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Colon Cancer Update 2019Dr. Andrew PippasMedical Oncology2/23/2019

Colon Cancer Update 2019DisclosuresI receive no financial support or remuneration from the companies or theproducts discussed in this presentation.2

Colon Cancer Update 2019Established Non-familial Risks of CRCBiom Research and Therapy: Vol 4 No 10 (2017) / 1656-1675. Gandomani HS, et al. Intake of fruits, vegetables, and high fiber diet decrease risk.High consumption of red meat and saturated fats increases risk.Alcohol (more than 30 gms/day 2 ‘standard' drinks) increases risk.Diabetes increases risk by 33% above baseline. Obesity known to increase RR of death1.55x.Inflammatory bowel disease: 30% of patients will develop CRC after 30 years.Cholecystectomy. RR –1.12x, only right sided colon cancer, due to abnormal exposure ofright bowel to biliary acids.Uretero-colic anastomosis. Increased risk at the site of surgery secondary to the exposureof the colonic mucosa to urinary carcinogens.Pelvic/Rectal radiation. Seen in patient with prior prostate cancer treatment and prior XRTfor lymphomas.Smoking increases risk after 45 years, independent of pack years.NSAIDS/ASA reduce risk by 30%, though amount, duration and mechanism are allunknown /372#ref58

Colon Cancer Update 2019Colorectal Cancer 52% DECLINE IN DEATH RATE SINCE 196951% IN MEN SINCE 198056% IN WOMEN SINCE 19694Used with Permission, Dr. Otis Brawley, Best of ASCO, 2018

Colon Cancer Update 2019Decline in Colorectal Cancer Mortality Rate From 1980–82 to 2013–15by State5

Colon Cancer Update 2019Colon Cancer: Quality of SurgeryA minimum 12 lymph nodes must be pathologicallyexamined in an adequate colorectal cancer surgeryAbout half of Americans have 12 or more LNs examined.Hispanics, Blacks and the poor have higher odds of receiving aninadequate dissection.Inadequate examination associated with hospital where care wasreceived.Inadequate staging leads to some of the talk that colorectal cancer is6more aggressiveamong Blacks!!!Rhoads et al, Cancer 2012 Jan 15;118(2):469-77

Colon Cancer Update 2019Adjusted Colorectal Cancer Survival by Stage and Insurance Status, among WhitePatients 18-64 years Diagnosed from 1999-2000, NCDBStage I, PrivatelyInsuredStage II, Privately Insured7

Colon Cancer Update 201980% by 2018 Goal: Northeastern States closest. In Georgia, the colorectal screening rate is 66.4%,slightly higher than average. Phoebe System is offering FIT testing for underinsured patients andnavigation to expedite colonoscopy. Open Access Colonoscopy Program--no office visit for fit patientsprior to procedure.70%8

Colon Cancer Update 2019Trends in CRC Incidence and Mortality: 2018 ACS (rates per -org. Accessed February 2, 2019

Colon Cancer Update 2019Early Onset Colorectal Cancer: A Challenge and an Opportunity Predominantly left sided colon cancer and rectal cancer, bepoorly differentiated, have mucinous or signet features Familial syndromes account for 20% of these cases: a thoroughfamily history and work up of CRC symptoms needed. Most guidelines do not recommend screening asymptomaticadults: The ACS updated 2018 “qualified recommendation” to beginscreening at 45.10Ahnen DJ, et al. The Increasing incidence of young-onset colorectal cancer: a call to arms. Mayo Clin Proc.2014Feb: 89(2): 216https://onlinelibrary.wiley.com/doi/abs10.3322. May 30, 2018

Colon Cancer Update 2019GI Oncology: Schema of Right and Left Colon11

Colon Cancer Update 201912Histopathology, 2013. Bettington.

Colon Cancer Update 2019Extent of Nodal Dissection: ACS standard of 12 / LNs. Are weremoving enough from RCC? Florida Hospital and McGill reviewed the NCDB, 2004 -2014. Resected non-metastatic colon cancer. Assessed 5 year overall survival,lymph nodes removed. N 505,000. 273,200 had RCC. RCCLCC ST 2 66%70% ST 3 56%60% BUT, RCC survival increased by 20% when 22 or more lymph nodes wereremoved; this would involve higher central venous ligation of the right side,a more complicated procedure. Requires validation in a prospective study.13American College of Surgeons. "Right-sided colon cancer patients have poorer survival than those with left-sideddisease." ScienceDaily. 23 July 2018. .htm.

