How Can We Evaluate Response to New Agents? Recent update of imaging response assessment for cancer immunotherapy

2018 KLCA Symposium How Can We Evaluate Response to New Agents? Recent update of imaging response assessment for cancer immunotherapy KYUNG WON KIM, MD, PhD Seoul Asan Medical Center Asan Medical Center

Contents I. Paradigm change in oncology From targeted agents to immunotherapy II. Role of Cancer Imaging Response evaluation Toxicity evaluation III. irecist

Overview of oncologic drug history 2000 2010 2017 Cytotoxic chemotherapeutic Agents Molecular Targeted Therapeutics (MTTs) Immunotherapy 2010 Ipilimumab (Anti-CTLA4) Peng W et al. Drug Dis Toda 2015 Jul y 2014 Pembrolizumab Nivolumab (Anti-PD1) 2016 Atezolizumab Avelumab (Anti-PD-L1) Drug approved from US-FDA

WHO Handbook for reporting results of cancer treatment 1 RECIST Response Evaluation Criteria In Solid Tumors 4 mrecist for HCC Proposed modifications to RECISTv1.1 for assessing response in HCC 6,7 irecist RECIST Working Group 1979 1992 2000 2001 2008 2009 2010 2012 2017 mwho Modified WHO criteria 2,3 EASL criteria Conclusions from the Barcelona 2000 EASL conference 5 RECIST v1.1 Revised RECIST guidelines 8 irrc mrecist Immune Related Response Criteria EASL, European Association for the Study of the Liver; HCC, hepatocellular carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors; WHO, World Health Organisation. 1. WHO 1979. Available at: http://whqlibdoc.who.int/offset/who_offset_48.pdf; 2. Green S, et al. Invest New Drugs 1992;10:239-53; 3. P. Therasse Ann Oncol (2002) 13(suppl 4): 127-129 ; 4. Therasse P, et al. J Natl Cancer Inst 2000;92:205-16; 5. Bruix J, et al. J Hepatol 2001;35:421-30; 6. Llovet JM, et al. J Natl Cancer Inst 2008;100:698-791; 7. Lencioni R, et al. Semin Liver Dis 2010;30:52-60; 8. Eisenhauer EA, et al. Eur J Cancer 2009;45:228-47; 9. EASL-EORTC Guidelines. J Hepatology 2012;56:908-43

Paradigm change Cancer Immunotherapy Immuno-oncology Therapeutics is Coming of Age

Immune checkpoints Immunomodulators T-cell boosting Immune-escape CTLA-4 -expressed on T reg s in lymphatic tissue -regulates activation of naïve and memory T cells PD-1 -binds PDL-1 or PDL-2 on APCs or Tumor cells -inhibits T cells -limits activity of T cells in periphery PD-L1 -binds PD-1 on T-cell -inhibits T cells -limits activity of T cells in periphery Ito F, Chang AE. Surg Oncol Clin N Am 2013;22:765

Immunotherapy for HCC Cancer Immunol Immunother (2018) 67:161 174

Role of Imaging Cancer Imaging Therapeutic effects (Drug-Tumor) Cytotoxic chemotherapy Size change MTTs Decreased vascularity Cystic or hemorrhagic change Adverse effects (Drug-Human) Immunomodulators Inflammatory reaction Cytotoxic chemotherapy Myelosuppresion Neutropenic colitis MTTs Drug-specific toxicities according to their mechanisms Immunomodulators Auto-immune disease-like

Role of Imaging Response patterns to immunomodulators Typical - Size Asan Medical Center Atypical - Tumor Flare - New lesions (pseudoprogression) O Regan KN et al. AJR. 2011;197:W241-6.

Tumor Flare Reaction T-cell infiltrate (white arrow) and extensive necrosis (black arrow) with no residual tumor cells. Clin Cancer Res 2009;15:7412-7420 2017 May 2017 July 2017 Oct Tumor Flare Reaction (=Pseudoprogression) : transient increase in size of existing lesions or appearance of new lesions after starting immunotherapy but does not persist.

Tumor Flare Reaction REF:www.sec.gov/Archives/edgar/data/310158/000031015814000025 /investorbriefingslidesma.htm

Webet JS et al J Clin Oncol 30:2691-2697 Topalian SL et al. N Engl J Med. 2012;366:2443-54 When tumor flare happen??

