Neo- and adjuvant treatment for gastric cancer: The role of chemotherapy

Neo- and adjuvant treatment for gastric cancer: The role of chemotherapy Priv. Doz. Dr. Dr. med. T.O. Götze Institute of Clinical Cancer Research Director: Prof. Dr. S.-E. Al- Batran University Cancer Center Frankfurt

Trials- Gastric/ GEJ

Gastric cancer: survival according to UICC 7th. edition Survival acc. pt-stage Survival acc. pn-stage Reim et al. J Clin Oncol 2012

Neoadjuvant therapy

Role of adjuvant therapy/ trials Randomisation

Adjuvant trials (Metaanalysis)

Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration)

Positive adjuvant trials

CLASSIC 2012- Korea/ China/ Taiwan

Adjuvant therapy

Adjuvant therapy - Intensification GISCAD ITACA-S

Adjuvant therapy Intensification Intensification of adjuvant chemotherapy did not improve outcome

Adjuvant Chemoradiotherapy in Stomach Tumors

7 years of follow-up, Adjuvant Chemoradiotherapy in Stomach Tumors DFS remained similar between treatment arms OS also was similar The effect of the addition of radiotherapy on DFS and OS differed by Lauren classification lymph node ratio Subgroup analyses : significantly improved DFS in node-positive and intestinal-type GC the ARTIST 2 trial evaluating adjuvant chemotherapy and chemoradiotherapy in patients with node-positive, D2-resected GC

Adjuvante Radiochemotherapie: SWOG intergroup 0116 Studie Surgery Stomach or GEJ of Stage Ib to IVM0 Curative resection R P=0.005 No treatment Chemoradiation 5-FU/leucovorin + radiation at 45 Gy in total Only 21% of patients had a GEJ (Cardiacarcinoma) D2-resection in only 10% of patients OS in radochemotherapy-arm was comparebale with OS in controll-arms of adjuvant studies in europe MacDonald et al. N Engl J Med 2001 Smalley et al. J Clin Oncol 2014

Intergroup CALGB 80101 Stomach and GEJ Surgery R FU/LV1x FU CI /RT 45Gy FU/LV 2x N=280 N=266 ECF 1x FU CI/ RT 45Gy ECF 2x Fuchs et al ASCO 2011

A Multicenter Randomized Phase III Trial of Neo-adjuvant Chemotherapy Followed by Surgery and Chemotherapy or by Surgery and Chemoradiotherapy in Resectable Gastric Cancer Presented By Marcel Verheij at 2016 ASCO Annual Meeting

Trial design Presented By Marcel Verheij at 2016 ASCO Annual Meeting

Results: Overall Survival Presented By Marcel Verheij at 2016 ASCO Annual Meeting

40% in CRT had T0 Post-op mortality 11 vs. 3% p=0.049 most patients had ct1-2 or cn0 Chemotherapy-regimen Cisplatin/5-FU

Neoadjuvant therapy

Neoadjuvant therapy MAGIC (Cunningham et al 2006) Localization Design N/regimen Histology 5 year OS Stomach 74% GEJ 12 % Oe 14% FFCD (Ychou et al 2011) Localization Design N/regimen Histology 5 year OS GEJ 65% Stomach 25% Oe 10% CT vs. no N=503 Epi/Cis/FU (ECF) CT vs. no N=224 Cis/FU (CF) Adeno 36% vs. 23% Δ13% Adeno 38% vs. 24% Δ14% CROSS (van Hagen et al 2012) Localization Design N/regimen Histology 5 year OS Oe 76% GEJ 24% CT/RT vs. no N=366 RT/Carbo/Taxol SCC/ Adeno 47% vs. 34% Δ13% Adeno, adenocarcinoma; Carbo, carboplatin; Cis, cisplatin; CT, chemotherapy; Epi, epirubicin; FU, fluorouracil; GEJ, gastroesophageal junction; Oe, oesophagus; OS, overall survival; RT, radiotherapy; SCC, squamous cell carcinoma. Cunningham D, et al. N Engl J Med 2006;355:11 20; Ychou M, et al. J Clin Oncol 2011;29:1715 21; van Hagen P, et al. N Engl J Med 2012;366:2074 84.

