Integrating New Therapies into Treatment Regimens for Gastric and Gastroesophageal Cancer
©2018 Rockpointe Oncology 1Activity Slides
Educational Objectives
• Evaluate the current evidence across multiple lines of therapy and appropriately sequence therapies for gastric and gastroesophageal (GEJ) cancers
• Mitigate toxicities associated with gastric cancer treatment regimens to improve patient outcomes
• Evaluate the safety and efficacy data for emerging therapies for gastric and GEJ cancers.
Agenda
• Introduction
• Overview
– Treatment in first-line setting
– Treatment in second-line setting
– Treatment in third-line setting
– Role of approved biologics.
– Emerging therapies
– Side effect management
• Questions and Answers
Worldwide Incidence
Ajani et al. Nature Reviews
Gastric Cancer Statistics
National cancer institute: Surveillance, Epidemiology, and End Results program (SEER) Stat Fact Sheet: Stomach Cancer: http://seer.cancer.gov/statfacts/html/stomach.html
Gastric Adenocarcinoma: Risk Factors
• Nutritional– Low fat or protein consumption– High consumption of salted,
smoked, or preserved foods – High nitrate consumption– Low consumption of fruits,
vegetables
• Medical– Previous gastric surgery– Helicobacter pylori infection (2x)– Chronic atrophic gastritis
• Environmental– P Helicobacter pylori infection (2x) – Poor food preparation (smoked)– Lack of refrigeration– Poor drinking water
(eg, well water)– Occupation (eg, rubber, coal
workers)– Cigarette smoking (1.6x)
• Hereditary Factors– Germline CDH1 mutation– Impaired function in Mistmatch
repair genes (MLH1)– Inactivating mutations in BRCA
geneSouza RF, et al. CA Cancer J Clin. 2005;55:334-351. National Cancer Institute: Gastric Cancer Treatment PDQ.
Integrating New Therapies into Treatment Regimens for Gastric and Gastroesophageal Cancer
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STAGING: AJCC TNM Classification for Gastric Cancer
NCCN Guidelines Version 2.2018 Gastric Cancer. J Natl Compr Canc Netw. 2018
STAGING: AJCC TNM Classification for Gastric Cancer
NCCN Guidelines Version 2.2018 Gastric Cancer. J Natl Compr Canc Netw. 2018
Histological Classification
Diffuse Type Intestinal Type
Ajani JA, Lee J, et al. Nature Reviews Disease Primers 3, 17036 (June 2017) doi:10.1038/nrdp.2017.36
Molecular Subtypes
Ajani JA, Lee J, et al. Nature Reviews Disease Primers 3, 17036 (June 2017) doi:10.1038/nrdp.2017.36
The Role of Chemotherapy in Advanced Gastric Cancer
• Survival with best supportive care (BSC) alone ~ 3 months• Chemotherapy affords survival in metastatic gastric cancer• Benefit in weighted mean average survival ~ 6 months.
Optimal chemotherapy for advanced gastric cancer: Is there a global consensus? Lordick, F., Lorenzen, S., Yamada, Y. et al. Gastric Cancer (2014) 17: 213
Multidisciplinary Care of Gastric and Locally Advanced GEJ Cancer
Integrating New Therapies into Treatment Regimens for Gastric and Gastroesophageal Cancer
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Role of Surgery in Treatment of Gastric Cancer
Refer to Medical OncologyFor Advanced Disease
Palliative Care YesNo
Yes
No
No
Yes
Surgical Candidate
Surgical Candidate
Perioperative Chemotherapy
Restaging
Diagnostic Laparoscopy
Peritoneal mets orCytology positive
Surgical Resection
Surgical Treatment of Locally Advanced Esophageal Cancer
Definitive Chemoradiotherapy
Patient is medically fitand agrees to surgery
Yes
No
No
Yes
Surgical Resection
Refer to Medical OncologyFor Advanced Disease
Palliative Care
Neoadjuvant Chemoradiotherapy
Restaging
Evidence of metastatic disease
First- Line Chemotherapy
Phase III Trials Supporting Standard Practice in Advanced Gastric Cancer
Webb A, et al. J Clin Oncol. 1997;15:261-267. Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.Koizumi W, et al. Lancet Oncol. 2008;9:215-221.
