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Oncology Grand Rounds
Gastrointestinal Cancers
Nurse and Physician Investigators
Discuss New Agents, Novel Therapies
and Actual Cases from Practice
Thursday, April 28, 2016
12:15 PM – 1:45 PM
Faculty
Johanna C Bendell, MD
Philip A Philip, MD, PhD
Robin Sommers, DNP, ANP-BC, AOCNP
Amanda K Wagner, MS, ANP-BC, AOCNP
Moderator
Neil Love, MD
Oncology Tumor Panel Series
Oncology Grand Rounds: Themes
• New agents and treatment strategies: Benefits and risks
• Counseling patients about side effects
– Practical implementation
• End-of-life care
• Psychosocial issues in patient care
• Supporting the supporters
• Job satisfaction and burnout in oncology professionals
• The oncology professional just entering practice
• The bond that heals
Module 1:
Management of Metastatic
Colorectal Cancer (Part 1) —
Sequencing Systemic
Treatments
Discussion Topics
• Expanded tissue testing and implications of RASmutant and wild-type colorectal cancer
• Sequencing of chemotherapy and biologic regimens
in metastatic colorectal cancer
• Role of EGFR antibodies for patients with metastatic
colorectal cancer; infusion reactions and
dermatologic toxicities
• Incidence and management of oxaliplatin-related
neuropathy
Discussion Topics
• Regorafenib: Mechanism of action, available
research data, current clinical role and management
of toxicities
• Considerations for initial dosing of regorafenib:
Importance of careful follow-up in the first month of
treatment
• TAS-102: Mechanism of action, available research
data, current clinical role and management of
toxicities
Overview of Colon Cancer
• Estimated number of new cases and deaths in the US in
2016:
– New cases = 95,270
– Deaths = 49,190
• Stage at diagnosis (Percent of patients who present with):
– Stage II disease = 40%
– Stage III disease = 36%
– Stage IV disease = 20%
• Estimated proportion of deaths in the US in 2016: 53%
men, 47% women
• ~15% present with MSI-high CRC
• Five-year survival estimates (2006-2012) = 65.1%
Cancer Facts and Figures 2016; Boland CR, Goel A. Gastroenterology 2010;138(6):2073-87;
http://seer.cancer.gov/statfacts/html/colorect.html.
65-Year-Old Man with RAS Wild-Type Metastatic
Colon Cancer (Ms Sommers)
• Presented with abdominal pain, decreased appetite and
weight loss
• Diagnosed with RAS wild-type metastatic colon cancer
• Treated with FOLFOX/bevacizumab 
FOLFIRI/bevacizumab  FOLFIRI/cetuximab
• Patient experienced severe infusion reaction to cetuximab
and was switched to panitumumab
– Severe dermatologic toxicity
• FOLFIRI/aflibercept
• TAS-102
• Currently receiving regorafenib
• Married with adult children and is being observed by social
services and psychiatry for anxiety, depression and
obsessive thinking
65-Year-Old Man with RAS Wild-Type Metastatic
Colon Cancer (Ms Sommers)
Case discussion points (Ms Sommers)
• What were some of the key patient education
points that you addressed when the patient was
started on FOLFOX/bevacizumab?
• What are the most common toxicity/tolerability
issues with FOLFOX/bevacizumab?
Case discussion points (Ms Sommers)
• What were some of the key patient education
points that you addressed when the patient was
started on FOLFIRI/cetuximab?
• What are the most common toxicity/tolerability
issues with FOLFIRI/cetuximab?
• What are the most common toxicity/tolerability
issues with panitumumab?
Tissue Testing in CRC
• RAS
• BRAF
• MSI testing
• HER2
• Next-generation sequencing
Case discussion points (Ms Sommers)
• What were some of the key patient education
points that you addressed when the patient was
started on regorafenib?
• What are the most common toxicity/tolerability
issues with regorafenib?
• How do you generally monitor patients who are
being started on regorafenib?
