Press Conference. Monday, Sept. 7, :45 a.m. 10:45 a.m. MDT

Transcription

1 Press Conference Monday, Sept. 7, :45 a.m. 10:45 a.m. MDT Dial-In Information & Agenda: wclc2015.iaslc.org/press-media/ Please hold all questions until the end.

2 Lung Cancer Prevention and Screening at the IASLC 2015 Meeting Claudia I. Henschke, PhD, MD Icahn School of Medicine at Mount Sinai New York, NY

3 Lung Cancer Prevention and Screening: IASLC 2015 Screening is a clinical activity that starts with early detection of suspicious findings on CT, followed by early diagnosis of lung cancer with the real benefit coming from the resulting early treatment requires careful attention to all these details to maximize its benefit and minimize its potential harms Requires continuous evaluation and updating and integration of latest advances to remain state of the art Screening leads to new definitions and new concepts, several of which have been important, large scale IASLC initiatives Feature identification of small, early lung cancers and how they differ from non lung cancer findings Refine the pathology definitions of early lung cancers Define new staging criteria for lung cancer Identify and rapidly assess optimal treatments for early lung cancers Develop and test new screening tools Provide alternative study designs and when they should be used for rapid scientific assessment Randomized trials, cohort studies, modeling The Institute of Medicine of the US National Academy of Science new recommendations suggest that methodlogy for continuous evaluation and research in the context of delivering high quality screening should be done Screening evaluation through collection of data in registries provide s a paradigm for such assessment You will see all these topics addressed throughout the next days of the conference in the context of both cohort and randomized control trials performed over the past 20 years

4 Initial CT Screening Studies Early Lung Cancer Action Program (ELCAP) : Cohort study at 2 institutions in NYC, funded by an R01 from the NCI Compared CT with chest x-ray in a cohort of 1,000 smokers 60 and older, partially funded by an R01 from the US National Cancer Institute Lancet 1999; 355: ; PI: C. Henschke PhD,MD Anti-Lung Association Project In Tokyo, Japan 9/1993: added CT as an additional option to the existing CXR screening program at National Cancer Center Hospital, Tokyo, Japan Reported on the initial cohort of 1,611 smokers and never smokers age 40 and older Radiology 1996; 201: PI: M. Kaneko MD Nagano Population-based Lung Screening : Cohort study in the region using mobile CT scanner Cohort of 5,483 Smokers and never smokers 40 and older Lancet 1998; 251: PI: S. Sone MD

5 I-ELCAP Cohorts: Typically provide ongoing screening and produce continuous reports and updates The size of each bar approximates the number of screening participants N=70, ELCAP Hadassah Medical University, Israel NY-ELCAP University of Navarra, Spain OTHER INSTITUTIONS I-ELCAP collaboration POOL data via common protocol 72 institutions in 8 countries N=70,000+ Japan has provided national screening for many years, either by chest x-ray or CT; initial 2 reported studies on CT are listed below Anti-Lung Cancer Association Japan N=1,611 Nagano Population-based lung screening, Japan N=5,483 European Institute of Oncology Milano, Italy N=5,201 Oct 04 Oct 05

6 Randomized Control Trials: screen for a limited time, results available years later The size of each bar approximates the number of screening participants DANTE N=2,472 (CT arm: 1276) National Lung Screening Trial N=53,454 (CT arm: 26,722) Aug 02-Apr 04 RESULT IN 2011 NELSON N=15,822 (CT arm: 7,557) Italian Lung Cancer CT Screening Trial (ITALUNG) N=3,206 (CT arm: 1406) Dec 03-Jul 06 RESULT EXPECTED IN 2016 Danish Lung Cancer Screening Trial (DLCST) N=4,104 (CT arm:2,052) Multicentric Italian Lung Detection (MILD) N=4,099 (CT arm: 2,376) German Lung Cancer Screening Intervention Study (LUSI) N=4,052 (CT arm: 2,029) United Kingdom Lung Cancer Screening Trial (UKLS) N=5,201, pilot project Oct 04-Mar 06 RESULT 2015 Sep 05-Jan 11 Oct 07-Apr 11 NO RESULT YET 2011-ongoing

