DECISION AND SUMMARY OF RATIONALE

Transcription

1 DECISION AND SUMMARY OF RATIONALE Indication under consideration Clinical evidence Crizotinib as 2nd line treatment for patients with anaplastic lymphoma kinase (ALK) positive lung cancer Score The application was for single agent crizotinib to remain in the CDF as 2nd line treatment for patients with locally advanced or metastatic ALK positive non-small cell lung cancer (NSCLC) who had received one prior treatment with platinum-based combination chemotherapy. The CDF panel was aware that this indication for crizotinib has been appraised but not recommended by NICE. PFS = 3 OS = 3 QoL= 2 Tox = 1 Unmet need = 0 There was one randomised trial (the PROFILE study) submitted by the manufacturer as the evidence base related to this indication. This randomised 347 patients with locally advanced or metastatic NSCLC previously treated with a platinum-based combination chemotherapy to crizotiniib or chemotherapy with either pemetrexed (57%) or docetaxel (41%). The primary end point was independently-assessed progression free survival (PFS). Cross over was allowed and occurred in 87% of the patients who were randomised to chemotherapy. Patients could continue on crizotinib beyond disease progression at the discretion of the investigator. PFS was significantly better with crizotinib than chemotherapy (7.7 vs 3.0, 4.7 mo, hazard ratio 0.49, 95% confidence interval , p<0.001) and overall survival (OS) was not significantly different (20.3 vs 22.8 mo), respectively. In considering toxicity, the CDF panel noted that patients were on crizotinib much longer than those randomised to chemotherapy (medians of 31 vs 12 weeks, respectively). Overall, the incidence of grade 3 and 4 treatment-related adverse events was similar in both arms (33% vs 32%, respectively), as was the incidence of of treatmentrelated serious adverse events (12% vs 14%, respectively). Grade 3 and 4 non-laboratory toxicities were similar in both arms. In terms of all grade toxicities, crizotinib was associated with more visual disturbances, diarrhoea, constipation, nausea, vomiting, oedema, taste change but less fatigue, rashes and alopecia. The panel again noted that patients were on crizotinib for a much longer duration than chemotherapy and this may have contributed significantly to the apparently increased all grade toxicities. The panel noted that the only worsening symptoms/side-effects as treatment continued were diarrhoea and constipation. Despite the similar number of adverse events and the differing toxicities observed between the crizotinib and chemotherapy arms, the CDF panel concluded that the toxicity profile of crizotinib was more favourable in view of the much greater treatment duration. Quality of life was assessed in the trial using the EORTC QLQ-C30 questionnaire and lung cancer scale. A clinically meaningful improvement in global QOL was statistically significantly shown in the crizotinib arm (p<0.001).

2 The median duration of treatment in the crizotinib arm was 31 weeks (7.2 mo) in terms of treatment time until evidence of radiological progression. The panel noted that in the NICE guidance on crizotinib paragraph 4.5 had referenced information that 53% of patients in the PROFILE crizotinib studies received crizotinib after disease progression for a median of 10 weeks (range 2-84 weeks). The CDF panel noted that a just over a half of these patients had thus received crizotinib for a median of 2.3 mo. The manufacturer informed the CDF panel that it had not been able to ascertain any reliable retrospective data as to the outcomes of patients with ALK positive NSCLC treated with 2nd line chemotherapy alone. The manufacturer used the Inverse Probability of Treatment and Censoring Weighted (IPTCW) to adjust for cross over in the crizotinib trial and this resulted in an OS gain of 12.3 mo (20.3 vs 8.0 mo). The panel was aware of the uncertainty inherent in methods for adjusting for crossover and noted too that the Scottish Medicines Consortium had considered that another method (the Rank Preserving Structural Failure Time approach) might have been more realistic; such an analysis had not yielded a significant difference in OS between crizotinib and BSC. The panel noted too that NICE had concluded that this same variant of the IPTCW chosen by the manufacturer (5 different variants of the IPTCW method had been submitted to NICE) produced an overly optimistic OS benefit with crizotinib. NICE chose another variant of the IPTCW method as its preferred way of adjusting for crossover, neither accepting the RPSFT approach nor the manufacturer s preferred variant of the IPTCW method. In consideration of all these issues, the CDF panel concluded that the gain in OS with crizotinib was thus very uncertain and an exact value could not be reliably established form the submitted data. The panel was struck by the PFS gain in a disease such as non small cell lung cancer as well as the very high response rate of 65% observed with crizotinib administered as a 2nd line therapy. The panel thus recognised that there would be a survival benefit with crizotinib and noted that NICE had come to the same conclusion. It was aware that the relationship between PFS and OS in any cancer was a complex one. It considered that for the purposes of the scoring tool that the OS gain for crizotinib should be scored as if the PFS gain equalled the OS gain. The panel noted that the median duration of treatment to disease progression was 31 weeks (7.2 months) and the above figure of an additional 2.3 mo. It debated as to which duration of treatment to use in assessing the median drug cost. It concluded that clinicians were likely to follow the practice in the clinical trial which had allowed use of crizotinib after disease progression and also considered it likely that crizotinib would be continued until there was a symptomatic change. The CDF panel noted that NICE had come to a similar conclusion. The panel therefore used the total duration of treatment in its measurement of the crizotinib treatment cost and thus considered that the current best estimate of likely median treatment duration in practice in England is 9.5 mo ( mo).

