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PERSONALIZED MEDICINE THERAPY THERA DIAGNOSTIC NOSTIC LABYT Charlotte, MAHIEU Aymeric, PECHON Philippe THERANOSTIC TARGETED THERAPY • Trastuzumab (Herceptin®) breast cancer • Cetuximab (Erbitux®) Panitumumab (Vectibix®) colorectal cancer TARGETED THERAPY : HERCEPTIN® OVER-EXPRESSED IN 25% OF THE TUMORS MONOCLONAL ANTIBODY HER2 Owen MA, Horten BC, Da Silva MM (2004) HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry. Clin breast cancer 5:63-69 TARGETED THERAPY : HERCEPTIN® Clinical trials on « HER2 + » population Herceptest® FDA/EMEA Approval: Herceptin’s labelling includes pathology test THERANOSTIC PERSONALIZED MEDICINE Colorectal cancer COLORECTAL CANCER The fourth largest cause of cancer deaths worldwide The third most common cancer in developed countries 370,000 people in Europe/year Five-year survival rates: as low as 5% COLORECTAL CANCER Before targeted therapies: First line regimens: 5FU/LV : Fluorouracil + levofolinate FOLFIRI : Irinotecan + 5FU/LV Second line regimens: FOLFOX : Oxaliplatin + 5FU/LV COLORECTAL CANCER new opportunities Monoclonal antibody : Anti-EGFR Over-expressed in 80% of the colorectal tumors COLORECTAL CANCER Clinical trials : population EGFR+ EGFR test : ICH COLORECTAL CANCER Anti-EGFR : Cetuximab ERBITUX® Panitumumab VECTIBIX® ImClone/BMS/Merck Amgen COLORECTAL CANCER : ERBITUX® Second line treatment: Patients with EGFR-expressing cancer: - FDA + EMEA : In combination with irinotecan refractory to irinotecan - FDA : As a single agent intolerant to irinotecan COLORECTAL CANCER : VECTIBIX® FDA : SECOND LINE Patients with EGFR-expressing cancer: - In combination with irinotecan refractory to irinotecan - As a single agent intolerant to irinotecan EMEA : NOT APPROVED !! COLORECTAL CANCER Discovery of New Factors affecting Erbitux/Vectibix response COLORECTAL CANCER • Clinical trials: : response to erbitux 22,9% maximal response rate EGFR+ • Mutation in Kras protein J Clin Oncol 23:1803-1810 Cancer Res 2006;66: (8). April 15, 2006 COLORECTAL CANCER KRAS MUTATION KRAS EGFR activated Kras activated EGFR non activated Kras non activated Kras is mutated in 35% of the colorectal tumors KRAS mKRAS Kras wild type Kras mutated KRAS K-RAS mutation involvement in the clinical response to AntiEGFR Market share First line treatment ? KRAS & ERBITUX Progression free survival 27,3% 7,2 % Mutated Kras The new england journal of medicine october 23, 2008 vol. 359 no. 17 Wild-type Kras KRAS & VECTIBIX Progression free survival 38,7 % 6,6 % Mutated KRAS EMEA:Annex 1 summary of product characteristics Vectibix panitumumab AMGEN Wild-type KRAS KRAS TEST KRAS TEST Many tests available, unknown quality Homebrew tests Commercial tests DxS Dakocytomotion CE mark in EU (not regulated by EMEA) FDA does not regulate KRAS tests yet Knowledge of KRAS statut benefit ? For patients For payers For patients PFS : The length of time during and after treatment in which a patient is living with a disease that does not get worse. Side-effects For patients 2 cases : KRAS Wild-type FOLFIRI* FOLFIRI* + Cetuximab KRAS Mutant In combination FOLFIRI* FOLFIRI* + Cetuximab * FOLFIRI = Irinotecan + 5FU/LV ++ 1,2 months For patients KRAS Wild-type : PFS : increase with addition of Cetuximab = 1,2 months (p=0,017) Side effects : increase with addition of Cetuximab : Acne like rash, diarrhea KRAS mutant PFS: decrease with addition of Cetuximab = 0,5 months not significant (p=0,47) Side effects : increase with addition of Cetuximab : Acne like rash, diarrhea For patients QALY : quality-adjusted life year A year in perfect health is considered equal to 1.0 QALY For example, a year bedridden might have a value equal to 0.5 QALY For patients With addition of Cetuximab you live longer but with worst quality of life For payers Incremental costs principally due to the cost of Cetuximab = 19 473 £ For Payers Cetuximab is very expensive in term of QALY (NICE generally accepts 30 000 £ per QALY) LY = Life Year Interest of KRAS test for payers 65% of patients are KRAS Wild Type 35% of patients are KRAS mutant Save money for 35% of patients who will not profit of cetuximab Low over cost of the test price 300 £ to compare to 19 000 £ of a treatment Nice for the first line treatment of metastasic colorectal cancer Key opinion leader Advice “ Treatment with cetuximab, which is relatively expensive, would be most cost-effective if it were given to patients with the highest chance of benefiting