October 10, 2019 ISGIO Comparing Efficacy: DFS, OS FLOT CROSS - - PowerPoint PPT Presentation

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October 10, 2019 ISGIO Comparing Efficacy: DFS, OS FLOT CROSS - - PowerPoint PPT Presentation

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Novel Targets and Immunotherapy Advances in Esophagogastric Adenocarcinoma How do we Sequence New Immunotherapy Agents? Daniel Catenacci, MD Associate Professor of Medicine Director GI Oncology Program October 10, 2019 ISGIO Comparing

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Daniel Catenacci, MD Associate Professor of Medicine Director GI Oncology Program

October 10, 2019 ISGIO

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

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Comparing Efficacy: DFS, OS

FLOT CROSS

2

Daniel Catenacci

mOS = 43.2 months mOS = 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%

MAGIC

Only Surgery

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

EGJ AC CROSS > just surg HR 0.75 EGJ AC FLOT > MAGIC > Surgery HR 0.76 HR 0.74

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First Line Management of Advanced Gastroesophageal Adenocarcinoma

  • 1. Murad, et al. Cancer 1993
  • 2. Vanhoefer, et al. JCO 2000
  • 3. Ajani, et al. ASCO 2009
  • 4. Van Cutsem, et al. JCO 2006
  • 5. 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 ONC 2016

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

mOS Months BSC 1 6 2 4 12 8 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 = ~10-11m 1yr OS = ~40% 2yr OS = ~15-20% 5yr OS < ~2%

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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!!

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mOS Months BSC 1 6 2 4 12 8 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 2006
  • 5. 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-comers mOS = ~10-11m 1yr OS = ~40% 2yr OS = ~15-20% 5yr OS < ~2% HER2+ mOS = ~14-16m 1yr OS = ~55-65% 2yr OS = ~25-30% 5yr OS < ~10-15%

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Line Trial N Treatment 10 Endpt mOS HR Δ mPFS HR Δ RR Δ 2L Fuchs et al Lancet 2013 REGARD 335 Placebo Ramucirumab OS 3.5 5.2 0.78

p=0.047

+1.7 1.3 2.1 0.48 +0.8 3% 3% 2L Wilke et al Lancet Oncol 2014 RAINBOW 665 Paclitaxel-Plbo Paclitaxel-Ram OS 7.4 9.6 0.8

p=0.017

+2.2 2.9 4.4 0.64 +1.5 16% 27% +11 3L Li et al J Clin Oncol 2016 267 Placebo Apatinib OS/PFS 4.7 6.5 0.71

p=0.015

+1.8 1.8 2.6 0.44 +0.8 3% +3

Antiangiogenesis for EGA: 2L

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Antiangiogenesis for EGA: 1L

Line Trial N Treatment 10 Endpt mOS HR Δ mPFS HR Δ RR Δ 1L

  • 1. Ohtsu et al

J Clin Oncol 2011 AVAGAST 774 Cis/F- placebo Cis/F - Bev OS 10.1 12.1 0.87 N.S. +2 5.3 6.7 0.8 p=0.004 +1.4 37.4 46 +8.6 p=0.03 1L

  • 2. Shen et al

Gastric Cancer 2015 AVATAR 202 Cis/Cape-placebo Cis/Cape-Bev OS 11.4 10.5 1.11 N.S.

  • 0.9

6 6.3 0.89 N.S. +0.3 34 41 +8 N.S. 1L

  • 3. Yoon et al

Annals Oncol 2016 JVBT 168 FOLFOX-placebo FOLFOX-Ramucirumab PFS 11.7 11.5 1.08 N.S.

  • 0.2

6.7 6.4 0.98 N.S.

  • 0.3

46 45

  • 1

N.S. 1L

  • 4. Enzinger et al

Cancer 2019 ZAMEGA 64 1:2 FOLFOX-placebo FOLFOX-Aflibercept 6m PFS

57.1%/60.5%

18.8 14.5 1.24 N.S.

  • 4.3

7.4 9.9 1.11 N.S. +2.5 75 61

  • 14

N.S. 1L

  • 5. Fuchs et al

Lancet Oncol 2019 RAINFALL 645 Cis/F – placebo Cis/F - Ram PFS/OS 10.7 11.2 0.962 N.S. +0.5 5.4 5.7 0.75 p=0.011 +0.3 36 41 +5 N.S. 1L

  • 6. Yoshikawa et al

JAMA Netw Open 2019 RAINSTORM 189 SOX - placebo  Pac/Ram SOX - Ram  Pac/Ram PFS1 14.26 14.65 1.11 N.S. +0.4 6.74 6.34 1.07 N.S.

  • 0.4

50 58 +8 N.S.

