Power to the Patient With Cancer: Aligning Communication Between Patients and Clinicians This program is supported by an educational grant from Genentech.

Power to the Patient With Cancer: Aligning Communication Between Patients and Clinicians
This program is supported by an educational grant from Genentech.

Critical Issues in Communicating and Individualizing Treatment for Patients With Colorectal Cancer

About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options ( Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Introduction by Dr. Sands
John L. Marshall, MD Chief, Division of Hematology/Oncology Department of Medicine Georgetown University Hospital Washington, DC Daniel Z. Sands, MD, MPH, FACP, FACMI Co-Founder and Co-Chair, Society for Participatory Medicine Newburyport, MA Assistant Clinical Professor of Medicine, Harvard Medical School Boston, MA

Faculty Disclosures John L. Marshall, MD, has disclosed that he has received consulting fees, fees for non-CME services, and funds for research from Amgen, Bayer, and Genentech. Daniel Z. Sands, MD, MPH, FACP, FACMI, has disclosed that he has ownership interest in Kinergy Health and Conversa Health and has received consulting fees from Kinergy Health, Conversa Health, and SeniorLink. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

Participatory Medicine

What Should Patient Care Ideally Be?
© Copyright 2014 D. Z. Sands, All Rights Reserved.

A Collaboration on the Patient’s Health
Sands - Engaging e-Patients A Collaboration on the Patient’s Health © Copyright 2014 D. Z. Sands, All Rights Reserved.

Collaboration Mutual respect Information sharing Shared decisions
Communication Engagement Collaboration © Copyright 2014 D. Z. Sands, All Rights Reserved.

Collaboration Applied to Health Care Is Participatory Medicine
A movement in which networked patients shift from being mere passengers to responsible drivers of their health, and in which providers encourage and value them as full partners.

Sands - Engaging e-Patients
Society for Participatory Medicine Community Advocacy Research Education © Copyright 2014 D. Z. Sands, All Rights Reserved. @DrDannySands

Benefits to Participatory Medicine
Better outcomes Triple Aim Reduced costs Improved satisfaction © Copyright 2014 D. Z. Sands, All Rights Reserved. @DrDannySands

Prerequisites for Participatory Medicine
Communication Involvement in Care Convenience Information © Copyright 2014 D. Z. Sands, All Rights Reserved. @DrDannySands

Barriers to Participatory Medicine
Arrogance Poor Communication Habits Inconvenience Lack of Transparency Poor General or Health Literacy © Copyright 2014 D. Z. Sands, All Rights Reserved.

Online Health Habits of US Adults
Sands - Engaging e-Patients Online Health Habits of US Adults 80% of online adults have looked for health info Rising over time Each day, more people search for health information than see a physician! More than half act on the information 1/3 have read about others’ health experiences 1/4 have tracked their health information online 1/3 use social media for health PwC HRI Social Media Consumer Survey, 2012. © Copyright 2014 D. Z. Sands, All Rights Reserved. @DrDannySands

What to Do Use a patient portal for communication, convenience, and to provide access to patients’ records Ask every patient what they know and where they get health information Admit when you don’t know something Encourage patients to connect with other patients Incorporate patient preferences into decisions Let patients help © Copyright 2014 D. Z. Sands, All Rights Reserved.

6 Steps of Shared Decision Making (SDM)
Invite the patient to participate Present options Provide information on benefits and risks Assist patient in evaluating options based on their goals and concerns Facilitate deliberation and decision making Implement SDM Kane HL, et al. CA Cancer J Clin. 2014;[Epub ahead of print].

Questions and Email Address
Sands - Engaging e-Patients Questions and Address @DrDannySands © Copyright 2014 D. Z. Sands, All Rights Reserved.