from it " (The new england journal of medicine) ERBITUX® & VECTIBIX® EMEA FIRST LINE treatment of patients with EGFR-expressing, KRAS wild-type metastatic colorectal cancer o In combination with chemotherapy Second line o Single agent in patients refractory/intolerant to irinotecan FDA Did not change its position ! FDA vs EMEA Why are EMEA and FDA looking at the same data and coming to different conclusions? Chronology Feb 04: FDA approved Erbitux June 04: EMEA approved Erbitux Sept 06: FDA approved Vectibix May 07: EMEA rejected Vectibix Biocentury, The case for retrospection, december 22, 2008 Biocentury, The jury is no longer out, june 9, 2008 Dec 07: EMEA approved Vectibix for mCRC WT KRAS June 08: EMEA approved Erbitux for mCRC WT KRAS Dec 08: FDA accepted retrospective analysis mCRC: Metastatic ColoRectal Cancer WT: Wild-Type = non mutated Issue FDA approved Vectibix in september 2006 EMEA rejected Vectibix in may 2007 EMEA approved Vectibix for KRAS WT in december 2007 FDA not eager to update Vectibix’s label Why are the FDA and EMEA looking at the same data and coming to different conclusions? The case for Vectibix Feb 04: June 04: Sept 06: FDA approved Erbitux EMEA approved Erbitux FDA approved Vectibix Equivocal clinical data: 8% of mCRC patients response Survival prolonged by only a few weeks Failed to improve overall survival vs. BSC FDA granted approval results « clinically modest, but highly significant » EMEA more skeptical BSC: Best Supportive Care Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008 EMEA’s opinion on Vectibix Feb 04: June 04: Sept 06: May 07: FDA approved Erbitux EMEA approved Erbitux FDA approved Vectibix EMEA rejected Vectibix Concerns about trial design Pivotal trial designed in collaboration with FDA Poor efficacy Highly toxic (89% dermatologic toxicity) AMGEN forced to discontinue a late-stage trial High price EMEA more cost-sensitive than FDA Benefits did not outweigh risks (and costs…) Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008 Therapeuticsdaily.com Rejected by EMEA Seeing the light at the end of the tunnel? Feb 04: June 04: Sept 06: May 07: FDA approved Erbitux EMEA approved Erbitux FDA approved Vectibix EMEA rejected Vectibix Vectibix left as a second-line (if not third-line) treatment in the US Not marketed in Europe KRAS mutated patients known to be resistant to Erbitux (another EGFR inhibitor) Then, AMGEN retrospectively genotyped patients’ tumors Retrospective analysis showed difference in response rate Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008 KRAS & VECTIBIX Progression free survival 38,7 % 6,6 % Mutated KRAS EMEA:Annex 1 summary of product characteristics Vectibix panitumumab AMGEN Wild-type KRAS EMEA’s conditionnal approval Feb 04: June 04: Sept 06: May 07: Dec 07: FDA approved Erbitux EMEA approved Erbitux FDA approved Vectibix EMEA rejected Vectibix EMEA approved Vectibix for mCRC WT KRAS EMEA’s Scientific Advisory Group on Oncology found the findings « interesting » but only « exploratory »… Nevertheless, EMEA granted approval for KRAS WT patients in tandem with a test Conditional approval: Availability of a test Prospective data from 2 large Phase 3 trials Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008 Biocentury, Proof is in the pudding, march 31, 2008 Ongoing studies AMGEN’s PRIME trial Results expected late 2009 AMGEN’s 181 trial Working along with DxS Why is the FDA reluctant? Feb 04: June 04: Sept 06: May 07: Dec 07: FDA approved Erbitux EMEA approved Erbitux FDA approved Vectibix EMEA rejected Vectibix EMEA approved Vectibix for mCRC WT KRAS Retrospective data = hypothesis generating Sampling bias Selective data dredging Would create a « free-for-all » Need for well-designed prospective trials Unlike EMEA, FDA regulates diagnostics Many commercial/homebrew tests Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008 Biocentury, Proof is in the pudding, march 31, 2008 AMGEN’s counterarguments Sample size similar to the original trial (427 vs 463 patients) Original pre-specified endpoints Vectibix already on US market, KRAS marker has a high clinical significance Strong biological rationale Saves the expenses and side-effects of futile therapy Idea of KRAS mutation emerged late after trials was started (2006) Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008 Place for an alternative? Create an alternative regulatory pathway Little safety risk attached to the diagnostic Provisional approval based on