Study Treatment (n) RR, % (95% CI) Median OS, Mos PFS, MosTTP, Mos(95% CI)
Webb et al[1]
FAMTX (108) 21 (13-29) 5.7 3.4 NA
ECF (111)45 (36-54)(P = .0002)
8.9(P = .0009)
7.4(P = .00006)
NA
V325[2]
CF (224) 25 (19.9-31.7)8.6 mo
(95% CI: 7.2-9.5)NA
3.7(3.4-4.5)
DCF (221)37 (30.3-43.4)
(P = .01)9.2 mo
(95% CI: 8.4-10.6)NA
5.6 (4.9-5.9)
SPIRITS[3]
S-1 (150) NA11.0 mo
(IQR: 5.6-19.8)4.0
(IQR: 2.1-6.8)NA
Cisplatin + S-1 (149)
NA13.0 mo
(IQR: 7.6-21.9)
6.0(IQR: 3.3-12.9)
(P < .0001)NA
Clinicaloptions.com/Oncology
REAL 2 : Study Design REAL-2 Results
HR: 0.86 (0.8-0.99)
Capecitabine is non-inferior to infused 5-FU
More G3/4 neutropenia and hand foot syndrome
HR: 0.92 (0.82-1.10)
Oxaliplatin is non-inferior to cisplatin
Less G3/4 neutropenia, tromboembolism, alopecia
More G3/4 diarrhea, G3/4 peripheral neuropathy.
Cunningham et al. NEJM 2008
Integrating New Therapies into Treatment Regimens for Gastric and Gastroesophageal Cancer
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ECF vs EOX
Improved efficacy of EOX compared to ECF for survival
Arm OS (m) 1 year survival p-value HR (95% CI)(95% CI)
ECF 9.9 37.7 (31.8-31.6)EOX 11.2 46.8 (40.4-52.9) 0.020 0.80
(0.66-0.97)
Cunningham et al. NEJM 2008
Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma with Fluorouracil, LeucovorinPlus Either Oxaliplatin or Cisplatin
Salah-Eddin Al-Batran; et al; JCO 2008, 26, 1435-1442.
V-325 Study Design
Kaplan-Meier estimates of (A) time to progression and (B) overall survival among chemotherapy-naïve advanced gastric cancer patients treated with docetaxel, cisplatin, and fluorouracil (DCF) or cisplatin and fluorouracil (CF; full analysis population).
Eric Van Cutsem; Vladimir M. Moiseyenko; Sergei Tjulandin; Alejandro Majlis; Manuel Constenla; Corrado Boni; Adriano Rodrigues; Miguel Fodor; Yee Chao; Edouard Voznyi; Marie-Laure Risse; Jaffer A. Ajani; JCO 2006, 24, 4991-4997. DOI: 10.1200/JCO.2006.06.8429 Copyright © 2006
TAX 325 Study Results
ECF vs FOLFIRI
Rosine Guimbaud; Christophe Louvet; Pauline Ries; Marc Ychou; Emilie Maillard; Thierry André; Jean-Marc Gornet; Thomas Aparicio; Suzanne Nguyen; Ahmed Azzedine; Pierre-Luc Etienne; Eveline Boucher; Christine Rebischung; Pascal Hammel; Philippe Rougier; Laurent Bedenne; Olivier Bouché; JCO 2014, 32, 3520-3526. DOI: 10.1200/JCO.2013.54.1011
Time-to-treatment failure (TTF) according to treatment arm (Kaplan-Meier estimation). ECX arm: epirubicin, cisplatin, and capecitabine as the first-line treatment; FOLFIRI arm: irinotecan, leucovorin, fluorouracil bolus, and continuous infusion as the first-line treatment. HR, hazard ratio.