Critical Issues in Communicating and Individualizing Treatment for Patients With Colorectal Cancer

Our Current Model of Colon Cancer
Spread to other organs Stage 0 Stage I Stage II Stage III Stage IV

Testing Today KRAS (codons 12, 13) Gene profiling MSI/MSS
Generally reserved for metastatic CRC BRAF test sometimes done if KRAS is wild type Gene profiling Adjuvant Metastatic MSI/MSS IHC for MLH1, MSH2, MSH6, and PMS2 proteins If MLH1 and PMS2 are absent, the patient likely has acquired methylation of the MLH1 If MSH2 and MSH6 are absent, the patient likely has Lynch syndrome If only MSH6 or PMS2 is absent, the patient may have LS. Up to 15% are still missed, family history still critical PCR for MSI-H CRC, colorectal cancer; IHC, immunohistochemistry; LS, Lynch syndrome; MSI/MSS, microsatellite instable/microsatellite stable; PCR, polymerase chain reaction.

Colon Cancer: More Than 1 Disease
Molecular MSI vs MSS RAS WT vs MUT Anatomic MSI, microsatellite instable; MSS, microsatellite stable; MUT, mutated; WT, wild type. Right vs Left Rectal vs Colon Stool Flora Types ?????

Current Recommendations: Adjuvant Treatment for Stage II/III CRC
T3N0M0 (no high-risk features) Clinical trial Observation Consider capecitabine or 5-FU/LV T3N0M0 at high risk of recurrence or T4N0M0 Capecitabine or 5-FU/LV FOLFOX, CapeOx, or FLOX Clinical trial Observation 5-FU, 5-fluorouracil; CapeOx, capecitabine/oxaliplatin; CRC, colorectal cancer; LV, leucovorin; FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin; FLOX, 5-fluorouracil, oxaliplatin, leucovorin. NCCN clinical practice guidelines: colon cancer (v ) nccn.org.

Adjuvant Therapy for CRC: Where Are We Now?
Relatively few positive studies Even in the best studies, adding oxaliplatin “fails” 95% of the time Oxaliplatin neuropathy does not really go away as first believed We have become more responsible, more balanced with our treatments Future metrics will be based on outcomes, not consumption CRC, colorectal cancer.

Phase III: Adjuvant FOLFOX ± Celecoxib in Stage III CRC
FOLFOX 12 cycles + celecoxib for 3 yrs FOLFOX 6 cycles + placebo for 3 yrs FOLFOX 6 cycles + celecoxib for 3 yrs CRC, colorectal cancer; FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin. ClinicalTrials.gov. NCT

Advances in the Treatment of Colorectal Cancer
2000 2005 2008 2012 2014 ? 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab 5-FU, 5-fluorouracil. Bevacizumab Targeted therapies Panitumumab Ziv-aflibercept Regorafanib KRAS 27

2012 ESMO Guidelines: Treatment Sequence by Line
Optional 1st-line (group 3 only) FU FU+Bev Chemo-triplet Oxaliplatin Based 1st- line Irinotecan Based 1st- line 1st- line FOLFOX+ Pan or Cet FU/Ox FU/Ox+ Bev FU/Iri+ Cet FU/Iri FU/Iri+Bev FU/Ox/Iri 2nd-line FU/Iri+ Bev FOLFIRI+ Aflibercept FU/Iri (FOLF)IRI +Pan/Cet FU/Ox+ Bev FU/Ox FOLFOX+ Cet (Pan) Pan/Cet+/-Iri or FU/Bev Bev, bevacizumab; Cet, cetuximab; FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin; FU, fluorouracil; Iri, irinotecan; Ox, oxaliplatin; Pan, panitumumab. 3rd-line Regorafenib Pan/Cet+/- Iri FU+Bev Regorafenib Pan/Cet+/-Iri FU+Bev Regorafenib 4th-line Regorafenib Regorafenib Schmoll HJ, et al. Ann Oncol. 2012;23:

Frontline Treatment of Metastatic CRC
Cure or not Symptoms or not Neurotoxicity vs alopecia Oral vs pump RAS WT or RAS MUT Rash or vascular toxicity CRC, colorectal cancer; MUT, mutated; WT, wild type.