7 NCI Directors NCI Directors Aug 1999 Sep 2001 Jan 2002 Jun 2006 Sep 2006 Jul 2010 Jul 2010-Mar 2015 Richard Klausner R. Wittes, P. Greenwald Andrew von Eschenbach started the NLST John. E. Niederhuber extended for a critical additional year Harold Varmus Stopped and reported results 1 st subject entered the study in Aug 02 Enrolled last subject Apr 04 1 st subject entered follow-up period Last enrolled subject entered follow-up period Study was halted Oct 10 Sept 02 Sept 03 Sept 04 Sept 05 Sept 06 Sept 07 Sept 08 Sept 09 Sept 10 Time Baseline T0 Round T1 Round T2 Lung cancers diagnosed in CT arm: 67% by screening and 33% without screening after it stopped UNDER SCREENING FOLLOW-UP

8 National Lung Screening Trial The largest RCT trial on CT screening for lung cancer led to the acceptance of screening in the US. Achieved its goal to show that CT screening met the stated mortality reduction threshold of 20% needed to provide national screening However, it was not designed to measure the full magnitude of its benefit nor to identify who should be screened Nor could it incorporate the latest advances needed for future implementation of screening Thus its screening process is not state of the art when screening is to be implemented

9 Development of Insurance Coverage in US December 2013: USPSTF report recommending screening Thus, private insurance coverage started Jan 2014 Centers for Medicare and Medicaid Services (CMS) Started coverage in Feb 2015, not yet fully implemented Veterans Administration Will start coverage in 2016 Required additional intensive efforts by advocacy organizations and medical associations Lung Cancer Alliance, L. Fenton, President Prevent Cancer Foundation, C. Aldige, Founder and President American Legacy Foundation, C. Healton, President American College of Radiology, E. Kazerooni, Prof. U of Michigan Society of Thoracic Surgeons, D. Wood, Prof. U of Washington And many others

10 Implementation of Screening Needs contribution from all these efforts NLST results and ongoing cohort studies provide the needed evidence and state of the art screening Identification of whom to screen and many other needed considerations For example, alternative approaches to nodule measurement Diameter vs. volumetrics Assessment of accuracy of each measurement Identification of optimum smoking cessation approaches Use of registries for continued improvement and quality assurance

11 2016 and Beyond: Lung Cancer Prevention and Screening Smoking cessation fully integrated in all screening programs More nimble methodology for assessing new potential screening tests to existing screening programs Integration of potential screening tests in programs of CT screening Assessment would be available after 2 rounds of screening (baseline and first annual repeat) and Thus a useful test could be quickly identified Collection of biologic samples for future integration in screening for discovery and validation blood, sputum, urine, buccal cells, If proven to be of value, new tests can rapidly be integrated into screening programs

12 Why is IASLC issuing a new Tobacco Declaration Statement? Last statement issued nearly a decade ago (i.e., 2008) Much has changed since 2008 In the US, FDA now has authority to regulate tobacco products There has been a rapid evolution in the economics of tobacco in different regions of the world, the types of tobacco products available to consumers, and tobacco use patterns Most countries (n=180) have now ratified the WHO Framework Convention on Tobacco Control (FCTC) obligating them to implement evidenced-based policies that create smoke-free environments, cessation programs, warning labels, mass media campaigns, advertising bans, and taxation of tobacco Press Conference 2 - ISALC Issues New Tobacco Declaration Statement - K. Michael Cummings, PhD, MPH

13 Effective implementation of FCTC articles is now the primary focus of global tobacco control efforts Source: 2013, WHO MPOWER report Press Conference 2 - ISALC Issues New Tobacco Declaration Statement - K. Michael Cummings, PhD, MPH

14 What has not changed Lung cancer remains the leading cause of cancer death worldwide, killing approximately 1.6 million people annually. At least 80% of lung cancer deaths are attributable to smoking.