Colon Cancer Update 2019Anatomic Differences between Right and Left Colon: Both contain Intra andRetroperitoneal features, vascular supply differ.YET, No differencein overall 30 day morbidity (15 vs 17.7%) or 30 Day mortality, (1.5 %) in a review of 251214patients, laparoscopic colectomy for cancer. -Subgroup analyses higher surgical site infections (9-6%), ureteralinjury, conversion open procedure, and LOS (10 vs 7 days)Cancer Treatment Communications 8(2016): 1-4. Analyzing clinical outcomes in laparoscopic right vs left colectomy in colon cancer patients using the NSQIP database. Nfonsam V, et al.

Colon Cancer Update 2019Stage 2 Colon Cancer: MSI-H, dMMR T3, NO MO Observation Consider Folfox/Capox for Higher Risk tumors. Durationunknown as IDEA data cannot be extrapolated to thestage 2 setting despite 4 of 6 trials have high risk Stage 2cohorts 3 to 6 months of oxaliplatin therapy reasonable.NCCN, Colon cancer. Version 4, 201815

Colon Cancer Update 201916PDQ . Coloncancer.gov Accessed Feb 9, 2019

Colon Cancer Update 2019STAGE 2 Colon Cancer: 2019 META-ANALYSES 5FU based chemotherapy: ASCO in 2014-- not routinely recommended. Intergroup Analysis: significant improvement in DFS from 72 to 76 %, No OS benefit, 76 to 81 % Oxaliplatin added to 5FU: 2015 updated analysis of the 2004 Mosaic Trial: No overall benefit fromFOLFOX( 78%). Yet, consider in high risk subgroups: even the definition of this varies between ASCO, NCCN, andESMO. T4 tumors: extension through visceral peritoneum or invades adjacent structures Poorly differentiated(signet ring and mucinous tumors): Not a poor risk feature indMMR/MSI-H Fewer than 12 LN removed( 13 LN, ASCO) LVI or perineural invasion Bowel obstruction or perforation17 Indeterminate or positive margins (NCCN)NCCN, Colon Cancer Guidelines, Version 4. 2018 Up to Date: January 2019.

Colon Cancer Update 2019Micro-Satellite InstabilityMSI: Luc Leyns/publication/224830481. 2/9/2019

Colon Cancer Update 2019Immunohistochemistry for MMR ProteinsCRC: MLH1 and PMS2 form stable Hetero-dimer19Hempel H, Genetics in Medicine, Vol 11, Number 11, Nov 2009

Colon Cancer Update 2019Mismatch repair deficiencypredicts response of solidtumorsto PD-1 blockadeDung T. Le,1,2,3 Jennifer N. Durham,1,2,3* Kellie N. Smith,1,3* Hao Wang,3*Bjarne R. Bartlett,2,4* Laveet K. Aulakh,2,4 Steve Lu,2,4 Holly Kemberling,3 Cara Wilt,3Brandon S. Luber,3 Fay Wong,2,4 Nilofer S. Azad,1,3 Agnieszka A. Rucki,1,3 Dan Laheru,3Ross Donehower,3 Atif Zaheer,5 George A. Fisher,6 Todd S. Crocenzi,7 James J. Lee,8Tim F. Greten,9 Austin G. Duffy,9 Kristen K. Ciombor,10 Aleksandra D. Eyring,11Bao H. Lam,11 Andrew Joe,11 S. Peter Kang,11 Matthias Holdhoff,3 Ludmila Danilova,1,3Leslie Cope,1,3 Christian Meyer,3 Shibin Zhou,1,3,4 Richard M. Goldberg,12Deborah K. Armstrong,3 Katherine M. Bever,3 Amanda N. Fader,13 Janis Taube,1,3Franck Housseau,1,3 David Spetzler,14 Nianqing Xiao,14 Drew M. Pardoll,1,3Nickolas Papadopoulos,3,4 Kenneth W. Kinzler,3,4 James R. Eshleman,15Bert Vogelstein,1,3,4 Robert A. Anders,1,3,15 Luis A. Diaz Jr.20Science 357(6349), 409 June 8,2017

Colon Cancer Update 201921Science 357(6349), 409 June 8,2017

Colon Cancer Update 2019MISMATCH REPAIR DEFICIENCY ACROSS 12,019 TUMORS: Le DT, et al: Science,357, 409-413 (2017);22

Colon Cancer Update 2019GI Oncology: Response Rates to PD1-Ab (Pembrolizumab-Merck)23Le DT et al. N Engl J Med 2015;372:2509-2520

