October 10, 2019 ISGIO · Daniel Catenacci, MD. Associate Professor of Medicine. Director GI Oncology Program. October 10, 2019. ISGIO Novel Targets and Immunotherapy Advances in

Daniel Catenacci, MDAssociate Professor of MedicineDirector GI Oncology Program

October 10, 2019ISGIO

Novel Targets and Immunotherapy Advances in Esophagogastric Adenocarcinoma How do we Sequence New Immunotherapy Agents?

Comparing Efficacy: DFS, OS

FLOT CROSS

2Daniel Catenacci

mOS = 43.2 monthsmOS = 50 months

5yrOS = 45%5yrOS = 43%

(mDFS = 29.9 months)(mDFS = 30 months)

LN+ disease: 78%T4 disease: 8%

SR/Diffuse GC: 27%

LN+ disease: 65%T4 disease: 0%

SR/Diffuse GC: 0%

MAGICOnly Surgery

Al-Batran et al. Phase III FLOT4. Lancet 2019 van Hagen et al. Phase III CROSS. NEJM 2012Shapiro et al. Phase III CROSS. Lancet Oncol 2015

EGJ ACCROSS > just surg

HR 0.75

EGJ ACFLOT > MAGIC > Surgery

HR 0.76 HR 0.74

First Line Management of Advanced Gastroesophageal Adenocarcinoma

1. Murad, et al. Cancer 1993 2. Vanhoefer, et al. JCO 20003. Ajani, et al. ASCO 2009 4. Van Cutsem, et al. JCO 20065. Dank, et al. Ann Oncol 2008

6. Cunningham, et al. NEJM 2008 7. Kang, et al. Ann Oncol 20098. Guimbaud, et al. JCO 2014 9. Shah, et al. JAMA ONC 2016

BSC = best supportive care; MTX = methotrexate; S = S-1; A = doxorubicinF = 5-FU; C/P = cisplatin; I = irinotecan; E = epirubicin; O = oxaliplatin; D = docetaxel

mOS Months

BSC 1

60 2 4 128 10

FAMTX 2

SP 3

EOX 6

XP 7

FP 4

IF 5

EOF 6

DCF 4

ECF 6

ECX 6

FOLFIRI 8

FOLFOX 9

mOS = ~10-11m1yr OS = ~40%2yr OS = ~15-20%5yr OS < ~2%

GEA Standard Therapy

• Cytotoxics: 5FU, platinum, irinotecan, taxane, TAS-102

• Few targeted therapies incorporated into routine care:

Marker Incidence Treatment Therapy Line Approval Benefit

HER2++ ~15% Chemo+Trastuzumab 1L 2010 HR 0.65

none 100% Chemo+Ramucirumab 2L 2014/15 HR 0.8

MSI-High ~2-3% Pembrolizumab 2L+ 2017* HR? (great)

PDL1+ >1% ~50-60% Pembrolizumab 3L+ 2017 * HR? (marginal)

* Conditional approvals

MANY NEGATIVE ‘TARGETED/IO’ STUDIES!!

mOS Months

BSC 1

60 2 4 128 10

FAMTX 2

SP 3

EOX 6

XP 7

FP 4

IF 5

EOF 6

DCF 4

ECF 6

ECX 6

FOLFIRI 8

1. Murad, et al. Cancer 1993 2. Vanhoefer, et al. JCO 2000 3. Ajani, et al. ASCO 2009 4. Van Cutsem, et al. JCO 20065. Dank, et al. Ann Oncol 2008 6. Cunningham, et al. NEJM 2008 7. Kang, et al. Ann Oncol 2009 8. Guimbaud, et al. JCO 2014 9. Shah et al. JAMA Oncol 2016. 10. Bang et al. Lancet 2010.

