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Please note, these are the actual videorecorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides. Oncology Tumor Panel Series Colorectal Cancer Oncologist and Nurse Investigators Consult on Actual Patients from the Practices of the Invited Faculty Friday, April 24, 2015 6:15 AM – 7:45 AM Faculty Tanios Bekaii-Saab, MD Axel Grothey, MD Jessica Mitchell, APRN, CNP, MPH Tammy Triglianos, RN, MS, APRN-BC, AOCNP Moderator Neil Love, MD Oncology Tumor Panel Series Cases to be presented • A 72-year-old man with KRAS-mutant metastatic colon cancer (mCC) (Ms Mitchell) • A 58-year-old man with KRAS wild-type mCC (Ms Triglianos) • A 36-year-old man with end-stage mCC who has 2 minor children (Ms Mitchell) • An 80-year-old woman with RAS-mutant mCC and a synchronous primary (Ms Triglianos) Theme of this series Applying evidence-based oncology to individual patients Oncology Treatment Timeline Case 1: A 72-Year-Old Man with KRAS-Mutant mCC (Ms Mitchell) Surgical resection, no adjuvant Rx FOLFOX + bevacizumab x6 FOLFIRI + bevacizumab x 18 Regorafenib TAS-102 on x6 clinical trial • Comorbidities: None • Psychosocial: Wife and 2 daughters; significant anxiety in patient and family; anger at diagnosis; poor coping skills; complex family dynamics; longstanding alcohol abuse RAS-Mutant versus Wild-Type CRC • New mutations demonstrated recently • Predicts for resistance to EGFR antibodies Common First-Line Treatments for Metastatic CRC • FOLFOX/CAPOX +/- bevacizumab • FOLFIRI/CAPIRI +/- bevacizumab • FOLFIRI/CAPIRI +/- EGFR antibody (RAS wild type only) • Capecitabine +/- bevacizumab • FOLFOXIRI +/- bevacizumab Patient Education Issues • Oxaliplatin Side Effects/Toxicities – Peripheral neuropathy – Hepatotoxicity – Pulmonary toxicity – Anaphylactic reactions • Irinotecan Side Effects/Toxicities – Diarrhea – Myelosuppresion – Nausea/vomiting – Hypersensitivity CALGB 80405: Bevacizumab vs Cetuximab in First-line KRAS WT mCRC Untreated KRAS WT mCRC (n=1500) Bevacizumab + FOLFOX or FOLFIRI PD Cetuximab + FOLFOX or FOLFIRI PD R • Primary endpoint: OS • Secondary endpoints: ORR, PFS, TTF, DOR, and safety Clinicaltrials.gov, April 2014 (NCT00265850). CALGB/SWOG 80405: Overall Survival OS (m) Arm N (Events) 95% CI Chemo + Cetux 578 (375) 29.9 27.0-32.9 Chemo + Bev 559 (371) 29.0 25.7-31.2 Median P = 0.34 HR 0.925 (0.78-1.09) With permission from Venook AP et al. Proc ASCO 2014;Abstract LBA3. FOLFOXIRI + Bevacizumab • 48-hour continuous infusion of fluorouracil to a total dose of 3200 mg/m2 • 120-minute infusion of oxaliplatin 85 mg/m2 • Plus 120-minute infusion of leucovorin 200 mg/m2 • 60-minute infusion of irinotecan 165 mg/m2 • 30-minute infusion of bevacizumab 5 mg/kg • Cycles repeat every 14 days Loupakis F et al. N Engl J Med 2014;371:1609-18. Phase III TRIBE Study Schema Eligibility • Untreated metastatic colorectal cancer • Unresectable R Endpoints: FOLFIRI/bev versus FOLFOXIRI/bev PFS: OS: Response rate: R0 resection rate: INDUCTION MAINTENANCE FOLFIRI + Bevacizumab (Up to 12 cycles) 5-FU/LV + Bev (N = 508) FOLFOXIRI + Bevacizumab (Up to 12 cycles) 5-FU/LV + Bev Maintenance until disease progression 9.7 vs 12.1 mo 25.8 vs 31.0 mo 53% vs 65% 12% vs 15% Loupakis F et al. N Engl J Med 2014;371(17):1609-18. Maintenance Treatment for Metastatic CRC • Oxaliplatin: Stop after defined # of cycles