• How is the patient tolerating treatment?
New Agent Profile: Regorafenib
• Mechanism of action:
– Oral multikinase inhibitor
• Indication:
– For 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
• Recommended dose:
– 160 mg orally, once daily for the first 21 days of each 28day cycle
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm321378.htm
Regorafenib package insert
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.
Recommended Dose Modifications for
Regorafenib
Interrupt dose
• Gr 2 HFSR that is recurrent or does not improve within 7 days
despite dose reduction
• Gr 3 HFSR (interrupt therapy for a minimum of 7 days)
• Symptomatic Gr 2 hypertension
• Any Gr 3 or 4 AE
Discontinue permanently
• Failure to tolerate 80-mg dose
• Any occurrence of AST/ALT >20 x ULN or >3 x ULN with
concurrent bilirubin >2 x ULN
• Recurrence of AST/ALT >5 x ULN despite reduction to 120 mg
• Any Gr 4 AE
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm321378.htm
Regorafenib package insert
Tumor Cavitation with Regorafenib in mCRC
Chest CT prior to treatment with regorafenib
A
B
C
1
Multiple lesions  size and tumor cavitation  2 cycles
A
B
C
2
•
Early tumor cavitation in lung metastasis demonstrates the predictive
potential of regorafenib in CRC
Kawasaki K et al. Oncol Lett 2016;11(1):231-233.
Case discussion points (Ms Sommers)
• What were some of the key patient education
points that you addressed when the patient was
started on TAS-102?
• What are the most common toxicity/tolerability
issues with TAS-102?
• How did the patient tolerate treatment with TAS102?
New Agent Profile: TAS-102
• Mechanism of action:
– Combination of trifluridine, a nucleoside metabolic
inhibitor, and tipiracil, a thymidine phosphorylase inhibitor
• Indication:
– For patients with mCRC who have been previously
treated with fluoropyrimidine-, oxaliplatin- and irinotecanbased chemotherapy, an anti-VEGF biologic product, and
an anti-EGFR monoclonal antibody, if RAS wild-type
• Recommended dose:
– 35 mg/m2/dose PO twice daily on days 1 through 5 and
days 8 through 12 of each 28-day cycle
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm463743.htm
TAS-102 package insert
TAS-102 Mechanism of Action
TPase
F3dThd (FTD)
Inhibition of
tumor growth
FTY
(inactive form)
TPI
F3dTMP
TAS-102
(Oral Combination
Drug)
FTD
TPI
DNA dysfunction
F3dTDP
F3dTTP
FTD incorporation
into DNA
Molar ratio = 1:0.5
FTD：Trifluridine
TPI：Tipiracil-HCl
Adapted from Yoshino et al., WCGIC 2014;Abstract O-0022.
RECOURSE: Overall Survival with TAS-102 versus
Placebo
Overall Survival (%)
Hazard ratio for death, 0.68, p < 0.001
TAS-102
Median OS: 7.1 mo
Median Time to ECOG PS ≥ 2
TAS-102: 5.7 mo
Placebo: 4.0 mo
Placebo
Median OS: 5.3 mo
Months since Randomization
Mayer RJ et al. N Engl J Med 2015;372(20):1909-19.
TAS-102 Common Adverse Events
TAS-102
(n = 533)
Placebo
(n = 265)
Any Grade
Gr ≥3
Any Grade
Gr ≥3
Neutropenia
67%
38%
<1%
0%
Anemia
77%
18%
33%
3%
Thrombocytopenia
42%
5%
8%
<1%
Nausea
48%
2%
24%
1%
Decreased appetite
39%
4%
29%
5%
Diarrhea
32%
3%
12%
<1%
Cytopenias
Gastrointestinal
Mayer RJ et al. N Engl J Med 2015;372(20):1909-19.
Case discussion points (Ms Sommers)
• How do you think this patient would compare the
tolerability/toxicity and quality-of-life issues of all of
the agents/regimens that he has received?