Treatment of Metastatic Disease (1st Line)
OXEOX/EOF
CapeECX/EOX
XP FLO FOLFIRI S-1/ Cis DCF ECF
#Pts 498 513 160 109 170 305 221 126
%RR 44% 45% 41% 34% 32% 54% 36% 45%
TTP, months
6.7 6.5 5.6 5.5 5.0 6.0 5.6 7.4
OS, months
10.9 10.4 10.5 10.7 9.0 13.0 9.2 8.9
Cunningham NEJM 358:36;2008, Kang Annals Oncol 20:666;2009, Al-Batran JCO 26:1435;2008, Dank Annals Oncol 19:450;2008, Koizumi Lancet Oncol 9:215; 2008, Van Cutsem JCO 24:4991;2006, Webb JCO 15:61;1997
Integrating New Therapies into Treatment Regimens for Gastric and Gastroesophageal Cancer
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Patients with HER2+
advanced gastric cancer(n = 810; 22% of successful screenings)
Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer: ToGAPrimary endpoint: OS
*Selected at investigator’s discretion: 5-FU 800 mg/m2/day infusional on Days 1-5 q3w x 6; capecitabine 1000 mg/m2 BID on Days 1-14 q3w x 6.
(n = 584)
R
Patients with advanced
gastric cancer screened for HER2 status(N = 3803)
Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ,
measurable disease, capecitabine vs 5-FU
5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6 +
Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose)
(n = 294)
5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6
(n = 290)
Bang YJ, et al. Lancet. 2010;376:687-697.
Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer (ToGA): OS
Pts at Risk, n
Events
167182
Mos
294
290
277
266
246
223
209
185
173
143
147
117
113
90
90
64
71
47
56
32
43
24
30
16
21
14
13
7
12
6
6
5
4
0
1
0
0
0
11.1 13.8
00.10.20.30.40.50.60.70.80.91.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Surv
ival
Pro
babi
lity FC + T
FC
HR
0.74
95% CI
0.60-0.91
P Value
.0046
MedianOS
13.811.1
Bang YJ, et al. Lancet. 2010;376:687-697.
Key Points First Line Treatment
• Chemotherapy with platinum compound (cisplatin, oxaliplatin) plus a fluoropyrimidine (fluorouracil [5-FU], capecitabine, or S-1) is the global standard
• Selective patients can benefit from triplet combinations but increased side effects must be considered. Overtoxic treaments like docetaxel-containing triplet regimens cannot be recommended in older patients.
• Oxaliplatin and Irinotecan can substitute for cisplatin without compromising the efficacy of chemotherapy
• Trastuzumab in combination with chemotherapy is the recommended treatment for patients with HER2+ tumors 3+ by IHC or 2+IHC + FISH positive.
Second Line Chemotherapy
Second Line Chemo Gastric Cancer Phase III Trials Improved Survival
Docetaxel/Irinotecan vs BSC Docetaxel vs BSC
Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; 2012
Phase III REGARD Trial BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer
• Primary objective: OS• Secondary endpoints: PFS, 12-wk PFS, ORR, DOR, QoL, safety
Fuchs CS, et al. Lancet. 2014 Jan 4;383(9911):31-9.
Patients with metastatic gastric or GEJ
adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine- containing combination therapy, ECOG
PS 0-1 (N = 355)
Ramucirumab 8 mg/kg IV q2w + BSC(n = 238)
BSC + Placebo(n = 117)
Treatment until PD, unacceptable toxicity,
or death
Stratified by geographic region, weight loss (> vs < 10% over 3 mos), location of primary tumor (gastric vs GEJ)
Integrating New Therapies into Treatment Regimens for Gastric and Gastroesophageal Cancer
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REGARD Trial of BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer: OS
Fuchs CS, et al. Lancet. 2014 Jan 4;383(9911):31-9.