X/FP+/-T10

X/FP+/-T10

HER2 IHC3+ or IHC2+/FISH+

HER2 (+) (IHC0-3+/FISH+)

X/FP+/-T10 HER2 IHC3+/FISH+

+T+T

14 16 18

FOLFOX 9

+T

All-comersmOS = ~10-11m1yr OS = ~40%2yr OS = ~15-20%5yr OS < ~2%

HER2+mOS = ~14-16m1yr OS = ~55-65%2yr OS = ~25-30%5yr OS < ~10-15%

Line Trial N Treatment 10 Endpt mOS HR Δ mPFS HR Δ RR Δ

2L Fuchs et alLancet 2013

REGARD

335 PlaceboRamucirumab

OS 3.55.2 0.78

p=0.047+1.7

1.32.1 0.48 +0.8

3%3% 0

2L Wilke et alLancet Oncol 2014

RAINBOW

665 Paclitaxel-PlboPaclitaxel-Ram

OS 7.49.6 0.8

p=0.017+2.2

2.94.4 0.64 +1.5

16%27% +11

3L Li et alJ Clin Oncol 2016

267 PlaceboApatinib

OS/PFS 4.76.5 0.71

p=0.015+1.8

1.82.6 0.44 +0.8

03% +3

Antiangiogenesis for EGA: 2L

Antiangiogenesis for EGA: 1LLine Trial N Treatment 10 Endpt mOS HR Δ mPFS HR Δ RR Δ

1L 1. Ohtsu et alJ Clin Oncol 2011

AVAGAST

774 Cis/F- placeboCis/F - Bev

OS 10.112.1

0.87N.S. +2

5.36.7

0.8p=0.004 +1.4

37.446

+8.6p=0.03

1L 2. Shen et alGastric Cancer 2015

AVATAR

202 Cis/Cape-placeboCis/Cape-Bev

OS 11.410.5

1.11N.S. -0.9

66.3

0.89N.S. +0.3

3441

+8N.S.

1L 3. Yoon et alAnnals Oncol 2016

JVBT

168 FOLFOX-placeboFOLFOX-Ramucirumab

PFS 11.711.5 1.08

N.S.-0.2

6.76.4 0.98

N.S.-0.3

4645 -1

N.S.

1L 4. Enzinger et alCancer 2019

ZAMEGA

641:2

FOLFOX-placeboFOLFOX-Aflibercept

6m PFS57.1%/60.5%

18.814.5

1.24N.S.

-4.3 7.49.9

1.11N.S. +2.5

7561

-14N.S.

1L 5. Fuchs et alLancet Oncol 2019

RAINFALL

645 Cis/F – placeboCis/F - Ram

PFS/OS 10.711.2

0.962N.S.

+0.5 5.45.7

0.75p=0.011

+0.3 3641

+5N.S.

1L 6. Yoshikawa et alJAMA Netw Open 2019

RAINSTORM

189 SOX - placebo Pac/RamSOX - Ram Pac/Ram

PFS1 14.2614.65

1.11N.S.

+0.4 6.746.34

1.07N.S.

-0.4 5058

+8N.S.

Le et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017

N= 86 MSI-H pts12 different tumor types

GEA:TCGA 23%Stage IV <3%

FDA Approves Pembrolizumab for Microsatellite Instability-High and Mismatch Repair Deficient Cancers. May 23, 2017

• ORR 3/5 = 60%

• KN059 3L+ORR 4/7 = 57%

• KN061 2LORR 7/15 = 47%

• KN062 1LESMO 2019 14 vs 14 vs 19 placebo

mOS NR NR 8.5

FDA approval 2L+ Pan-tumorN=149, historical control

Immune Checkpoint Blocakade for EGA

MSI-High

IO Trials: Gastroesophageal Cancer3L+

KN-059ATTRACTION-2

JAVELIN-300

2L

KN-061KN-181 (SCC 64%)

ATTRACTION-3 (SCC 100%)

1L Maintenance

KN-062

(CM-649)(KN590 AC/SCC)

(KN859)(ATTRACTION-4)

(JAVELIN-100)

Com

plet

edO

ngoi

ng

KN 059 Cohort 1 3L+: Response in All Patients

All patients (N = 259)Response* % 95% CI

ORR (CR+PR) 11.6 8.0–16.1DCR‡ 27.0 21.7–32.9

CR 2.3 0.9–5.0PR 9.3 6.0–13.5

SD 16.2 11.9–21.3PD 56.0 49.7–62.1

Data cutoff: Jan16, 2017*Only confirmed responses were included

‡CR+PR+SD≥2 months

• Median (range) follow-up: 5.8 months (0.5-21.6)

KN 059 Cohort 1:Response by PD-L1 Expression

Response* PD-L1 positive ( n= 148) PD-L1 negative (n = 109)

