1. Public observer slides
Chair’s presentation Daratumumab for treating relapsed and refractory multiple myeloma after a proteasome inhibitor and an immunomodulatory agent [ID933]
2nd Appraisal Committee B meeting
Lead team: John Cairns, Sumeet Gupta, Dani Preedy
Chair: Amanda Adler
ERG: BMJ Technology Appraisals Group
NICE technical team: Jessica Maloney, Ahmed Elsada
Company: Janssen
April 20th 2017

2. ACD preliminary recommendation
Daratumumab monotherapy is not recommended, within its marketing authorisation, for treating relapsed and refractory multiple myeloma in adults, that is, after therapy including a proteasome inhibitor and an immunomodulatory agent and whose disease has progressed on the last therapy.

3. Daratumumab (Darzalex, Janssen)
Human monoclonal antibody that binds to CD38 protein
Indicated for relapsed and refractory multiple myeloma in adults whose prior therapy included:
proteasome inhibitor (e.g. bortezomib) and
immunomodulatory agent (e.g. lenalidomide or pomalidomide), and
whose disease progressed on their last therapy
Intravenous infusion, 16 mg/kg of body weight
Weekly for weeks 1–8
Every 2 weeks for weeks 9–24
Every 4 weeks from week 25 onwards

4. Multiple myeloma treatment pathway
Confidential
Multiple myeloma treatment pathway
Thalidomide + alkylating agents (e.g. melphalan, cyclophosphamide) (TA228)
Bortezomib if thalidomide is contraindicated or cannot be tolerated (TA228)
Bortezomib + thalidomide + dexamethasone (TA311)
1st line treatment
Bortezomib initial treatment (TA129)
Bortezomib retreatment (TA129)
Lenalidomide + dexamethasone ongoing (ID667)
2nd line treatment
Lenalidomide (TA171)
Panobinostat with bortezomib and dexamethasone (TA380)
Daratumumab?
3rd line treatment
Accepted by committee
Pomalidomide + dexamethasone (TA427)
Panobinostat with bortezomib and dexamethasone
Daratumumab?
(company choice)
4th line treatment
5th line treatment
Other agents e.g. bendamustine
Daratumumab?
National Institute for Health and Care Excellence Pre-meeting briefing – insert title in notes master view
Issue date: [Month year]

5. Summary of evidence 2 single-arm trials (MMY2002 and GEN501 part 2) Comparisons with POM+DEX and PANO+BORT+DEX based on matching-adjusted indirect comparisons (MAIC)
Design
Phase II
Phase I/II
Population
≥3 line of therapy OR refractory to PI + IMiD
Relapsed or refractory to ≥2 line of therapy
Comparison
None
1° outcome
Overall response rate
Safety
2° outcomes
OS and PFS
MMY2002
GEN501
16 mg/kg N=148
Company naively pooled data from 2 trials in model (‘integrated’ analysis)

6. Indirect treatment comparison Matching-adjusted indirect comparison
High-dose DEX
POM + Low-dose DEX
MM-003
n=302
Study-level data
GEN501 + MMY2002
Individual patient-level data,
company included only data that ‘matched’ other studies
Daratumumab POOLED 16 mg/kg
PANORAMA 2
n=55
Study-level data
PANO + BORT + DEX

7. Uncertainty in clinical effectiveness
Data limited to single-arm trials
Small numbers of patients on licensed dose (n=148)
Immature data overall survival (>40% patients alive at end)
Mismatch between populations in MMY2002 and GEN501
Poor generalisability of trials to people who would have daratumumab in NHS because of differences in:
Treatments received before daratumumab
Treatments received after daratumumab not available to NHS
Fitness of patients
Potential confounding effect of therapies before and after trials
Very uncertain estimates of relative effect from MAIC relating to:
Confounding by differences in people on different therapies
Number of characteristics (covariates) adjusted
Lack of validation of MAIC estimates with other sources

8. Uncertainty in cost-effectiveness
Extrapolating large proportion of patients (~50%), over a lifetime time horizon, based on few patients at risk of dying at end of follow-up (3 patients)
Modelled hazard ratios for POM+DEX and PANO+BORT+DEX reflected effect of each treatment relative to daratumumab in respective trial population for that treatment (not the same population)
Not reflecting psychological benefit and improved safety of daratumumab in utility
Including effect of treatments received after progression, but not associated costs

9. Committee’s discussion
Issue
Committee preference
Satisfied by company? (yes/no/partially)
Population
97% of patients in MMY2002 reflect marketing authorisation (disease progression on last therapy) vs. only 76% in GEN501
Use MMY2002 trial population
Yes – in scenario analyses
MAIC
Company adjusted only for selected characteristics, against DSU recommendation
Adjust for all potential confounders
Partially – only with pooled data set, not with MMY2002
High degree of uncertainty in the MAIC results
Validate results with data from other sources No
Abbreviations: DSU, NICE Decision Support Unit.

