Chemotherapy for metastatic gastric cancer

Transcription

1 ESMO Asia GI Preceptorship 2018 Chemotherapy for metastatic gastric cancer Sun Young Rha, MD, PhD Yonsei Cancer Center, Institute for Cancer Research, Yonsei University College of Medicine

2 Disclosures I have nothing to disclose for this presentation.

3 Difference in global outcome: Five-year survival of major cancer sites in Korean: Male % GC year survival USA ( ) % Canada ( 06-08) % Mortality to - incidence ratio Most of countries: > 0.8 USA Colon and Gallbladder Stomach Lung Liver Prostate Thyroid Bladder Pancreas Kidney rectum Japan ( 03-05) % Japan 0.43 etc Korea ( 08-12) % Korea difference* ) Major cancer sites selected based on 2011 crude rates * difference in the cancer survival probability between '93~'95 and '07~'11, 2) Howlader N, Noone AM, et alseer Cancer Statistics Review, , National Cancer Institute. Bethesda, MD, based on November 2013 SEER data submission, posted to the SEER web site, April 2014, 3) Canadian Cancer Society, Statistics Canada and Provincial/Territorial Cancer Registry. Canadian Cancer Statistics 2014, 4) Center for Cancer Control and Information Services, National Cancer Center, Monitoring of Cancer Incidence in Japan - Survival report 2013, 5) Kyu-Won Jung, Young-Joo Won et al.. Cancer Res Treat 2015:47(2):

4 Stage-oriented therapeutic strategy at Yonsei Cancer Center 5 year survival rate of Gastric Cancer Clinic Year (n= 10,620 resected cases) Increasing EGC from national screening program 61% EGC at 2015 (1922/3150) Stage 1: 95.3% EMR/ESD, QoL; minimal surgery Stage 2: 79.8% probability Overall Survival 73.0% Stage 3: 48.2% Stage Improve II: S1 for survival; 1year Stage Neo/adjuvant III: Xelox for 6 Tx M Stage 4: 12.4% Survival Systemic vsctx QoL Suppportive New drugs/tx care Overall survival (months)

5 Goals of palliative chemotherapy QoL maintenance: better PS Survival prolongation: longer PFS Conversion to surgery in oligometastasis: chance for cure

6 Factors affecting outcomes: Difference between East vs West -> affects clinical trial outcome 1) Tumor characteristics -> affects statistical power 2) Host characteristics including pharmacogenetics/ pharmacogenomics and tumor microenvironment -> toxicity profiles 3) Treatment and practice pattern 4) Cultural(Pts, Drs), regulatory and political issues -> Careful interpretation of global clinical trials -> Rational application in the clinical practice

7 Current trend in palliative treatment Asia (5-FU analogue + platinum doublet) Adding trastuzumab in Her-2 + patients(1 st line) North America (5-FU/cisplatin, DCF) Europe (ECF) More doublet! No more epirubicin! 2 nd line Tx with angiogenesis inhibitor

8 Current treatment of metastatic GC (median 16-18months) 1 st line Tx Pembrolizumab in MSI-H/dMMR 2 nd line Tx (3 rd - 4 th line Tx) Supportive 90 % 60-65% 30-40% 5-fluorouracil/platinum (+/- docetaxel) 5-7 Mo Paclitaxel or Irinotecan (3-5 Mo) + Trastuzumab in Her Ramucirumab Nivolumab, Pembrolizumab Chemotherapy in PD-L1 + Apatinib? Ethnic differences: Asians vs Westerns Chemotherapy is the main Tx Doublet vs triplet Various doublets are similar Sequential treatment improved survival Angiogenesis inhibitor showed benefit in 2 nd line and more Role of molecular targeted agents? IO showed the potential benefit New strategy: Conversion surgery, IP chemotherapy

9 Approved/available agents for mgc Chemotherapeutics Targeted/immune agents 5-FU S-1 Capecitabine Docetaxel Paclitaxel Cisplatin Oxaliplatin Doxorubicin/ Epirubicin Irinotecan + Trastuzumab (2010) + Ramucirumab (2015) Nivolumab/ Pembrolizumab (2017) Increasing toxicity & decreasing tolerability Monotherapy < Doublet << Triplet Increasing efficacy

10 1 st line Tx Are there any superior regimens? Is the more the better? Any role of targeted agents? IO?

