between the AXIS and RECORD-110 trials (everolimus compared with BSC). The STC analysis showed improvements in PFS (5·8 months for axitinib and 1·7 months for BSC) and overall survival (15·2 months for axitinib and 8·3 months for BSC); hazard ratios were not reported. The company submitted an economic model comparing axitinib with BSC in patients previously treated with a cytokine or those treated with sunitinib. The model consisted of a progression-free, progressed disease, and death state, with a lifetime horizon of 15 years consisting of 4 weekly cycles and a half-cycle correction. Utility values were derived directly from the AXIS trial using the EuroQol-5D (EQ-5D) questionnaire. The company and the UK Department of Health agreed a confidential patient access scheme discount to be applied to the list price of axitinib. The incremental cost-effectiveness ratios (ICERs) for the group previously treated with a cytokine was £55 300 and for those previously treated with sunitinib was £33 500 per quality-adjusted life-year (QALY) gained compared with BSC. The company also estimated an ICER of £52 900 per QALY gained for the population previously treated with sunitinib using the assumption of no QALY or survival gain after progression. For the comparison with sunitinib and pazopanib in the population previously treated with a cytokine, the company performed a naive economic analysis showing that BSC was more effective and less costly than were sunitinib and pazopanib as a result of a lower cost and higher median overall survival of 24 months with BSC. The review by the evidence review group raised concerns about the reliability of the overall survival indirect
Published Online February 25, 2015 http://dx.doi.org/10.1016/ S1470-2045(14)70484-X
367
News
comparison analysis because of crossover, and no clear evidence showed that any treatment for the group previously treated with a cytokine was superior. It also questioned the robustness and reliability of the STC method because it involved major assumptions, such as the comparability of patients between the trials and that the results of one trial would apply in the setting of the other. For the group previously treated with a cytokine, the Committee considered that the median survival of 24 months estimated from the indirect comparison for the BSC arm was implausible and that the true median survival was closer to the lower 95% CI of 17·46 months, with an ICER of £36 500 per QALY gained. Based on the comparable clinical-effectiveness evidence in patients previously treated with a cytokine and the differences in National Health Service costs, the Committee concluded that axitinib, sunitinib, and pazopanib could have comparable cost effectiveness. For the group previously treated with sunitinib, the Committee considered that the use of the STC method was uncertain and that the model results showed that an implausibly high proportion of the total QALY gains with axitinib occurred after disease progression when active treatment with axitinib had stopped. It considered the plausibility of a post-progression survival gain in the context of a PFS and overall survival relationship. It examined the evidence from Grunwald and colleagues,11 which suggests a plausible post-progression benefit with active targeted therapies because of tumour shrinkage, and concluded that this relationship was likely to lie midway between the company’s estimate of 1:1·6 (ratio of PFS to overall survival; ICER of £33 500 per QALY gained) and the evidence review group’s estimate of 1:1 (£52 900 per QALY gained). The Committee considered the ICERs in the context of NICE’s supplementary advice on appraising life-extending, 368
end-of-life treatments12 and concluded that axitinib met these criteria in the group previously treated with sunitinib and only for the BSC comparison of the group previously treated with a cytokine. It did not accept that axitinib was superior to sunitinib and pazopanib in patients previously treated with a cytokine, and therefore did not accept that the end-of-life criteria had been met for these comparisons, but it was aware that axitinib, sunitinib, and pazopanib are used interchangeably in clinical practice. The Committee concluded that it was comparable with the alternative treatments recommended by NICE that meet the end-of-life criteria, and that only a very small population is now included in the group previously treated with a cytokine and more uncertainty could be accepted. It therefore concluded that an ICER compared with best supportive care above but close to the upper limit of the normal range was acceptable for the group previously treated with a cytokine. The Committee was aware that the marketing authorisation of axitinib (and the remit referred to NICE by the Department of Health for this technology appraisal) specified sunitinib or a cytokine as prior treatments and not pazopanib. However, it did not consider it reasonable to limit its recommendation to people whose prior-TKI was sunitinib, because of the growing, if not majority use, of pazopanib as a first-line treatment. Such a restriction would leave an unmet need and would not reflect clinical practice. Therefore the Committee recommended axitinib after failure of a first-line TKI or a cytokine. However, the use of axitinib after treatment with TKI other than sunitinib is not subject to statutory funding.
*Nwamaka Umeweni, Boglarka Mikudina, Frances Sutcliffe, Andrew Stevens
The authors declare no competing interests. 1
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6
7
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NICE. Axitinib for treating advanced renal cell carcinoma, 2015. http://www.nice.org.uk/ guidance/TA333 (accessed Feb 25, 2015). Pfizer. Axitinib for the treatment of advanced renal cell carcinoma after failure of prior systemic treatment, 2012. http://www.nice. org.uk/guidance/ta333/documents/renal-cellcarcinoma-advanced-axitinib-manufacturersubmission-pfizer2 (accessed Feb 9, 2015). Riemsma R, Al M, Corro Ramos I, et al. Axitinib for the treatment of advanced renal cell carcinoma after failure of prior systematic treatment: a Single Technology Appraisal. York: Kleijnen Systematic Reviews Ltd, 2012. http://www.nice.org.uk/guidance/ta333/ documents/renal-cell-carcinoma-advancedaxitinib-evidence-review-group-report2 (accessed Feb 9, 2015). NICE. Appeal hearing. Advice on the Single Technology Appraisal of Renal cell carcinoma for locally advanced and/or metastatic (2nd line)—axitinib, 2013. http://www.nice.org.uk/ guidance/ta333/documents/renal-cellcarcinoma-advanced-axitinib-appealdecision2 (accessed Feb 9, 2015). Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378: 1931–39. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009; 27: 3312–18. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 16–24. Motzer RJ, Michaelson MD, Rosenberg J, et al. Sunitinib efficacy against advanced renal cell carcinoma. J Urol 2007; 178: 1883–87. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010; 28: 1061–68. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010; 116: 4256–65. Grunwald V, Lin X, Kalanovic D, et al. Tumor response is an independent prognostic factor in patients (pts) treated for metastatic renal cell carcinoma (mRCC). European Cancer Congress; Amsterdam, Netherlands; Sept 27–Oct 1, 2013: abstr 2702. NICE. The appraisal of the evidence and structured decision-making: guide to the methods of technology appraisal 2013. http://publications.nice.org.uk/guide-to-themethods-of-technology-appraisal-2013pmg9 (accessed Feb 9, 2015).
National Institute for Health and Care Excellence, Level 1A City Tower, Piccadilly Plaza, Manchester M1 4BT, UK [email protected] www.thelancet.com/oncology Vol 16 April 2015