Pts at Risk, nRamucirumabPlacebo
Prop
ortio
n R
emai
ning
Aliv
e
Mos
Ramucirumab PlaceboPatients/events 238/179 117/99Median, mos 5.2 (4.4-5.7) 3.8 (2.8-4.7)(95% CI)6-mo OS, % 42 3212-mo OS, % 18 11
HR: 0.776 (95% CI: 0.603-0.998; P = .0473)
1.0
0.8
0.6
0.4
0.2
00 2 4 6 10 14 208 12 171 3 5 7 11 15 169 13 18 19 26 2827
238117
15466
9234
4920
177
74
32
01
00
RamucirumabPlaceboCensored
REGARD Trial of BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer: PFS
Fuchs CS, et al. Lancet. 2014 Jan 4;383(9911):31-9.
Prop
ortio
n W
ithou
t Pro
gres
sion
RamucirumabPlaceboCensored
Ramucirumab PlaceboPatients/events 238/199 117/108Median, mos 2.1 (1.5-2.7) 1.3 (1.3-1.4)(95% CI)12-wk PFS, % 40 16
HR: 0.483 (95% CI: 0.376-0.620; P < .0001)
1.0
0.8
0.6
0.4
0.2
00 2 4 6 10 148 12 171 3 5 7 11 15 169 13
Mos
238117
21392
11327
6511
112
52
21
10
00
10
10
10
41
182
617
454
302
182
Pts at Risk, nRamucirumabPlacebo
RAINBOW Study
1:1
Treat until disease progression or intolerable toxicity
Ramucirumab 8 mg/kg day 1&15+ Paclitaxel 80 mg/m2 day 1, 8 &15 of a 28-day cycleN = 330
Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1, 8 &15N = 335
SCREEN
RANDOMIZE
Important inclusion criteria:Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinomaProgression after 1st line platinum/fluoropyrimidine-based chemotherapy
Stratification factors:Geographic region Measurable vs non-measurable disease Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)
*GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC
Wilke H. Lancet Oncol. 2014 Oct;15(11):1224-35.
HR (95% CI) = 0.807 (0.678, 0.962)Stratified log rank p-value = 0.0169
RAM + PTX PBO + PTXPatients / Events 330 / 256 335 / 260Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38)
6-month OS 72% 57%12-month OS 40% 30%
RAM + PTX 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0
PBO + PTX 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0
No. at risk
Censored
Δ mOS difference: 2.3 months
RAM = ramucirumab; PTX = paclitaxel; PBO = placebo.
Ove
rall
surv
ival
pro
babi
lity
Wilke H. Lancet Oncol. 2014 Oct;15(11):1224-35.
RAINBOW: Overall Survival
The Role of Biologics
TrialLine of
TherapyDrugs
PatientSelection
Survival Results
ToGaBang et al. Lancet.2010;376:687-697
1st Line Trastuzumab +Cis/5-FU vs Cis/5-FU
HER2 + 13.8 mos vs 11.1 mosHR (0.74; 95% CI 0.60-0.91)
FDA approval in 2010
LOGICHecht et alJ Clin Oncol. 2016;34:443-451
1st Line Cape Ox+ Lapatinib vs CapeOx + P
IHC 2+ and FISH + or IHC 3 or FISH+
12.2 mos vs 10.5 mosHR(0.901 (0.73-1.12)
No improvement in PFS or OS
JACOBTabernero et al. Ann Oncol. 2017;28(Supp5):v209-v268.
1st Line Pertuzumab +Trastuzumab + chemo vs Trastuzumab+chemo
IHC 3+ vs IHC 2+ and ISH
17.5 mos vs 14.2 mosHR 0.84; [CI] 0.71-1.00;
NS
TYTANSatoh et al. J ClinOncol. 2014;32:2039-2049.
Second Line Lapatinib + Paclitaxelvs Paclitaxel
HER2+ 11.0 mos vs 8.4 mosP=0.01044
Did not improve OS significantly
GATSBYThuss-Patience et al.Lancet Oncol. 2017;18:640-653.