3 The CDF panel considered whether crizotinib fulfilled the CDF criteria for the scoring of unmet need. It recognised that there were other systemic therapies available in ALK positive non small cell lung cancer and crizotinib had been compared with one of these options. It also did not regard the benefits of crizotinib in this indication to be a step change in the management of ALK positive non small cell lung cancer when considering the absence of proven survival benefit in the trial and the absence of any differential tail in the PFS curve over time. The CDF panel thus declined to award crizotinib a positive score for unmet need. The CDF panel was also aware of all the background papers, including the manufacturer s submission to NICE, submitted for consideration to the CDF. The panel knew of the continued requests to the CDF for the use of crizotinib in ALK positive NSCLC and regarded this as evidence of clinical support. The CDF panel understood that its decision making could affect the opportunity for patients and clinicians in England to participate in international trials of the systemic therapy of ALK positive NSCLC. The panel s scores for crizotinib for the treatment of patients with ALK positive NSCLC who have previously received platinum-based chemotherapy for locally advanced or metastatic NS NSCLC were as follows: - 3 for PFS (7.7 vs 3.0 mo, 4.7 mo) - 3 for OS (see above considerations) - 2 for QOL - 1 for toxicity - 0 for unmet need - and this resulted in a total of 9B. Cost Conclusion CDF criteria for use Total clinical score 9B The cost of crizotinib per 4-week cycle at the list price (including VAT) is The median drug cost of crizotiinib resulted in this indication scoring a value within the confidential CDF cost scoring system which when combined with the clinical score of 9 resulted in an overall score which represented sufficient value for retention within the CDF as 2nd line treatment of locally advanced or metastatic ALK positive NSCLC for progressive disease following a 1st line platinum-based combination. As per current criteria

4 Key for strength of evidence: Criteria Two or more good quality Phase III Randomised Controlled Trials, both published One good quality Phase III Randomised Controlled Trial, published Comparative Phase II trial, published Non-Comparative Phase II, published Unpublished data (in abstract form only) 1 Unpublished data (in abstract form only) 2 Grade A B C D U1 U2

