pan-Canadian Oncology Drug Review Final Economic Guidance ... · interpretation, analysis, or opinion provided in a pCODR report). FUNDING ... second generation ALK inhibitors would

pan-Canadian Oncology Drug Review

Final Economic Guidance Report

Alectinib (Alecensaro) for Non-Small Cell Lung Cancer

March 29, 2018

pCODR Final Economic Guidance Report - Alectinib (Alecensaro) for Non-Small Cell Lung Cancer ii pERC Meeting: January 18, 2018; Reconsideration Meeting: March 15, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW

DISCLAIMER Not a Substitute for Professional Advice This report is primarily intended to help Canadian health systems leaders and policymakers make well-informed decisions and thereby improve the quality of health care services. While patients and others may use this report, they are made available for informational and educational purposes only. This report should not be used as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision making process, or as a substitute for professional medical advice. Liability pCODR does not assume any legal liability or responsibility for the accuracy, completeness or usefulness of any information, drugs, therapies, treatments, products, processes, or services disclosed. The information is provided "as is" and you are urged to verify it for yourself and consult with medical experts before you rely on it. You shall not hold pCODR responsible for how you use any information provided in this report. Reports generated by pCODR are composed of interpretation, analysis, and opinion on the basis of information provided by pharmaceutical manufacturers, tumour groups, and other sources. pCODR is not responsible for the use of such interpretation, analysis, and opinion. Pursuant to the foundational documents of pCODR, any findings provided by pCODR are not binding on any organizations, including funding bodies. pCODR hereby disclaims any and all liability for the use of any reports generated by pCODR (for greater certainty, "use" includes but is not limited to a decision by a funding body or other organization to follow or ignore any interpretation, analysis, or opinion provided in a pCODR report).

FUNDING The pan-Canadian Oncology Drug Review is funded collectively by the provinces and territories, with the exception of Quebec, which does not participate in pCODR at this time.

pCODR Final Economic Guidance Report - Alectinib (Alecensaro) for Non-Small Cell Lung Cancer iii pERC Meeting: January 18, 2018; Reconsideration Meeting: March 15, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW

INQUIRIES

Inquiries and correspondence about the pan-Canadian Oncology Drug Review (pCODR) should be directed to: pan-Canadian Oncology Drug Review 154 University Avenue, Suite 300 Toronto, ON M5H 3Y9 Telephone: 613-226-2553 Toll Free: 1-866-988-1444 Fax: 1-866-662-1778 Email: [email protected] Website: www.cadth.ca/pcodr

pCODR Final Economic Guidance Report - Alectinib (Alecensaro) for Non-Small Cell Lung Cancer iv pERC Meeting: January 18, 2018; Reconsideration Meeting: March 15, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW

TABLE OF CONTENTS DISCLAIMER .................................................................................................................. i

FUNDING .................................................................................................................... ii

INQUIRIES .................................................................................................................. iii

TABLE OF CONTENTS ..................................................................................................... iv

1 ECONOMIC GUIDANCE IN BRIEF ................................................................................. 1

1.1 Submitted Economic Evaluation ............................................................................ 1

1.2 Clinical Considerations ....................................................................................... 3

1.3 Submitted and EGP Reanalysis Estimates ................................................................. 5

1.4 Detailed Highlights of the EGP Reanalysis ................................................................ 7

1.5 Evaluation of Submitted Budget Impact Analysis ...................................................... 10

1.6 Conclusions ................................................................................................... 10

2 DETAILED TECHNICAL REPORT ............................................................................... 11

This section outlines the technical details of the pCODR Economic Guidance Panel’s evaluation of the economic evidence that is summarized in Section 1. Pursuant to the pCODR Disclosure of Information Guidelines, this section is not eligible for disclosure. It was provided to the pCODR Expert Review Committee (pERC) for their deliberations.

3 ABOUT THIS DOCUMENT ....................................................................................... 12

REFERENCES .............................................................................................................. 13

pCODR Final Economic Guidance Report - Alectinib (Alecensaro) for Non-Small Cell Lung Cancer 4 pERC Meeting: January 18, 2018; Reconsideration Meeting: March 15, 2018 © 2018 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW

metastases. The economic model does incorporate the impact of progression free survival on both costs and QALYS. The toxicity profile is addressed through the costs of adverse events for each comparator and the utility values applied to each comparator treatment.

Alectinib was found to be a bit more tolerable as ceritinib appears to cause more frequent transaminitis, QT prolongation, hyperglycaemia, increased amylase/lipase, and diarrhea. Tolerability of alectinib is partially addressed as tolerability would likely impact the time to off-treatment, progression free survival and overall survival which all impact the economic results.

