Evolution of Response Evaluation in Oncology Trials

Transcription

1 Evlutin f Respnse Evaluatin in Onclgy Trials Presented by: Dr. Dhiraj Abhyankar, Directr, Scientific Develpment March 30, 2017 Wrking with yu t create a healthier wrld.

2 Welcme & Intrductins Sessin Mderatr Dr. Yamin M Khan Executive Vice President, Clinical Develpment Asct, UK Tpic Expert Dr. Dhiraj Abhyankar Directr, Scientific Develpment Bangalre, India

3 What We ll Cver Tday A Brief Histry and Overview f Respnse The Principles f Respnse Evaluatin Respnse Evaluatin Criteria (slid tumurs) The Future f Respnse Evaluatin Q&A

4 27 Offices with Emplyees in 40 Cuntries, Cnducting Trials in 65 Cuntries Americas: USA (Hustn Glbal HQ, Research Triangle Park) Brazil (Sã Paul) Canada (Trnt) Méxic (Méxic City) Eurpe: UK (Lndn Eurpe HQ) Belgium (Brussels) Bulgaria (Sfia) Cratia (Zagreb) Czech Rep. (Prague) France (Paris) Germany (Munich) Hungary (Budapest) Italy (Milan) Pland (Warsaw) Rmania (Bucharest) Serbia (Belgrade) Spain (Madrid) ROW: Suth Africa (Pretria) India (Bangalre) Cmmnwealth f Independent States & Eurasia: Belarus (Minsk) Russia (Mscw, St. Petersburg, Nvsibirsk) Gergia (Tbilisi) Kazakhstan (Almaty) Ukraine (Kiev) Lcal Staff: Estnia Israel Krea Latvia Lebann Lithuania Prtugal Slvakia Turkey

5 Intrductin Respnse evaluatin necessary in clinical trial and practice Respnse in slid tumrs dne radilgically Respnse evaluatin evlved ver time Reliability f data Advances in radilgical technique Changes in mechanism f actin drugs Cvering nly slid tumrs

6 A Brief Overview

7 Overview Criteria WHO RECIST 1 RECIST 1.1 PERCIST irrc Technlgy X-Ray/CT CT MRI CT MRI PET PET CT MRI Drugs Cyttxic Cyttxic Targeted Therapy Targeted Therapy Immun

8 Overview Prstate EASL, mrecist, RECICL RENO & ireno Other Cancer Respnse Criteria CHOIR Mesthelima Ovary

9 The Principles f Respnse Evaluatin Quantitative evaluatin f measurable lesins Qualitative evaluatin f nt measurable lesins Befre and at regular intervals Same methds f investigatin Fur categries: Cmplete respnse (CR) Partial respnse (PR) Stable disease (SD) Prgressive disease (PD) CR PR t be cnfirmed

10 Respnse Criteria

11 Pre-WHO Mertel and Hanley evaluated tumr size by palpatin High false tumr deductin in 19-25% cases Recmmended true tumr respnse t be >50% 25% reductin in prduct f diameters as a respnse 50% reductin as a significant reductin in size

12 WHO Criteria (1979) Unavailability f CT scan. Tumr measurements by palpatin x-ray Sum f Bi-dimensinal measurement (greatest perpendicular dimensins) CR: Cmplete disappearance fr at least 4 weeks PR: 50% r greater reductin frm baseline cnfirmed at 4 weeks N change PD: At least 25% increase r new lesin Limitatins:- PD with can ccur with 11% increase in each dimensin Nt explicit n n f tumr fci t be measured Hw small a lesin culd be measured

13 RECIST (2000) Up t 10 target lesins t assess Transaxial imaging with CT Only sum f single lngest dimensin Minimum size f the lesins 1 cm Target and nn-target lesins Respnse CR: Disappearance f all tumr fr at least 4 weeks PR: At least 30% decrease fr at least 4 weeks SD: Neither PR nr PD PD: At least a 20% increase frm nadir f new lesin

14 Cmparing WHO and RECIST 20% Increase is 44% increase in the bi-dimensinal Less Frequent PD using RECIST than WHO Time t PD can be shrter with WHO

15 Limitatins with RECIST Is assessing less than 10 lesins adequate? Phase III trials has OS as endpints Use f FDG-PET and MRI Assessment f lymph ndes? Respnse cnfirmatin is truly needed? Applicability fr targeted nn-cyttxic drugs Vlumetric r functinal assessment?