CROSS- Trial: AC vs. SCC Shapiro J, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-8.

CROSS: Subgroups 24% of patients had a GEJ AEG, HR not known?? van Hagen P, et al. N Engl J Med 2012;366:2074 84.

neoadjuvant chemoradiation Resectable adenocarcinoma of esophagus and Type 1-2 Gastro-esophageal Junction

neoadjuvant chemoradiation

neoadjuvant chemoradiation vs. chemotherapy

neoadjuvant chemoradiation vs. chemotherapy

neoadjuvant chemoradiation vs. chemotherapy

Correlation between pathological response and survival Becker et al.: 480 patients with gastric cancer/ GEJ; 1991-2007 Neoadjuvant Cisplatin- therapy; Becker 1a(pCR) 3.3%; Becker 1a + b 21%

Correlation between pathological response and survival

Taxanes in neoadjuvant therapy pcr is associated with a better DFS and OS

Resection status and pathological response Survival after perioperative ECX+/- Bev by resection status by Mandard TRG 1.00 0.75 R0 vs. others p<0.001 R0 1.00 0.75 TRG1/2 vs. others p<0.001 TRG1/2 0.50 0.50 TRG3 0.25 R1 0.25 TRG4/5 0.00 0 12 24 36 48 60 0.00 0 12 24 36 48 60 72 84 R0 R1 Not available 1-2 3 1 0 0 4-5 No resection No resection N=1063 N=908 TGR, tumor regression status Cunningham et al. ESMO/ECCO 2015

Neoadjuvant Chemotherapy for Resectable Oesophageal and Junctional Adenocarcinoma: Results from the UK MRC OE05 trial Histologically confirmed adenocarcinoma lower oesophagus and GOJ (Type I and II) MDT - resectable following EUS and CT R 2 cycles CF Surgery Surgery (excluded T1/2 N0) 4 cycles ECX CF: Two 3-weekly cycles of cisplatin (80mg/m 2 D1) and 5FU (1g/m 2 D 1-4) ECX: Four 3-weekly cycles of epirubicin (50mg/m 2 D1), cisplatin (60mg/m 2 D1) and capecitabine (1250mg/m 2 daily) Cunningham et al ASCO 2015

Neoadjuvant Chemotherapy for Resectable Oesophageal and Junctional Adenocarcinoma: Results from the UK MRC OE05 trial OE 05 Kurven Folie

pathological response after chemotherapy Reference N Therapy pcr% Geh 2000 23 Epirubicin/Cisplatin/5-FU (ECF) 4.3% Starling 2009 26 Epirubicin/Cisplatin/Capecitabine (ECX) 5.9% Becker 2011 480 Cisplatin-based 3.3% Lorenzen 2008 24 Cisplatin/5-FU/Docetaxel (GastroTax) 17.4% Thuss-Patience 2010 44 Cisplatin/Cape/Docetaxel (DCX) 15.9% Biffi 2010 32 Cisplatin/5-FU/Docetaxel (TCF) 11.7% Homann 2011 46 Oxaliplatin/5-FU/Docetaxel (FLOT) 17.4% Schulz 2015 50 Oxaliplatin/5-FU/Docetaxel (FLOT) 6x FLOT 20%

EORTC 40954

EORTC 40954

FLOT4 Study Design Gastric cancer or adenocarcinoma of the gastroesophageal junction type I-III Medically and technically operable stages T2-4, every N, M0 or every T, N+, M0 S T R A T I F I C A T I O N R n=714 4xFLOT - OP - 4xFLOT FLOT: docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1; leucovorin 200 mg/m², d1; oxaliplatin 85 mg/m², d1, every two weeks 3xECF(X) - OP - 3xECF(X) ECF(X): Epirubicin 50 mg/m2, d1; cisplatin 60 mg/m², d1; 5-FU 200 mg/m² (or capecitabine 1250 mg/m² p.o. divided into two doses d1-d21), every three weeks Primary endpoint Phase II (n=300): rate of complete pathological remission (pcr) Primary endpoint for phase III (n=714): OS, HR 0.76, power 80%, two sided p<0.05 Al- Batran et al. Lancet Oncol in press

