Colorectal Cancer. Sal Bottiglieri, PharmD, BCOP Clinical Oncology Pharmacist, GI & Head & Neck Clinics Moffitt Cancer Center, Tampa, FL

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1 Colorectal Cancer Sal Bottiglieri, PharmD, BCOP Clinical Oncology Pharmacist, GI & Head & Neck Clinics Moffitt Cancer Center, Tampa, FL Disclosures Dr. Bottiglieri has no relevant financial disclosures. 1

2 Learning Objectives Describe the epidemiology, risk factors, and pathology of colorectal cancer. Discuss the screening, diagnosis, and staging for colorectal cancer. Outline typical treatment regimens for adjuvant and metastatic colorectal cancers. Describe the side effects and monitoring parameters associated with with oral chemotherapy and targeted treatments in colorectal cancer. Discuss counseling strategies to maximize compliance and adherence. Colorectal Cancer (CRC) Epidemiology Third most common cause of cancer Incidence 2016: 70,820 Men & 63, 670 Women Third most common cause of cancer related deaths Mortality 2016: 26,020 Men & 23,170 Women 5 year survival: 65.1% Localized: 90.1% Metastatic: 13.5% Stage at presentation Localized: 39% Regional: 35% Metastatic: 21% Siegel RL, et al. CA Cancer J Clin 2016; 66: National Cancer Institute: SEER Database. Available at: Accessed: 2/5/

3 Risk Factors Obesity & Physical Inactivity Diet Smoking Heavy Alcohol Use Age > 50 years old History of colorectal polyps Inflammatory bowel disease African American race and Ashkenazi Jews Family history of CRC Genetic risk factors Familial adenomatous polyposis (FAP) Lynch syndrome Rare disorders Colorectal Cancer Risk Factors; American Cancer Society. Available at: rectalcancer/causes risks prevention/risk factors.html. Accessed on: 2/5/17. Colorectal Cancer Screening Average Risk: Age 50 years old Colonoscopy every 10 years If adenoma or sessile polyp rescreen every 3 5 years Flexible sigmoidoscopy every 5 10 years +/ Guaiac based or immunochemical base testing at 3 year intervals CT Colonography every 5 years Stool Testing Guaiac (FOBT) or immunochemical based testing (FIT) annually DNA based testing every 3 years NCCN. Colorectal Cancer Screening. V Available at: Accessed on: February 11,

4 Colorectal Cancer Screening Inflammatory bowel disease (IBD) 8 10 years after IBD diagnosis colonoscopy Family History First degree relative diagnosed <60 years old or two first degree relatives diagnosed at any age Colonoscopy every 5 years at age 40 or 10 years before relatives age of diagnosis High Risk Syndromes NCCN. Colorectal Cancer Screening. V Available at: Accessed on: February 11, Multitarget Stool DNA Testing Stool DNA Test: Methylated BMP3 & NDRG4 Mutated KRAS Beta actin Asymptomatic persons between with average risk (N=9989) Stool sample and colonoscopy within 90 days No dietary or medication restrictions FIT and DNA tests on stool samples in blinded fashion 65 (0.7%) had colon cancer on colonoscopy 757 (7.6%) had precancerous lesions on colonoscopy Sensitivity Analysis Sensitivity Colon Cancer: 92.3% vs. 73.8% (DNA vs. FIT p=0.002) Sensitivity precancerous: 42.4% vs. 23.8% (DNA vs. FIT p<0.001) Specificity Analysis 86.6% vs. 94.9% (p<0.001) Imperiale TF, et al. N Engl J Med 2014; 370(14):

5 Symptoms Blood in the stool Narrow stools Change in bowel habits Unexplained stomach discomfort Frequent gas pains Unexplained weight loss Rectal Cancer: Straining during bowel movements Libutti SK, et al. Colon Cancer. In Cancer: Principle & Practice of Oncology, edited by DeVita VT Jr., et al., Philadelphia: Lippincott Williams & Wilkins, Diagnosis Physical exam and history Digital rectal exam Stool Testing FOBT or FIT or DNA Colonoscopy if positive Colonoscopy or Sigmoidoscopy with biopsy Pathology Adenocarcinoma Signet ring carcinoma Mucinous carcinoma High grade neuroendocrine Medullary carcinoma NCCN. Colon Cancer. v Available at: Accessed 12/18/2016. NCCN. Rectal Cancer v Available at: Accessed 12/18/2016. Libutti SK, et al. Colon Cancer. In Cancer: Principle & Practice of Oncology, edited by DeVita VT Jr., et al., Philadelphia: Lippincott Williams & Wilkins,