15 Lung Cancer Mortality by Sex in 2012 Source: Globocan,

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17 Solutions 1. Advocate for the forceful implementation of the WHO s Framework Convention on Tobacco Control, especially higher cigarette prices via taxation (to at least 70% of the retail price); 2. Support legal reforms that hold tobacco manufacturers civilly and criminally accountable for their actions; 3. Support policies that prevent tobacco initiation by youth such as raising the legal age for purchase of tobacco to 21 years; 4. Ensure the provision of evidence based tobacco cessation services to all who use tobacco, including cancer patients as a standard of care; 5. Support policies that address alternative nicotine delivery devices, such as aerosolized nicotine products that are evidence based and promote overall population health

18 Why increase cigarette taxes? Tripling inflation adjusted specific excise taxes on tobacco would in many low and middle income countries double the price of cigarettes, which in turn would reduce consumption by about 1/3 rd.. N Engl J Med, 2014, vol. 370 (1): p The Lancet Commission on Investing in Health has identified a substantial increase in specific excise taxes on tobacco as the single most important intervention against noncommunicable diseases. The Lancet, 2013; Vol. 382, No. 9908, p

19 Trade Policies & Tobacco Interference IASLC also strongly supports keeping tobacco out of trade agreements such as the Trans-Pacific Partnership Agreement (TPP) IASLC also strongly supports policies that prevent tobacco manufacturers from circumventing the freedom of sovereign nations to enact tobacco control policies that advance public health goals for their citizens (e.g., Australia, Ireland, UK standardized packaging legislation; Uruguay s larger product warnings and ban on brand line extensions)

20 Symposium: Regulation of Tobacco Products Monday, September 7: 2:15-3:45pm, Rooms Taxing tobacco Luk Joossen, Belgium FCTC Geoffrey Fong, Canada FDA regulation of tobacco Mitch Zeller, USA Tobacco litigation Richard Daynard, USA

21 Impact of time to drug approval on potential years of life lost: the compelling need for improved trial and regulatory efficiency. DJ Stewart et al New anticancer drugs can prolong life expectancy Worldwide, steadily increasing regulatory complexity has: Driven up the cost of drug development much faster than the rate of inflation, and this contributes directly to high health care costs Minimal demonstrable impact on clinical trials safety Slows progress, leading to increased suffering & premature death Accelerated Approval, Breakthrough Drug Designation, etc: Cut time to drug approval substantially (& this is important) But predominantly just remove the requirement for phase III trials Don t fix the escalating burden of clinical research bureaucracy Would be expected to have progressively less beneficial effect unless the clinical research bureaucracy is fixed: Shorter distance to the goal posts, but the mud on the way to these closer goal posts keeps getting deeper

22 Method: Illustrative examples: 21 drugs that significantly prolonged survival in incurable malignancies in phase III trials published Calculated life-years lost due to delays in drug approval Results: Cumulatively, worldwide: Median of 12 years from drug discovery to approval 2,541,274 life-years lost per year of delay (1 every 12 seconds) 31,537,958 life-years lost from drug discovery until approval 19,355,028 life-years would have been saved by reducing time from discovery to approval to 5 years Enhanced safety through more stringent clinical research regulation estimated to have saved <700 life years for these drugs Life-years lost due to delays in drug approval vs life-years saved through greater clinical research safety: ~50,000:1

23 Conclusions Huge number of life-years unnecessarily lost Even if only 1-10% of patients had drug access, losses still enormous Does not take into account added effect of: Drugs abandoned prematurely Drugs that can t be accessed since high cost / no payer Ultimate impact of massive research costs on high health care costs Accelerated Approval & Breakthrough Drug Designation, etc help, but we must do much more: Every additional step to further cut time to drug approval saves lives There are solutions! (eg, Stewart et al: Clin Cancer Res 21:2015 In Press; J Popul Ther Clin Pharm 21:e56, 2014; BMC Cancer 13:193, 2013; J Clin Oncol 28:2925, 2010; J Clin Oncol 27:328, 2009) We all share the blame: investigators, research staff, institutions, IRBs, sponsors, CROs, regulators, tort systems, the press We all share responsibility to solve this It is time to act! [email protected]