5 NATIONAL CANCER DRUG FUND PRIORITISATION SCORES Drug Indication Regimen (where appropriate) Crizotinib 2nd line treatment for patients with anaplastic lymphoma kinase (ALK) positive lung cancer As above 1 Magnitude of Survival Benefit (progression free survival and overall survival) Additional incremental benefit over comparator treatment in pivotal Phase III trial. Abstracts will be accepted if they are updates of published and peer-reviewed papers Phase II data allowable only for: rare cancers or rare subgroups, e.g. of common cancers or patients with refractory/relapsed disease when Phase III trial is unlikely because of rarity of condition and small case numbers. Quality trial criteria would be when a valid historical control group is available or there are several preferably large studies with similar patient eligibility or inclusion criteria and pre-specified patient outcomes. Score half the points for Phase II evidence (PFS only) i.e. divide PFS score by 2. For phase II trials, do not score for OS. Phase I data is not appropriate. Record exact score to one decimal place if necessary (e.g. 2.5). Specify where Phase III data may be in progress, where Phase II data have been quoted. If the main evidence base is a randomized phase II study, then score as for phase III study if comparator(s) appropriate; indicate clearly in this situation that this is data from a randomized phase II study NB where the time falls halfway between two scores, use the higher score. 1.A Disease Free Survival, Progression Free Survival, Time to Treatment Progression (Specify) DFS Y/N PFS Y/N TTP Y/N Other (specify) Of trials which report measures of PFS,DFS and TTP, it is the primary specified outcome measure for the trial which is to be used for scoring purposes Criteria Score Absolute values for benefit e.g months versus 8. 4 months = 3.9 months (Please quote p value below) Less than 2 months 0 Recorded Score 2.0 to 3.0 months 2 4 to 5 months 3 6 to 7 months 4 8 to 9 months 5 10 to 11 months 6 12 to 13 months 7 14 to 15 months months (crizotinib) vs Pooled chemo 3.0 months = 4.7 months (3) 3

6 16 to 17 months 9 18 to 19 months to 21 months to 23 months months 13 Precision of PFS/DFS/TTP (Please quote p value) HR (quoted in trial) Absolute values (HR) e.g ; 95%CI to ; p= Hazard Ratio HR 0.49 (0.37, 0.64), p< B Overall Survival If Phase II data, the score for OS benefit will automatically be set at zero, unless it is a randomized phase II study (with appropriate comparators and marked clearly as a randomized phase II study) or there is a very robust comparison possible with a contemporaneous study of equivalent patients who did not receive the treatment under evaluation. Criteria Score Absolute values for benefit e.g months versus 8. 4 months = 3.9 months (Please quote p value below) Less than 2 months 0 Recorded Score 2 to 3 months 2 4 to 5 months 3 6 to 7 months 4 8 to 9 months 5 10 to 11 months 6 12 to 13 months 7 14 to 15 months 8 16 to 17 months 9 18 to 19 months to 21 months to 23 months months 13 OS benefit of at least 4.7 months This is an estimate of the true benefit (please see text below and CDF panel s considerations) 3 Precision of OS (Please quote p value) HR (quoted in trial) Absolute values (HR) e.g ; 95%CI to ; p= Hazard Ratio No HR as not directly comparative OS

7 2 Quality of life Criteria Score Recorded Score Published evidence of significant improvement in overall Quality of Life (QOL), using a validated tool. 2 Measurable evidence of significant improvement in relevant aspect(s) of QOL using a validated tool or evidence of lack of deterioration in overall QOL using a validated tool or clear evidence of major improvement in QOL without validated tool (e.g. clinically significant reduction in blood transfusion) No QOL data collected in the trial or QOL data not analysed Measurable evidence of significant deterioration in relevant aspect(s) of QOL using a validated tool or clear evidence of major deterioration in QOL without a validated tool (e.g. clinically significant increase in incidence of febrile neutropenia) Published evidence of significant deterioration in overall QOL using a validated tool. Minus 1 Minus 2 3 Toxicity compared to the existing active standard therapy (best supportive care is considered an active standard therapy for the purposes of scoring toxicity). Criteria Score Recorded Score Significant improvement 2 Improved 1 Equal 0 Worsened Minus 1 1 Significantly worsened Minus 2 4 Degree of clinical unmet need, i.e. either the first demonstration of efficacy of a systemic therapy for the disease concerned or a step change for the clinical setting concerned. N.B. If there has been no score in section 1 of this tool, then no score can be assigned for this section unless case made for exception Criteria Score Recorded Score or N/A This drug is the first demonstration of efficacy of a systemic therapy for the disease concerned or a step change for the clinical setting concerned 3 0 Neither of the above applies 0 5 Cost per QALY if available. The Costs per QALY calculated by NICE in the course of an appraisal are the most accurate costs per QALY for use in England and Wales. NB Cost per QALY scores will only be used as a tie-breaker for prioritisation in the event of the overall scores incorporating evaluation of clinical efficacy and median drug cost being equal and cost per QALY data is available for compared options at the same drug prices offered to the CDF. The NICE TA number must also be identified below. Cost per QALY, NICE TA identification number and confirmation that this cost/qaly has incorporated the same price as offered to the CDF must be set out here.