Pathological Remission with ECF/ECX vs. FLOT Central Evaluation, ITT group* Pathological regression ECF/ECX n(%) N=137 FLOT n(%) N=128 P-Value (2-sided) Complete (pcr) 8 5,8 20 15,6.015 Subtotal (psr) 23 16,8 27 21,1 pcr+psr 31 22,6 47 36,7.015 Partial (ppr) 28 20,4 23 18,0 Minor (pmr) 44 32,1 45 35,2 No response (pnr) 8 5,8 4 3,1 Not resectable 26 19,0 9 7,0 *primary Endpoint phase II STO3 (ITT) 5.4% Al- Batran et al. Lancet Oncol in press

FLOT4: Pathological Remission with ECF/ECX vs. FLOT Central Evaluation Pathological 1 regression ECF/ECX n(%) N=137 FLOT n(%) N=128 P-Value (2-sided) pcr (TRG1) 8 6% 20 16% 0.015 pcr+psr (TRG1/2) 31 23% 47 37% 0.015 1 ITT group pcr, pathological complete remission; psr, pathological subtotal remission; TRG, tumor regression grade pcr by histology (total population) pcr by histology CROSS adeno 23% Al- Batran et al. Lancet Oncol in press

Complette and subtotal pathological remission according to subtype of Lauren Al-Batran et al Lancet Oncol 2016 (in press)

Pathological Remission in the Lymph Nodes (Central Evaluation) ECF/ECX (n=51) FLOT (n=66) n % n % CR 3 5,9 15 22,7 SR 9 17,6 15 22,7 CR+SR 12 23,5 30 45,5 PR 8 15,7 6 9,1 MR 22 43,1 25 37,9 NR 9 17,6 5 7,6 Note: percentages refer to patients with histologically suspected/confirmed LN involvement, from whom LN paraffin blocks were provided Al- Batran et al. Lancet Oncol in press

If a thrid drug is needed Docetaxel=FLOT! Cunningham ECCO 2015, discussion of FLOT4 pcr-daten

conclusion GEJ I: perioperative chemotherapy FLOT (or neoadj. radiochemoth./ CROSS) GEJ II and III: perioperative chemotherapy FLOT (no CROSS)

forthcoming studies of FLOT4- trial HER2+ HER2- PETRARCA/FLOT6 resectable gastric cancer Her2 positiv LKP Hofheinz, Mannheim RAMSES/FLOT7 resectable gastric cancer Her2 negativ LKP Al-Batran, Frankfurt FLOT 4x Op FLOT4x FLOT4x/Herceptin/Pertuzumab Op FLOT4x/Herceptin/Pertuzumab FLOT 4x Op FLOT4x FLOT4x/RAM Op FLOT4x/RAM

VEGF/R?

VEGF/R: 2nd - 3rd - Line

VEGF/R: 1st- Line

ST03 trial design n= 1063 Histologically confirmed, resectable (MDT review) stage Ib-IV adenocarcinoma of the lower oesophagus, OGJ or stomach ECX ECX 3 cycles Surgery Randomised 1:1 5-6 week break 6-10 week break ECX + Bevacizumab ECX + Bevacizumab 3 cycles Surgery ECX Chemotherapy regimens 21-day cycles Epirubicin 50mg/m 2 IV on day 1 Cisplatin 60mg/m 2 IV on day 1 Capecitabine 1250mg/m 2 PO daily ECX + Bevacizumab Bevacizumab 7.5mg/kg IV on day 1 added to each ECX cycle ECX 3 cycles ECX + Bevacizumab 3 cycles Maintenance Bevacizumab 6 doses