16 RECIST 1.1 (2009) Lngest dimensin fr tumur and shrt axis fr lymph ndes Minimum measurable lesin size Lng axis 10 mm (CT + MRI) and 2x slice thickness Lng axis 20 mm n chest x-ray Lymph Ndes: Shrt Axis 15 mm Up t 5 target lesins ttal, 2 per rgan PD: Same but the increase shuld als be at least 5 mm frm nadir Nn-measurable assessment: substantial wrsening PET: May fr PD, cnfirmatin f CR Cnfirmatin f PR r CR Only fr nn-randmized trials with ORR as endpint

17 Definitin f Nntarget = Nntarget Lesins Small lesins and nt qualifying as Target Lesins Truly nn-measurable lesins: Bne lesins Leptmeningeal disease Pleural/pericardial effusin and ascites Inflammatry breast disease Lymphagitis Cystic lesins

18 Als Wrth Nting Patients with measurable disease shuld be included in prtcls with ORR Select largest reprducibly measurable lesins T recrd multiple nn-target lesins f same rgan as a single item Lesins with prir lcal treatment nt as (unless PD) Ostelytic lesins (sft tissue cmpnent) Lesins that split r calesce n treatment Additinal requirement fr PD Als a 5 mm abslute increase in the SLD Nn-target representative f change in verall tumur burden

19 RECIST 1 vs. RECIST 1.1 RECIST 1 RECIST 1.1 Tumur Burden 10 Targets (5 per rgan) 5 Targets (2 per rgan) Lymph Ndes Like any ther lesin Shrt axis, defined Nr size PD Definitin 20% Increase in SLD 20% Increase in SLD 5 mm abslute increase Nn- Measurable PD Unequivcal Mre details Cnfirmatin New Lesins Required fr CR & PR Required in nn-randmised trials with RR as 1ry endpint Sectin n FDG-PET

20 Cmmn Mistakes Made in RECIST Assignment f nn-qualifying lesins (number, size etc.) 2. Measurement f irregular, nn-reprducible targets 3. Inclusin f bne metastases 4. Evaluatin f cystic/necrtic tumr changes 5. Reappearing lesins as PD 6. Baseline/Nadir as reference fr PD 7. Incnsistencies in fllw-up

21 Limitatins f Anatmic Respnse Criteria Cytstatic drugs with lngstanding stable disease OS benefit with limited antitumr size seen in hepatmas treated by srafenib

22 PET Respnse Criteria in Slid Tumrs (PERCIST) 18F-FDG PET fr tumr respnse f breast cancer in 1993 PET can detect cancers that are smaller than depicted n CT The EORTC PET prpsed in 1999 and PERCIST 1.0 in 2009 Respnse is assessed as cntinuus variable as % SUL peak (r sum f lesin SULs) CR: Disappearance f all metablically active tumrs PR: <30% and 0.8 unit decline in SUL peak between the mst intense lesins (nt necessarily the same lesin) PD: >30% and 0.8 unit increase in SUL peak r new lesins r >75% increase in ttal lesin glyclysis

23 RECIST may nt d justice t Immun-Onclgy Drugs Ipilimumab Trials Have Shwn: SD and then decrease in tumur mass PD (increase and/r new lesins) fllwed by respnse r SD May take lnger Discntinuatin f therapy unless PD is cnfirmed Allwance fr clinically insignificant PD is recmmended Durable SD may represent antitumr activity

24 Immune Related Respnse Criteria (irrc) Assessment as a cntinuus variable (lesins at baseline r new) Only measurable lesins with bidimensinal measurement Sum f the perpendicular diameters (SPD) at baseline is added t new lesins t calculate ttal tumr burden Respnse categries (ircr, irpr, irsd, and irpd) same as WHO New lesins alne is nt irpd (if nt >25% add t tumr burden) New lesins but verall tumr burden decrease = irpr (50% decrease) r irsd (<50% decrease t >25% increase)

25 T Revisit RENO & ireno Mesthelima Ovary Bne Mets Other Cancer Respnse Criteria Prstate Chi EASL, mrecist, RECICL

26 RANO Criteria fr High-Grade Glimas Macdnald (1990) respnse criteria fr high-grade glimas Based n CT scan (like WHO), crticsterids use and changes in the neurlgic status Pseudprgressin (20%) fllwing TMZ/RT TMZ PD after 3 mnths pst t/t unless new lesin, path cnfirmatin RANO permits PD t cntinue t/t pending fllw-up imaging