or symptoms? – Peripheral neuropathy • Irinotecan: Stop after defined # of cycles or symptoms? – GI/diarrhea • Role, if any, of treatment holidays? Common Second-Line Treatments for Patients with CRC Receiving FOLFOX/CAPOX +/Bevacizumab • Switch to irinotecan versus restart oxaliplatin • Biologic: – Continue bevacizumab – Ziv-aflibercept – Ramucirumab – EGFR antibody (RAS wild type only) Oncology Treatment Timeline Case 1: A 72-Year-Old Man with KRAS-Mutant mCC (Ms Mitchell) Surgical resection, no adjuvant Rx FOLFOX + bevacizumab x6 FOLFIRI + bevacizumab x 18 Regorafenib TAS-102 on x6 clinical trial Agents Targeting the VEGF Pathway VEGF-A Anti-VEGF antibody (bevacizumab) Soluble VEGF receptor (Ziv-aflibercept) Anti-VEGFR2 antibody (ramucirumab) VEGFR-1 P P P P VEGFR-2 P P P P VEGFR-3 P P P P Endothelial cell Small-molecule inhibitors of VEGFR (regorafenib, vatalanib, cediranib, motesanib, sunitinib, sorafenib, pazopanib, axitinib, etc) Mode of Action of Regorafenib Regorafenib inhibits multiple cell-signaling kinases: • Angiogenic - VEGFR1-3, TIE2 • Stromal - PDGFR-ß, FGFR • Oncogenic - KIT, BRAF, RET Inhibition of neoangiogenesis Inhibition of stromal signaling Inhibition of proliferation of certain tumor cells Adapted from Grothey A et al. Gastrointestinal Cancers Symposium 2012;Abstract LBA385. CORRECT: Study Design and Survival Outcome Regorafenib + BSC Pts with refractory metastatic CRC (n = 760) 2:1 R Placebo + BSC Grothey A et al. Lancet 2013;381(9863):303-12. Regorafenib • FDA approval September 27, 2012 – Patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, with an anti-VEGF therapy and, if KRAS wild type, with an anti-EGFR therapy. • Pivotal CORRECT Phase III study of regorafenib/BSC versus placebo/BSC for patients with mCRC after disease progression on last standard therapy (N = 760): – Median OS: 6.4 mos versus 5.0 mos – Median PFS: 2.0 mos versus 1.7 mos http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm321378.htm Grothey A et al. Lancet 2013;381(9863):303-12. CORRECT: Overall Survival (Primary Endpoint) Median Regorafenib Placebo 6.4 mos 5.0 mos Hazard ratio: 0.77 p-value: 0.0052 Grothey A, et al. Lancet. 2013;381(9863):303-12. CONCUR Trial Design Regorafenib in Asian Patients Regorafenib 160 mg daily 3 weeks on / 1 week off (4-week cycle) Asian patients with mCRC who progressed after standard therapies 25 Centers: mainland China, Hong Kong, South Korea, Taiwan, Vietnam n = 136 R 2:1 Primary endpoint: overall survival (OS) Secondary endpoints: progression-free survival, response rate, disease control rate • All patients received best supportive care • Treat until progression, unacceptable toxicity, or withdrawal Placebo n = 68 Li et al., WCGIC 2014;Abstract O-0023; Kim et al. Proc ESMO 2014;Abstract 500O. CONCUR: Overall Survival (OS) Primary Endpoint Events, n (%) Median, months Regorafenib (n = 136) Placebo (n = 68) 95 (69.9) 60 (88.2) 8.8 6.3 p = 0.0002 45% reduction in risk of death in the regorafenib group Li et al., WCGIC 2014;Abstract O-0023; Kim et al. Proc ESMO 2014;Abstract 500O. What is the usual starting dose of regorafenib that you employ for an otherwise healthy patient with mCRC? % of respondents Research To Practice Patterns of Care Survey 2014 (N = 101 practicing oncologists) Regorafenib Dose Optimization Study (ReDOS): Randomized Phase II Study of Lower- versus Standard-Dose