integrating new therapies into treatment regimens for ...bang yj, et al. lancet. 2010;376:687-697....

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.



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



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



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



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)



REGARD Trial of BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer: OS


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


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



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.



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



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



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



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



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.

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