11 Trials with molecular targeted agents in mgc Therapy Target molecule Compound Study 1 st line HER2 Trastuzumab ToGA (Bang et al., 2010) VEGF Bevacizumab AVAGAST (Ohtsu et al., 2011) HER2 Lapatinib LOGiC (Hecht et al., 2013) EGFR Panitumumab REAL 3 (Waddell et al., 2013) EGFR Cetuximab EXPAND (Lordick et al., 2013) VEGF Bevacizumab AVATAR (Shen et al., 2015) HGF Rilotumumab RILOMET-1 (Cunningham et al., 2015) Met Onarutuzumab MET Gastric (Shah et al., 2015) HER2 Perutuzumab JACOB(Tabernero et al., ESMO2017) 2 nd, 3 rd line HER2 Lapatinib TyTAN (Bang et al., 2012) mtor Everolimus GRANITE-1 (Ohtsu et al., 2013) HER2 TDM-1 GATSBY (Kang YK, et al., ASCO-GI 2016) PARP Olaparib GOLD (Yung-Jue Bang et al., ESMO 2016) STAT3 BBI-608 BRIGHTHER EGFR Nimotuxumab ENRICH VEGFR Ramucirumab REGARD, RAINBOW VEGFR Apatinib Li et al, ASCO 2015 positive negative positive Revised from Lordick F, et al: Cancer Treatment Reviews 40: , 2014 Table2

12 Evolving regimen based on Phase III Trials JCOG 9205 (2003) F ( FP, UTFM) Kim (2001) FP ( F, FAM) AIO (2008) FP ( FOLFIRI) FLAGS (2010) FP ( SP) JCOG 9912 (2009) S1 ( F, CPT+P) ML17032 (2009) XP ( FP) V325 (2005) DCF (>FP) > 12months for mgc!! SPIRIT (2009) SP (>S1) G-SOX (2016) SOX ( SP>S1) ECF EOX FLOT START (2014) S1 ( S1+DOC) SOX XELOX FOLFOX SP XP FP GC0301/TOP002 (2011) S1 ( S1+CPT-11) REAL2 (2008)/FLOT4(2017) EOX ECF < FLOT mdcf FP FOLFOX

13 ABSTRAT S-1 vs. capecitabine Randomised multicentre phase II study elderly (>or=65 years) chemo-naive Capecitabine (n=46) 1250 mg/m bid, D1-14, q 3 weeks or S-1 (n=45) 40mg/m bid D1-28, q 6 weeks ORR: 27.2% vs 28.9% Median TTP : 4.7 vs 4.2 months Median OS: 9.5 vs 8.2 months Similar toxicities, but RDI decreasing in capecitabine arm G3/4 capecitabine S-1 ANC 6.8% 4.8% Asthenia 9.1% 7.1% Anorexia 6.8% 9.5% Darrhoea 2.3% 0% HFS 6.8% 0% JL Lee et al. Brit J Cancer (2008), 1 7

14 Doublets: FP = XP = SP = SOX = CapOX(Xelox) Trial Arm RR(%) PFS(M) OS(M) ML17032 FP Korean XP Japanese XP Retrospective SP Doublet is tolerable and better than monotherapy G-SOX SP Various combinations of platinum and 5-FU analogues are similar YamadaY et al Ann Oncol 2014 SOX(100) Korean RPII SOX(130) Kim GM, et al. 5-FU ci -> oral 5-FU analogue FP -> SP/XP Cisplatin -> oxaliplatin Role of Taxanes Eur J Cancer 2012 CapOX(130) Similar toxicity (more G1/2 HFS in Capecitabine containing arm) Shitara et al. Int J Clin Oncol 2012, YamadaY et al Ann Oncol 2014, Kim GM, et al. Eur J Cancer 2012

15 ABSTRAT Comparing doublets in Yonsei Cancer Center (I) Her-2 negative mgc st line doublet Tx With efficacy information (PFS, OS) Retrospective analysis N=841 P-value = Group Total Death Censored mos (95% CI) FOLFOX 169 (20.10%) (11.24%) (13.933, ) XELOX 286 (34.01%) (22.38%) (17.833, ) SP 321 (38.17%) (14.64%) (17.567, ) XP 65 (7.73%) 56 9 (13.85%) (12.267, ) Oxaliplatin based(n=372, mos 19.7m) = Cisplatin based (n= 386, mos 19.8m) Not published

16 Comparing doublets (II): Taxane vs platinum Single center, randomized phase II study (NCT ) 1 SP (S-1/Cisplatin) Metastatic or recurrent gastric cancer R 1 1 FOLFOX6 DF (Docetaxel/5FU) 1 TF (Paclitaxel/5FU) Stratification factor Use of adjuvant platinum (Yes vs. No) ECOG performance status (0-1 vs. 2)