2nd/ 3rd Line TDM-1 + Taxanevs Taxane alone
HER2+ (IHC or ISH)
7·9 months for T-DM1 vs 8·6 mos for taxane( [HR] 1·15 [95% CI 0·87–1·51]; p=0·86)
No efficacy
HER-2 Inhibition
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EGFR Inhibition / EGFR Targeting
• Targeted Agents Phase III: Negative Trials for EGFr
• REAL 3: ECX + / - Panitumumab (U.K.) Negative: Panitumumab had inferior outcomes
• EXPAND: Cape-Cis + / Cetuximab (E.U.) –Negative: Cetuximab trended inferior
• COG: BSC vs Gefitinib (U.K.): Negative
• Trials conducted with no biomarker
• Selection of patients
• No biomarker identified in EG Cancer
Waddell T Lance Oncol 14: 481; 2013 Lordick F et al Lancet 14:490; 2013 Sutton JCO 30: 2012 (suppl 34 abstr 6)Figure from Oncotarget, 2017, Vol 8 (No 34), pp: 57654-57669
Hepatocyte Growth Factor
TRIAL DrugsPatient
Selection Results
RILOMET-1Rilotumumab + ECX vs ECX
MET +/HER2-Closed due to
toxicity
RILOMET-2Rilotunumab +
CX vs CXMET+/HER2-
Closed due totoxicity
MET GastricOrnatuzumab +
FOLFOX vs FOLFOX
MET+/HER2- Inefective
Phase IINCT 007255712
Foretinib UnselectedNo improvement in
PFS or OS
Figure from Oncotarget, 2017, Vol 8 (No 34), pp: 57654-57669
VEGF/VEGFR Pathway
Trial Line of Therapy Drugs Patient
Selection Survival Results
AVAGAST 1st LineXP +
Bevacizumab vs XP+P
No selection12.1 mos vs 10.1 mosHR 0.87; 95% CI, 0.73
to 1.03; P = .1002NS
REGARD 2nd Line Ramucirumabvs BSC No selection 5.3 mos vs 3.8 mos
p=0.047
hazard ratio 0.87; 95% CI, 0.73 to 1.03; P = .1002
RAINBOW 2nd LinePaclitaxel +
Ram vs Paclitaxel
No selection 9.6 mos vs 7.4 moshazard ratio 0.87; 95% CI, 0.73 to 1.03; P = .1002
Phase IIINCT01512745 3rd Line Apatinib vs
Placebo No selection 195 days vs 140 daysImprovement in
PFS/OS Asian study
Emerging Therapies
Immunotherapy Approaches in GEJ Cancer
Immunotherapy
Passive
Active
Specific: Cancer Vaccines, MAGE-3, G17DT,
FGFR peptide, DC vaccines
Non-specific: Checkpoint inhibitors: anti CTLA-4,
anti PD-1, Anti PDL-1
Monoclonal antibodies: trastuzumab, ramucirumab, ACT, CTL, TIL, CART-T
Cancer Vaccines
Aim to prime and expand tumor-specific T cells by delivering tumor antigens to drive effective T cell activation.
Integrating New Therapies into Treatment Regimens for Gastric and Gastroesophageal Cancer
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Cancer Vaccines
• Peptides derived from VEGFR 1 and 2 in combination with chemotherapy in patients with advanced gastric cancer resulted in partial response 55%. Masuzawa T et al. Int J Oncol. 2012; 41 (4):1297-1304
• Early phase studies of a DC vaccine combined with HER2 peptide in a small group of advance HER-2 positive patients and a pulsed DC MAGE3 peptide vaccine appeared to show modes effect.
• Further clinical development of DC-based vaccine approaches has been limited.
Cassian Yee Clin Cancer Res 2013;19:4550-4552© 2013 by American Association for Cancer Research
In ACT, tumor-specific T cells are isolated from a patient, amplified and primed in vitro to tumor antigens or through genetic modification before being transfused into the patient.