6 Staging Colorectal Cancer Treatment; National Cancer Institute. Available at: treatmentpdq#section/_112. Accessed on: February 11, Treatment Modalities Stage I, II, III considered curable Surgery Generally partial colectomy with complete resection of tumor and minimum of 12 lymph nodes sampled Chemotherapy Utilized after surgical resection to eradicate micrometastatic disease and reduce risk of recurrence Radiation Minimal role in colon cancer primarily neoadjuvant rectal cancer NCCN. Colon Cancer. v Available at: Accessed 12/18/2016. NCCN. Rectal Cancer v Available at: Accessed 12/18/

7 Surgery Curative Partial or total colectomy Primary and regional lymph node removal Isolated liver/lung metastatic resection Palliative Decrease bleeding Relieve obstruction Increase QOL NCCN. Colon Cancer. v Available at: Accessed 12/18/2016. NCCN. Rectal Cancer v Available at: Accessed 12/18/2016. Adjuvant Therapy AJCC Stage Groupings Adjuvant Therapy Stage 0 Stage I Stage II Stage III Stage IV Surveillance Surveillance Consider? Yes Palliation NCCN. Colon Cancer. v Available at: Accessed 12/18/2016. NCCN. Rectal Cancer v Available at: Accessed 12/18/

8 Adjuvant Therapy Summary Initiate 4 8 weeks after surgery Colon Stage II Fluorouracil/Leucovorin (Roswell Park or Simplified) Modified FOLFOX6 (Fluorouracil/Leucovorin/Oxaliplatin) CAPEOX (Capecitabine/Oxaliplatin) Stage III (6 months) Modified FOLFOX6* CAPEOX* FLOX (Bolus Fluorouracil/Leucovorin/Oxaliplatin) Rectal (6 months perioperative chemotherapy) Chemoradiation: Fluorouracil or Capecitabine Chemotherapy: Follow colon NCCN. Colon Cancer. v Available at: Accessed 12/18/2016. NCCN. Rectal Cancer v Available at: Accessed 12/18/2016. Mosaic Trial: Role of Adjuvant Therapy 3 Year Outcomes Disease free Survival (DFS) Stage II and III 78.2% versus 72.9% (FOLFOX versus Fluorouracil/Leucovorin, p=0.002) Stage II: FOLFOX and Simplified 5FU/LV has no difference in risk of recurrence (HR:0.8; 95% CI, ) Stage III: FOLFOX confers 23% risk reduction versus Fluorouracil/Leucovorin alone (HR: 0.77, p=0.002) Risk of recurrence similar for stage II and III with FOLFOX adjuvant therapy (p=0.77) 6 Year Outcomes DFS 73.3% versus 67.4% Stage II and III, HR: 0.8; 95% CI, (FOLFOX vs 5FU/LV) Overall Survival Stage III: 72.9% vs 68.7%, HR: 0.8; 95% CI, (FOLFOX vs 5FU/LV) No difference in DFS and OS for stage II disease Andre T, et al. N Engl J Med 2004; 350: Andre T, et al. J Clin Oncol 2009; 27(19):

9 Adjuvant Chemotherapy: Stage II Colon Cancer Clinical Controversy Consider in the following patients Less than 12 lymph nodes analyzed Poorly differentiated histology Lymphatic/vascular or perineural invasion Bowel obstruction or perforation on presentation Close, intermediate, or positive margins Microsatellite Instability High do not benefit from adjuvant therapy Minimal improvement in survival 5% NCCN. Colon Cancer. v Available at: Accessed 12/18/2016. NCCN. Rectal Cancer v Available at: Accessed 12/18/2016. Adjuvant Therapy: 5 Year Survival Data Stratification Group Chemotherapy No Chemotherapy Stage II No Poor Prognosis: 69% Stage II Poor Prognosis: 57% Hazard Ratio 70% 69.5% HR: 1.02; 95% CI, % 56.1% HR: 1.03; 95% CI, Stage III: 44% 48.9% 35.2% HR: 0.64; 95% CI, O Connor ES, et al. J Clin Oncol 2011; 29:

10 Mismatch Repair Defective mismatch repair (dmmr) in 15% of CRC Microsatellite Instability (MSI) Loss of protein products for genes involved in DNA mismatch repair (MMR) MLH1, MSH2, MSH6, & PMS2 Tumor features Proximal colon predominance, poor differentiation, mucinous histology, lymphocytic infiltration, diploid DNA content Improved stage independent survival Ionov Y, et al. Nature 1993; 363: Thibodeau SN, et al. Science 1993; 260: Adjuvant Regimens Roswell Park Fluorouracil (5FU) 500mg/m 2 & Leucovorin (LCV) 500mg/m 2 IV weekly X 6 weeks Cycled every 8 weeks X 3 cycles CapeOx Oxaliplatin 130mg/m 2 IV over 2 hours day 1, Capecitabine 1000mg/m 2 PO twice daily days 1 14 every 3 weeks X 8 cycles Capecitabine 1250mg/m 2 PO twice daily days 1 14 every 3 weeks X 8 cycles FLOX Fluorouracil 500mg/m 2 IV bolus, LCV 500mg/m 2 IV weekly X 6weeks Oxaliplatin 85mg/m2 IV weeks 1, 3, and 5 Cycled every 8 weeks X 3 cycles FOLFOX Oxaliplatin 85mg/m 2 & LCV 400mg/m 2 over 2 hours, 5FU 400mg/m 2 IV bolus Day 1 5FU 2400mg/m 2 IV over 46 hours Cycled every 14 days X 12 cycles NCCN. Colon Cancer. v Available at: Accessed 12/18/2016. NCCN. Rectal Cancer v Available at: Accessed 12/18/

11 Adjuvant Therapy Counseling Fluorouracil Diarrhea Loperamide Oral fluids Bland foods Mucositis Oral fluids Soft foods Mouth rinse Hand Foot Syndrome Oral fluids Urea based creams Photosensitivity Oxaliplatin Neutropenia & Thrombocytopenia Neuropathy Cold sensitivity Avoid cold objects or food/drink Monitoring: CBC and CMP prior to treatment Skin/Mouth examination Neurotoxicity examination Metastatic Colorectal Cancer: Initial Therapy Intensive Therapy Options FOLFOX +/ Bevacizumab CAPEOX +/ Bevacizumab FOLFOX + Cetuximab or Panitumumab KRAS Wild Type & Left Sided Tumors Fluorouracil/Leucovorin/Irinotecan (FOLFIRI) +/ Bevacizumab FOLFIRI + Cetuximab or Panitumumab KRAS Wild Type & Left Sided Tumors Fluorouracil/Leucovorin/Oxaliplatin /Irinotecan (FOLFOXIRI) +/ Bevacizumab Fluorouracil/Leucovorin +/ Bevacizumab Capecitabine +/ Bevacizumab Non intensive Therapy Options Fluorouracil/Leucovorin +/ Bevacizumab Capecitabine +/ Bevacizumab Cetuximab or Panitumumab KRAS Wild Type & Left Sided Tumors Nivolumab or Pembrolizumab dmmr or MSI H NCCN. Colon Cancer. v Available at: Accessed 12/18/2016. NCCN. Rectal Cancer v Available at: Accessed 12/18/