retrospective data might be granted if: Endpoints pre-specified Sampling non-biased Provide prospective data later “In cases like this, in which the test merely excludes nonresponding patients, is the extra level of regulation really necessary?” Nature Biotechnology Nature Biotechnology; Looking forward, looking back; 26, 5, May 2008 June 2008 Feb 04: FDA approved Erbitux June 04: EMEA approved Erbitux Sept 06: FDA approved Vectibix May 07: EMEA rejected Vectibix Dec 07: EMEA approved Vectibix for mCRC WT KRAS June 08: EMEA approved Erbitux for mCRC WT KRAS ASCO Annual Meeting Results of Erbitux retrospective analysis EMEA granted Erbitux approval in WT KRAS patients Key Opinion Leaders encourages KRAS testing HMO (US) beginning to implement routine and to establish reimbursement guidelines Still not approved by the FDA for WT KRAS patients ASCO: American Society for Clinical Oncology HMO: Health Management Organisation December 2008 Feb 04: FDA approved Erbitux June 04: EMEA approved Erbitux Sept 06: FDA approved Vectibix May 07: EMEA rejected Vectibix Dec 07: EMEA approved Vectibix for mCRC WT KRAS June 08: EMEA approved Erbitux for mCRC WT KRAS Dec 08: FDA accept retrospective analysis FDA convened a panel meeting 6 trials: retrospective analysis Accepted retrospective biomarker analysis Set guidelines for forthcoming personalized drugs approval Benefit segmentation of market Is it better to have the market of second line entirely or a part of the market of first line? Benefit segmentation of market 55 000 to 83 000 patients so an increase of 51 % of patients Treatment duration is longer 32 weeks vs 20 weeks Patients stratification’s effect on sales « the pond is smaller but deeper » says Phyllis Carter, Merck spokeswoman • Patients living longer • Use in 1st line •Deeper market Predictible sales increase • Narrowed market • Sales decline in 2nd and 3rd line A Market in expansion Sales of Erbitux Sales in europe Q3 2007 118 m€ Q3 2008 134 m€ Growth up of 13 % Erbitux sustained double digit growth due to : Increasing market penetration in established 2nd/3rd line head & neck cancer indication Translation/line extension to 1st line in metastatic colorectal (mCRC) Merck kgaa Sales of Erbitux 160 Erbitux sales in europe 140 120 100 80 60 40 20 0 Q1 Q2 Q3 2004 Q4 Q1 Q2 Q3 2005 Q4 Q1 Q2 Q3 2006 Indication EMEA Head and neck cancer Q4 Q1 Q2 Q3 Q4 Q1 2007 Janvier 2007 publication étude Crystal with Kras Continuous growth during four years Q2 Q3 Q4 2008 Mai 2008 First line with Kras Sales of Erbitux Erbitux sales in europe 150.0 145.0 140.0 135.0 130.0 125.0 120.0 115.0 110.0 105.0 100.0 Q1 Q2 Q3 2007 Q4 Q1 Q2 Q3 2008 Mai 2008 1 ère ligne après Kras Sales decrease since last quarter Q4 Are KRAS test really performed ? Number of KRAS test declarated In France : 2007: 1 100 test KRAS have been performed 2008 : January August 4 000 tests have been performed 2008 : September December 5 700 tests (estimation) 10000 +1000 % 8000 6000 4000 At medium term 20 000 tests by year are planned 2000 0 2007 2008 KRAS test are performed in France that means that in France EMEA recommendation are followed Réunion des biologistes de France Inca compte rendu de réunion Sales of Vectibix 2008 Vectibix can’t explain the sales stagnation US Erbitux CA repartition without KRAS test allowed by FDA CRC represents 50% of sales of Erbitux The first line represent 35 % of the sale without MA and growth by 30 % since 3Q07 First line + ASCO ASCO 2005 : presentation phase II international study 2nd Q05 : positive data 1st Q06 : large phase III 2nd Q06 WCGIC: 2 positive phase II 3rd Q06 : Crystal Phase III 1241 patients ASCO 2007 and WCGIC : presentation of Crystal Q4 07 : retrospective data analysis show benefit for wt-KRAS ASCO 2008 : presentation of restrospective data analysis of Crystal Conclusion Theranostic : a step forward in health care “tailoring the right drugs, to the right patients, at the right time” Patient stratification ( market ) Regulatory update (FDA + EMEA) KRAS and now… BRAF BRAF is part of the same enzymatic cascade (MAPK) BRAF mutation may explain another 12% resistance Adding Sorafenib (BRAF inhibitor) restores the sensitivity to Cetuximab Even considering BRAF and KRAS, still 52% of non-responsive patients… Is there another mutation involved? J Clin Oncol. 2008 Dec 10, 26, 5668-70 Symposium on Molecular Targets and Cancer Therapeutics in Geneva on Thursday, October 23 2008 To be continued . . . Thank you for your attention