Case discussion points (Ms Sommers)
• In addition to referring this patient for social
services and psychiatry, how, if at all, have you
personally tried to assist him with his anxiety,
depression and obsessive thinking?
Module 2:
Gastric Cancer
Discussion Topics
• First-line treatment for HER2-negative and HER2positive gastroesophageal (GE) cancer in the
neoadjuvant, adjuvant and metastatic settings
• Evidence-based integration of ramucirumab into
clinical algorithms for metastatic GE cancer; ongoing
clinical trials of ramucirumab
• Management of hypertension and other antiangiogenic class-related side effects of ramucirumab
• Biologic rationale for and available clinical trial data
with anti-PD-1/PD-L1 antibodies for metastatic
GE junction cancer
Overview of Gastric Cancer
• Estimated number of new cases and deaths in the US in
2016:
– New cases = 26,370
– Deaths = 10,730
• Stage at diagnosis (Percent of patients who present with):
– Localized disease = 35%
– Advanced-stage = 65%
• Estimated proportion of deaths in the US in 2016: 61%
men, 39% women
• Five-year survival estimates (2006-2012) = 30.4%
Cancer Facts and Figures 2016; Dicken BJ et al. Ann Surg 2005;241(1):27-39;
http://seer.cancer.gov/statfacts/html/stomach.html.
Gastric Cancer
CIN
• Intestinal histology
• TP53 mutation
• RTK-RAS activation
•
•
•
•
•
•
•
•
•
GS
Diffuse histology
CDH1, RHOA mutations
CLDN18-ARHGAP fusion
Cell adhesion
Adapted from Nature Genetics 2014;24:2903
EBV
PIK3CA mutation
PD-L1/2
overexpression
EBV-CIMP
CDKN2A silencing
Immune cell signaling
•
•
•
•
MSI
Hypermutation
Gastric-CIMP
MLH1 silencing
Mitotic pathways
40-Year-Old Woman with HER2-Positive Gastric
Cancer (Ms Sommers)
• A 40-year-old woman with metastatic HER2-positive gastric
cancer
• CAPOX/bevacizumab/trastuzumab
• Ramucirumab/paclitaxel
• Clinical trial of pembrolizumab
• Mother of 2 children aged 10 and 12
• Employed by an insurance firm
• Closely followed by a social worker
40-Year-Old Woman with HER2-Positive Gastric
Cancer (Ms Sommers)
Progression on CAPOX/bevacizumab/trastuzumab
HER2-Directed Therapies in GE Cancers
Pertuzumab
HER2
HER1/3/4
Trastuzumab
Subdomain IV
Dimerization
domain
Trastuzumab:
Pertuzumab:
• Inhibits ligand-independent HER2
signaling
• Inhibits ligand-dependent HER2
dimerization and signaling
• Activates ADCC
• Activates ADCC
• Prevents HER2 ECD shedding
ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain;
HER2, human epidermal growth factor receptor 2
Adapted from Baselga J et al. Cancer Res 2011;71(24 Suppl);Abstract S5-5.
ToGA Phase III Trial of Cis/5-FU or Cape ±
Trastuzumab in HER2-Positive GC or GEJ Cancer
Survival probability
Median Overall Survival
Events
OS
HR
95% CI
p-value
FC + T
167
13.8 mo
0.74
0.60-0.91
0.0046
FC
182
11.1 mo
ORR: 47% vs 35% (p = 0.00175)
Most common AEs in both groups:
Nausea, vomiting and neutropenia
Time (months)
Bang YJ et al. Lancet 2010;376(9742):687-97.
Case discussion points (Ms Sommers)
• What were some of the key patient education
points that you addressed when the patient was
started on ramucirumab/paclitaxel?
• What are the most common toxicity/tolerability
issues with ramucirumab?
• How did the patient tolerate treatment with
ramucirumab?