12 Bevacizumab Anti vascular endothelial growth factor (VEGF) antibody that inhibits tumor angiogenesis Approved: first or second line with 5FU chemotherapy 5mg/kg every 2 weeks or 7.5mg/kg every 3 weeks In combination with FOLFOX or XELOX Improved progression free survival (PFS) In combination with FOLFIRI Improved PFS & Overall Survival (OS) Toxicities Hypertension, Bleeding, Venous Thromboembolism, Wound healing impairment, Proteinuria Drugs (4): Cetuximab Binds to and blocks epidermal growth factor receptor (EGFR) Approval: KRAS wild type metastatic colorectal cancer (mcrc) In combination with FOLFIRI in first line therapy In combination with irinotecan in refractory disease Single in refractory disease 400mg/m 2 IV infusion once over 120 minutes, then 250mg/m 2 IV over 60 minutes weekly In combination with irinotecan PFS=4.1 months, RR=22.9% Monotherapy in patients who have progressed on irinotecan OS=6.1 months One year survival=21% Toxicities: Infusion reactions, Acneiform rash, Hypomagnesemia, Fatigue, Abdominal Pain, & Diarrhea Anti Cancer Drugs (2): Erbitux (package insert). Indianapolis, IN: Eli Lilly;

13 Panitumumab Fully human antibody Approved for mcrc with FOLFOX chemotherapy in first line or as monotherapy in refractory disease 6mg/kg IV over one hour every 14 days Multi center trial vs. best supportive care PFS=96 v 60 days 75% pts in BSC crossed over No difference in OS, RR or symptoms Toxicities Infusion reactions, Acneiform rash, Hypomagnesemia, Fatigue, Abdominal pain, & Diarrhea Clin Cancer Res 2008; 14(5): Vectibix (package insert). Thousand Oaks, CA: Amgen; 2016 EGFR Monitoring & Management Acneiform Rash Grade 1: Continue EGFR agent Topical 1 2.5% hydrocortisone cream or clindamycin 1% gel Grade 2: Continue EGFR agent Topical 2.5% hydrocortisone cream or clindamycin 1% gel or pimecrolimus 1% cream Doxycycline 100mg PO BID or Minocycline 100mg PO BID Grade 3 or 4: Hold EGFR agent As above plus methylprednisolone dose pack Diarrhea Management Electrolytes periodically Infusion reactions Hirsch V. Curr Oncol. 2011; 18(3):

14 Second Line Therapy of Colorectal Cancers Previous Oxaliplatin Therapy FOLFIRI OR Irinotecan +/ Bevacizumab OR Ziv aflibercept OR Ramucirumab KRAS WT: FOLFIRI OR Irinotecan + Cetuximab OR Panitumumab MSI H: Nivolumab or Pembrolizumab Previous Irinotecan Therapy FOLFOX OR CAPEOX +/ Bevacizumab KRAS WT: Irinotecan + Cetuximab OR Panitumumab MSI H: Nivolumab or Pembrolizumab NCCN. Colon Cancer. v Available at: Accessed 12/18/2016. NCCN. Rectal Cancer v Available at: Accessed 12/18/2016. Ziv Aflibercept Recombinant fusion protein Approval: Second line mcrc in combination with FOLFIRI following progression on first line FOLFOX Median OS: 13.5 vs months (FOLFIRI + zivaflibercept vs. FOLFIRI + Placebo) p= Decoy receptor: Vascular endothelial growth factor A (VEGF A), VEGF B and Placental Growth Factor (PlGF) Administer via IV infusion over one hour Boxed warnings Hemorrhage GI perforation Compromised wound healing Hold 4 weeks prior and post surgery Warnings and precautions: Fistula, hypertension, thromboembolic events, proteinuria, neutropenia, diarrhea, reversible posterior leukoencephalopathy syndrome Abraham J, et al. Commun Oncol. 2012; 9:

15 Ramucirumab Fully human IgG 1 monoclonal antibody Binds to VEGF receptor 2 (VEGFR 2) Indications/dosage: Single agent or combination with paclitaxel for gastric or gastro esophageal adenocarcinoma (8mg/kg IV every two weeks) Combination with docetaxel in non small cell lung cancer (10mg/kg IV every three weeks) Combination with FOLFIRI in mcrc (8mg/kg IV every two weeks) Median OS: 13.3 vs months (FOLFIRI + Ramucirumab vs. FOLFIRI + Placebo) Administration: Pre medicate with IV anti histamine If Grade 1 or 2 infusion reaction add acetaminophen and dexamethasone and decrease rate by 50% Administer dose in normal saline with final volume of 250ml over one hour Boxed warnings: Hemorrhage Gastrointestinal perforation Impaired wound healing Warnings and precautions: Arterial thromboembolic events, hypertension, infusion reactions, RPLS, proteinuria, thyroid dysfunction, cirrhosis Cyramza (package insert). Indianapolis, IN: Eli Lilly; mcrc: Refractory Treatment Options Regorafenib Trifluridine + Tipiracil Nivolumab or Pembrolizumab (MSI H) Clinical trial Best supportive care (BSC) NCCN. Colon Cancer. v Available at: Accessed 12/18/2016. NCCN. Rectal Cancer v Available at: Accessed 12/18/

