STUDI ADATTATIVI IN ONCOLOGIA Workshop RAPPORTO COSTO-BENEFICIO DEI NUOVI TRIAL. Armando Santoro. ISTITUTO SUPERIORE DI SANITA 17 novembre 2017

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1 STUDI ADATTATIVI IN ONCOLOGIA Workshop RAPPORTO COSTO-BENEFICIO DEI NUOVI TRIAL Armando Santoro ISTITUTO SUPERIORE DI SANITA 17 novembre 2017

2 DISCLOSURE BMS MSD Bayer Roche Novartis Amgen Celgene AbbVie Pfizer Sandoz Astra Zeneca Lilly Takeda Mundipharma Servier Arqule Incyte Gilead Daiichi Sanofi

3 OBJECTIVES To understand why, in general, development of new drugs is changing the methodology of clinical research To understand the advantages of adaptative studies To critically analyse the costs/benefits of such approach in terms of: - clinical results - data consistency/reproducibility - patient s benefit - regulatory policy - economic affordability

4 FASI DI SVILUPPO DEI CHEMIOTERAPICI FASI DI SVILUPPO DI NUOVI FARMACI PRECLINICA FASE 1 FASE 2 FASE 3

5 I PROBLEMI DELLA RICERCA CLINICA

6 I PROBLEMI DELLA RICERCA CLINICA RANDOMIZED CLINICAL TRIALS REMOVING UNNECESSARY OBSTACLES Reith C et al ; NEJM 2013 UNLESS RADICAL IMPROVEMENTS ARE MADE TO THE REGULATORY ENVIRONMENT, THE POTENTIAL OF CLINICAL TRIALS,...TO PRODUCE SUBSTANTIAL IMPROVEMENTS IN HEALTH CARE AND PUBLIC HEALTH WILL NOT BE FULFILLED IMPACT OF CANCER RESEARCH BUREAUCRACY ON INNOVATION, COSTS, AND PATIENT CARE Steensma DP et al ; JCO 2014 IMAGINE IF, EVERY TIME EDISON OR WESTINGHOUSE HAD AN IDEA, THEY HAD TO WAIT.. TO GET APPROVAL TO TRY THE IDEA. WE WOULD HAVE NO RECORDED MUSIC AND NO ELECTRIC FANS, AND INSTEAD OF SEEING FILMS, WE WOULD SIT AT HOME AND READ BY GASLIGHT

7 I PROBLEMI DELLA RICERCA CLINICA È SEMPLICE RENDERE LE COSE COMPLICATE, MA È COMPLICATO RENDERLE SEMPLICI BASKET TRIALS Arthur Bloch, Legge di Mayer, Legge di Murphy UMBRELLA TRIALS

8 I PROBLEMI DELLA RICERCA CLINICA Graphic Courtesy of the American Association of Cancer Research 2011 Cancer Progress Report

9 THE SEAMLESS ONCOLOGY-DRUG DEVELOPMENT FROM BASKET & UMBRELLA TRIALS TO EXPANSION COHORTS BASKET TRIALS UMBRELLA TRIALS EXPANSION COHORTS

10 FROM BASKET & UMBRELLA TRIALS TO EXPANSION COHORTS BASKET UMBRELL A

11 IMMUNOTHERAPY IN ONCOLOGY NIVOLUMAB: CHECKMATE BASKET TRIAL

12 IMMUNOTHERAPY IN ONCOLOGY PEMBROLIZUMAB: KEYNOTE BASKET TRIAL

13 IMMUNOTHERAPY EXPANSION COHORTS

14 PD-1/PD-L1 INHIBITORS (SEPTEMBER 2017) PD-1 NIVOLUMAB PEMBROLIZUMAB Melanoma NSCLC RCC HL Uro Melanoma NSCLC HNSCC HL Uro HNSCC MSI-H/dMMR MSI- H/dMMR CRC Uro NSCLC Bladder ATEZOLIZUMAB PD-L1 AVELUMAB DURVALUMAB Merkel Bladder Uro

