Le Coût fait-il Partie de l Equation dans le Traitement du Cancer (?) ou Clinical versus Statistical Significance in advanced Solid Tumors

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1 Le Coût fait-il Partie de l Equation dans le Traitement du Cancer (?) ou Clinical versus Statistical Significance in advanced Solid Tumors PARIS TAO Decembre 2016 M. DICATO M.D., FRCP. Hematology- Oncology Centre Hospitalier de Luxembourg L-1210 Luxembourg

2 Clinical versus Statistical Significance in advanced Solid Tumors

3 Metastatic Breast Cancer Paclitaxel + bevacizumab vs Pacl +placebo PFS prolonged 11.8 vs 5.9 mo, p<0.001 OS = no difference QOL? NEJM 2007, 357:2666

4 Bevacizumabin MetastaticBreastCancer Febr FDA acceleratedapproval, single trial: improvementof PFS 5,9 mo AVADO & RIBBON-1: PFS benefit but less, OS no benefit July 2010: ODAC* vote: 12:1 for withdrawal. FDA: withdrawal December 2010 *ODAC: Oncology Drug Advisory Committee (to FDA)

5 LBA3, ASCO 2014

6 A. Grothey

7 Chemotherapy +/- Bevacizumab in mcrc

8 Metastatic CRC

9 VELOUR Study: mcrc

10 CORRECT Study: mcrc Patients after Standard Therapy

11 CORRECT Trial: mcrc Patients after Standard Therapy

12 In mcrcneweranti-angiogenicdrugs Licensed Rigorafenib(Stivarga- Bayer) OS vs control: 6.4 vs 5 months PFS vs control: 2 vs 1.7 months Aflibercept(Zalltrap- Sanofi) + FOLFIRI: OS vs control 13.5 vs 12 months PFS vs placebo 6.9 vs 4.7 months

13 Pancreatic Cancer Gemcitabine+/- erlotinib: OS improved by 10 days (6,24 vs 5,91 mos) JCO 2007, 25:1960

14 ASCO 2012: LBA 5002 AURELIA. Phase III: Bev + CT for Platinum (Pt) resistant Ovarian Cancer. JCO 2014,32:1302 N= 361 pts, progressed <6 mo after >4 cycles of Pt based therapy; after chemotherapy selection by treating physician randomized +/- bevacizumab PFS median 6.7 vs 3.4 mo, HR 0.38 design.: 80% power to detect PFS with a HR of 0.7, assuming median PFS of 4.0 with CT vs 5.7 mo with CT + Bev

15 Top Story ECCO 2015 (LBA4) Cabozantinib outperforms Everolimus. & NEJM Aug. METEOR study: Cabozantinib vs Everolimus in advanced RCC.

16 Clinical activity in patients with non small-cell lung cancer (NSCLC) receiving nivolumab. Scott N. Gettinger et al. JCO 2015;33: by American Society of Clinical Oncology

17 ASCO 2012, abstract#3: Indolent & mantle cell NHL: R-CHOP vs R-CHOP + Bendamustine N= 514 PFS: 69.5 vs 31.2 mo HR 0.58 (CI 05% ), p< OS: no difference Crossover, indolent NHL has a prolonged survival PFS= QoL

18 Experimental cancer treatment results Authors: 25-50% of new cancer treatment clinical benefits prove successful In 15% of trials, itisestimatedthatresultsshould immediately become standard Data: Comparisonof pooledresultsof real effectof new vs standard treatmentsin termsof patient outcomes: HR 0,95 for OS. Majority of new treatments are of marginal clinical benefit Arch Int Med 2008, 168: 632

19 Take Home Messages The p value tells that the result did not occur by chance. It does not necessarily mean that the result is due to the treatment RCT as of now is still the golden standard Surrogate markers (for OS) have to be proven that they are surrogates. PFS can but must not be a marker for OS Results should be expressed in absolute and not relative benefit

20 Presented By Leonard Saltz at 2015 ASCO Annual Meeting

21 Value The money spent should yield the best outcome for patients Define high value to be incentivize and eliminate low value ASCO 2015: value - Not treating patients with progressive incurable disease and poor PS - Avoiding staging studies in asymptomatic early breast cancer and prostate cancer - No routine screening with labs and imaging in patients without symptoms with history of early breast cancer - No growth factors for FN prevention in low risk (<20%) regimens

22 P. Cornes, in M. Dicato Edit., Targeted Oncology, Springer UK 2012

23 Presented By Leonard Saltz at 2015 ASCO Annual Meeting

24 Presented By Leonard Saltz at 2015 ASCO Annual Meeting

25 Do prices reflect development costs?<br />Does competition bring down those prices? <br /><br />Not for Gleevec: <br /><br /> Presented By Leonard Saltz at 2015 ASCO Annual Meeting

26 N.T. Mason et al.: Modeling the cost of immune checkpoint inhibitorrelated toxicities. ASCO 2016, abstract #6627 N= 627 patients.

27 Cost issues in Oncology: Statistical vs clinical significance in advanced solid tumors. (M. DICATO) Exploding costs with marginal clinical benefit: - Look at end results: mortality. Most improvements due to surgery. - Historical comparisons are doubtful. Survival in placebo arms have significantly improved over time. - Expression of benefit/risk in relative and not absolute percentage;

28 Leaving pricing efficacy out of the equation is no longer an option J. Tabernero for ESMO, Ann Oncol (2) and other issues (M.DICATO). 1. Does Qaly have a bearing to anything: e.g.: Qaly ~50.000$ or 3x per capita GDP = $. How to explain or justify? 2. Pay for performance, e.g.: UK Velcade, 3. Cancer agents are used in different indications with different efficacies: same price? 4. Anchor the price to the use of the drug and not the drug itself = indication specific pricing (P. Bach JCO ) Payers could reimburse differently. 5. Overall treatment is costly, so when it is highly effective enormous costs are added 6. Value?: adding one month OS to 3 or to 30 months. Relative vs absolute benefit scale (ASCO 2015).

29 Inflated expectations, prematurely positioned as breakthroughs while the benefit is marginal and the cost disproportionate. Cost of life-year added: 1995: $, 2014: $ (ASCO 2015) Cost: preference in therapy: young vs elder patient? Out of 124 agents 74% overlapping, me too drugs. (Fogotet al. JAMA Otolaryngol. H&N Surgery 2014,140: ) (J. Tabernero for ESMO, Ann Oncol. 2015)

30 Savingscanbeimplemented immediately There isan urgent needto decreasecost: - Negociating costs: hospital groups, bundling - Try to avoid inefficient drugs with poor results - Use the least expensivedrugfor the same result: choicebetweentargetedtherapy, biosimilars..

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32 Further Reading ESMO: ESMO Magnitude of Clinical Benefit Scale (ESMO- MCBS), N. I. Cherny et al. Ann Oncol. 2015,26: (But ESMO does not address cost.) ASCO: Assess the Value of Cancer Treatment Options. L.E. Schnipper et al. JCO 2015, 61: The critical elements: - clinical benefit (efficacy) - toxicity (safety) - cost (efficiency

33 Take Home Message: Leaving pricing efficacy out of the equation is no longer an option. J. Tabernero for ESMO, Ann Oncol

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35 Thank You