Regorafenib Lower-Dose Regorafenib + Pre-emptive clobetasol Refractory metastatic CRC (N = 120) R Lower-Dose Regorafenib + Reactive clobetasol Placebo + BSC Lower-Dose Regorafenib + Pre-emptive clobetasol Primary Endpoint • Proportion of patients who complete 2 courses and intend to initiate 3rd Secondary Endpoints • OS, PFS, etc Clinicaltrials.gov, April 2015 (NCT02368886) Lower-Dose Regorafenib + Reactive clobetasol CORRECT: Treatment-Emergent AEs Over Time Cycle of Therapy Adverse event 1 (n = 500) 2 (n = 417) 3 (n = 229) 4 (n = 193) 5 (n = 119) 6 (n = 91) 7 (n = 55) 8 (n = 43) HFSR 32 26 24 24 26 25 15 5 Fatigue 45 23 16 24 17 22 11 9 Hypertension 21 11 3 4 4 2 0 5 Rash, desquamation 24 7 3 4 5 1 0 0 • Most common AEs peaked early during treatment • No evidence of cumulative toxicity Grothey A et al. Gastrointestinal Cancers Symposium 2013;Abstract 467. Risk of Hepatotoxicity with Regorafenib • Severe and sometimes fatal hepatotoxicity has been observed • Obtain liver function tests (ALT, AST, bilirubin) before initiation of regorafenib – Monitor at least every 2 weeks during first 2 months of treatment – Thereafter monitor monthly or more frequently as clinically indicated – Monitor LFTs weekly in patients with elevated LFTs until improvement to less than 3 x ULN or baseline • Interrupt and then reduce dose or permanently discontinue regorafenib for hepatotoxicity as manifested by elevated LFTs or hepatocellular necrosis, depending on severity and persistence Regorafenib package insert Incidence of Hand-Foot Syndrome with Regorafenib • “Palmoplantar erythrodysesthesia” • Most clinically significant dermatologic adverse event associated with multikinase inhibitors, with all-grade incidences of: – Sorafenib = 60% – Sunitinib = 30% – Regorafenib = 46% • May affect palms, soles and other areas exposed to friction or trauma • Reaction usually appears within first 6 weeks of therapy Lacouture ME. ASCO Post 2012;3(18). www.ascopost.com. Hand-Foot Skin Reaction Classification • Grade 1 (mild) – Minimal skin changes OR dermatitis (e.g., erythema, oedema, or hyperkeratosis) without pain • Grade 2 (moderate) – Skin changes (e.g., peeling, blisters, bleeding, oedema, or hyperkeratosis) with pain; slightly limiting Instrumental ADL • Grade 3 (Severe) – Severe skin changes (e.g., peeling, blisters, bleeding, oedema, or hyperkeratosis) with pain; limiting self-care ADL • Grade 4 – Infectious complications, bed ridden/hospitalized Farr KP, Safwat A. Case Rep Oncol 2011;4(1):229-235. Management of Hand-Foot Syndrome Topicals Inflammation (Tenderness, edema, erythema) Hyperkeratosis (Thickening, peeling, cracking) Urea/lactic acid Orals Pyridoxine Celecoxib Topicals Urea 40% cream Salicylic acid cream Clobetasol 0.05% cream Patient Education Plan 72-Year-Old Man with KRAS-Mutant mCC Time point: Initiation of regorafenib Goals of treatment Antitumor effects of treatment Dose and schedule Follow-up plan, including restaging Related psychosocial issues Important potential side effects/toxicities – Hand-foot syndrome – Hepatotoxicity – Other Oncology Treatment Timeline Case 1: A 72-Year-Old Man with KRAS-Mutant mCC (Ms Mitchell) Surgical resection, no adjuvant Rx FOLFOX + bevacizumab x6 FOLFIRI + bevacizumab x 18 Regorafenib TAS-102 on x6 clinical trial TAS-102 Mechanism of Action TPase F3dThd (FTD) Inhibition of tumor growth FTY (inactive form) TPI