Clinician input suggested that alectinib may be used for ALK+ treatment naïve NSCLC, patients who have progressed on crizotinib, or those who failed both crizotinib and ceritinib; where multiple second generation ALK inhibitors would provide the maximum number of treatment lines for patients who acquire treatment resistance. This issue is not addressed in the economic evaluation.

Summary of patient input relevant to the economic analysis

Patients considered the following factors important in the review of alectinib:

Reducing the size of tumours. This issue is not directly addressed in the economic evaluation. Though it may be indirectly addressed as the evaluation takes into account the longer overall survival and progression free survival which may be linked to the reduction of tumour size.

Delay or avoid permanent cognitive damage from whole brain radiation (to treat brain metastases). The cost impact of treatment of CNS metastases is addressed in a sensitivity analysis in the economic evaluation.

Improvement in survival, quality of life, more manageable side effects and relief of lung cancer symptoms. Favourable effects of alectinib on survival and quality of life were addressed in the economic model by applying utility score and measuring outcomes in QALYs.

Reduction in productivity loss for patients and their caregivers due to the oral administration of alectinib. This is not considered in the economic analysis as the analysis adopted the perspective of the publicly funded health care system.

Summary of Provincial Advisory Group (PAG) input relevant to the economic analysis PAG considered the following factors (enablers or barriers) important to consider if implementing a funding recommendation for alectinib which are relevant to the economic analysis: o PAG had concerns about the additional costs to treat and manage adverse events. The costs

of treating adverse events are included in the economic evaluation. o PAG stated concerns that an enabler of implementation of alectinib was that dose

adjustment is accomplished by adjusting the number of capsules taken and that alectinib is available only in one capsule strength. This issue is not addressed in the economic analysis.

o PAG sought clarity on the definition of “until loss of clinical benefit”, treatment duration,

and treatment discontinuation. The economic analysis does address these issues in terms of their impact on the cost of alectinib treatment. The duration of treatment of alectinib is based on statistical modeling of the time to off treatment data observed in the ALUR trial. In the ALUR trial, patients were to remain on treatment until “loss of clinical benefit”.


1.5 Evaluation of Submitted Budget Impact Analysis

The overall approach of the BIA appears to be reasonable and appropriate. The factors that most influence the BIA are the estimated number of patients eligible for alectinib in the next three years, the assumed proportion of eligible patients that would be prescribed alectinib if it was reimbursed and

the cost of alectinib and alternative treatments. A key limitation of the BIA is that it did not include the costs of administering alectinib and alternative treatments (ceritinib, chemotherapy). The BIA was taken from an Ontario third party payer perspective. It should be noted that in Ontario, oral anti-cancer medications may not be reimbursed for patients under the age of 65. This is not necessarily the case in other provinces. In the ALUR trial the median age of patients was 57 years. Furthermore, 83% of patients in the ALUR trial were under 65 years old.

1.6 Conclusions

The EGP’s best estimate of C and E for alectinib when compared to chemotherapy is:

Between $87,357/QALY and $159,544/QALY

The extra cost of alectinib is between $120,560 and $152,170. Incremental costs were most impacted by drug acquisition costs.

The extra clinical effect of alectinib is between 0.95 to 1.38 QALYs. Incremental QALYs were most impacted by overall survival estimates and time horizon.

The EGP’s best estimate of C and E for alectinib when compared to ceritinib is:

Between $36,935/QALY and $224,235/QALY

The extra cost of alectinib is between $120,560 and $152,170. Incremental costs were most impacted by drug acquisition costs.

The extra clinical effect of alectinib is between 0.20 to 0.77 QALYs. Incremental QALYs were most impacted by overall survival estimates and time horizon.

When choosing between alectinib, chemotherapy and ceritinib (sequential analysis) the cost per QALY of alectinib ranges from $87,537 to $224,235.

Overall conclusions of the submitted model:

The overall structure and much of the data used for parameter inputs the economic model were appropriate. However there is considerable uncertainty around the estimates of overall survival for alectinib and its comparators. No direct comparative evidence was used to estimate survival for alectinib, chemotherapy and ceritinib. In the ALUR trial, OS data was immature at the time of the primary analysis and there was heavy cross-over. Therefore, alectinib data from single arm phase 2 studies were used to estimate overall survival (pooled analysis), an observational study was used to estimate and project overall survival for chemotherapy, and a network meta-analysis was used to estimate the relative OS for ceritinib compared to alectinib. Furthermore no direct comparative evidence was available for the PFS, utility, TTOT or adverse event data used for ceritinib in the model.


2 DETAILED TECHNICAL REPORT This section outlines the technical details of the pCODR Economic Guidance Panel’s evaluation of the

economic evidence that is summarized in Section 1. Pursuant to the pCODR Disclosure of Information

Guidelines, this section is not eligible for disclosure. It was provided to the pCODR Expert Review

Committee (pERC) for their deliberations.