Mechanism of Action of Ramucirumab
Anti-VEGFR2
antibody
(ramucirumab)
VEGF-A
Anti-VEGF
antibody
(bevacizumab)
Soluble
VEGF
receptor
(Ziv-aflibercept)
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)
New Agent Profile: Ramucirumab
• Mechanism of Action:
- Anti-VEGFR2 monoclonal antibody
• Indication:
- Single agent or in combination with paclitaxel for
advanced gastric or gastroesophageal junction (GEJ)
adenocarcinoma with disease progression on or after
prior treatment with fluoropyrimidine- or platinumcontaining chemotherapy
• Dose/Schedule:
- 8 mg/kg, 60-minute IV infusion q2wks of 4-week cycle
Wilke H et al. Lancet Oncol 2014;15(11):1224-35.
Phase III REGARD Trial of Ramucirumab Monotherapy
for Pretreated Advanced Gastric or GEJ
Adenocarcinoma
• Advanced gastric or
gastroesophageal
junction adenocarcinoma
• Progression after
1st-line platinum or
fluoropyrimidine
treatment
• N=355
R
2:1
randomization
1° endpoint: OS
Fuchs CS et al. Lancet 2014;383(9911):31-9.
Ramucirumab
8 mg/kg q2weeks +
best supportive care
N=238
Placebo + best
supportive care
N=117
Phase III RAINBOW Trial of Ramucirumab ± Paclitaxel
for Pretreated Advanced Gastric or GEJ
Adenocarcinoma
1° endpoint: OS
N = 665
Ramucirumab
8 mg/kg q2 weeks +
Paclitaxel 80 mg/m2
• ECOG PS < 1
• Progression after 1st-line
platinum/fluoropyrimidine
treatment
R
Wilke H et al. Lancet Oncol 2014;15(11):1224-35.
Placebo +
Paclitaxel 80 mg/m2
Blockade of PD-1/PD-L1 or CTLA-4 Signaling in
Tumor Immunotherapy
Adapted from Ribas A et al. N Engl J Med 2012;366:2517-9.
KEYNOTE-012: Best Response to
Pembrolizumab in Advanced Gastric Cancer
Change from baseline in sum of
longest diameter of target lesion, %
ORR = 22.2% (N = 36)
Bang YJ et al. Proc ASCO 2015;Abstract 4001.
53.1% of patients
experienced a decrease
in target lesions
KEYNOTE-012: Treatment Exposure and
Response Duration
• Median time to response:
8 weeks (range, 7-16)
• 4 of 8 responses ongoing at the
time of data cutoff
• Median response duration:
40 weeks (range, 20+ to 48+)
Partial response
Progressive disease
Progressive disease after non-progressive disease
Last pembrolizumab dose
Pembrolizumab treatment ongoing
Time (weeks)
Bang YJ et al. Proc ASCO 2015;Abstract 4001.
Module 3:
Pancreatic Cancer
Discussion Topics
• Ongoing evaluation and current role of chemotherapy,
including FOLFIRINOX and gemcitabine/nab paclitaxel,
in the neoadjuvant, adjuvant and metastatic settings
• Effects of age, performance status and symptomatology
on the selection of first-line therapy for patients with
metastatic pancreatic cancer
• Management of side effects associated with currently
available agents; palliative considerations in advanced
pancreatic cancer
Discussion Topics
• Nal-IRI: Mechanism of action, available clinical trial data
and optimal integration into patient care
• Patient education issues in the use of nal-IRI;
amelioration of GI and hematologic toxicities associated
with nal-IRI
• New agents and treatment strategies currently in
development
Overview of Pancreatic Cancer
• Estimated number of new cases and deaths in the US in
2016:
– New cases = 53,070
– Deaths = 41,780
• Stage at diagnosis (Percent of patients who present with):
– Localized disease = 33.3%
– Advanced-stage disease = 66.7%
• Estimated proportion of deaths in the US in 2016: 52%
men, 48% women
• Five-year survival estimates (2006-2012) = 7.7%
Cancer Facts and Figures 2016; Riall TS et al. Ann Surg 2007;246(2):181-182;
http://seer.cancer.gov/statfacts/html/pancreas.html.