24 Change in Lean Body Mass and Hand Grip Strength over 12 weeks Primary Endpoints, Median (95% CI) Placebo (N = 161) ROMANA 1 ROMANA 2 ANAM 100 mg (N = 323) p Value Placebo (N = 165) ANAM 100 mg (N = 330) p Value Lean body mass, kg (-0.88, 0.20) 1.10 (0.75, 1.42) < (-1.27, -0.46) 0.75 (0.51, 1.00) <0.001 Hand grip strength, kg (-2.69, -1.05) (-1.60, -0.30) (-1.60, 0.00) (-2.05, -0.45) 0.74 Intent-to-treat population: All randomized patients. ANAM: anamorelin HCl; CI: confidence interval.

25 Change in FAACT Anorexia/Cachexia Domain over 12 weeks FAACT Anorexia/Cachexia Domain I have a good appetite The amount I eat is sufficient to meet my needs I am worried about my weight Most food tastes unpleasant to me I am concerned about how thin I look My interest in food drops as soon as I try to eat I have difficulty eating rich or heavy foods My family or friends are pressuring me to eat I have been vomiting When I eat, I seem to get full quickly I have pain in my stomach area My general health is improving Placebo ANAM Mean change from baseline ROMANA 1 p= N = 141 N = 282 ROMANA 2 p= N = 133 N = 266 Improving Modified intent-to-treat population: All randomized patients who received any study drug and had at least 1 post-baseline lean body mass or hand grip strength measurement. ANAM: anamorelin HCl ; FAACT: Functional Assessment of Anorexia/Cachexia Therapy.

26 Conclusions In NSCLC patients, ANAM treatment significantly improved LBM and BW compared with placebo in ROMANA 1 and 2 Pre-specified exploratory responder analysis showed that approximately twice as many ANAM-treated patients maintained or gained LBM compared with placebo No significant difference in HGS change between ANAM and placebo arms was observed ANAM significantly improved anorexia-cachexia symptoms in patients with advanced NSCLC and cachexia Daily ANAM administration over 12 weeks was well tolerated Pooled median 1-year OS was similar between the two treatment arms, although analysis by LBM responders revealed median 1-year OS was significantly improved in patients who maintain/gain LBM compared with those who lose LBM ROMANA 1 and ROMANA 2 results concur, underlining the consistency between these two independent phase III clinical trials ANAM: anamorelin HCl; BW: body weight; HGS: hand grip strength; LBM: lean body mass; NSCLC: non-small cell lung cancer; OS: overall survival.

27 Results of the IFCT-GFPC 0701 MAPS randomized phase 3 trial: Bevacizumab 15mg/kg plus cisplatin -pemetrexed (CP) triplet versus CP doublet in Malignant Pleural Mesothelioma (MPM) EUDRACT N : ClinicalTrials.gov : NCT MPM: an aggressive cancer originating from parietal pleura with NO validated curative treatment (mos <13 months), NO improvement achieved in the last decade... and NO validated 2 nd line treatments (Scherpereel et al, Eur Respir J 2010) Arnaud SCHERPEREEL* 1, Julien MAZIERES, Jacques MARGERY, Laurent GREILLER, Clarisse AUDIGIER-VALETTE, Denis MORO-SIBILOT, Olivier MOLINIER, Romain CORRE, Isabelle MONNET, Valérie GOUNANT, Henri JANICOT, Radj GERVAIS, Chrystèle LOCHER, Bernard MILLERON, Quan TRAN, Marie-Paule LEBITASY, Franck MORIN, Christian CREVEUIL, Jean-Jacques PARIENTI & Gérard ZALCMAN*, on behalf of the French Cooperative Thoracic Intergroup (IFCT) *PI; 1 Hospital of the University (CHRU) of LILLE, FRANCE [email protected]