3 ABOUT THIS DOCUMENT

pCODR considers it essential that pERC recommendations be based on information that can be publicly disclosed. Information included in the Economic Guidance Report was handled in accordance with the pCODR Disclosure of Information Guidelines. There was no information redacted from this publicly available Guidance Report.

pCODR considers it essential that pERC recommendations be based on information that can be publicly disclosed. Information included in the Economic Guidance Report was handled in accordance with the pCODR Disclosure of Information Guidelines. There was no non-disclosable information in the Economic Guidance Report provided to pERC for their deliberations.

This Final Economic Guidance Report is publicly posted at the same time that a pERC Final Recommendation is issued. The Final Economic Guidance Report supersedes the Initial Economic Guidance Report.

The Economic Guidance Panel is comprised of economists selected from a pool of panel members established by the pCODR Secretariat. The panel members were selected by the pCODR secretariat, as outlined in the pCODR Nomination/Application Information Package and the Economic Guidance Panel Terms of Reference, which are available on the pCODR website (www.cadth.ca/pcodr). Final selection of the pool of Economic Guidance Panel members was made by the pERC Chair in consultation with the pCODR Executive Director. The Economic Guidance Panel is editorially independent of the provincial and territorial Ministries of Health and the provincial cancer agencies.


REFERENCES

1. Novello S, Maziäres JOIJ, de Castro J, Migliorino MR, Helland A, et al. Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK+ non-small-cell lung cancer (NSCLC). Slide deck presented at: ESMO Congress; 2017 September 8-12; Madrid Spain.

2. pan-Canadian Oncology Drug Review manufacturer submission: AlecensaroT (alectinib),

150 mg capsules. Company: Hoffmann-La Roche Limited. Mississauga (ON): Hoffmann-La Roche Limited; 2017.

3. Ou SH, Ahn JS, De PL, Govindan R, Yang JC, Hughes B, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol. 2016;34(7):661-8.

4. Chih-Hsin Yang J, Ou S-H, De Petris L, Gadgeel S, Gandhi L, Kim D-W, et al. P3.02a-016 547 Pooled Efficacy and Safety Data from Two Phase II Studies (NP28673 and NP28761) of Alectinib in 548 ALK+ Non-Small-Cell Lung Cancer (NSCLC). Journal of Thoracic Oncology. 2016;12(1):S1170-S1.

5. Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncology. 2016;17(2):234-42.

6. Shaw AT, Kim TM, Crino L, Gridelli C, Kiura K, Liu G, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(7):874-86.

7. Ou S-H, Jänne P, Bartlett C, Tang Y, Kim D-W, Otterson GA, et al. Clinical benefit of continuing 550 ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-551 positive NSCLC. Annals of oncology. 2014;25(2):415-22.

8. Davies J, Martinec M, Martina R, Delmar P, Coudert M, Bordogna W, et al. Retrospective indirect comparison of alectinib phase II data vs. certitinib real-world data in ALK+ NSCLC after progression on crizotinib (poster #379). Poster presented at: European Lung Cancer Conference (ELCC); 2017 May 5-8; Geneva, Switzerland.

9. Davies J, Crane G, Martinec M. Comparative effectiveness in ALK-positive non-small cell lung 553 cancer patients following progression with crizotinib: a comparison of alectinib phase II data versus 554 ceritinib real-world data. Data on file. TBD. 2017.

10. Labbé C, Leung Y, Lemes JGS, Stewart E, Brown C, Cosio AP, et al. Real-World EQ5D Health 556 Utility Scores for Patients With Metastatic Lung Cancer by Molecular Alteration and Response to 557 Therapy. Clinical lung cancer. 2017;18(4):388-95. e4

11. MacGilchrist K, Orme M. Anaplastic lymphoma kinase-positive ad-vanced/metastatic Non-543 Small Cell Lung Cancer: Chemotherapy & crizotinib experienced treatment population.


Direct Meta-544 Analysis, Bucher Indirect Comparisons and Network Meta-Analysis Report. Data on file. Basel: 545 Hoffmann-La Roche Limited; 2017

12. NICE Terminates Appraisal for Alectinib in Previously Treated ALK-positive Advanced NSCLC. April 2017. Available from: http://esmo.org/Oncology-News/NICE-Terminates-Appraisal-for-Alectinib-in-Previously-Treated-ALK-positive-Advanced-NSCLC

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pan-Canadian Oncology Drug Review Final Economic Guidance ... · interpretation, analysis, or opinion provided in a pCODR report). FUNDING ... second generation ALK inhibitors would