Four response patterns (A) Response in baseline lesions (B) Slow, steady decline in tumor volume (C) Response after initial rapid increase in tumor volume (D) Tumor volume reduction after new lesions New lesions Clin Cancer Res 2009;15:7412 Kaehler KC et al. Semin Oncol. 2010;37(5):485-98

O Regan KN et al. AJR Am J Roentgenol. 2011;197:W241-6. Four response patterns # Type A response : Response in baseline lesions : no problem # Type B response : Slow, steady decline in tumor vol. : usually no problem to clinician

Four response patterns # Type C response : Response after initial rapid increase in tumor volume : chaos to radiologists (PD?, Flare? # Type D response : Tumor volume reduction after new lesions : chaos to radiologists (PD?, Flare?) 15 O Regan KN et al. AJR Am J Roentgenol. 2011;197:W241-6.

Incidence of pseudo-progression Initial report : melanoma treated with ipilimumab 1 22 patients/227 patients (PD on WHO criteria but SD/PR on irrc) 9.7% Melanoma with nivolumab 2 10% (11/107 patients) In general, all across the tumor type with all immune checkpoint inhibitors 4% (44/1,126 patients) 3 1.Wolchok JD. Clin Cancer Res. 2009 Dec 1;15(23):7412-20. 2. Hodi FS.J Clin Oncol 32, 2014 (suppl 15s; abstr9002) 3. Chiou VL. J Clin Oncol. 2015 Nov 1;33(31):3541-3.

Role of Imaging Toxicity patterns to immunomodulator GI toxicity : colitis, diverticulitis Pneumonitis Hepatitis (LFT abnormality) Pancreatitis (Amylase/Lipase ) Endocrinopathy: hypophysitis, thyroiditis Sarcoid-like reaction Asan Medical Center Cases Immune Related Adverse Events (irae)

Spectrum of irae CTLA4 inhibitor Data from DFCI, Harvard Types of irae Number of patients [%] Months since therapy start to irae (median, [range])* Number of patients with clinical diagnosis of irae $ Colitis (total) 28 (19%) 1.9 [0.4-4.7] 25 Diffuse colitis 26 (18%) 1.9 [0.4-4.7] 23 SCAD # 2 (1%) 1.8 [1.1-2.5] 2 Sarcoid-like lymphadenopathy 8 (5%) 3.16 [0.2-9.1] 0 Pneumonitis 8 (5%) 2.3 [1.1 8.3] 0 Hepatitis 3 (2%) 1.4 [0.3-2.7] 1 Thyroiditis 2 (1%) 4.3 [4.0-4.7] 0 Pancreatitis 1 (0.6%) 3.8 [3.8] 1

Pneumonitis Cryptogenic organizing pneumonitis (COP) pattern Nonspecific interstitial pneumonia (NSIP) pattern Hypersensitivity pneumonitis (HP) pattern Acute interstitial pneumonia/acute respiratory distress syndrome (AIP/ARDS) pattern

Pneumonitis patterns COP pattern (m/c) NSIP pattern It s not an infection

Pneumonitis HP pattern AIP/ARDS pattern It s not a disease progression

Pneumonitis treatment Most patients were successfully treated with steroids. Can restart the immunotherapy again

Response Assessment irecist 2017 March: RECIST Working Group http://recist.eortc.org/irecist/

irrc Immune-related Response Criteria (irrc) WHO-based response criteria for immunomodulator (proposed in 2009) Consider Tumor Flare Reaction Confirmation of Progressive Disease after two consecutive observation at least 4 weeks apart Wolchok JD et al. Clin Cancer Res 2009;15:7412

irrc: Baseline Assessment 30 18 15 20 15 11 Index lesion1 + Index lesion2 + Index lesion 3 The sum of the products of diameters (SPD) of all index lesions is documented. (Bi-demensional) All index lesions might include 5 lesions per organ, up to 10 visceral lesions and 5 cutaneous index lesions. Wolchok JD et al. Clin Cancer Res 2009;15:7412-7420

irrc: Subsequent Assessment 5 x 5 mm <5 x 5 mm 15 20 9 15 20 New (measurable) 10 6 9 New (Nonmeasurable) 4 X 4 Index lesion1 + Index lesion2 + Index lesion 3 + Index lesion 4 +? Tumor Burden= SPD index lesions + SPD new, measurable lesions The SPD of new, measurable lesions: 5 x 5 mm, up to 5 new lesions per organ, 5 new cutaneous lesions and 10 new visceral lesions Wolchok JD et al. Clin Cancer Res 2009;15:7412-7420