% 95% CI % 95% CIORR 15.5 10.1-22.4 6.4 2.6-12.8DCR‡ 33.1 25.6-41.3 19.3 12.3-27.9

CR 2.0 0.4-5.8 2.8 0.6-7.8PR 13.5 8.5-20.1 3.7 1.0-9.1

* Includes MSI-High tumors (13.3% MSS/PDL1+; 2-3 patients out of 20)FDA grants accelerated approval to pembrolizumab for advanced 3L+ PDL1+ gastric cancerhttps://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577093.htmSeptember 22, 2017

Fuchs et al. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol 2018

https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577093.htm

• PD-L1 expression in gastric cancer is determined by Combined Positive Score (CPS)

• A specimen is considered to have positive PD-L1 expression if CPS ≥ 1

Tumor CellsImmune Cells

PD-L1 Expression IHC*

*22C3 pharmDx™IHC DAKO, Carpinteria, CA

Tumor Cells

Immune Cells

# PD-L1 staining cells (tumor cells, lymphocytes, macrophages) CPS = ----------------------------------------------------------------------------------- X 100

Total # viable tumor cells

PD-L1-positive PD-L1-negative

PD-L1 22C3 pharmDX assay

Progression-Free Survival

Presented By Yoon-Koo Kang at 2017 Gastrointestinal Cancers Symposium

Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial.

TPS, PD-L1 28-8 pharmDX assay

Overall Survival

Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial.

Kang et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017


ORR DCRKang et al. ASCO GI 201922C3 pharmDX assay

Bang et al. Phase III, randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol 2018

Avelumab vs SOC 3L Phase III JAVELIN-300

Avelumab vs chemoIrinotecan/taxane

Worse OSWorse PFS

PFS

PFS by PDL1

Immunotherapy in 3L+ Summary• KN059 COHORT1 – single arm

– pembrolizumab– PDL1+ CPS >1 only (conditional approval US only)

• ATTRACTION-02 – randomized to placebo – Nivolumab, all patients (Asia only)– PDL1 TPS (vs CPS?)

• JAVELIN300 – randomized to standard irinotecan/taxane– avelumab

Catenacci DVT, Hochster H, Klempner S. Keeping Checkpoint Inhibitors in Check. JAMA Netw Open 2019

TAS-102

Overall Survival, CPS ≥1

RAINBOWmPFS 4.4 mmOS 9.6 m

KEYNOTE 061 vs paclitaxel 2L

Shitara et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer(KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 2018

PFS1.5 m4.1 m

(<0.0135)

Overall Survival by PD-L1 CPS

Presented By Kohei Shitara at 2018 ASCO Annual Meeting

ITT: N1=592 (296 vs 296)PDL1+ >1%: N2=395 (66%) (199 vs 196)

N2= NAN1= 195/592 = 33% 287/592 = 48% 108/592 = 18%

108/395 = 27%287/395 = 73%CPS >1 to <10% CPS >10%CPS <1%

OS, ORR, and DOR for MSI-H Tumorsa

Presented By Kohei Shitara at 2018 ASCO Annual Meeting


Pembrolizumab Versus Chemotherapy as Second-line Therapy for Advanced Esophageal Cancer: The Phase 3 KEYNOTE-181 Study

Presented By Takashi Kojima at 2019 Gastrointestinal Cancer Symposium

Overall Survival (ITT)


Overall Survival (SCC)


Overall Survival (PD-L1 CPS ≥10)


OS in Key Subgroups


~24% adeno CPS >10

FDA approves pembrolizumab for advanced esophageal squamous cell cancerhttps://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-esophageal-squamous-cell-cancerJuly 30, 2019

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-esophageal-squamous-cell-cancer

ATTRACTION-03 nivolumab vs taxane 2/3L+

Kato et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy ATTRACTION-3 a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019

(bad biomarker)

31% docetaxel69% paclitaxel


SCC

Immunotherapy in 2L Summary• KN061 – randomized to paclitaxel

– Pembrolizumab (MSI-H, >CPS 10?)

• KN181 SCC – randomized to paclitaxel – pembrolizumab, – SCC with PDL1+ CPS >10 only 2L+

• KN181 AC – randomized to paclitaxel– pembrolizumab (>CPS 10?)

• KNs MSI-High – single arm studies, KN061– pembrolizumab, (conditional approval US only) 2L+


ATTRACTION-3 SCC – randomized to taxane

nivolumab, SCCYin Yang!(PDL1 CPS >10, >1?)