F3dTMP F3dTDP TAS-102 DNA dysfunction (Oral Combination Drug) FTD TPI F3dTTP FTD incorporation into DNA Molar ratio = 1 : 0.5 FTD:Trifluridine TPI:Tipiracil-HCl With permission from Yoshino et al., WCGIC 2014;Abstract O-0022. Global Randomized Phase III study RECOURSE: Refractory Colorectal Cancer Study Metastatic colorectal cancer (mCRC) • 2 or more prior regimens • Refractory / Intolerable – fluoropyrimidine – irinotecan – oxaliplatin – bevacizumab – anti-EGFR if wild-type KRAS • ECOG PS 0-1 • Age ≥ 18 (target sample size: 800) R A N D O M I Z A T I O N TAS-102 + BSC (n = 534) 35 mg/m2 b.i.d. p.o. d1-5, 8-12 q4wks 2:1 Placebo + BSC Endpoints Primary: OS Secondary: PFS, Safety, Tolerability, TTF, ORR, DCR, DoR, Subgroup by KRAS (OS and PFS) (n = 266) d1-5, 8-12 q4wks Yoshino et al., WCGIC 2014;Abstract O-0022; Van Cutsem. ESMO 2014;Abstract LBA13. RECOURSE Phase III Study of TAS-102 versus Placebo for Patients with mCRC Refractory to Standard Treatments • Median OS: 7.1 versus 5.3 months • Median PFS: 2.0 versus 1.7 months • Most frequent AEs: Gastrointestinal and hematologic AEs Van Cutsem E et al. Proc ESMO 2014;Abstract LBA13. Overall Survival 100 Events # (%) 90 Placebo N = 266 364 (68) 210 (79) HR (95% CI) 0.68 (0.58-0.81) Stratified Log-rank test p<0.0001 80 Survival Distribution function TAS-102 N = 534 Median OS, months 70 7.1 5.3 Median follow-up: 8.4 months 60 Alive at, % 50 6 months 58 44 12 months 27 18 40 30 20 10 0 N at Risk: TAS-102 Placebo 0 3 6 534 266 459 198 294 107 9 12 Months from Randomization 137 47 64 24 15 18 23 9 7 3 With permission from Yoshino et al., WCGIC 2014;Abstract O-0022; Van Cutsem ESMO 2014;Abstract LBA13. Progression-free Survival 100 Progression-free Distribution function 90 Events # (%) 80 TAS-102 N = 534 Placebo N = 266 472 (88) 251 (94) HR (95% CI) 0.48 (0.41-0.57) Stratified Log-rank test p<0.0001 70 Median PFS, months 60 2.0 1.7 Tumor assessments performed every 8 weeks 50 40 30 20 10 0 0 N at Risk: TAS-102 Placebo 2 4 6 8 10 12 14 16 5 1 4 1 2 0 Months from Randomization 534 266 238 51 121 10 66 2 30 2 18 2 With permission from Yoshino et al., WCGIC 2014;Abstract O-0022; Van Cutsem. ESMO 2014;Abstract LBA13. Typical Day in The Life of an Oncology Nurse — Jessica Mitchell Patients Seen in Clinic: • 40 yo man, metastatic rectal cancer • 64 yo man, metastatic colon cancer • 71 yo woman, metastatic pancreatic adenocarcinoma • 59 yo man, metastatic hepatocellular carcinoma • 76 yo woman, metastatic colon cancer • 47 yo woman, pancreatic adenocarcinoma • 50 yo man, metastatic rectal cancer • 58 yo woman, metastatic colon cancer • 29 yo woman, metastatic colon cancer • 55 yo man, recurrent rectal cancer Additional Duties: • Respond to 20 phone calls from patients • Respond to 4 email inquiries from patients Typical Day in The Life of an Oncology Nurse — Tammy Triglianos Patients Seen in Clinic: • 45 yo man, metastatic esophageal cancer • 62 yo man, metastatic rectal cancer • 70 yo woman, metastatic colon cancer • 50 yo woman, metastatic appendiceal cancer • 73 yo man, hepatocellular carcinoma • 52 yo man, GIST • 55 yo man, hepatocellular carcinoma • 74 yo woman, metastatic colon cancer • 59 yo man, hepatocellular carcinoma • 59 yo man, metastatic colon cancer • 52 yo man, hepatocellular carcinoma • 55 yo man, metastatic colon cancer • 72 yo man, metastatic gastric cancer Patients