16 Regorafenib Multikinase inhibitor Inhibits VEGFR, RET, KIT, PDGFR, BRAF tyrosine kinases Fluorinated phenyl ring added to sorafenib Indications mcrc post progression of chemotherapy & targeted therapies Gastrointestinal stromal tumor (GIST) post progression with imatinib and sunitinib Dose: 160mg PO daily days 1 21 every 28 day cycle Take with a low fat breakfast (<30% fat) Boxed Warnings Severe and fatal hepatotoxicity Warnings/Precautions Hemorrhage, dermatologic toxicity, hypertension, cardiac ischemia, reversible posterior leukoencephalopathy syndrome (RPLS), GI perforation, and wound healing impairment Avoid use in Child Pugh C Drug Interactions Regorafenib inhibits: CYP2B6, 2C8, 2C9, 2C19, and 3A4 M2 metabolite inhibits: 2C8, 2C9, 2D6, and 3A4 Avoid CYP3A4 inhibitors and inducers Stivarga (package insert). Whippany, NJ: Bayer HealthCare Pharmaceuticals; CORRECT Phase III Trial Patients required exposure if available in each site: fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab (KRAS WT) Randomization: 2:1 ratio (Regorafenib: placebo) Stratification: Previous anti VEGF therapy Time from diagnosis of metastatic disease Geographical region KRAS MT: 51% vs. 51% (Regorafenib vs. Placebo) BRAF MT 4% vs 2% Number of previous therapies: 1 2: 27% vs. 15% 3: 25% vs. 28% 4: 49% vs. 47% Grothey A, et al. Lancet. 2013; 381: Regorafenib + BSC (N=505) MCRC adenocarcinoma Received locally and currently approved standard therapies Known KRAS status (N=760) Placebo + BSC (N=255) End Point Regorafenib Placebo Hazard Ratio P Value Median OS (Months) ; 95% CI, Median PFS (Months) ; 95% CI, < CR+PR=ORR (%) Disease control= PR+SD (%) <

17 Regorafenib Toxicity Adverse Event Regorafenib + BSC Placebo + BSC All (%) Grade 3 (%) Grade 4 (%) All (%) Grade 3 (%) Grade 4 (%) Any Fatigue 47 9 < <1 Hand foot <1 0 syndrome (HFS) Diarrhea 34 7 < Anorexia Voice changes 29 < Hypertension Mucositis Rash Taste alteration Thrombocytopenia 13 3 <1 2 <1 0 Hyperbilirubinemia Proteinuria <1 0 Anemia 7 2 < Hypophosphatemia <1 <1 0 Death related to adverse events (N=8) One fatality due to drug induced liver injury Grade 1 5 hemorrhage: 21% Fatal hemorrhage: 0.6% (CORRECT & GRID) GI perforation: 0.6% Hypertensive crisis: 0.25% Grothey A, et al. Lancet. 2013; 381: Crona DJ, et al. Ann Oncol. 2013; 47(12): Regorafenib Dose Modifications Toxicity Hepatotoxicity Grade 3 AST and or ALT elevation AST or ALT > 20 X ULN AST or ALT > 3 X ULN and bilirubin > 2 X ULN Reoccurrence of AST or ALT > 5 X ULN despite dose reduction to 120mg Dermatological Toxicity Grade 2 HFS Grade 3 HFS Grade 2 hypertension Additional grade 3 or 4 events GI perforation or fistula Severe or life threatening hemorrhage Wound dehiscence RPLS Failure to tolerate 80mg dose Dose Modification Withhold dose until recovered, resume at 120mg dose* Permanently discontinue Permanently discontinue Permanently discontinue *If recurrence of AST or ALT > 5 X ULN permanently discontinue 120mg daily for first occurrence Interrupt therapy X 7 days then reduce to 120mg daily If recurrence of grade 2 3 HFS may reduce to 80mg daily Interrupt therapy Interrupt therapy, on recovery reduce to 120mg daily Permanently discontinue Permanently discontinue Permanently discontinue Stivarga (package insert). Whippany, NJ: Bayer HealthCare Pharmaceuticals;