Pembrolizumab With or Without Chemotherapy Versus Chemotherapy in Advanced G/GEJ Adenocarcinoma: The Phase 3, KEYNOTE-062 Study

Presented By Josep Tabernero at 2019 ASCO Annual Meeting

Statistical Considerations


KN-062: A Story of Multiplicity Testing!!!1L HER2 neg: Chemo +/- Pembo or Pembro alone

Overall Survival: P+C vs C (CPS ≥1)


(<0.0125)

KN-062 Primary Endpoint: Overall Survival –(HER2negative patients)

Overall Survival: P+C vs C (CPS ≥10)


(<0.0075)


Overall Survival: P vs C (CPS ≥1)


Keynote 061 2L phase IIIpaclitaxel vs Pembro CPS>1


Overall Survival: P vs C (CPS ≥10)



MSI-HighEBV+?PDL1 >30,40,50?TMB-high?PS 0 ?Low Disease Burden?

~10-15%

MSI-High KN-062

Shitara et al. ESMO 2019

MSS in KN-062

Shitara et al. ESMO 2019

ITT in KN-062

Immunotherapy in 1L Summary• KN062 monotherapy – randomized to Cis/5FU/placebo

– pembrolizumab – (some bad, some good: MSI-High, ??)

• KN062 chemotherapy – randomized to Cis/5FU/placebo– Pembrolizumab (some good: MSI-High, ??)

• Checkmate 649 1L pending• KEYNOTE 590 1L (AC/SCC) pending• KEYNOTE 859 1L pending• ATTRACTION-4 1L pending• JAVELIN 100 1L maintenance pending


Anti-HER2 + IO Combination?

Anti-HER2 Ab

Anti-HER2 + IO Combination

Janjigian et al. GI ASCO 2019 Catenacci et al. GI ASCO, 2017/18/19, ESMO 2019

Second Line: Margetuximab/PembrolizumabFirstLine: Chemo/Trastuzumab/Pembrolizumab

KN-811 1L Phase IIIChemo/Tras +/- pembro

MAHOGANY 1L Phase II/III

24 24 22 22 22 21 21 18 18 16 13 12 11 10 9 8 8 8 8 8 5 4 3 3 3 1 1 1 1 1 032 32 31 29 28 28 25 25 22 20 17 13 13 12 10 9 8 6 6 5 4 2 1 1 08 7 6 6 6 6 6 6 5 3 3 3 3 3 2 1 06 6 5 4 3 1 1 0

IHC3+/PDL1+IHC3+/PDL1-IHC2+/PDL1+IHC2+/PDL1-

01

23

45

67

89

1011

1213

1415

1617

1819

2021

2223

2425

2627

2829

30

OS: Months from treatment initiation

0.0

0.2

0.4

0.6

0.8

1.0

Surv

ival P

roba

bility

01

23

45

67

89

1011

1213

1415

1617

1819

2021

2223

2425

2627

2829

30

OS: Months from treatment initiation

0.0

0.2

0.4

0.6

0.8

1.0

Surv

ival P

roba

bility

+ Censored

IHC3+/PDL1+

IHC3+/PDL1-

IHC2+/PDL1+IHC2+/PDL1-

GEA Standard Therapy1L 2L 3L+

HER2-/MSS/PDL1- FOLFOX Pac/Ram IrinotecanHER2 + FOLFOX-T FOLFIRI-Ram Taxane

TAS102PDL1 CPS >1 pembroMSI-High pembro

Few targeted therapies incorporated into routine care:

Marker Incidence Treatment Therapy Line Approval Benefit

HER2++ ~15% Chemo+Trastuzumab 1L 2010 HR 0.65

none 100% Chemo+Ramucirumab 2L 2014/15 HR 0.8

MSI-High ~2-3% Pembrolizumab 2L+ 2017* HR? (great)

PDL1+ >1% ~50-60% Pembrolizumab 3L+ 2017 * HR? (marginal)

* Conditional approvals

Molecular:

Thank You!

Documents

October 10, 2019 ISGIO · Daniel Catenacci, MD. Associate Professor of Medicine. Director GI Oncology Program. October 10, 2019. ISGIO Novel Targets and Immunotherapy Advances in