17 Study regimen SP regimen S-1 80mg/m2 bid D1-D14 Cisplatin 60mg/m2 D1 q3wks DF regimen FOLFOX6 regimen Oxaliplatin 100mg/m2 D1 5-FU 400mg/m2 bolus D1 5-FU 1200mg/m2 CI D1-2 LV 20mg/m2 D1 q2wks TF regimen Docetaxel 75mg/m2 D1 5FU 1000mg/m2 D1-3 q3wks Paclitaxel 175mg/m2 D1 5FU 1000mg/m2 D1-3 q3wks

18 Study Profile Accrual period: Mar 2010 May 2015 (Discontinued due to poor accrual) Data cut-off: Dec Median follow-up duration: 12.4 months 179 patients randomized 45 patients to SP arm 45 patients to FOLFOX arm 45 patients to DF arm 44 patients to TF arm 1 did not start chemo 1 did not start chemo 45 received treatment 44 received treatment 45 received treatment 43 received treatment

19 Survival Analysis Intent-to-treat analysis Surviving (%) OS SP: 14.7 ( ) FOLFOX: 11.3 ( ) 5FU/DCT: 11.7 ( ) 5FU/PCT: 10.8 ( ) P= Time (months) Surviving (%) All patients OS Platinum 1st: 13.3 mo Taxane 1st: 11.7 mo P=0.431 Surviving (%) Time (months) Patients received Both platinum and taxane OS Platinum 1st: 13.3 mo Taxane 1st: 14.4 mo P= Time (months) Optimal sequence of chemotherapy was not known Routine sequence: fluoropyrimidine and platinum taxanes Reverse sequence: similar OS Kim et al. In revision

20 Things to consider in selecting optimal CTx Treatment goal Disease status Patient s tolerability Availability of treatment Convenience: schedule

21 Doublet vs Triplet Phase III, DCF vs. CF (V325): TTP Probability (%) DCF CF Log-rank p <0.001 Hazard ratio: 1.47 (95% CI: ) Risk reduction: 32% TTP DCF CF Median (mo) % CI Time (months) 1.9 mo DCF q3w (n=221) Docetaxel 75 mg/m 2, D1 Cisplatin 75 mg/m 2, D1 5-FU 750 mg/m 2 /day, D1-5 CF q4w (n=224) Cisplatin 100 mg/m 2, D1 5-FU 1000 mg/m 2 /day, D 1-5 Van Cutsem, et al. J Clin Oncol 2006;24:

22 DCF vs. CF (V325): OS Probability (%) DCF CF Log-rank p=0.02 Hazard ratio: 1.29 (95% CI: ) Risk reduction: 22.7% OS DCF CF Median (mo) % CI year (%) year (%) Time (months) Time (months) 0.6 mo Van Cutsem, et al. J Clin Oncol 2006;24:

23 DCF vs. CF (V325): G3/4 AEs Patients (%) * Roughly halfof the pts were taken off treatment either due to treatment refusal or toxicity *p<0.05 DCF (n=221) CF (n=224) * * * Van Cutsem, et al. J Clin Oncol 2006;24:

24 Phase II Studies of Triplet Regimens N ORR PFS/TTP OS Docetaxel/irinotecan/oxaliplatin % 6.5 mo 11.5 mo Paclitaxel/cisplatin/5-FU % 6.9 mo 12.7 mo Docetaxel/cisplatin/S % 7.4 mo 22.6 mo Docetaxel/cisplatin/5-FU/LV % 8.9 mo mo Docetaxel/oxaliplatin/5-FU % 7.66 mo mo Docetaxel/oxaliplatin/capecitabine % 5.55 mo mo Docetaxel/cisplatin/5-FU % 6.5 mo 12.6 mo Modified DCF % 9.7 mo 18.8 mo Irinotecan/oxaliplatin/5-FU/LV % 7.5 mo 12.1 mo Paclitaxel/cisplatin/S % 9.4 mo 11.2 mo Irinotecan/oxaliplatin/S % 10.2 mo 17.6 mo Docetaxel/cisplatin/S % 8.7 mo 18.5 mo Docetaxel/oxaliplatin/capecitabine % 6.9 mo 13 mo Docetaxel/oxaliplatin/S % 7.6 mo 12.0 mo 1 Di Lauro L et al, Br J Cancer 2007;97:593, 2 Hwang J et al, J Korean Med Sci 2008;23:586, 3 Sato Y et al, Cancer Chemother Pharmacol 2010;66:721, 4 Tomasello G et al, Gastric Cancer 2014;17:711, 5 Van Cutsem et al, Ann Oncol 2015;26:149, 6 Shah MA, et al, J Clin Oncol 2015;33:3874, 7 Comella P, et al, Cancer Chemother Pharmacol 2009;64:893, 8 Kim JY, et al, Cancer Chemother Pharmacol 2011;67:527, 9 Park SR, Ann Oncol 2011;22:890, 10 Koizumi, W et al, Cancer Chemother Pharmacol 2014;69:407, 11 Stein A et al, Acta Oncol 2014;53: Kim HS, et al. Gastric Cancer 2016;19:579,