Phase III: CAPOX vs FOLFOX-4 + Bev or Placebo in mCRC
Recruitment June May 2004 Recruitment February February 2005 CAPOX (n = 317) CAPOX + placebo (n = 350) CAPOX + bevacizumab (n = 350) FOLFOX-4 (n = 317) FOLFOX-4 + placebo (n = 351) FOLFOX-4 + bevacizumab (n = 350) Initial 2-arm open-label study (N = 634) Bev, bevacizumab; CAPOX, capecitabine/oxaliplatin; FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin; mCRC, metastatic colorectal cancer. Publication of bevacizumab phase III data (Hurwitz H, et al. N Engl J Med. 2004;350: ). Original protocol amended to a 2 x 2 placebo-controlled design Cassidy J, et al. J Clin Oncol. 2008;26: 30

CAPOX/FOLFOX-4: “General” and “On-Treatment” PFS
On-treatment HR: (PFS: 10.4 vs 7.9 mos; P < .0001) 6 mos FOLFOX-4/CAPOX + bevacizumab FOLFOX-4/CAPOX + placebo 1.0 0.8 0.6 PFS Probability General HR: 0.83 (PFS: 9.4 vs 8.0 mos; P = .0023) CAPOX, capecitabine/oxaliplatin; FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin; PFS, progression-free survival. 0.4 0.2 5 10 15 20 Mos Saltz LB, et al. J Clin Oncol. 2008;26:

FOLFOX 4 until progression
OPTIMOX Studies FOLFOX 4 until progression OPTIMOX-1: Maintenance therapy (N = 620) FOLFOX 7 sLV5FU2 mFOLFOX 7 FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin; sLV5FU2, simplified biweekly 5-fluorouracil + leucovorin. OPTIMOX-2: Chemotherapy-free interval (N = 202) sLV5FU2 mFOLFOX 7 Chemotherapy-free interval Tournigand C, et al. J Clin Oncol. 2006;24: Maindrault-Goebel, et al. ASCO Abstract 4013.

OPTIMOX Studies: PFS Progression-Free Survival 1.0
OPTIMOX-1: Median 36 wks 0.8 OPTIMOX-2: Median 29 wks 0.6 P = .08 Probability 0.4 PFS, progression-free survival. 0.2 0.0 10 20 30 40 50 60 70 80 90 100 Wks Maindrault-Goebel, et al. ASCO Abstract 4013.

OPTIMOX Studies: OS Overall Survival 1.0 OPTIMOX-1: Median 26 mos 0.8
0.6 P = .0549 Probability 0.4 OS, overall survival. 0.2 0.0 10 20 30 40 50 Mos Maindrault-Goebel et al. ASCO Abstract 4013.

Phase III CAIRO-3: Maint Cape + Bev vs Obs in mCRC
PFS1 PFS2 Observation (n = 279) Patients with mCRC and SD or better after 6 cycles CAPOX-B, WHO PS 0-1 (N = 558) Reintroduce CAPOX-B PD PD Capecitabine + Bevacizumab (n = 279) OR Any treatment, including CAPOX-B PD Primary endpoint: PFS2 Time from randomization to progression upon reintroduction of CAPOX-B PFS2 considered equal to PFS1 in patients who do not receive CAPOX-B again (for any reason) Median follow-up: 40 mos Bev, bevacizumab; Cape, capecitabine; CAPOX-B, capecitabine/oxaliplatin/bevacizumab; mCRC, metastatic colorectal cancer; Obs, observation; PD, progressive disease; PFS, progression-free survival; SD, stable disease; TT2PD, time to progressive disease; WHO PS, World Health Organization performance status. TT2PD Koopman M, et al. ASCO Abstract 3502.

CAIRO-3 - Maint Cape + Bev vs Obs in mCRC: PFS-1
Median PFS1 Observation 4.1 m [95%CI: ] Maintenance 8.5 m [95%CI: ] Stratified HR 0.44 [95%CI: ] P value < 1.0 0.8 0.6 PFS Probability Maintenance 0.4 Adjusted HR 0.41, P <0.001 Bev, bevacizumab; Cape, capecitabine; metastatic colorectal cancer; Obs, observation; PFS, progression-free survival. 0.2 Observation 0.0 6 12 18 24 30 36 Time (Mos) Koopman M, et al. ASCO Abstract 3502.