15 IMMUNOTHERAPY IN ONCOLOGY CHECKMATE 205: PHASE II STUDY IN chl COHORT A NIVO IN ASCT ( 60 PTS) COHORT C NIVO IN BV-ASCT- BV ( 100 PTS) COHORT B NIVO IN ASCT+BV ( 60 PTS) COHORT D NIVO PLUS AVD ( 50 PTS)

16 CHECKMATE 205: PHASE II STUDY IN chl COHORT B NIVO IN ASCT+BV ( 60 PTS) EFFICACY OBJECTIVE RESPONSE: 66.3%, CR 9%, PR 58% MEDIAN DOR: 7.8 MS

17 REGULATORY APPROVAL OF NEW DRUGS/INDICATIONS

18 THE SEAMLESS ONCOLOGY-DRUG DEVELOPMENT TRIALS ENROLLING 51 TO 100 PTS 5.3% to 40.5% 100 PTS 1.8% to 13.5%. 16/60 (26.7%) trials in 2011 enrolled pts to 3 sub-cohorts in the expansion phase 60% of studies provided no statistical justification of the sample size, although 91.7% of trials stated response as an objective Dahlberg SE, JNCI; 7, 2014

19 THE SEAMLESS ONCOLOGY-DRUG DEVELOPMENT SEAMLESS ONCOLOGY-DRUG DEVELOPMENT WE BELIEVE THAT THE DESIRE TO PROVIDE EARLIER ACCESS TO HIGHLY EFFECTIVE DRUGS SHOULD ENCOURAGE FURTHER USE OF SEAMLESS EXPANSION- COHORT TRIALS WE CANNOT ABANDON OUR COMMITMENT TO WELL- DESIGNED, WELL-CONDUCTED CLINICAL TRIALS T. M. PROWELL, M. R. THEORET, R. PAZDUR NEJM, 2016

20 THE SEAMLESS ONCOLOGY-DRUG DEVELOPMENT SEAMLESS ONCOLOGY-DRUG DEVELOPMENT

21 CANCER GENETICS AND APPROVAL FOR NEW DRUGS CHIN L. ET AL. NED. 2011; 17:297

22 WHEN ARE POSITIVE CLINICAL TRIALS IN ONCOLOGY TRULY POSITIVE? 2007 TRIALS SHOULD NOT BE DECLARED POSITIVE BASED ONLY ON A STATISTICALLY SIGNIFICANT P VALUE, BUT SHOULD ALSO REQUIRE DETECTION OF A DIFFERENCE IN SURVIVAL OUTCOME THAT EQUALS OR EXCEEDS A CLINICALLY IMPORTANT VALUE THAT IS SPECIFIED IN THE PROTOCOL Ocana A and Tannock IF, JNCI 2010 ASCO PERSPECTIVE 2016 TRUE ADVANCES WHICH CHANGE PARADIGMS IN CANCER CARE AND PROVIDE CLINICALLY MEANINGFUL OUTCOMES FOR OUR PATIENTS Ellis LM et al, JCO 2014

23 WHEN ARE POSITIVE CLINICAL TRIALS IN ONCOLOGY TRULY POSITIVE? Salas-Vega, JAMA Oncol 2017

24 NIVOLUMAB IN 2nd LINE HCC

25 NIVOLUMAB IN 2nd LINE HCC

26 IL VALORE DELLA RICERCA CLINICA the clinically valid comparison is between strategies of overall, not just primary treatment JM Connors NEJM, 2011

27 THE PRICING What Determines A Morally Justifiable Just Price For Cancer Drug? KANTARJIAN et al, Blood 2013 If drug price reflects value, then it should be proportional to the benefit in objective measures, such as survival prolongation, tumor shrinkage or improved quality of life JCO 2014

28 CANCER CARE SPENDING BY NEW DRUGS

29 CANCER CARE SPENDING BY NEW DRUGS FOR INSTANCE, THE COST OF THE COMBINATION OF NIVOLUMAB AND IPILIMUMAB IS PRICED AROUND $252,000, EXCEEDING THE MEDIAN COST OF A US HOME ($240,000 IN 2016). WITH A LIFETIME RISK OF DEVELOPING CANCER OF CLOSE TO 40%, THE PROBLEM IS CLEAR. INNOVATION IS MEANINGLESS IF NOBODY CAN AFFORD IT. Workman, Cell 2017