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

N= 86 MSI-H pts

12 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 2L

ORR 7/15 = 47%

  • KN062 1L

ESMO 2019 14 vs 14 vs 19 placebo mOS NR NR 8.5 FDA approval 2L+ Pan-tumor N=149, historical control

Immune Checkpoint Blocakade for EGA MSI-High

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IO Trials: Gastroesophageal Cancer

3L+

KN-059 ATTRACTION-2 JAVELIN-300

2L

KN-061 KN-181 (SCC 64%) ATTRACTION-3 (SCC 100%)

1L Maintenance

KN-062 (CM-649) (KN590 AC/SCC) (KN859) (ATTRACTION-4) (JAVELIN-100)

Completed Ongoing

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

All patients (N = 259) Response* % 95% CI ORR (CR+PR) 11.6 8.0–16.1 DCR‡ 27.0 21.7–32.9 CR 2.3 0.9–5.0 PR 9.3 6.0–13.5 SD 16.2 11.9–21.3 PD 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)
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KN 059 Cohort 1: 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 DCR‡ 33.1 25.6-41.3 19.3 12.3-27.9 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

* 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 cancer

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

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  • 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 Cells Immune 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

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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

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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

TPS, PD-L1 28-8 pharmDX assay ORR DCR Kang et al. ASCO GI 2019 22C3 pharmDX assay

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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 chemo Irinotecan/taxane Worse OS Worse PFS

PFS PFS by PDL1

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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

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Overall Survival, CPS ≥1

RAINBOW mPFS 4.4 m mOS 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

PFS 1.5 m 4.1 m

(<0.0135)

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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= NA N1= 195/592 = 33% 287/592 = 48% 108/592 = 18% 108/395 = 27% 287/395 = 73% CPS >1 to <10% CPS >10% CPS <1%

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OS, ORR, and DOR for MSI-H Tumorsa

Presented By Kohei Shitara at 2018 ASCO Annual Meeting

KEYNOTE 061 vs paclitaxel 2L

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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

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Overall Survival (ITT)

Presented By Takashi Kojima at 2019 Gastrointestinal Cancer Symposium

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Overall Survival (SCC)

Presented By Takashi Kojima at 2019 Gastrointestinal Cancer Symposium

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Overall Survival (PD-L1 CPS ≥10)

Presented By Takashi Kojima at 2019 Gastrointestinal Cancer Symposium

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OS in Key Subgroups

KEYNOTE 181 vs paclitaxel 2L

~24% adeno CPS >10

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

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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% docetaxel 69% paclitaxel TPS, PD-L1 28-8 pharmDX assay

SCC

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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+

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

ATTRACTION-3 SCC – randomized to taxane

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

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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

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Statistical Considerations

Presented By Josep Tabernero at 2019 ASCO Annual Meeting

KN-062: A Story of Multiplicity Testing!!!

1L HER2 neg: Chemo +/- Pembo or Pembro alone

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Overall Survival: P+C vs C (CPS ≥1)

Presented By Josep Tabernero at 2019 ASCO Annual Meeting

(<0.0125)

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

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Overall Survival: P+C vs C (CPS ≥10)

Presented By Josep Tabernero at 2019 ASCO Annual Meeting

(<0.0075)

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

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Overall Survival: P vs C (CPS ≥1)

Presented By Josep Tabernero at 2019 ASCO Annual Meeting

Keynote 061 2L phase III paclitaxel vs Pembro CPS>1

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

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Overall Survival: P vs C (CPS ≥10)

Presented By Josep Tabernero at 2019 ASCO Annual Meeting

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

MSI-High EBV+? PDL1 >30,40,50? TMB-high? PS 0 ? Low Disease Burden? ~10-15%

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MSI-High KN-062

Shitara et al. ESMO 2019

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MSS in KN-062

Shitara et al. ESMO 2019

ITT in KN-062

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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

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

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Anti-HER2 + IO Combination?

Anti-HER2 Ab

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Anti-HER2 + IO Combination

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

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

KN-811 1L Phase III Chemo/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 32 32 31 29 28 28 25 25 22 20 17 13 13 12 10 9 8 6 6 5 4 2 1 1 8 7 6 6 6 6 6 6 5 3 3 3 3 3 2 1 6 6 5 4 3 1 1

IHC3+/PDL1+ IHC3+/PDL1- IHC2+/PDL1+ IHC2+/PDL1- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

OS: Months from treatment initiation

0.0 0.2 0.4 0.6 0.8 1.0

Survival Probability

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

OS: Months from treatment initiation

0.0 0.2 0.4 0.6 0.8 1.0

Survival Probability

+ Censored

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

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GEA Standard Therapy

1L 2L 3L+

HER2-/MSS/PDL1- FOLFOX Pac/Ram Irinotecan HER2 + FOLFOX-T FOLFIRI-Ram Taxane TAS102 PDL1 CPS >1 pembro MSI-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:

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Thank You!