Overall survival 472 deaths (233 ECX, 239 ECX+B) have been observed Proportion surviving Median follow-up is 33 months in both arms N ECX ECX+B 1.00 0.75 0.50 0.25 0.00 0 12 24 36 48 60 72 84 Time from randomisation (months) 533 394 226 97 49 17 5 0 530 383 208 98 41 14 6 0 ECX ECX+B Overall survival Median OS ECX 33.97 months ECX+ B 34.46 months Hazard Ratio 1.067 (95% CI) (0.8911 to 1.279) Log-rank p-value 0.4784 3-year overall survival (95% CI) ECX 48.9% (43.6% to 53.8%) ECX+B 47.6% (42.3% to 52.7%) Secondary outcomes PFS HR=1.026 p=0.7683 DFS HR=1.006 p=0.9425

Survival by Mandard TRG Based on assessment by local pathology departments Proportion surviving 1.00 0.75 0.50 0.25 0.00 N 1-2 3 4-5 No resection 0 12 24 36 48 60 72 84 Time from surgery (months) 132 92 60 22 11 1 0 0 146 101 57 26 9 5 1 0 439 269 125 45 17 6 0 0 191 30 11 4 1 1 0 0 1-2 3 4-5 No resection 3 year survival (95% CI) Grade 1-2 73.3% (60.9% to 82.3%) Grade 3 57.9% (47.3% to 67.1%) Grade 4-5 43.7% (37.8% to 49.4%) No resection 7.2% (3.4% to 12.9%) Hazard ratio (1-2 vs. others) 0.281 (0.189 to 0.418) p < 0.0001

LBA26 A randomised phase II study of perioperative epirubicin, cisplatin and capecitabine (ECX) ± lapatinib for operable, HER-2 positive gastric, oesophagogastric junctional (OGJ) or lower oesophageal adenocarcinoma: Results from the UK MRC ST03 lapatinib feasibility study (ISRCTN 46020948)

Methods Eligible patients : HER-2 positive (IHC 3+ or IHC 2+ and DDISH HER-2:CEP17 ratio 2) operable, gastric/ogj/lower oesophageal adenocarcinoma random 1:1 ECX, 3 pre- and 3 post-operative cycles vs. ECX plus lapatinib d1-21 in each cycle and for 6 maintenance doses pre-operative toxicity was then reviewed according to pre-defined criteria to determine doses for subsequent patients The primary objective is to establish a recommended dosing regimen for a phase III trial Results 46 pts were randomised 44 (24 ECX, 20 ECX + L) included in the analysis Conclusions Administration of lapatinib at 1250mg/day in combination with ECX chemotherapy was feasible with some increase in toxicity which did not compromise operative management.

Her2 signaling and inhibition

Targeting HER 2 +

Her2+ Gastric cancer resectable gastric or GEJ cancer Surgery Primary endpoint: pcr

Primary endpoint

Trastuzumab improved outcomes in patients with HER2-positive tumours ToGA 1 (n=584) HER2 IHC HER2 SISH Al-Batran. Data on file Survival probability 1. 0. 0 8. 0 6. 0 4. 2 0 Trastuzumab + XC/FC Events 120 XC/FC 136 HR=0.65 (95% CI: 0.51 0.83) 11 16 0 4.8 8 12.0 16 20 24 28 32 36 Time (months) 15 20% of gastroesophageal cancers are HER2 positive Median survival for HER2 IHC 3+ patients 18 months! 1. Bang, et al. Lancet 2010

TOGA trial: subgroup analysis

Targeting HER 2 +: 1st vs. 2nd

LANCET 376: 687, 2010- Trastuzumab Lancet 376:687, 2010

Update Trastuzumab Survival Benefit Updated Trastuzumab Survival Benefit

FDA- Update Trastuzumab Trastuzumab: The FDA Update

PETRARCA / FLOT6 FLOT vs. FLOT/Herceptin/Perjeta for perioperative therapy of adenocarcinoma of the stomach and gastroesophageal junction expressing HER-2 a phase II/III trial of the AIO

Trials - gastric-/ GEJ- cancer Current Trials for Esophagogastric Cancer