8 Manufacturer stated: Most plausible ICER (NICE, TA296): crizotinib vs. docetaxel: > 100,000. Pricing information submitted to the Patient Access Scheme Liaison Unit (PASLU) during a NICE Technology Appraisal is confidential, therefore the CDFcannot confirm whether or not this incorporates the same price as offered to the CDF 6 Cost A further score will be given depending on the median cost of the drug under evaluation. This score will depend on the cost bands used by the NCDF Panel. This scoring system and the score for a drug in this scoring system remains commercially confidential as it would provide an indication of the cost at which the drug was offered to the CDF. 7 Treatment pathway and other key clinical issues Describe the place in the treatment pathway that this application refers to. Set out what the standard comparators are to this application in terms of everyday practice in England State the treatments that this drug will replace and thus be potentially eligible for de-commissioning State whether introduction of this drug/indication into the treatment pathway will increase, decrease or not change the other treatment options in the pathway Set out the eligibility criteria for treatment with this drug/indication State what the rules should be for continuation and discontinuation of the drug/indication Set out the evidence of national support for this application

9 Manufacturer stated: Describe the place in the treatment pathway that this application refers to. Second line treatment in anaplastic lymphoma kinase positive advanced non-small cell lung cancer patients, following platinumwhat the standard comparators are to this application in terms of everyday practice in England Docetaxel is the only alternative treatment available following first-line double chemotherapy in patients with ALK+ NSCLC. Although it featured in the pivotal Phase III trial along with docetaxel, pemetrexed is not commonly used at second line in UK clinical practice due to routine use at first-line. It is therefore not considered a standard comparator. Note the draft NSCLC National Chemotherapy Algorithms include crizotinib as the only 2nd line treatment option for ALK+ patients (13). State the treatments that this drug will replace and thus be potentially eligible for decommissioning Docetaxel chemotherapy. State whether introduction of this drug/indication into the treatment pathway will increase, decrease or not change the other treatment options in the pathway It will increase the treatment options. Crizotinib is a novel and first-in-class multi-targeted tyrosine kinase inhibitor and offers increased choice of treatment for patients and physicians. Set out the eligibility criteria for treatment with this drug/indication An accurate and validated ALK assay is necessary for the selection of patients for treatment and ALK-positive NSCLC status should be established prior to initiation of therapy. Patients must have had progressive disease after a prior platinum-based chemotherapy regimen. State what the rules should be for continuation and discontinuation of the drug/indication Patients may continue treatment until they gain no clinical benefit and discontinue if intolerant or disease progresses. Set out the evidence of national support for this application The draft NSCLC National Chemotherapy Algorithms include crizotinib as the only 2nd line treatment option for ALK+ patients (13). Furthermore, several NHS Trusts have crizotinibspecific protocols developed for use (14; 15). Clinical desire to use crizotinib is demonstrated through its current usage in the UK in the indication, with 181 notifications for use on the National CDF from April 2013 to March Supporting letters from clinicians (Dr. Sanjay Popat and Dr. Fiona Blackhall), patient groups and other stakeholders (RCP, NLCF for Nurses, Roy Castle Foundation) were submitted during the NICE TA296 appraisal process. A letter of support from the British Thoracic Oncology Group was submitted to the CDF as part of a previous assessment. 8 Strength of Evidence Criteria Grade Recorded Grade Two or more good quality Phase III Randomised Controlled Trials, both published A One good quality Phase III Randomised Controlled Trial, published Comparative Phase II trial, published B C B Non-Comparative Phase II, published Unpublished data (in abstract form only) 1 Unpublished data (in abstract form only) 2 D U1 U2 1 Appropriate methodology for the treatment setting, presented at an international meeting 2 Methodology inappropriate for treatment setting and/or not presented at international meeting