18 Regorafenib Monitoring Toxicity Monitoring Parameter Outcome and Frequency Hepatotoxicity Liver function tests (LFT) Baseline then every 2 weeks X 2 months then monthly Hemorrhage Dermatologic Signs and symptoms of bleeding or bruising Signs and symptoms of rash, erythema, pain, blisters or swelling on palms of hands or soles of feet Permanently discontinue in patients with severe or life threatening hemorrhage Modify dose or permanently discontinue depending on severity Hypertension Blood pressure Weekly X 6 weeks then monthly, temporarily or permanently withhold for severe or uncontrolled hypertension Cardiac Ischemia Physical Exam/Patient Report Withhold in patient who develop new or acute onset cardiac ischemia RPLS RPLS evaluation Perform in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental status. Permanently discontinue GI perforation or Physical examination Permanently discontinue fistula Wound Healing Examination prior to surgery Stop treatment two weeks prior to surgery, reinitiate after surgery based on adequate healing Crona DJ, et al. Ann Oncol. 2013; 47(12): Toxicity Management Fatigue Conduct Brief Fatigue Inventory Check thyroid function Consider dosing at night HFS Full skin exam prior to initiation Keratolytic agents Urea 10% cream Salicylic acid 3% cream Ammonium lactate 12% cream Topical steroids Clobetasol 0.05% ointment Betamethasone ointment Topical analgesics (lidocaine cream) Mucositis: Oral care Diarrhea Loperamide, Atropine/Diphenoxylate, Tincture of opium IV fluids Octreotide Hypertension Consider angiotensin converting enzyme inhibitors or beta blockers Hofheinz R D, et al. Oncol Res Treat. 2015; 38:

19 Regorafenib Counseling Take every morning with low fat breakfast 2 slices of white toast, 1 tablespoon of low fat margarine, 1 tablespoon of jelly and 8 ounces of skim milk Do not take two doses in one day if a dose is missed Swallow whole, do not crush or chew Open one bottle at a time Liver function monitoring and risk of liver damage Blood pressure monitoring at home Signs of hypertension: headache & lightheadedness Diarrhea Loperamide for initial symptoms, oral fluid intake, avoid exacerbating foods HFS Symptoms: Redness, pain, blisters, and/or bleeding and swelling on their palmar and plantar surfaces Wear comfortable shoes, avoid stress to hands and feet, keep skin moisturized, avoid exposure to hot water, and vigorous exercise Seek attention for severe bleeding, chest pain, or dyspnea Inform provider of any recent or pending surgery Inform their pharmacist of any new medications Appropriate contraception (pregnancy category D) Crona DJ, et al. Ann Oncol. 2013; 47(12): Trifluridine + Tipracil (TAS 102) Oral combination thymidine nucleic acid analogue (Trifluridine) and thymidine phosphorylase inhibitor (Tipracil) 35mg/m 2 PO twice daily days 1 5 and 8 12 every 28 day cycle after meals Do no initiate a cycle if ANC< 1500, Platelets <75,000 or Grade 3 or 4 nonhematologic toxicity Hold within a cycle if ANC<500, febrile neutropenia (FN), platelets <50,000, or Grade 3 or 4 non hematologic toxicity Supplied as 15mg and 20mg tablets Warnings/Precautions: Myelosuppression Embryo Fetal Toxicity Monitoring CBC with Differential Day 1 and 15 X 2 cycles then monthly CMP monthly Physical exam monthly Consider monitoring patient with CrCl ml/min closer Mayer RJ, et al. N Engl J Med 2015; 372: Lonsurf (package insert). Princeton, NJ: Taiho Oncology;

