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 Efficacy: DFS, OS FLOT CROSS LN+ disease: 78% LN+ disease: 65% T4 disease: 8% T4 disease: 0% SR/Diffuse GC: 27% SR/Diffuse GC: 0% 5yrOS = 43% 5yrOS = 45% EGJ AC EGJ AC MAGIC CROSS > just surg Only Surgery FLOT > MAGIC > Surgery mOS = 50 months HR 0.75 HR 0.76 HR 0.74 mOS = 43.2 months (mDFS = 30 months) (mDFS = 29.9 months) van Hagen et al. Phase III CROSS. NEJM 2012 Al-Batran et al. Phase III FLOT4. Lancet 2019 Shapiro et al. Phase III CROSS. Lancet Oncol 2015 2 Daniel Catenacci
First Line Management of Advanced Gastroesophageal Adenocarcinoma BSC 1 mOS = ~10-11m FAMTX 2 1yr OS = ~40% SP 3 2yr OS = ~15-20% 5yr OS < ~2% FP 4 IF 5 EOF 6 DCF 4 ECF 6 ECX 6 EOX 6 XP 7 FOLFIRI 8 FOLFOX 9 mOS Months 0 2 4 6 8 10 12 1. Murad, et al. Cancer 1993 6. Cunningham, et al. NEJM 2008 2. Vanhoefer, et al. JCO 2000 7. Kang, et al. Ann Oncol 2009 BSC = best supportive care; MTX = methotrexate; S = S-1; A = doxorubicin 3. Ajani, et al. ASCO 2009 8. Guimbaud, et al. JCO 2014 4. Van Cutsem, et al. JCO 2006 9. Shah, et al. JAMA ONC 2016 F = 5-FU; C/P = cisplatin; I = irinotecan; 5. Dank, et al. Ann Oncol 2008 E = epirubicin; O = oxaliplatin; D = docetaxel
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!!
BSC 1 FAMTX 2 SP 3 FP 4 IF 5 EOF 6 DCF 4 All-comers mOS = ~10-11m ECF 6 1yr OS = ~40% 2yr OS = ~15-20% ECX 6 5yr OS < ~2% EOX 6 XP 7 FOLFIRI 8 FOLFOX 9 HER2+ mOS = ~14-16m +T X/FP+/-T 10 HER2 (+) (IHC0-3+/FISH+) 1yr OS = ~55-65% +T X/FP+/-T 10 HER2 IHC3+ or IHC2+/FISH+ 2yr OS = ~25-30% 5yr OS < ~10-15% +T X/FP+/-T 10 HER2 IHC3+/FISH+ mOS Months 16 0 2 4 6 8 10 12 14 18 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.
Antiangiogenesis for EGA: 2L 1 0 Endpt Line Trial N Treatment mOS HR Δ mPFS HR Δ RR Δ 2L Fuchs et al 335 Placebo OS 3.5 1.3 3% Lancet 2013 Ramucirumab 5.2 0.78 +1.7 2.1 0.48 +0.8 3% 0 p=0.047 REGARD 2L Wilke et al 665 Paclitaxel-Plbo OS 7.4 2.9 16% Lancet Oncol 2014 Paclitaxel-Ram 9.6 0.8 +2.2 4.4 0.64 +1.5 27% +11 RAINBOW p=0.017 3L Li et al 267 Placebo OS/PFS 4.7 1.8 0 J Clin Oncol 2016 Apatinib 6.5 0.71 +1.8 2.6 0.44 +0.8 3% +3 p=0.015
Antiangiogenesis for EGA: 1L 1 0 Endpt Line Trial N Treatment mOS HR Δ mPFS HR Δ RR Δ 1L 1. Ohtsu et al 774 Cis/F- placebo OS 10.1 0.87 5.3 0.8 37.4 +8.6 J Clin Oncol 2011 Cis/F - Bev 12.1 N.S. +2 6.7 p=0.004 +1.4 46 p=0.03 AVAGAST 1L 2. Shen et al 202 Cis/Cape-placebo OS 11.4 1.11 6 0.89 34 +8 Gastric Cancer 2015 Cis/Cape-Bev 10.5 N.S. -0.9 6.3 N.S. +0.3 41 N.S. AVATAR 1L 3. Yoon et al 168 FOLFOX-placebo PFS 11.7 6.7 46 Annals Oncol 2016 FOLFOX-Ramucirumab 11.5 1.08 -0.2 6.4 0.98 -0.3 45 -1 JVBT N.S. N.S. N.S. 1L 4. Enzinger et al 64 FOLFOX-placebo 6m PFS 18.8 1.24 -4.3 7.4 1.11 75 -14 Cancer 2019 1:2 FOLFOX-Aflibercept 57.1%/60.5% 14.5 N.S. 9.9 N.S. +2.5 61 N.S. ZAMEGA 1L 5. Fuchs et al 645 Cis/F – placebo PFS/OS 10.7 0.962 +0.5 5.4 0.75 +0.3 36 +5 Lancet Oncol 2019 Cis/F - Ram 11.2 N.S. 5.7 p=0.011 41 N.S. RAINFALL 1L 6. Yoshikawa et al 189 SOX - placebo Pac/Ram PFS 1 14.26 1.11 +0.4 6.74 1.07 -0.4 50 +8 JAMA Netw Open 2019 SOX - Ram Pac/Ram 14.65 N.S. 6.34 N.S. 58 N.S. RAINSTORM