Phase III TRIBE: First-line Bev + FOLFIRI or FOLFOXIRI in mCRC
Stratified by PS (0-1 vs 2), center, previous adjuvant chemo Max 12 cycles Patients with unresectable mCRC, no previous chemotherapy for advanced disease (N = 508) FOLFIRI* + Bevacizumab 5 mg/kg (n = 256) Maintenance with 5-FU + bevacizumab until PD FOLFOXIRI† + Bevacizumab 5 mg/kg (n = 252) 5-FU, 5-fluorouracil; Bev, bevacizumab; FOLFIRI, folinic acid/fluorouracil/irinotecan; FOLFOXIRI, folinic acid/5-fluorouracil/oxaliplatin/irinotecan; mCRC, metastatic colorectal cancer; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PS, performance score; q2w, every 2 weeks. *FOLFIRI: irinotecan 180 mg/m2, leucovorin 200 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/m2 over 48 hrs, q2w †FOLFOXIRI: irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, 5-FU infusion 3200 mg/m2 over 48 hrs, q2w Primary objective: PFS Secondary endpoints: OS, safety, R0 resection, biomarkers Loupakis F, et al. N Engl J Med. 2014;371:

First-line Bev + FOLFIRI or FOLFOXIRI in mCRC: Responses
Best Response, % FOLFIRI + Bev (n = 256) FOLFOXIRI + Bev (n = 252) P Value Complete response 3 4 PR 50 61 Response rate 53 65 .006 SD 32 24 Progressive disease 5 2 Not assessed 10 9 Bev, bevacizumab; FOLFIRI, folinic acid/5-fluorouracil/irinotecan; FOLFOXIRI, folinic acid/5-fluorouracil/oxaliplatin/irinotecan; mCRC, metastatic colorectal cancer; PR, partial response; SD, sudden death. Loupakis F, et al. N Engl J Med. 2014;371:

First-line Bev + FOLFIRI or FOLFOXIRI in mCRC: PFS
100 FOLFIRI + Bev, median PFS: 9.7 mos FOLFOXIRI + Bev, median PFS: 12.1 mos HR: 0.75; P = .003 90 80 Median follow-up: 32.2 mos FOLFIRI + Bev: n = 256/progressed = 226 FOLFOXIRI + Bev: n = 252/progressed = 213 70 60 Progression-free Survival (%) 50 40 30 FOLFOXIRI + bevacizumab 20 Bev, bevacizumab; FOLFIRI, folinic acid/5-fluorouracil/irinotecan; FOLFOXIRI, folinic acid/5-fluorouracil/oxaliplatin/irinotecan; mCRC, metastatic colorectal cancer; PFS, progression-free survival. 10 FOLFIRI + bevacizumab 6 12 18 24 30 36 42 48 54 Mos At Risk, n FOLFIRI + bevacizumab FOLFOXIRI + bevacizumab 94 125 46 74 26 35 14 21 7 11 3 5 0 2 0 1 Loupakis F, et al. N Engl J Med. 2014;371:

First-line Bev + FOLFIRI or FOLFOXIRI in mCRC: OS
FOLFIRI + Bev, median OS: 25.8 mos FOLFOXIRI + Bev, median OS: 31.0 mos HR: 0.75; P = .003 100 90 Median follow-up: 32.2 mos FOLFIRI + Bev: n = 256/deaths = 155 FOLFOXIRI + Bev: n = 252/deaths = 131 80 70 60 Overall Survival (%) 50 FOLFOXIRI + bevacizumab 40 30 20 Bev, bevacizumab; FOLFIRI, folinic acid/5-fluorouracil/irinotecan; FOLFOXIRI, folinic acid/5-fluorouracil/oxaliplatin/irinotecan; mCRC, metastatic colorectal cancer; OS, overall survival. FOLFIRI + bevacizumab 10 6 12 18 24 30 36 42 48 54 Mos At Risk, n FOLFIRI + bevacizumab FOLFOXIRI + bevacizumab 69 70 36 35 15 15 5 4 0 0 Loupakis F, et al. N Engl J Med. 2014;371:

