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Evolution in Treatment for Esophageal and Gastric Cancer

Weijing Sun, MD, FACP Spring Professor of Medical Oncology Director, Medical Oncology Division Associate Director of KUCC Global Incidence of Gastric & Esophageal Cancer: 2018 Bray F, Ferlay J, et al CA Cancer J Clin 2018; 68:394‐424

Mortality:#2 Incidence: #4 8.2% +5.3% =13.5% 5.7% +3.2% =8.9% Siewert JR and Stein HJ. Br J Surg. 1998;85(11):1457-1459. Type 1 5cm Cancer of the distal esophagus

1cm Type 2 GE Junction Cancer of the cardia 2cm

Type 3 Subcardial cancer 5cm Roles of vs. Radiotherapy in Peri‐operative Setting • Chemotherapy –broader benefits  Systemic and local benefits  Either early or locally advanced

• Radiation  Local  early local disease –may not needed  more locally advanced –may not enough  Adding with chemo –may increased toxicity

Sensitization: which to which? Peri‐operative Therapy MacDonald NEJM 2001; 345:725 Cunningham NEJM 2006; 355:11 Sasako JCO 2011; 29:4387 • (Europe) Pre‐ and Post‐Operative Chemo Noh Lancet Oncol 2014; 15:1389  Magic: ECF  FLOT4: FLOT > ECF

• (Asia) Post‐Op Chemo (with D2 Resection)  ACTS‐GC: S‐1 for 1 yr.  CLASSIC: CAPOX for 6 months  ARTIST2: SOX for 6 months > S1, (no benefit for RT)  JACCRO GC‐07: S‐1+Doctaxel > S1

• (US) Post‐OP Chemo/XRT (D1 Resection or less)  INT 116: 5‐FU/LV + XRT  (FOLFOX) Preoperative Chemoradiotherapy CROSS Trial

- Carboplatin AUC 2, Paclitaxel 50 mg/m2, days 1, 8, 15, 22, 29, - Radiation dose of 41.4 Gy in 23 fractions of 1.8 Gy each -  surgery R N=180

Clinical Stage: Surgery alone T1N1 or T2-3N0-1 N=188 Van Hagen P et al. N Engl J Med. 2012 Preoperative Chemoradiotherapy CROSS Trial Van Hagen P et al. N Engl J Med. 2012 mOS: 49.4 vs 24.0 months

Issues: • No adjuvant (post‐op) treatment • SCC vs Adeno CA • Dose of XRT

Cross trial FLOT4 trial Cross trial FLOT4 trial (ChemoXRT Arm) (FLOT Arm) (ChemoXRT Arm) (FLOT Arm) N=178 N=356 N=178 N=356

Medan Age 60 (37‐79) 62 (54‐69) cT

Male (%) 134 (75%) 268 (75%) cT1 1 (1%) 3 (1%) cT2 26 (15%) 49 (14%) PS WHO ECOG cT3 150 (84%) 267 (75%) 0 144 (81%) 246 (69%) cT4 0 28 (8%) 134 (19%) 109 (31%) N Adenocarcinoma 134 (75%) 356 (100%) (Signet cell 28%; diffuse 27 %, N0 59 (33%) 77 (22%) (N‐) intestinal 45%;) N1 116 (65%) 279 (78%) (N+) Location

Distal Esophageal 104 (58%) Siewert type 1: 80 (23%) Van Hagen P. et al NEJM 2012; 366:2074‐84 Al‐Batran S‐E et al Lancet 2019 393:1948‐57

GEJ 39 (22%) Siewert type 2&3: 118 (33%)

Stomach ‐ 158 (44%)

