AVANCES EN METODOLOGÍA DE LA INVESTIGACIÓN. Alberto Ocaña Hospital Universitario de Albacete

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1 AVANCES EN METODOLOGÍA DE LA INVESTIGACIÓN Alberto Ocaña Hospital Universitario de Albacete

2 Endpoints PFS as an endpoint Surrogate endpoints PCR-FDA accelerated approval Factors afecting PFS: censoring due to toxicity Companion diagnostics Right target=right population

3 Endpoints Which is the better endpoint for the design of RCTs in metastatic breast cancer? 3

4 39 drugs approved by the US FDA between January 2000 and April 2014 for the treatment of 59 different adult solid tumor Characteristic N (%) Primary Endpoint Overall survival 27 (47%) Breast Cancer Progression-free survival or time to progression Response rate Chemotherapies: Albumin-bound paclitaxel, Capecitabine, EribulinMesylate, Gemcitabine, Ixabepilone Targeted agents non companion diagnostics Bevacizumab, Everolimus BREAST CANCER Targeted agents companion diagnostics 27 (47%) 3 (5%) 11drugs and 12 studies OS as primary endpoint.3 PFS as primary Endpoint.9 OS as secondary endpoint 8 Lapatinib, Pertuzumab, Trastuzumab Transtuzumab emtansine

5 Drug primary endpoint secondary end point HR overall survival HR for PFS/TTP CHEMOTHERAPIES ALBUMIN-BOUND PACLITAXEL Gradishar 2005 Overall Response Rate Time to progression 0,9 0,75 (TTP) CAPECITABINE O'Shaughnessy 2002 Time to progression Overall survival 0,775 0,652 (TTP) ERIBULIN MESYLATE Cortes 2011 Overall Survival Progression free survival 0,81 0,87 (PFS) GEMCITABINE Albain 2008 Overall Survival Time to progression 0,82 0,7 (TTP) IXABEPILONE Sparano 2010 Overall Survival Progression free survival 0,9 0,79 (PFS) Progression free Thomas 2007 survival Overall survival not reported 0,75 (PFS) TARGETED AGENTS endpoint NON COMPANION for drug approval if the DIAGNOSTICS BEVACIZUMAB Miller 2007 EVEROLIMUS Baselga 2012 TARGETED AGENTS COMPANION DIAGNOSTICS HER2 LAPATINIB Progression free survival Overall survival 0,88 0,6 (PFS) Progression free survival Overall survival not reported 0,43 (PFS) Geyer 2006 Time to progression Overall survival 0,92 0,49 (TTP) PERTUZUMAB Baselga 2012 TRASTUZUMAB Progression free survival Overall survival 0,64 0,62 (PFS) Slamon 2001 Time to progression Overall survival 0,8 0,51(TTP) TRANSTUZUMAB EMTANSINE Verma 2012 PFS is considered as a valid magnitude of benefit is relevant Progression free survival Overall survival 0,68 0,65 ( PFS)

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7 Surrogate endpoints PFS is a weak surrogate endpoint of OS Gains in PFS do not translate into gains in OS due to SPP Is there any other accepted surrogate endpoint? What about Pathological Complete Response in the neoadjuvant setting?

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10 Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS.

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12 This assumption raises a number of questions: 1. Is an observed effect in pcr consistent with improved outcome in all tumor subtypes? 2. What is a clinically relevant increase in pcr? 3. With neoadjuvant studies generally reporting data at an early stage in follow-up, do we know enough about potentially long-term adverse effects? 4. What is an optimal duration of treatment with drugs which are approved on the basis of pcr reported in neoadjuvant studies?

13 Examples A lack of association between increased in pcr rate and survival benefit in the neoadjuvant setting have been observed with bevacizumab. In HER2-positive disease, treatment with anti-her2 therapies showed increases in pcr of around 15% to 25%. It is unclear if translates to a significant clinical benefit in the adjuvant setting for some drugs.

14 Problems with censoring Censoring of patients (as non-progressors) due to withdrawal for toxicity can markedly influence apparent PFS! New endpoint P/DFS: Progression and Discontinuation-Free Survival 14

15 Toxicity: Dose selection and phamacodynamic Phase III trial-everolimus-letrozol in breast cancer A higher percentage of patients discontinued group than discontinued placebo in the control group because of adverse events (19% vs. 4%) and withdrawal of consent (5% vs. 2%). everolimus in the combination-therapy Biomarkers-phase I-Everolimus 15

16 Companion Diagnostic The specific diagnostic test has been named as companion diagnostic and defined by the FDA as an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product.

17 Companion diagnostic HR: 0.71 No companion diagnostic HR: 0.80

18 RIGHT TARGET = RIGHT POPULATION Pfizer To Submit Palbociclib New Drug Application With FDA Based On Final Results Of PALOMA-1 Friday, May 16, :12pm EDT This decision was based on discussions with the FDA regarding the final results of PALOMA-1, a randomized, Phase 2 trial comparing palbociclib plus letrozole versus letrozole alone in this population of patients. Palbociclib received Breakthrough Therapy designation from the FDA in April 2013, for the first-line systemic treatment of women with advanced or metastatic ER+, HER2- breast cancer. This designation was based on interim data from the PALOMA-1 trial.

19 SUMMARY PFS IS CONSIDERED AN ACCEPTED ENDPOINT IF THERE IS A SIGNIFICANT MAGNITUDE OF BENEFIT PCR IS NOT A VALID SURROGATE OF OS FDA APPROVAL OF NEW DRUGS BASED ON PCR? CENSORING DUE TO TOXICITY SHOULD BE TAKEN IN CONSIDERATION DRUGS WITH COMPANION DIAGNOSTICS INCREASE MAGNITUDE OF BENEFIT RIGHT TARGET=RIGHT POPULATION

20 Thanks to: Atanasio Pandiella-CIC Salamanca, Spain Eitan Amir- Princess Margaret Hospital, Toronto, Canada Ian Tannock-Princess Margaret Hospital, Toronto, Canada Bostjan Seruga- Institute of Oncology, Lujbiana, Slovenia Saroj Niraula- Manitoba Cancer Care, Canada Arnoud Templeton-Flims, Swizerland. Francisco Vera-Badillo. Monterrey México. Funding: ISCIII, RTICS, FISCAM, CRIS, AMAC, Diputación 20

21 Thank you?????? Questions??? 21