10. Committee’s discussion
Issue
Committee preference
Satisfied by company?
Time to treatment discontinuation
Estimated post-hoc, methods and calculations not clear to ERG
Clearly define time to treatment discontinuation and calculations No
Extrapolation
ERG log-log plots showed crossing curves, uncertain whether or not proportional hazards holds
Explore both assumptions in scenario analyses
Partially – MMY2002 not used when fitting independent curves (i.e. assuming no proportional hazards)
Utility
Utility values do not reflect all benefits perceived by patients
Capture benefits in utility estimates
Partially – alternative values explored

11. Committee’s discussion
Issue
Committee preference
Satisfied by company
Model validity
Internal quality assurance process did not assure committee of the validity of the economic model
Carry out and document further internal quality assurance on the model
Yes
ICERs
Only pairwise and deterministic ICERs presented
Present fully incremental and probabilistic ICERs
Partially – probabilistic ICERs presented, fully incremental are not
Abbreviations: ICER, Incremental cost effectiveness ratio.

12. ACD consultation responses
Consultees
Janssen (company) - submitted additional evidence (new data cut) and revised analyses
Myeloma UK
UK Myeloma forum
Commentators
Celgene
Patient expert
No web comments

13. Comments – comparators
Celgene
Bendamustine… a relevant comparator
Available via Cancer Drugs Fund as 4th line treatment
A relevant comparator in TA472 (POM+DEX)
ERG original report
‘ERG’s clinical experts agree with the company’s views... that is... bendamustine is considered the last available treatment option for rrMM’
N.b.
Bendamustine not licenced for relapsed multiple myeloma
CDF does not specify line of therapy… ‘relapsed disease where all other treatments contraindicated or inappropriate’
Is bendamustine a relevant comparator?

14. Comments – innovation Committee discussion
Comparative effectiveness issues meant the committee could not assess whether daratumumab was innovative
Company comments
‘New and unique’ mechanism of action… ‘sets [daratumumab] apart’ in terms of efficacy and safety…‘resets’ disease, so patients benefit from treatments that previously failed
Uncertainty consequence of ‘accelerated regulatory assessment and early licensing’
Efficacy of daratumumab confirmed in phase III randomised controlled trials earlier in treatment pathway
Other comments
First-in-class monoclonal antibody targeting CD38
‘Extremely innovative’… Potential to ‘significantly improve survival rates’
Demonstrates effectiveness as single agent
‘Well tolerated’
‘… game changing in myeloma’
‘… breakthrough status’ by FDA
Is daratumumab innovative?

15. Comments – therapies before daratumumab
Committee discussion
Some patients had as few as 2, or as many as 14, prior therapies… Neither trial fully reflected the place of daratumumab in NHS (after 3 prior therapies) Some treatments would not be available in NHS before daratumumab: Carfilzomib (MMY %, GEN501 19%); POM+DEX (MMY %, GEN501 36%)
Company comments
Similar to POM+DEX trial and highlight disease heterogeneity
73% of patients had >3 prior therapies
UK patients will be less pre-treated… Outcomes would only improve
Other comments
Trial population ‘more heavily pre-treated than the UK target patient group’... Outcomes would be better in UK population
Reflect heterogeneous condition and treatment
ERG comments
Some prior therapies not available in the NHS, and impact unclear
Has the Committee heard anything to change its stance?

16. Comments – POM+DEX (comparator) before daratumumab
Committee discussion: ~2/3 of patients in MMY2002 had POM+DEX before daratumumab… POM+DEX 3rd line or before not standard practice in UK
Company comments
Overall survival estimates for POM+DEX conservative
No comment on difference in PFS across POM+DEX-naïve and non-POM+DEX-naïve patients
ERG comments
Found inconsistencies in data originally provided by the company for POM+DEX-naïve patients
Company did not submit any new data to mitigate the original concerns raised by the ERG
Is the appropriate population ‘naïve’ for POM+DEX?