10 9 Overall score The overall score will take into account the score of clinical benefit in conjunction with the assessment of median drug cost. This score is subject to interpretation and modification by the NCDF Panel if the scoring tool does not adequately reflect the assessed clinical benefit. This overall score is commercial in confidence as it includes the price at which the drug is made available to the CDF. 10 References and Search Strategy: PubMed Search Strategy: Indicate below e.g.: Search terms (MeSH Terms) used in PubMed searches and dates of access for websites viewed. N/A References: Please provide Word, pdf or hard copy references with the application

11 (1) SPC. Taxotere 160mg/8ml concentrate for solution for infusion. 25 April 2014 Sanofi. Accessed 12/11/14. Available at: (2) SPC. Xalkori 200mg and 250mg hard capsule. Accessed 12/11/14. Available at: (3) Shaw AT, Kim DW, Nakagawa K. et al. Crizotinib versus chemotherapy in advanced ALKpositive lung cancer. N Engl J Med Jun 20;368(25): (4) NICE. Submission, Technology Appraisal TA296: Crizotinib for previously treated nonsmall-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. Available at: August (5) Royal College of Physicians. Professional organisation template for TA296. Accessed on 28/11/14, available at: (6) NHS England. Cancer Drugs Fund Decision Summary crizotinib. Jan Accessed 14/07/2015, Available at: (7) Fossella F, DeVore R, Kerr R. et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol Jun;18(12): (8) Hanna N, Shepherd F, Fosella F et al. Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non Small-Cell Lung Cancer Previously Treated With Chemotherapy. 2004, 22(9): (9) Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet Aug 23;384(9944): (10) Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O Rourke M, et al. Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non SmallCell Lung Cancer Previously Treated With Platinum-Based Chemotherapy. J Clin Oncol 2000;18: (11) Vergnenegre A, Corre R, Berard H et al. Cost-effectiveness of second-line chemotherapy for non small cell lung cancer: an economic, randomized, prospective, multicenter phase III trial comparing docetaxel and pemetrexed. The GFPC study (Provisional abstract). Journal of Thoracic.Oncology 2011; 6: (GFPC study) (12) Blackhall F, Kim D-W, Besse B, et al. Patient-reported outcomes and quality of life in profile 1007: a randomized trial of crizotinib compared with chemotherapy in previously treated patients with alk-positive advanced non small-cell lung cancer. J Thorac Oncol. 2014; 9: (13) NHS England. National Chemotherapy Algorithms: non-small cell lung cancer. DRAFT v (14) Cumbria, Northumberland, Tyne and Wear NHS. Crizotinib (Xalkori ) The treatment of ALK+ve advanced or metastatic non-small cell lung cancer. Accessed on 21/11/14. Available at: pdf (15) Royal Surrey NHS. Crizotinib; For the treatment of ALK+ve advanced NSCLC patients who have received at least one previous line of treatment. Accessed on 21/11/14. Available at: 11 Additional Information: For example: Definitive benefits of new treatment not captured above Trial data planned to prove non-inferiority with existing standard treatment. No unpublished/ In-House/Data on File Pharma contributions to be submitted

12 Manufacturer states Summary: There is an unmet need in a small ALK+ population in the UK for whom standard chemotherapy has poor outcomes (14;15;16). Standard chemotherapy in the UK is docetaxel, against which direct head-to-head evidence has demonstrated that crizotinib has a greater PFS benefit (7.7 vs. 2.6 months) (3). In the absence of unconfounded OS data, a comparison of the PROFILE 1007 data to that from other NSCLC trials suggests that crizotinib must confer some survival benefit, given the magnitude of difference between the OS observed in PROFILE 1007 and that in the other trials. Crizotinib is well tolerated with the most frequent treatment-related grade 3/4 adverse events that do occur being manageable. Significant QOL benefits are associated with crizotinib over chemotherapy (whether docetaxel or pemetrexed) (13). Crizotinib represents a step change in therapy for NSCLC and is the only treatment included for this patient population in the draft NSCLC National Chemotherapy Algorithms. Due to the small patient population size, crizotinib has a low overall budget impact to the NHS, with only 111 patients notified through CDF in year-to-date (Mar 14 to Apr 15). For NCDF Panel use only Total Score Additional Notes 9B and a confidential cost score