Spoken with by Phone/Email: • 66 yo man, hepatocellular carcinoma • 82 yo woman, anal cancer • 69 yo woman, hepatocellular carcinoma • 71 yo woman, metastatic neuroendocrine tumor • 60 yo man, metastatic hepatocellular carcinoma Oncology Treatment Timeline Case 2: A 58-Year-Old Man with KRAS Wild-Type mCC (Ms Triglianos) Treatment break Surgical resection, FOLFOX 2008 FOLFIRI + bevacizumab (on CALGB-80405) 2011 Resumed Irinotecan + FOLFIRI + bev 5-FU/bev panitumumab maintenance Apr 2013 CAPOX Jan 2015 • Comorbidities: Diabetes (initially uncontrolled) • Psychosocial: When on chemo tx break, had better adherence and control of diabetes (ie, exercised, diet adherence). Being on tx more challenging for him emotionally and he was not as strict with diet/exercise. Panitumumab with Irinotecan as Secondor Third-Line Therapy for mCRC • Panitumumab + irinotecan in KRAS wild-type mCRC refractory to standard chemotherapy (n = 65)1 – ORR = 29.2% – Median PFS = 5.5 mos – Median OS = 9.7 mos • Phase II trial of panitumumab + irinotecan as secondline treatment in patients with advanced KRAS wildtype CRC (n = 53)2 – Median PFS = 4.5 mos – Median OS = 15.1 mos 1 Andre T et al. Ann Oncol 2013;24(2):412-9; 2 Carrato A et al. Clin Transl Oncol 2013;15(9):705-11. EGFR Antibody-Induced Rash • Red papulopustules – Pruritus, tenderness in 62% • Cetuximab – All grades: 85% – Grade 3: 10% Sheperd et al. N Engl J Med 2004; Rosell et al. Ann Oncol 2007; Van Cutsem et al. J Clin Oncol 2008; Geyer et al. J Clin Oncol 2008. STEPP: Preemptive versus Reactive Treatment for Skin Toxicities Associated with the EGFR Antibodies • Preemptive skin treatment consisted of: – Skin moisturizer applied daily – Sunscreen before heading outdoors – Topical steroid applied at bedtime – Doxycycline • Preemptive skin treatment resulted in: – Decreased Grade ≥2 dermatologic toxicities – Less impairment of quality of life Lacouture ME et al. J Clin Oncol 2010;28(8)1351-7. Oncology Treatment Timeline Case 2: A 58-Year-Old Man with KRAS Wild-Type mCC (Ms Triglianos) Treatment break Surgical resection, FOLFOX 2008 FOLFIRI + bevacizumab (on CALGB-80405) 2011 Resumed Irinotecan + FOLFIRI + bev 5-FU/bev panitumumab maintenance Apr 2013 CAPOX Jan 2015 Oncology Treatment Timeline Case 3: A 36-year-old man with end-stage mCC who has 2 minor children (Ms Mitchell) Adjuvant FOLFOX FOLFIRI + bevacizumab Capecitabine Hospice + RT • Comorbidities: None • Psychosocial: Patient lost his job after disease recurrence, filed for bankruptcy and had to move into his mother’s home with his girlfriend and 2 young sons, ages 3 and 6 Comprehensive Care for Patients with Incurable Cancers and Limited Survival • Providing support for patients’ loved ones – Age-appropriate interventions for minor children • Early use of palliative care specialists: ENABLE study • Advance directives • Chemotherapy/hospitalization/ICUs at the end of life • Hospice, palliative issues in the last week of life Epub Online March 23, 2015 N Engl J Med 2010;363:733-42 Oncology Treatment Timeline Case 4: An 80-year-old woman with RAS-mutant mCC and a synchronous primary (Ms Triglianos) FOLFOX + bevacizumab FOLFIRI + bevacizumab 1-year treatment break Hospice De novo lung and liver mets • Comorbidities: None • Psychosocial: Married for 60 years, with 2 adult children; cares for her husband with Parkinson’s disease and cardiac disease