17. Comments – therapies after daratumumab
Committee discussion
Trials did not reflect NHS e.g. carfilzomib, bortezomib and lenalidomide would not be available in NHS post dara’mab
Post-dara’mab treatments prolonged life in trials
Effect of POM+DEX less biased: smaller proportion had
Company comments
‘… high degree of bias in these analyses’, particularly ‘immortality’ and selection bias
‘No conclusions can be drawn’
More reasonable to consider response to subsequent treatment to which previously refractory
subsequent therapy in POM+DEX trial, and of those, smaller proportion had carfilzomib, lenalidomide and bortezomib (and POM+DEX)
Subsequent treatment
N (%)
ORR
Any
31 (41)
39%
Bortezomib/ thalidomide/ lenalidomide
21 (28)
38%
Key: ORR, overall response rate

18. Comments – therapies after daratumumab (cont.)
Company comments (cont.)
Subsequent treatments in trials similar to NHS
Higher rate of subsequent therapy in daratumumab trials… ‘a testament to daratumumab’s novel MoA and favourable safety profile’
Other comments
Response category and overall survival ‘closely associated’… Highly unlikely high response rates would be seen if survival benefit due to other therapies
ERG comments
Impact of subsequent treatments on survival unknown
Survival better among POM+DEX-naïve patients than overall population… could be because patients were eligible for POM+DEX as subsequent therapy
Does the committee wish to re-consider its conclusion about the impact of subsequent therapies received in the trials?

19. Comments – pooling data
Committee discussion
MMY2002 and GEN501 differed in
Median number of lines of previous therapy (5 vs 4)
Proportion of patients refractory to last treatment (97% vs 76%)
Pooling data not appropriate
Company comments
Pooled dataset most appropriate
Makes full use of available data, reduces uncertainty, and increases degree of similarity between datasets used to inform MAIC
ERG comments
Pooling data inappropriate as trials and their 1° outcomes differ
ISS stage and cytogenetics missing from GEN501 part 2
Pooling data compromises generalisability of individual studies rather than increase external validity
Does pooling the data from the 2 trials remain inappropriate?
ISS, International Staging System

20. Comments – comparative effectiveness Company: daratumumab demonstrates survival benefit versus POM+DEX
Benefit holds true under 3 different methods
Unadjusted MAIC (pooled data vs. comparator trial data)
Fully adjusted MAIC (revised base case)
Multivariate regression against ‘real-world’ data - International Myeloma Foundation
OS HR for daratumumab vs POM+DEX ranges from to 0.61
MVR, multivariate regression.

21. Comments – validating the MAIC
Committee discussion
MAIC highly uncertain, and effect of daratumumab sometimes ‘reversed’ when ERG adjusted for more characteristics
All MAIC estimates unreliable
Company could validate MAIC with data from the International Myeloma Foundation chart review
Company comments
Unable to validate MAIC using external data sources… No established methods to do this
Similar issues around uncertainty of MAIC were present in TA427 (POM+DEX) and TA380 (PANO+BORT+DEX)
Is the MAIC robust enough to be used for decision-making?

22. New data on overall survival Additional 10 months follow up (cut off 18 November 2016) 42% patients alive at end of follow-up
Dec 2015
Nov 2016

23. New data on overall survival Additional 10 months follow up (cut off 18 November 2016) 42% patients alive at end of follow-up
Pooled analysis (n=148)
Previous data-cut1
Median PFS
4.0 (2.8, 5.6)
Median OS, months (95% CI)
(16.6, NR)
Number of events OS, n (%) 73
(49.3%)
New data- cut2 NR
20.5
(16.6, 28.1) 86
(58.1%)
Key: CI, confidence interval; NE, not evaluable; NR, not reported; OS, overall survival; PFS, progression free survival.
Company also presented subgroup analyses of survival outcomes based on response
OS and PFS were longer for ‘responders’ than those with minimal response or progressive disease
1 PFS taken from January 2015 data-cut for MMY2002 and December 2015 for GEN501 Part 2. OS taken from 31 December 2015 data cut-off 2 Data-cut November 2016

24. Comments – end of life criteria
Committee discussion
Life expectancy <24 months
Unable to conclude whether criterion of life extension was met because of uncertainties in relative effectiveness and survival modelling
Company comments
Daratumumab… ‘clearly meets the end of life criteria’
In unadjusted cross-trial comparison, daratumumab can extend life by 7 months vs POM+DEX, and 3 months vs PANO+BORT+DEX
N.b. ‘unadjusted’

25. Comments – end-of-life criteria
UK Myeloma forum
‘Over 60% of the patients treated with daratumumab are alive after 31 months’
Certainty of relative benefit of daratumumab greater than that accepted in TA427 (POM+DEX)
Myeloma UK
Clinical trial data supports life extension by >3 months
ERG comments
Uncertainty on survival benefit of daratumumab not mitigated
No new data to help inform whether the life extension criterion is met
Does daratumumab meet the end-of-life criteria?