65-Year-Old Man with Borderline-Resectable
Pancreatic Cancer (Ms Wagner)
• Late 2012: Borderline-resectable pancreatic cancer
– Neoadjuvant FOLFIRINOX x 2 cycles
– Pancreaticoduodenectomy (T3N0M0 pancreatic adenocarcinoma)
• Adjuvant gemcitabine x 6 months
• 2014: Local recurrence
– Gemcitabine/nab paclitaxel x 8 cycles
– Nab paclitaxel discontinued due to neurotoxicity
• 12/2015: Disease progression
• 5-FU/liposomal irinotecan (nal-IRI, MM-398)
– 20% dose reduction due to mucositis, diarrhea and anorexia
• Lives alone and has no family
• Relies on neighbors for care and is very concerned about how he will
manage side effects on his own
Case discussion points (Ms Wagner)
• What were some of the key patient education
points that you addressed when the patient was
started on FOLFIRINOX?
• What are the most common toxicity/tolerability
issues with FOLFIRINOX?
• How did the patient tolerate treatment with
FOLFIRINOX?
Case discussion points (Ms Wagner)
• What were some of the key patient education
points that you addressed when the patient was
started on gemcitabine/nab paclitaxel?
• What are the most common toxicity/tolerability
issues with gemcitabine/nab paclitaxel?
• How did the patient tolerate treatment with
gemcitabine/nab paclitaxel?
Common First-Line Systemic Regimens for
Metastatic Pancreatic Cancer
• FOLFIRINOX dose/schedule1:
• Oxaliplatin, 85 mg/m2 (IV 2 hours)
• Leucovorin, 400 mg/m2 (IV 2 hours)
• Irinotecan, 180 mg/m2 (IV 90-minute)
• Fluorouracil, 400 mg/m2 (IV bolus, followed by a
continuous IV of 2,400 mg/m2 over a 46-hour period every
2 weeks)
• Nab paclitaxel/gemcitabine dose/schedule2:
• Nab paclitaxel (125 mg/m2) on d 1, 8 and 15 q4wk
• Gemcitabine (1,000 mg/m2) on d 1, 8 and 15 q4wks
1Conroy
T et al. N Engl J Med 2011;364:1817-1825; 2Von Hoff DD et al. N Engl J Med
2013;369(18):1691-703.
Case discussion points (Ms Wagner)
• What were some of the key patient education
points that you addressed when the patient was
started on 5-FU/nal-IRI?
• What are the most common toxicity/tolerability
issues with 5-FU/nal-IRI?
• How did the patient tolerate treatment with 5FU/nal-IRI?
Nanoliposomal Irinotecan (nal-IRI, MM-398)
PEG-DSPE
Internal
aqueous
space
~ 100
nm
Lipid
membrane
Irinotecan
~80,000 irinotecan
molecules/liposome
Courtesy of Johanna Bendell, MD.
