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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