27 RANO irano (<6m f t/t) irano (>6m f t/t) Is repeat scan required t cnfirm PD w/ significant change in clinical? Minimum time t cnfirm PD (clinically stable) N/A >3m N/A If further immn t/t allwed after initial PD (if clinically stable) pending PD cnfirmatin N/A N/A Dse a new lesin define PD

28 MDA Criteria fr Bne Metastasis Bne mets nn-measurable in WHO and RECIST Hamaka (2004) using X-ray (XR), CT, MRI, r Skeletal scintigraphy and SPECT Scans (supprtive) Recmmended fllw up imaging every 2-6 mnths CR: Cmplete fill-in r sclersis f lytic lesin, nrmalizatin f steblastic lesin PR: Sclertic rim abut initially lytic lesin r sclersis f previusly undetected lesin, partial fill-in r sclersis f lytic lesin r regressin f measurable lesin, decrease in blastic lesin Every lesin need nt regress, but n lesin shuld have prgressed WHO criteria are retained

29 Chi Criteria fr Gastrintestinal Strmal Tumr RECIST 1.0 significantly underestimated initial tumr respnse t imatinib in GISTs Significant changes in tumr density, enhancing intratumral tumr ndules, and tumr vessels was nted Chi criteria used a cmbinatin f the values f tumr size and tumr density n CT scan CR: Disappearance f all lesins, n new lesins PR: Decrease in size f 10% r a decrease in tumr density 15% n CT SD: N change PD: Increase in tumr size f 10% r new lesins r new intra-tumral ndules r increase in the size f the existing intra-tumral ndules

30 Chi Criteria fr Gastrintestinal Strmal Tumr Rules fr definitins f lesins, measurement rules, calculatin rules, respnse determinatin rules, reprting guidelines were nt reprted Als used in metastatic renal cell carcinma, high grade sft tissue sarcma, slitary fibrus tumr and hepatcellular carcinma respnse evaluatin

31 Hepatcellular Carcinma: EASL, mrecist, RECICL Simple bi-dimensinal determinatins as tumr necrsis is nt accunted Eurpean Assciatin fr the Study f Liver (EASL) criteria is based n WHO criteria American Assciatin fr the Study f Liver Disease (AASLD) mdifying RECIST Liver Cancer Study Grup f Japan prpsed revisins t Respnse Evaluatin Criteria in Cancer f the Liver (RECICL) Tumrs are measured in tw dimensins, and the dense accumulatin f lipidl is regarded as necrsis 3 tumr markers including alpha-fetprtein, AFP-L3 and des-gamma-carbxy prtein (DCP) were als added

32 Prstate Ca (PCWG2 Criteria) Limitatins with RECIST: Bne scans have shwn PD far mre quickly Uncertainty f interpreting the significance f PSA change Apprvals fr CRPC drugs n reductin in skeletal-related events Fr sft-tissue disease in ndes and/r viscera fllw RECIST PSA prgressin as an increase f >25% r increase f >2 ng/ml frm nadir PSA decline t be cnfirmed by 3 r mre weeks later PSA prgressin alne is nt an indicatin t stp treatment Bne scan prgressin as either: Tw new lesins nted n the first n-treatment scan fllwed by tw additinal lesins n the next scan Or tw new lesins seen n any scan after the first n-treatment scan that are cnfirmed n a subsequent scan

33 Malignant Pleural Mesthelima Typically demnstrates a nn-spherical grwth pattern Difficult t dcument tumur respnse by RESIST New functinal imaging techniques, such as PET, diffusin-weighted MRI and dynamic cntrast-enhanced MRI (DCE-MRI) imprve assessment

34 Ovarian Cancer Gyneclgic Cancer Intergrup (GCIG) criteria PD n basis f either RECIST criteria r CA 125 criteria Dubling in CA 125 frm the upper limit f nrmal reliably predicts bjective prgressin

35 IN CONCLUSION The Future f Respnse Evaluatin Use f cntinuus, as ppsed t discrete, sets f respnse Individualized medicine era (type f cancer and the patient) Tumr respnse criteria shuld be based n treatment and type f tumr Validatin f functinal bimarkers like FDG PET t prve crrelatin with OS

36 Questins? THANK YOU FOR JOINING US TODAY. FOR MORE INFORMATION, VISIT PHARM-OLAM.COM