Adoptive Cell Therapy
Immune Checkpoint Inhibitors
Immune CheckpointsCTLA-4 and PD-1/PD-L1
MHC II
TCR CD4
CTL-4
B7-1B7-2
APC
1- Prevent Co-
stimulationAntigen specific presentation
PD-L1
PD-1
Co-inhibition
MHC II
TCR
CD4
CD28
B7-1B7-2
APC
1-
Antigen specific presentation
Adapted from Immunobiology 8th edition, Garland Science 2012)
CTL-4 Directed Approaches
Phase DrugNo of pts
Line of Therapy
Outcome P value
II
Ralph et al
Tremelimumab(CTL-4 antibody)
18 2nd/3rd lineORR:5%
TTP: 2.83 months MOS: 4.83 months
II
NCT01585987
Ipilimumab(CTL-4 ab) vs best
supportive care114
Sequential after 1st line
PFS: 2.92 vs 4.89 (mos)
OS: 16.75 vs. 12.05 (mos)
P=0.0036P=0.6433
PD-1 Directed Approaches
Phase DrugNo of
PatientsLine of
TherapyResults
IbKEYNOTE-012
Pembrolizumab(PD-1 antibody)
39PD-L1 +
Any lineORR 22%
mPFS: 1·9 (mos)mOS: 11·4 (mos)
ISegal et al.
Durvalumab(MEDI4736, PD-L1 antibody)
16 Any line ORR 25%
I/IICheckmate 032
Nivolumab (PD-1 antibody) 59 >2 linesORR was 12%
Median OS was 6.8 mo(95% CI, 3.3–12.4)
I (Japan) Avelumab 20 2nd/3rd line ORR 15%mPFS: 11.6 weeks
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Phase 3 Study of NIvolumab (NIvo) In Previously Treated Advanced Gastrıc or Gastroesophageal Junctıon (G/GEJ) Cancer
The Lancet DOI: (10.1016/S0140-6736(17)31827-5)
Updated results and subset analysIs by PD-L1 expressIon (ATTRACTION-02)
The Lancet DOI: (10.1016/S0140-6736(17)31827-5)
Phase 3 Study of NIvolumab (NIvo) In Previously Treated Advanced Gastrıc or Gastroesophageal Junctıon (G/GEJ) Cancer: ATTRACTION-02
Response by PDL-1 Expression
The Lancet DOI: (10.1016/S0140-6736(17)31827-5)
KEYNOTE-059: Study DesignOpen-label, Multicohort Phase II Study
• Primary endpoints: ORR, safety; secondary endpoints: DoR, PFS, OS
• Exploratory biomarker endpoints: efficacy by MSI, GEP
Cohort 1≥ 2 prior
lines of CT
Pts with recurrent or metastatic gastric or
GEJ adenocarcinoma; ECOG PS 0/1;
HER2/neu negative*; no prior PD-1/PD-L1 tx,
systemic steroids, autoimmune disease, ascites, or CNS mets
(N = 259)
Pembrolizumab200 mg Q3W
Pembrolizumab 200 mg Q3W +Cisplatin 80 mg/m2 Q3W +5-FU 800 mg/m2 Q3W or
Capecitabine 1000 mg/m2 BID Q3W
Tx continued for 24 mos or until PD,
intolerable toxicity, or withdrawal of consent; survival follow-up until study end, death, or
withdrawalPembrolizumab200 mg Q3W
Cohort 2No prior tx
Cohort 3No prior
tx, PD-L1+
Fuchs CS, et al. ASCO 2017. Abstract 4003.
*HER2/neu positive allowed in cohort 1 if prior trastuzumab administered.
KEYNOTE-059 (Cohort 1): Survival
Fuchs CS, et al. ASCO 2017. Abstract 4003. Reproduced with permission.