Immune-Related Response Criteria (irrc) irrc New, measurable lesions (i.e., 5 x 5 mm) New, nonmeasurable Lesion (i.e., <5 x 5 mm) Non-index lesions CR PR SD PD Incorporated into tumor burden Do not define progression (but preclude ircr) Contribute to defining ircr (complete disappearance required) Disappearance of all lesions in two consecutive Observations not less than 4 wk apart 50% decrease in tumor burden compared with baseline in two observations at least 4 wk apart 50% decrease in tumor burden Compared with baeline cannot be estalblished Nor 25% increase compared with nadir Bidimensional Many target lesions!! At least 25% increase in tumor burden compared With nadir,(at any single time point), in two consecutive Observation at least 4 wk apart

Definition of PD WHO RECIST 1.1 irrc PD Target lesion Non-target lesion New lesion 25% increase in the sum of the products of the two largest perpendicular diameters of all index lesions Unequivocal progression of non-index lesions. Appearance of new lesions 20% increase in the sum of diameters of target lesions and the sum demonstrates an absolute increase of at least 5mm Unequivocal progression of non-target lesions Appearance of new lesions 25% increase in the tumor burden (index +new measurable) - new measurable new unmeasurable Time point Any single time point Any single time point Two consecutive observations at least 4weeks apart Miller AB, et al. Cancer 47:207 214, 1981, Eisenhauer EA et al. Eur J Cancer. 2009;45:228-47, Wolchok JD et al. Clin Cancer Res 2009;15:7412-7420

Pitfalls of irrc Not approved in FDA. Validated in only melanoma treated with ipilimumab Not in PD1/PD-L1 inhibitor Not in other tumor type Using bidimensional measurement Inconvenient Not popular (Most clinical trials of solid tumor in past decade utilized unidimensional measurement based on RECIST) Larger variability Nishino M. Eur J Radiol. 2015 Jul;84(7):1259-68.

irecist Nishino M. Clin Cancer Res. 2013 Jul 15;19(14):3936-43. Unidimensional & 5 target lesions Simple Good reproducibility Concordance with irrc

irecist

irecist Modified from RECIST 1.1 Principles of irecist follow RECIST 1.1, except Management of new lesions What constitues confirmation of progression Still, RECIST 1.1 should be the primary criteria irecist is the exploratory criteria

Change in irecist

Terminology i : immune icr: immune complete response ipr: immune partial response iupd: immune unconfirmed PD icpd: immune confirmed PD isd: immune stable disease isom: immune sum of measurements

PD in irecist CR, PR, SD by RECIST 1.1 at index date of response evaluation Continue to check with regular schedule using RECIST 1.1 Subsequent imaging (4-8 weeks) PD by RECIST 1.1 iupd by irecist PD confirm icpd by irecist PD not-confirmed Stop treatment Treatment and regular evaluation *Treatment past RECIST 1.1 PD should only be considered if patient clinically stable.

PD in irecist

PD in irecist Confirming Progression (icpd) Existing iupd gets worse Lesion category without iupd now meets the (RECIST 1.1) criteria for PD Remaining iupd Existing iupd unchanges

TL TP2 (confirmatory scan, 4 weeks later) BL TL : remains 20% + 5 mm absolute increase compare to nadir isom iupd icpd TP1 120% 100% BL TP1 TP2 TP2 Keep increasing Confirmed as icpd

TL TP2 (confirmatory scan, 4 weeks later) BL TL : remains 20% + 5 mm absolute increase compare to nadir isom iupd iupd TP1 120% 100% BL TP1 TP2 TP2 No change Remaining as iupd

TL NT BL TP1 TP1 - TL : unchanged - NT peritoneal nodule : unequivocally progressed = iupd (RECIST 1.1 PD) TP2 ( 4 weeks later) - TL : unchanged - NT peritoneal nodule continue to unequivocally progress = icpd (RECIST 1.1 PD) Unequivocal Worsening Confirmed as icpd TP2

TL BL NL TP1 TP1 - TL : unchanged - New Lesion TP2 ( 4 weeks later) - TL : unchanged - NL from DLE 2 : worsens TP2 Another New Lesion Confirmed as icpd

Summary: RECIST 1.1 vs irecist

Conclusion New agents with New evaluation criteria!! The assessment based solely on changes in tumor size Misleading when applied to novel anti-cancer drugs Role of Radiologist To take an active part in developing and further optimizing new evaluation criteria

Thank you very much. Special Thanks to Dr. Nikhil Ramaiya, DFCI Dr. Mizuki Nishino, DFCI Dr. Seong Ho Park, Asan Medical Center Dr. Dae Ho Lee, Asan Medical Center