26. Company new data on utility
EQ-5D-5L from the early-access programme (n=90)
Multi-centre, open-label, early-access treatment protocol*
People had ≥3 prior lines of therapy
Weighted average mean change from baseline utility increase 0.04
ERG comments
Company’s approach double counts benefit of daratumumab
Utility decrement for adverse events
Utility increment associated with daratumumab
Increment does not indicate if daratumumab or disease status improves utility
Statistical significance not tested by company
ERG calculated 95% confidence intervals… Change in utility from baseline unlikely to be statistically significant
clinicaltrials.gov* (NCT ) outcome study. ‘Participants will primarily be assessed for overall response rate.’

27. Other comments General Myeloma UK
Lack of ICERs in the ACD… ‘made it difficult for stakeholders to consider this a way forward for accessing daratumumab’
UK Myeloma Forum
Patient care and outcomes ‘will suffer’ as a direct result of this negative ACD
Patient expert
‘Encouraged and excited’ by new treatment possibilities
Patients need new drugs that minimise toxicity
Recommendations ‘will be a strong disappointment’
Cancer Drug Fund (CDF)
CDF would ‘widen access to daratumumab whilst collecting more data on the use of the drug in clinical practice’

28. Other comments Nature of evidence Myeloma UK
Available data from early-phase trials… NICE unable to assess such data
Need to consider solutions and ‘disjoint between EMA regulatory and UK HTA data requirements’
UK Myeloma Forum
Patient and clinician demand for access to daratumumab in UK demonstrated by quick recruitment to Expanded Access Programme (MMY3010)
NCT Open-label, Multicenter, Phase 2 Trial Efficacy and Safety >3 Prior Lines of Therapy
Patient expert
Agree with Myeloma UK’s statement on systemic issues, these should be ‘addressed urgently’
Utility
Celgene
Should apply a disutility to daratumumab to reflect IV administration
Should a disutility be applied to daratumumab for IV administration?

29. Company’s new modelling
Adjustment
Match committee’s preference?
MAIC
Adjusted for all potential confounders imputing for ISS-stage and cytogenetics
Partially – results not validated with external data
Approach to relative effectiveness
Base case used independently fitted curves for OS and PFS based on ERG preference, scenario analysis with ‘dependent’ fit
Partially – independent curves fit with pooled data only (not MMY2002)
Extrapolation
Weibull for overall survival based on
N/A (ERG preference)
Utility benefit of daratumumab
Utility benefit of 0.04 for daratumumab based on QoL data from the Early Access Programme
Partially – alternative values explored
Model corrections
As per section 6.1 of ERG report
Yes
Quality assurances
Checked by vendor who built model, an external vendor, and Janssen
ERG comment: None of the initial concerns mitigated by company's new evidence and analysis

30. Scenario analyses Approach to relative effectiveness
Dependent curve fitting
Clinical data
MMY2002 for daratumumab (only with dependent curve fitting i.e. assuming proportional hazards)
Utility
Alternative utility values
Extrapolation
Different assumptions about the long-term effects of daratumumab
Costs, resource use
Based on ERG estimated resource use

31. Key issues for consideration
Is bendamustine a relevant comparator?
Does pooling data from the 2 trials remain inappropriate?
Is the appropriate population ‘naïve’ for POM+DEX?
Would UK patients be less pre-treated than trials and would outcomes improve in those patients compared with trials?
Does the committee wish to re-consider its conclusion about the impact of subsequent therapies received in the trials?
Is the MAIC robust enough to be used for decision-making?
Is daratumumab innovative?
Does daratumumab meet the end-of-life criteria?
Suitability of a recommendation within the CDF
Can the clinical uncertainty be reduced through CDF data collection?
Does daratumumab have a plausible potential to be cost-effective?