Metastatic Dz‐Four Genomic Subsets Emerge from the US Cancer Genome Atlas: Gastric Cancer • Genomically Unstable • Associated Amplification  HER‐2 • MSI‐H • Immune Checkpoint Inhibitor • CPI +/‐ chemo > chemo • Genomically Stable • Not Clearly Targetable • Epstein‐Barr Virus • PIK3CA, sensitive o CPI Metastatic Gastro‐Esophageal Cancer • Two‐drug regimens are preferred  FOLFOX, CAPOX, FOLFIRI, SOX (S‐1/cis) (Japan) • Three‐drug regimens (adding Docetaxel): FLOT, DCF, mDCF –more toxicities  FLOT –no survival benefit in >65 yr old  S‐1/Cis + Docetaxel (no survival benefit, JCOG 1013)  Epirubicine (ECF, EOF,ECX,EOX) no longer recommended • Anti‐ agents  (anti‐VEGFR2) as the 2nd line  Single agent– REGARD  Combination with Paclitaxol – RAINBOW Metastatic Gastro‐Esophageal Cancer • + chemo in Her‐2;  add • + FOLFOX the 1st line • Pembrolizumab + 5‐FU/Cis (1st line)

• + Nivolumab (Fukuoka JCO 2020;38:2053)

• + Pembrolizumab (Shitara Lancent Oncol 2020; 21:1057) Her‐2: in Gastric and Esophageal Cancer– ‘NOT EXACTLY’ as in Breast Cancer

 Trastuzumab + 5FU/Cap and Cis (TOGA) × + CAPOX (TRIO‐013/LOGiC) Improved RR, PFS, OS No difference in OS (12.2 vs. 10.5 months) ×(JACOB) No difference in OS (17.5 vs. 14.2 months,p=0.056)

Bang et al, Lancet 2010; 376:687 Hecht et al, JCO 2016; 34:443 Tabemero et al, Lancet Oncol 2018; 19:1372 Anti‐Her‐2 as the 2nd line: TDM‐1 () Potential Mechanism of Loss of Her2 Expression: TDM‐1 vs. Taxane (GATSBY) Paclitaxel +/‐ TDM‐1 (WJOG7112G) De novo and acquired No difference in PFS, OS no difference in PFS, OS

Thuss‐Patientce, Lancet Oncol 2017; 18:640 Makiyama JCO 2020; 38: J Clin Oncol 38:1919 Saeki, EJC 2018; 105:41 “INNOVATION”: Peri‐operative Chemo alone vs. Chemo + Trastuzumab, vs. Chemo + trastuzumab & pertuzumab, in HER2 +, gastric and GEJ adenocarcinoma Wagner et al. BMC Cancer (2019) 19:494 Her‐2: Pembrolizumab + Trastuzumab & 5‐FU/Cap and Cis/Ox

Janjigian et al, Lancet Oncol 2020; 21:821

Keynote 811 (Pembrolizumab + Trastuzumab & chemo)

Nivo + Chem vs Chemo Nivo + Ipi vs Chemo Bi‐Specific Monoclonal Abs

•  Trastuzumab conjugated toa topo‐I inhibitor  Phase I/II, 23 pts RR 43%  DESTINY: Chemo vs Trastuzumab Deruxtecan • Margetuximab  Anti‐Her2 with optimized Fc to increase CD16 activation on NK cells  MAHOGANY: phase III– 1st line • Zanidatamab (Her2/Her3) Trastuzumab Deruxtecan Iwata H, ASCO 2018 Abs 2501 2020;382:2419

Trastuxumab Deruxtecan

Physicians’ choice MAHOGANY: PHASE 2/3 TRIAL Regorafenib + Nivolumab (Fukuoka JCO 2020;38:2053) Lenvatinib + Pembrolizumab (Shitara Lancent Oncol 2020; 21:1057 FIGHT: mFOLFOX6 +/‐ Bemarituzumab

Summary • Immunotherapy (IO):  MSI, PD‐L1, TMB  IO + IO  IO + Chemo • Her‐2/Her3  Bio‐specific  Conjugated • FGFR2 • Anti‐angiogenic+ IO

 Adjuvant setting