Immune Checkpoint Blocakade for EGA MSI-High N= 86 MSI-H pts 12 different tumor types GEA: TCGA 23% Stage IV <3% • 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 Le et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017 FDA Approves Pembrolizumab for Microsatellite Instability-High and Mismatch Repair Deficient Cancers. May 23, 2017
IO Trials: Gastroesophageal Cancer 1L Maintenance 2L 3L+ Completed KN-062 KN-061 KN-059 KN-181 (SCC 64%) ATTRACTION-2 ATTRACTION-3 (SCC 100%) JAVELIN-300 (CM-649) Ongoing (KN590 AC/SCC) (KN859) (ATTRACTION-4) (JAVELIN-100)
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 • Median (range) follow-up: 5.8 months (0.5-21.6) Data cutoff: Jan16, 2017 * Only confirmed responses were included ‡ CR+PR+SD≥2 months
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 33.1 25.6-41.3 19.3 12.3-27.9 DCR ‡ 2.0 0.4-5.8 2.8 0.6-7.8 CR 13.5 8.5-20.1 3.7 1.0-9.1 PR * 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
PD-L1 Expression IHC * PD-L1 22C3 pharmDX assay • PD-L1 expression in gastric cancer is determined by Combined Positive Score (CPS) # PD-L1 staining cells (tumor cells, lymphocytes, macrophages) CPS = ----------------------------------------------------------------------------------- X 100 Total # viable tumor cells • A specimen is considered to have positive PD- L1 expression if CPS ≥ 1 PD-L1-negative PD-L1-positive Immune Cells Tumor Tumor Immune Cells Cells Cells *22C3 pharmDx™IHC DAKO, Carpinteria, CA
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. Progression-Free Survival TPS, PD-L1 28-8 pharmDX assay 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 22C3 pharmDX assay Kang et al. ASCO GI 2019 ORR DCR 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
Avelumab vs SOC 3L Phase III JAVELIN-300 PFS by PDL1 PFS Avelumab vs chemo Irinotecan/taxane Worse OS Worse PFS 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
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 TAS-102 – avelumab Catenacci DVT, Hochster H, Klempner S. Keeping Checkpoint Inhibitors in Check. JAMA Netw Open 2019
KEYNOTE 061 vs paclitaxel 2L (<0.0135) Overall Survival, CPS ≥1 PFS RAINBOW 1.5 m mPFS 4.4 m 4.1 m mOS 9.6 m 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
ITT: N1=592 (296 vs 296) PDL1+ >1%: N2=395 (66%) (199 vs 196) Overall Survival by PD-L1 CPS CPS >1 to <10% CPS >10% CPS <1% N2= NA 287/395 = 73% 108/395 = 27% N1= 195/592 = 33% 287/592 = 48% 108/592 = 18% Presented By Kohei Shitara at 2018 ASCO Annual Meeting
KEYNOTE 061 vs paclitaxel 2L 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) Presented By Takashi Kojima at 2019 Gastrointestinal Cancer Symposium
Recommend
More recommend