Phase III CRYSTAL: FOLFIRI ± Cetuximab in EGFR+ mCRC
Cetuximab IV 400 mg/m2 on Day 1, then 250 mg/m2 wkly + irinotecan 180 mg/m FU 400 mg/m2 bolus+ 2400 mg/m2 as 46-hr CI + FA q2w Cetuximab + FOLFIRI EGFR-expressing mCRC R Stratification factors Regions ECOG PS Populations Randomized patients: n = 1217 Safety population: n = 1202 ITT population: n = 1198 Irinotecan 180 mg/m FU 400 mg/m2 bolus + 2400 mg/m2 as 46-hr CI + FA q2w FOLFIRI 5-FU, fluorouracil; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; FA, folinic acid; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; ITT, intent to treat; IV, intravenous; mCRC, metastatic colorectal cancer; R, randomization. Van Cutsem E, et al. N Engl J Med. 2009;360:

FOLFIRI ± Cetuximab in EGFR+ mCRC: PFS (ITT)
1.0 Cetuximab + FOLFIRI (n = 599) FOLFIRI (n = 599) 0.9 0.8 HR: (95% CI: ; stratified log-rank P = .0479) 0.7 0.6 8.9 mos Probability of PFS 0.5 1-yr PFS rate: 23% vs 34% 8.0 mos 0.4 0.3 0.2 EGFR, epidermal growth factor receptor; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; ITT, intent to treat; mCRC, metastatic colorectal cancer; PFS, progression-free survival. 0.1 2 4 6 8 10 12 14 16 18 20 PFS (Mos) At Risk, n FOLFIRI alone Cetuximab + FOLFIRI 83 103 35 58 16 29 7 12 4 5 1 1 Van Cutsem E, et al. N Engl J Med. 2009;360:

MABs Target Tumor Cell-Bound EGFR
Ligand Extracellular EGFR Ras PI3K Intracellular PTEN Raf Akt MEK EGFR, epidermal growth factor receptor; MABs, monoclonal antibodies. MAPK Cell survival Cell Motility DNA Proliferation Metastasis Angiogenesis

FOLFIRI ± Cetuximab in EGFR+ mCRC: PFS w/ WT KRAS
FOLFIRI (n = 350) FOLFIRI + Cetuximab (n = 316) Events, n 189 146 Median PFS 8.4 mos 9.9 mos [95% CI] [ ] [ ] HR [95% Cl] P value 0.70 [ ] 1.0 0.9 0.8 0.7 0.6 Probability of PFS 0.5 0.4 0.3 EGFR, epidermal growth factor receptor; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; ITT, intent to treat; mCRC, metastatic colorectal cancer; PFS, progression-free survival; WT, wild type. 0.2 FOLFIRI FOLFIRI + cetuximab 0.1 0.0 4 8 12 16 20 Patients, n FOLFIRI FOLFIRI + cetuximab Time (Mos) 22 40 4 8 0 1 Van Cutsem E, et al. J Clin Oncol. 2011;29:

PRIME – FOLFOX ± Panitumumab: PFS by KRAS
WT KRAS MT KRAS 100 100 90 90 80 80 70 70 60 60 Proportion Event-Free (%) 50 50 40 40 30 30 20 20 10 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin; MT, mutated; PFS, progression-free survival; WT, wild type. Mos Mos Median, Mos (95% CI) Panitumumab + FOLFOX4 10.0 (9.3 – 11.4) FOLFOX4 8.6 (7.5 – 9.5) Median, Mos (95% CI) Panitumumab + FOLFOX4 7.4 (6.9 – 81) FOLFOX4 9.2 (8.1 – 9.9) HR: 0.80 (95% CI: 0.67 – 0.95) Log-rank P value = .01 HR: 1.27 (95% CI: 1.04 – 1.55) Log-rank P value = .02 Douillard J, et al. J Clin Oncol. 2014;25:

FIRE-3: First-line FOLFIRI + Cetux or Bev in KRAS-WT mCRC
FOLFIRI + Cetuximab 400 mg/m2 loading then 250 mg/m2 q1w (n = 297) Patients with mCRC and KRAS WT, ECOG PS 0-2 (N = 592) FOLFIRI + Bevacizumab 5 mg/kg q2w (n = 295) Bev, bevacizumab; Cetux, cetuximab; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFIRI, folinic acid/fluorouracil/irinotecan; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; q1w, every week; q2w, every 2 weeks; TTF, time to treatment failure WT, wild type. Primary endpoint: ORR Secondary endpoints: PFS, OS, TTF, tumor shrinkage, secondary curative resections, safety Heinemann V, et al. Lancet Oncol. 2014;15:

First-line FOLFIRI + Cetux or Bev in KRAS-WT: Responses
RECIST, n (%) FOLFIRI + Cetuximab (n = 297) FOLFIRI + Bevacizumab (n = 295) CR 13 (4.4)* 4 (1.4)* PR 171 (57.6) 167 (56.6) SD 53 (17.5)* 85 (28.8)* PD 21 (7.1) 16 (5.4) Not evaluable 39 (13.1) 23 (7.8) Bev, bevacizumab; Cetux, cetuximab; CR, complete response; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; WT, wild type. *Significant differences in response. Heinemann V, et al. Lancet Oncol. 2014;15:

First-line FOLFIRI + Cetux or Bev in KRAS-WT: PFS
100 Events Median 10.0 mos mos 95% CI 75 Progression-free Survival (%) 50 FOLFIRI + cetuximab FOLFIRIR + bevacizumab 25 Bev, bevacizumab; Cetux, cetuximab; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; PFS, progression-free survival; WT, wild type. 12 24 36 48 60 72 Mos At risk, n FOLFIRI + cetuximab FOLFIRI + bevacizumab 100 99 19 15 10 6 5 4 3 0 0 0 Heinemann V, et al. Lancet Oncol. 2014;15:

First-line FOLFIRI + Cetux or Bev in KRAS-WT: OS
100 Events Median 28.7 mos mos 95% CI 75 FOLFIRI + cetuximab FOLFIRIR + bevacizumab Overall Survival (%) 50 25 Bev, bevacizumab; Cetux, cetuximab; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; OS, overall survival; WT, wild type. 12 24 36 48 60 72 Mos At risk, n FOLFIRI + cetuximab FOLFIRI + bevacizumab 60 47 29 184 9 2 0 0 Heinemann V, et al. Lancet Oncol. 2014;15:

SWOG 80405: Cetuximab and/or Bev + Combo Chemo
Stratified by FOLFOX/FOLFIRI, prior adjuvant Tx, prior XRT Cetuximab 400 mg/m2 IV on Day 1, then 250 mg/m2 once wkly Patients with untreated mCRC, and WT KRAS (codons 12,13) (N = 1140) Patient/physician choice: mFOLFOX6 or FOLFIRI Bevacizumab 5 mg/kg IV q2w Bev, bevacizumab; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin; IV, intravenous; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival; q2w, every 2 weeks; SWOG, Southwest Oncology Group; Tx, treatment; WT, wild type; XRT, radiation therapy. Primary endpoint: OS Secondary endpoints: PFS, response rate *Recruitment ongoing. Lenz H, et al. ESMO Abstract 5010.

SWOG 80405: Cetuximab and/or Bev + Combo Chemo
100 Arm N (Events) Median (95% CI) HR (95% CI) P Chemo + Bev 256 (178) 31.2 ( ) 0.9 ( ) .40 Chemo + Cetux 270 (177) 32.0 ( ) 80 60 Patients Event Free (%) Chemo + bevacizumab Chemo + cetuximab 40 Bev, bevacizumab; Cetux, cetuximab; SWOG, Southwest Oncology Group. 20 12 24 36 48 60 72 84 96 Mos From Study Entry Lenz H, et al. ESMO Abstract 5010.

Second Line and Beyond Readdress the patient’s goal of care
Reconsider surgery or other local therapies Assess toxicity to date and QOL priorities going forward RAS mutation testing done? Biologics beyond progression QOL, quality of life.