New Agent Profile: Nal-IRI
• Mechanism of action:
– Topoisomerase inhibitor
• Indication:
– In combination with 5-FU and leucovorin to treat patients
with metastatic pancreatic cancer who have been previously
treated with gemcitabine-based chemotherapy
• Dosing/schedule:
– 70 mg/m2 intravenous infusion over 90 minutes every 2
weeks
- Recommended starting dose in patients homozygous for
UGT1A1*28 allele is 50 mg/m2 every 2 weeks
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm468654.htm
Progression-Free Survival Proportion
NAPOLI-1: PFS — MM-398 + 5-FU/LV
1
PFS, months
0.9
Median (95% CI)
0.8
MM-398 + 5-FU/LV
5-FU/LV
0.7
0.6
3.1
1.5
HR = 0.56; p = 0.0001
0.5
0.4
0.3
0.2
0.1
0
0
3
6
9
Months
Von Hoff et al. ESMO GI 2014;Abstract O-0003
12
15
18
NAPOLI-1: Overall Survival with nal-IRI with
5-FU/LV in Metastatic Pancreatic Adenocarcinoma
Overall Survival Proportion
1
Median OS
0.9
0.8
MM-398 + 5-FU/LV
0.7
6.1 months
4.2 months
HR = 0.67; p = 0.0122
0.6
0.5
0.4
5-FU/LV
0.3
0.2
0.1
0
0
3
6
9
Months
Von Hoff et al. ESMO GI 2014;Abstract O-0003
12
15
18
Adverse Events Associated with Nal-IRI
•
•
•
•
•
•
•
•
•
•
•
Febrile neutropenia
Abdominal pain
Asthenia
Diarrhea
Nausea
Vomiting
Hypokalemia
Decreased appetite
Hypernatremia
Decreased hemoglobin
Decreased platelet count
Ko AH et al. Br J Cancer 2013;109(4):920-5; Von Hoff D et al. Ann Oncol 2014:25(Suppl 2):ii105ii106.
Safety
MM-398 +
5-FU/LV
(n = 117)
MM-398
(n = 147)
Grade ≥3 hematologic AEs based on laboratory values, %1,2
Neutrophil count decreased
20
16
Hemoglobin decreased
6
7
Platelet count decreased
2
1
2
4
Febrile neutropenia, %
Growth factors received, %
17
Grade ≥3 nonhematologic AEs in >5% patients, %1
Fatigue
14
Diarrhea
13
Vomiting
11
Nausea
8
1 Includes
only patients with ≥1 postbaseline assessment
2 Per CTCAE version 4
Von Hoff et al. ESMO GI 2014;Abstract O-0003
5-FU/LV
(n = 134)
2
5
0
0
12
1
6
21
14
5
4
5
3
3
Palliative Issues in Advanced Pancreatic
Cancer
•
•
•
•
•
•
•
Biliary obstruction
Depression
Pain
Intestinal obstruction
Fatigue
Cachexia
Weight loss
Brescia FJ et al. Cancer Control 2004;11:39-45.
Module 4:
Management of Metastatic
Colorectal Cancer (Part 2) —
Special Situations
and Issues
Discussion Topics
• Checkpoint inhibitors in patients with MSI-high
cancers
• Timing of recurrence in colorectal cancer; usual
surveillance regimens
• Care of patients presenting with primary colorectal
cancer and metastatic disease
• Surgical removal of metastatic disease in the liver,
lungs and other locations: Cure rates and use of
pseudoadjuvant therapy
• Other local modalities to treat metastatic disease:
cryotherapy, radiofrequency ablation, transarterial
infusions, radiolabeled spheres
27-Year-Old Woman with Lynch Syndrome and
Metastatic MSI-High Colon Cancer (Ms Wagner)
• 2014: Diagnosed with Stage IV MSI-high colon cancer
• FOLFOX/bevacizumab
– Disease progression with worsening, debilitating bony
metastases
– Radiation therapy
• 2/2015: Enrolled on a clinical trial of pembrolizumab
• Patient was depressed and wheelchair-bound at the time
pembrolizumab was started
• Currently working full-time as a stage manager at a local
theater and enjoys sharing stories about her job
What Is Microsatellite Instability (MSI)?
Microsatellites:
• Repetitive segments of DNA
• The same number of repeats are present
in every cell
Normal microsatellite
with 2 repeats
Microsatellite Instability:
• The number of microsatellite repeats
differs between normal cells/tissue and
tumor cells/tissue
MSI is a pathology finding specific to Lynch
syndrome colon tumors
Tumor tissue with
MSI variable repeat
size 5 & 3
http://www.slideshare.net/Pammy98/hereditary-colorectal-cancer-powerpoint-educational-module
Immunotherapy in Cancers with Mismatch
Repair Deficiency
Waterfall Plot: Radiographic Response
Le DT et al. N Engl J Med 2016;372:2509-20.