All Pts (N = 259)
Median OS, mos (95% CI) 5.6 (4.3-6.9)
12-mo OS rate, % 23.4
All Pts (N = 259)
Median PFS, mos (95% CI) 2.0 (2.0-2.1)
100
80
60
40
20
0
OS
(%)
Mos220 2 4 6 8 10 12 14 16 18 20
Pts at risk, n259 199 144 112 51 27 22 12 7 287 0
100
80
60
40
20
0
PFS
(%)
Mos220 2 4 6 8 10 12 14 16 18 20
Pts at risk, n259 136 51 34 17 4 2 2 2 022 0
OS PFS
Response by PD-L1 Expression
Response PD-L1 Positive (n=148) PD-L1 Negative (n=109)
% 95% CI % 95% CI
ORR 15.5 10.1-22.4 6.4 2.6-12.8
CR 2.0 0.4-5.8 2.8 0.6-7.8
PR 13.5 8.5-20.1 3.7 1.0-9.1
DCR 33.1 25.6-41.3 19.3 12.3-27.9
Integrating New Therapies into Treatment Regimens for Gastric and Gastroesophageal Cancer
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Checkmate 032 Gastric Cohort Best Reductions in Target Lesions
Key Points
• Immunotherapy including immune checkpoint inhibition is a growing area of research in gastric and esophageal cancers. Certain tumor characteristics may predict favorable responses to these approaches.
• Checkpoint inhibitor with anti-PD-1 mAB pembrolizumab and nivolumabhas led to increased response rates in advanced heavily pre-treated patients
• Higher response rates in PDL-1 expression
• Combination approaches with chemotherapy, radiotherapy and targeted agents are likely to improve outcomes
• Clinical trials applying modern sequence technology that allows for identification of unique, tumor-specific neoantigen profiles are ongoing.
Side Effect and Management
5-Fluorouracil/Capecitabine Toxicity
• Toxicity similar to continuous infusion 5-Fluorouracil
• Common
– *Palmar-plantar erythrodysesthesia(Hand-foot syndrome)• More common with
capecitabine than 5-Fluorouracil
– Mucositis– Diarrhea– Photosensitivity
• Rare– Nausea/vomiting– Hyperbilirubinemia– Cardiac toxicity– Ocular toxicity
• *Grade 2 stop drug until resolved or grade 1. Consider dose reduction.
Oxaliplatin Toxicity
• Two types of neuropathy
– Acute neuropathy
• Cold sensitivity for first 5 to 7 days after each dose
– Chronic neuropathy
• Dose limiting cumulative peripheral neuropathy
• *Moderate emetogenic potential
• Myelosuppression
• Extravasation risk
• Delayed hypersensitivity
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Prevention and Management of Platinum Induced Nausea and Vomiting
Level 2: Patients receiving a moderately emetogenic agent or patients receiving midly emetogenic agent who have failed to respond to or are intolerant of at least two level 1 regimens:
Aprepitant 125 mg PO before chemotherapy on day 1, then 80 mg PO daily on days 2 and 3, andPalonosetron 0.25 mg IV before chemotherapy, andDexamethasone 10-12 mg IV/ PO before chemotherapy, then 8 mg PO daily on days 2-4
With or withoutLorazepan 1 mg PO or IV before q4-6 hrs p.r.n., orProchlorperazine 10 mg PO q4h-6 h p.r.n; or both
Irinotecan Toxicity
• Diarrhea– Early diarrhea
• < 24 hours after irinotecan
• Cholinergic type reaction
– Anticholinergics (Atropine) can be beneficial. Atropine 0.25 -1 mg IV before Irinotecan
– Late diarrhea• > 24 hours after irinotecan
• Prolonged diarrhea if not controlled.