Aflibercept Fusion protein of key domains from human VEGF receptors 1 and 2 with human IgG Fc¹ Blocks all human VEGF-A isoforms, VEGF-B, and placental growth factor (PlGF)² High affinity – binds VEGF-A and PlGF more tightly than native receptors Contains human amino acid sequences¹ Fc, fragment crystallizable region; IgG, immunoglobulin G; PIGF, phosphatidylinositol-glycan biosynthesis class F protein; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. 1. Holash J, et al. Proc Natl Acad Sci. 2002;99: Tew WP, et al. Clin Cancer Res ;16: 53

Phase III VELOUR: Aflibercept as Second-line Therapy in mCRC
Stratified by ECOG PS (0 vs 1 vs 2), prior bevacizumab (Y/N) Arm A: FOLFIRI + Aflibercept 4 mg/kg q2w Patients with mCRC progressing on first-line oxaliplatin-based chemotherapy (N = 1226) PD or toxicity Arm B: FOLFIRI + Placebo q2w ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; mCRC, metastatic colorectal cancer; OS, overall survival; PD, progressive disease; q2w, every 2 weeks. Primary endpoint: OS Van Cutsem E, et al. J Clin Oncol. 2012;30:

Phase III ML18147: Bev + Crossover Fluoropyrimidine
Stratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 mos, >9 mos), time from last BEV dose (≤ 42 days, > 42 days), ECOG PS at baseline (0/1, 2) Bevacizumab* + standard second-line chemotherapy† (n = 591) Patients with progressive mCRC after first-line bevacizumab/ chemotherapy (planned N = 822) Standard second-line chemotherapy‡ (n = 595) AIO, Arbeitsgemeinschaft Internistische Onkologie; BEV, bevacizumab; CAPIRI, capecitabine/irinotecan; CT, chemotherapy; CAPOX, capecitabine/oxaliplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFIRI, irinotecan/fluorouracil/leucovorin; FOLFOX, leucovorin/fluorouracil/oxaliplatin; FUFOX, fluorouracil/oxaliplatin; IRI, irinotecan; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; XELIRI, capecitabine/irinotecan. *5 mg/kg on Days 1, 14 of 4-wk cycle or 7.5 mg/kg on Days 1, 22 of 6-wk cycle. †AIO-IRI, FOLFIRI, CAPIRI, or XELIRI. ‡ FUFOX, FOLFOX, or CAPOX. Primary endpoint: OS Secondary endpoints: PFS, ORR, safety Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

CORRECT: Regorafenib After Failure of Standard Therapy in mCRC
Arm A: Regorafenib 160 mg po qd + BSC 3 wks on, 1 wk off (n = 505) Patients with progression after all available standard therapy (N = 760) 2:1 Arm B: Placebo + BSC 3 wks on, 1 wk off (n = 253) BSC, best supportive care; mCRC, metastatic colorectal cancer; po, orally; qd, daily. Global trial: 16 countries, 114 active centers Primary endpoint: overall survival (90% power to detect 33.3% increase) Approximately 60% of patients with ≥ 4 systemic therapies All patients had received bevacizumab Grothey A, et al. Lancet. 2013;381:

Regorafenib After Failure of Standard Therapy in mCRC: OS
1.00 Regorafenib Placebo Median OS: 6.4 mos mos 95% CI 0.75 HR: 0.77 (95% CI, ) 1-sided P = .0052 Survival Distribution Function 0.50 mCRC, metastatic colorectal cancer; OS, overall survival. 0.25 Placebo (n = 255) Regorafenib (n = 505) 50 100 150 200 250 300 350 400 450 Days From Randomization Grothey A, et al. Lancet. 2013;381:

Regorafenib After Failure of Standard Therapy in mCRC: PFS
1.00 Regorafenib Placebo Median PFS 1.9 mos mos 95% CI 0.75 HR: 0.49 (95% CI, ) 1-sided P < Survival Distribution Function 0.50 Placebo (n = 255) mCRC, metastatic colorectal cancer; PFS, progression-free survival. 0.25 Regorafenib (n = 505) 50 100 150 200 250 300 350 Days From Randomization Grothey A, et al. Lancet. 2013;381:

End-of-Life Care Palliative care Phase 1/2 trials? Recycle chemo?
Hope vs reality of benefit Hospice, end-of-life planning

Go Online for More CCO Coverage of Colorectal Cancer!
Capsule Summaries of all the key data Additional CME-certified slideset on Colorectal Cancer with expert faculty commentary on all key studies clinicaloptions.com/oncology

Power to the Patient With Cancer: Aligning Communication Between Patients and Clinicians This program is supported by an educational grant from Genentech.

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Power to the Patient With Cancer: Aligning Communication Between Patients and Clinicians This program is supported by an educational grant from Genentech.

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