Colon Cancer Update 2019Immune-Checkpoint Update: ESMO 2108Dual PD1/CTLA-4 Therapy: Improved RR with Increased ToxicitiesDr. H-J Leinz, ESMOFIRST- LINE MSI-H, dMMR CRCRR: 60%CR: 7%74% of the responses lasting longerthan 6 monthsObjective Response Rate: 31%Objective Response Rate: 55%Obrade 3-4 toxicities(diarrhea, nausea, fever, fatigue): 14.3% vs 26.7%24Discontinuation rates: 2.9% vs 13.3%Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 studyMichael J Overman, Ray McDermott, Joseph L Leach, Sara Lonardi, Heinz-Josef Lenz, Michael A Morse, Jayesh Desai, Andrew Hill, Michael Axelson, Rebecca A Moss, Monica V Goldberg, Z Alexander Cao, Jean-MarieLedeine, Gregory A Maglinte, Scott Kopetz*, Thierry André* Lancet Oncol 2017; 18: 1182–91: JCO January 20, 2018. Overman et al. Durable Clinical Benefit with Nivolumab Plus Ipilimimab in DNA mismatch repairdeficient/MSI –H metastatic Colorectal Cancer.

Colon Cancer Update 2019PD-L1 Ab as Adjuvant Therapy for MMR Deficient Stage 3Colon Cancer A021502 ATOMIC Protocol Title: Randomized Trial of Standard Chemotherapy Alone orCombined with Atezolizumab as Adjuvant Therapy for Patients withStage III Colon Cancer and Deficient DNA Mismatch Repair Assess the addition of the anti-PD-L1 antibody, atezolizumab(Genentech ) for 12 months, FOLFOX (6 months) vs FOLFOX. 10 FEB, 2019: Accrual 152/700.25CTEP/CTSU. CTSU.org. Accessed Feb 10,2019

Colon Cancer Update 2019Adjuvant Oxaliplatin based Chemotherapy for Stage 2/3 Colon Cancer: The 70 year old (patient) question.ASSENT data base of 11,953 patients on 7 clinical trials from 1997 to 2004. Data censored to removed other death from othercauses.NODFSBENEFITOSTime toReoccurrence26JCO: 2013 Jul 10: 31 McCleary NJ, et al. Ann Oncol.2015;269(4).Haller DG, et alMore recent 2015 series suggestsimprovement in the DFS (0.77, p .014) andOS (HR, 0.78,P .045) for FOLFOX/CAPEOX in patientsThe benefits of adjuvantOxaliplatin-based chemotherapyare controversial for patientsabove the age of 70 years. Patientcare in this setting needs to beindividualized, cognizant of comorbidities.

Colon Cancer Update 2019Maintenance Therapy(MT) for Stage 4 CRC OPTIMOX 2 GERCOR( Dr deGramont), 2009: FOLFOX 7 X6, alone, with Infusional 5-FU,as MT. Trend to improved OS( median survival 24 months versus 20 months, p 0.42) YET, chemotherapy was not started until tumors had progressed back to preFOLFOX status. MRC COIN, 2011: Continuous therapy with oxaliplatin-based chemo vs 12 weeks oftherapy followed by chemotherapy free interval: no improvement in MS at 19.6 monthsversus 18 months, yet non-inferiority boundary crossed. Chemotherapy-free treatment remains an option for some patients: subgroupanalyses showed patients with baseline NORMAL platelet count gain the benefitsof intermittent therapy; those with elevated platelets have impaired survival andshould not “receive a treatment break.”27JCO. 2009: 27(34): 5727 Lancet Oncol.2011: 12(7): 642

Colon Cancer Update 20192015 Meta-analysis: Eleven RCTs, 4854 PatientsRandomized to Continuous vs Intermittent TreatmentIntermittent strategies ofdelivering systemictreatment of mCRC do notresult in a clinicallysignificant reduction in OScompared with acontinuous strategy ofdelivery, and should be partof an informed discussionof treatment options withpatients with mCRC.28Annals of Oncology, Volume 26, Issue 3, 1 March 2015, Pages 477–485. Berry, SR, et al.

Colon Cancer Update 2019BRAF V600E Mutations in CRC:Mutations in KRAS and BRAF result in constitutive activation of the signaling cascade resulting inuninhibited cellular proliferation and tumor growth29J Gastrointest Oncol. 2015 Dec; 6(6): 660–667. Kopetz and Clarke

Colon Cancer Update 2019BRAF V600E Mutated CRC Median survival one year Unlike Melanoma where RR 50% to monotherapy, RR are 5% in BRAFmutCRC. MSI-unstable in 15-25 % : BRAF V600E mutation results hyper-methylationof MLH1 promoter, silencing the gene. NCCN, updated 2018 guidelines: Vemurafenib, EGFR inhibitor, Irinotecanoption for progressive CRC.30 BRAF MEK(mitogenactivated protein kinase) inhibitors have been studiedwith variable results.Cancer Discov. 2018: 8(4); 428. Corcoran RB, et al.