28 IFCT-GFPC-0701 trial: MAPS Mesothelioma Avastin cisplatin Pemetrexed Study MPM proved by pleural biopsies (thoracoscopy...) Written informed consent Age 18 - <75 years PS 0-2 Chemonaïve patients not candidate to curative intent surgery according to Multidisciplinary Board At least 1 evaluable or measurable lesion by CT Weight loss <10% within 3 months prior to enrolment No significant cardiovascular comorbidity and/or other usual chemo or beva contra-indications (HTA, GI perforation ) Prophylactic radiotherapy (3 x 7 Gy) before chemo IFCT-sponsored, open-label, multi-centre randomized phase II-III trial (bevacizumab supplied by Roche) R 1:1 A B Pemetrexed 500 mg/m 2 D1 + Cisplatin 75mg/m 2 D1 x 6 cycles, Q21D Pemetrexed 500 mg/m 2 D1 + Cisplatin 75mg/m 2 D1 + Bevacizumab 15 mg/kg D1 x 6 cycles, Q21D Surveillance (n=225) PD: No cross-over allowed Maintenance Bevacizumab 15 mg/kg D1, Q21D until PD (n=223) CT-scan Q 3 cycles in both arms; Response assessed with modified RECIST criteria for MPM Phase 3 primary goal = OS; Secondary goals: PFS, QoL, ancillary studies Stratification: center, histology (epithelioid vs sarcomatoid/mixed), PS (0-1 vs 2), smoking status

29 IFCT 0701 MAPS randomized phase 3 trial Progression free survival (PFS) probability mpfs Time (months) Arm A (PC; n=225): 7.48 mo, 95%CI [ ] Arm B (PCB; n=223): 9.59 mo [ ] Efficacy: median Survival (ITT) median follow-up= 39.4 months [ ] Overall Survival Probability mos Time (months) Arm A (PC): mo, 95%CI [ ] Arm B (PCB): mo [ ] stratified HR=0.61 [ ]; p< [best median PFS in literature 6-7 months; Kindler and al; J Clin Oncol 2012] stratified HR=0.76 [ ]; p= [best median OS from 8.5 months (1rst-generation regimens) to 13 months (CP doublet) Vogelzang and al; J Clin Oncol 2003]

30 Conclusions - MAPS randomized phase 3 trial Adding bevacizumab 15 mg/kg to pemetrexed cisplatin doublet significantly increased both PFS (by 2 months) and OS (by 2.75 months) with only a slight, manageable increase of toxicity (G3-4: 62 vs 71% of cases; p=0.04) Moreover, bevacizumab did not show a detrimental effect on QoL, despite its higher specific non-hematological toxicity (HTA, arterial/venous thrombo-embolic events...) No significant difference between arms for %drug delivery or %2 nd line treatment In this study, standard arm patients (P+C) had a longer OS than patients from historical series or previous trials: role of eligibility criteria for bevacizumab? Talc pleurodesis?... But this was true for both arms and still beva arm did better!!! No predictive clinical/biological marker found yet but other ongoing studies => Therefore the triplet pemetrexed, cisplatin and bevacizumab is a new treatment paradigm for MPM patients eligible for bevacizumab, and not candidate to curative surgery +++

31 Clinical Research Unit B. MILLERON, A LANGLAIS, F. MORIN E. AMOUR, Q.TRAN & M.P. LEBITASY Biomarkers ancillary studies G. LEVALLET, E. CHEVALLIER, S. BROSSEAU, G. ZALCMAN (Caen) A. SCHERPEREEL (Lille) Statistical Group F. CHAILLOT C. CREVEUIL A.D. PHAM JJ PARIENTI Programme Hospitalier de Recherche Clinique (PHRC) National 2007 ROCHE-France: Drug supplying Research grant on biomarkers

32 Q & A