30 CANCER CARE SPENDING BY NEW DRUGS Chemy N et al, Ann Oncol 2016

31 IMMUNOTHERAPY RESEARCH EXPECTED LAUNCHES WITH COMBINATION IMMUNOTHERAPY +/- TARGETED THERAPY Global Oncology Trend Report 2015 IMS Health

32 CANCER CARE SPENDING BY NEW DRUGS Global Oncology Trend Report 2015 IMS Health

33 HOW TO OVERCOME THE PROBLEM? IF COMPANIES WORK WITH US TO PRICE DRUGS REASONABLY AND MANAGE ANY UNCERTAINTIES IN THE EVIDENCE BASE, WE CAN CONTINUE TO RECOMMEND PATIENTS HAVE ROUTINE ACCESS TO THE TREATMENTS THEY NEED. Carole Longson, Director of the NICE Centre for HTA

34 WHEN ARE POSITIVE CLINICAL TRIALS IN ONCOLOGY TRULY 2007 POSITIVE? CANCER DRUGS APPROVED BY FDA IN (N=54) 36 (67%) APPROVED BASED ON SURROGATE ENDPOINTS 5 DRUGS IMPROVED OS; 18 FAILED; 13 UNKNOWN 2016 Kim, JAMA Intern Med 2015

35 WHEN ARE POSITIVE CLINICAL TRIALS IN ONCOLOGY TRULY POSITIVE? Davis C et al, BMJ 2017

36 IMMUNOTHERAPY RESEARCH ONGOING CLINICAL TRIALS WITH PD1/PD-L1 INHIBITORS (2016) 20 AGENTS 803 TRIALS >166,000 PTS Brawley, Cancer Letter 2016

37 IMMUNOTHERAPY RESEARCH THERE ARE TOO MANY EXPERIMENTAL CANCER DRUGS IN TOO MANY CLINICAL TRIALS, AND NOT ENOUGH PATIENTS TO TEST THEM ON THERE ARE > IMMUNOTHERAPY TRIALS UNDERWAY, AND THE NUMBER KEEPS GROWING. IT S HARD TO IMAGINE WE CAN SUPPORT >1.OOO STUDIES SAID DR. DANIEL CHEN, A VICE PRESIDENT AT GENENTECH IN NEW TRIALS, ADDITIONAL ANTI-PD1 DRUGS ARE BEING TESTED ALL OVER AGAIN AGAINST THE SAME CANCERS A ME-TOO BUSINESS STRATEGY TAKEN TO MULTIBILLION-DOLLAR EXTREMES

38 IMMUNOTHERAPY RESEARCH TRIALS INVOLVING LIMITED NUMBERS OF PATIENTS CAN BE PERILOUS. THE SMALLER THE STUDY AND THE SHORTER ITS DURATION, THE MORE LIKELY THAT WHAT LOOKS LIKE AN EFFECT IN A TRIAL MIGHT BE SIMPLY BE A RESULT OF CHANCE, DR BACH OF MEMORIAL SLOAN KETTERING SAID THE PROBLEM IS THAT MANY OF THE TRIALS ARE UNINTERESTING FROM A SCIENTIFIC VIEW, SAID DR ROY HERBST. THE COMPANIES SPONSORING THESE TRIALS ARE NOT ADDRESSING NEW RESEARCH QUESTIONS, HE SAID; THEY ARE TRYING TO GET PROPRIETARY DRUGS APPROVED

39 I PROBLEMI DELLA RICERCA CLINICA INDUSTRY- SPONSORED REGISTRATION-ORIENTED ACADEMY- SPONSORED PATIENT-ORIENTED

40 HOW TO OVERCOME THE PROBLEM? VI3C WE HAVE THE RESOURCES TO ORGANIZE OUR BOARD AND WHAT WE DO NOT HAVE IN HAND RIGHT NOW ARE THE FUNDS TO ACTUALLY DO THE STUDIES.

41 CONCLUSIONI

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