20 RECOURSE Phase III Trial Patients required exposure: fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab (KRAS WT) Randomization: 2:1 ratio (TAS 102: placebo) Stratification: KRAS status Time from diagnosis of metastatic disease Geographical region KRAS MT: 51% vs. 51% (TAS 102 vs. Placebo) Previous therapies: All patients received previous fluoropyrimidine, oxaliplatin, and irinotecan Bevacizumab: 100% vs. >99% Anti EGFR: 52% vs. 54% Regorafenib: 17% vs. 20% Mayer RJ, et al. N Engl J Med 2015; 372: TAS BSC (N=534) MCRC adenocarcinoma At least two previous standard therapies Known KRAS status (N=800) Placebo + BSC (N=266) End Point TAS 102 Placebo Hazard Ratio P Value Median OS (Months) ; 95% CI, < Median PFS (Months) ; 95% CI, < CR+PR=ORR (%) Disease control= PR+SD (%) <0.001 TAS 102 Toxicity Data Adverse Event TAS BSC All (%) Grade 3 (%) Placebo + BSC All (%) Grade 3 (%) Any Nausea Vomiting <1 Decreased Appetite Fatigue Diarrhea <1 Asthenia Febrile Neutropenia Stomatitis 8 <1 6 0 HFS Neutropenia <1 0 Leukopenia Anemia Thrombocytopenia <1 Mayer RJ, et al. N Engl J Med 2015; 372:

21 Trifluridine/Tipiracil Dose Modifications Toxicity Hematologic Febrile Neutropenia Uncomplicated Grade 4 neutropenia or thrombocytopenia that results in more than 1 week delay of the next cycle Non Hematologic Events Grade 3 or 4 Events Exception: Grade 3 nausea/vomiting controlled by antiemetic Grade 3 diarrhea responsive to antidiarrheal medication Dose Modification Reduce dose by 5mg/m 2 Reduce dose by 5mg/m 2 Maximum Dose: 80mg/dose Maximum of three dose reductions permitted to a minimum dose of 20mg/m 2 Lonsurf (package insert). Princeton, NJ: Taiho Oncology; 2016 Trifluridine/Tipiracil Counseling Swallow tablets whole do not crush or chew Take within one hour of morning and evening meal Do not take additional doses for missed doses Proper storage and out of reach of children (cytotoxic agent) Anyone who handles the medication should wear gloves Neutropenic precautions Handwashing Avoid crowds and/or people with active infection Call your provider with a fever > Anti emetic discussion As needed prochlorperazine Avoid exacerbating foods Diarrhea Loperamide for initial symptoms, oral fluid intake, avoid exacerbating foods Appropriate contraception including barrier Avoid breast feeding 21

22 PD1 Data and MSI H CRC Pembrolizumab KEYNOTE 177 (Phase III) First line vs investigators choice KEYNOTE 164 (Phase II) Previously treated all standard therapies 200mg IV Q3 weeks Nivolumab Checkmate 142 (Phase II) Previously treated or intolerance 1 therapy Nivolumab 3mg/kg Q 2 weeks (N3)or Nivolumab 3mg/kg + Ipilimumab 1mg/kg Q 3 weeks X 4 does then Nivolumab 3mg/kg Q 2 weeks (N3 +I1) ORR: N3 (27%) N3+I1 (15%) Leal AD, et al. ASCO Meeting Abstracts Le DT, et al. ASCO Meeting Abstracts 2016; 34: TPS787. Overman MJ, et al. ASCO Meeting Abstracts 2016; 34: Conclusions Although the incidence and mortality of CRC is declining the disease continues to affect many Americans each year Optimization adjuvant therapy has improved tolerability and efficacy outcomes Targeted therapies have increased survival and treatment options in the metastatic setting The tolerability and adherence to oral therapies in mcrc can be challenging Clinical pharmacists can be at the forefront to manage these patients 22

23 Colorectal Cancer Sal Bottiglieri, PharmD, BCOP Clinical Oncology Pharmacist, GI & Head & Neck Clinics Moffitt Cancer Center, Tampa, FL 23