• Aggressive loperamide can be beneficial
• Myelosuppression• Moderate emetogenic potential • Mucositis
Ramucirumab Adverse Effects
• GI perforation—permanently discontinue • Thromboembolism
– ATE—permanently discontinue – VTE
• Continue with full dose anticoagulation with DVT or asymptomatic PE• Permanently discontinue if symptomatic PE
• CHF—permanently discontinue • Delayed wound healing
– Hold 4-8 weeks prior to and 4-8 weeks after surgery
ATE-arterial thromboembolism DVT—deep venous thromboembolismVTE-venous thromboembolism PE—pulmonary embolism CHF—congestive heart failure
Clinical Pharmacology Online. Accessed Nov 2012Gressett SM, et al. Ann Pharmacother. 2009 Mar; 43 (3): 490-501Saif MW. J Support Oncol. 2009; 7(6): 245-251
Trastuzumab: Adverse Effects
• Infusion related reactions– Occur during or within 24 hours 21-40%– Can cause severe pulmonary toxicity ((can be delayed)– Discontinue if life-threatening severe reactions– Cardiotoxicity: LVEF decreased (4-22%)– LVEF decreased and congestive heart failure– Use caution in patients with heart failure, cardiomyopathy,
ventricular dysfunction– Recommended to undergo monitoring before and during therapy
(MUGA or ECHO)– May require holding trastuzumab and CHF treatment
Clinical Pharmacology Online. Accessed November 2012. .
Side Effects vs Immune Related Adverse Events
PD-L1 inhibitors
PD-1 Inhibitors
CTLA-4 Inhibitors
CTLA-4 Inhibitors + PD-1 Inhibitors
Immune related adverse event (irAE)
• Type of side effect
• Result of immune infiltration and inflammation
• May be diagnosed with a biopsy of the affected anatomic location
• May be a diagnosis of exclusion
• Responsive to corticosteroids
Most common side effects of immunotherapy occur in 20-30% of patients
Immune related adverse events are generally UNcommon
irAEs
Inci
denc
e an
d Se
verit
y
Side Effects: Immunotherapy
• Dermatological toxicities – Rash– Folicullar dermatitis– Vitiligo– Bullous pemphigoid
• Endocrine Toxicities– Hypophysitis– Hypothyroidism– Hyperthyroidism– Thyroiditis– Adrenal Insufficiency
• Hepatic Toxicity– Hepatitis– Hepatomegaly
• Pneumonitis– Acute interstitial pneumonia
• Diarrhea colitis
Integrating New Therapies into Treatment Regimens for Gastric and Gastroesophageal Cancer
©2018 Rockpointe Oncology 12Activity Slides
Management of Immune-related Adverse Events Excluding Skin and Endocrine Toxicities
Boutros, C. et al. (2016) Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combinationNat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.58
Conclusions
• Targeted therapies– Biomarkers needed to identify patients
– Gene amplification> mutation in gastric cancer
– Trastuzumab: HER2+/amplified gastroesophageal/gastric cancers, only a minority are eligible for HER-2 targeting antibody therapy
– Newer HER2 agents –Pertuzumab trial in the front line did not meet endpoint
– Ramucirumab + paclitaxel: translated into survival benefit
• Negative trials in unselected patients:– EGFR agents + chemo
• Panitumumab, Cetuximab+ chemo detrimental
– VEGF-A• Bevacizumab + chemo
• cMET trials in selected population– highlight importance of biomarker use
Conclusions (cont)
• Heterogeneity of GC has led to differentiating those tumors that depend on an immune regulatory mechanism: EBV driven tumors and the MSI subtypes.
• Distinct biology subtypes will allow for application of more targeted therapies.
• Developing effective immunotherapy will require further knowledge of the complex relationship between tumor and environment.
• Immunologic checkpoint blockade with anti CTLA-4 and PD-1/PDL-1 have shown promising results. Further combination with immunotherapies might have synergistic effects.
CME/MOC Credit• Requesting MOC and CME
– If you are seeking MOC and CME credit, you do not need to complete the remainder of the paper form. Visit the website URL at the top of your evaluation form, or scan the QR code, then complete the online evaluation and pass the post-test for MOC credit. Please give your completed Activity Survey to on-site staff.
• Requesting only CME– If you are seeking only CME credit, the remaining
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– Return all forms to on-site CME staff.
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