25 FLOT4 Study Design Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

26 Doublet is preferred based on benefit-risk ratio

27 When needs high antitumor activity For palliation Symptom control in patients with severe symptoms associated with high tumor burden For prolongation of survival Patients with rapidly progressing disease For cure Locally advanced unresectable or borderline resectable disease Metastatic disease with the possibility of conversion surgery

28 Sequential Tx improves outcome! Not overlapping MoA No cumulative toxicity

29 Phase III Korean Study: Salvage Chemo + vs. BSC Alone Primary endpoint: OS Patients with metastatic gastric cancer, 1-2 previous chemo* regimens, ECOG PS 0-1 (N = 202) Docetaxel 60 mg/m 2 on Day 1 q3w or Irinotecan 150 mg/m 2 q2w (n = 133) Best Supportive Care (n = 69) Treatment continued until progression, toxicity, or withdrawal *Fluoropyrimidines and/or platinum agents. Including analgesics, paracentesis, psychosocial care, nutritional support, blood transfusion, palliative radiotherapy, or nonprotocol BSC measures. Kang JH, et al. J Clin Oncol. 2012;30:

30 Phase III UK trial (COUGAR-02) Primary endpoint: OS Patients with metastatic esophagus, EGJ, or gastric cancer, 1 previous chemo regimens, ECOG PS 0-2 (N = 168) Docetaxel 75 mg/m 2 on Day 1 q3w (n = 84) BSC (n=84) Treatment continued until progression, toxicity, or withdrawal Lancet Oncol 2014; 15: 78 86

31 Phase III Japan trial (WJOG 4007) Paclitaxel vs. Irinotecan Primary endpoint: OS Patients with metastatic gastric cancer, 1 previous chemo regimens, ECOG PS 0-2 (N = 223) Paclitaxel 80 mg/m 2 on Day 1,8, 15 q 4wks (n = 108) irinotecan 150 mg/m2 on days 1 and 15, q 4 wks (n=111) Treatment continued until progression, toxicity, or withdrawal J Clin Oncol. 2013;31:

32 Safety issues Types and frequency of toxicity Dose/exposure-toxicity/response relationship Monitoring and management of toxicity Ethnic differences Novel drug related toxicity profiles 20 th century: predictable, common toxicities 20 th century unpredictable, drug specific and individualized toxicities need special concerns and education Esp. Immune-related toxicities Interstitial lung disease by gefitinib ILD 3.2 ~ 5.8% vs 0.36% Mortality 1.3 ~ 2.5% vs 0.06% Toxicity from sunitinib in mrcc Thrombocytopenia 32~37% vs 6.5~8% HFS/stomatitis 11 ~ 13% vs 2~5%

33 Palliative sequential treatments in Asia 1 st -line 2 nd -line 3 rd -line 90-95% 60-70% 40-50% HER2 negative 5FU analogue +/- platinum Paclitaxel /Docetaxel Irinotecan Paclitaxel +Ramucirumab 5-FU analogue +/- platinum Irinotecan Paclitaxel /Docetaxel HER2 positive XP/FP (SP) +Trastuzumab Ramucirumab 5-FU analogue +/- platinum Oral fluoropyrimidine monotherapy for elderly or poor PS Gastric cancer treatment guideline ver (additional information)

34 Recent trial with new chemotherapeutics in mgc Trifluridine/tipiracil (Lonsurf): trifluridine(a nucleoside analog) + tipiracil (thymidine phosphorylase inhibitor, prevents rapid metabolism of trifluridine) approved by the U.S. FDA (Sep 2015) and EMA (April 2016) for refractory CRC TAGS: a phase 3, randomised, double-blind study of trifluridine/ tipiracil (TAS-102) versus placebo in patients with refractory mgc Key patient inclusion criteria Metastatic gastric/gej cancer 2 prior regimens Age 18 years ( 20 years in Japan) ECOG PS 0/1 (n=507) R TFD/TPI (TAS-102) + BSC 35 mg/m 2 bid orally on D1 5 and 8 12 of each 28-day cycle (n=337) Stratification ECOG PS (0 vs. 1) Region (Japan vs. rest of world) Prior ramucirumab (yes vs. no) Placebo + BSC bid orally on D1 5 and 8 12 of each 28-day cycle (n=170) PD PD PRIMARY ENDPOINT : OS SECONDARY ENDPOINTS: PFS, ORR, DCR, QoL, time to ECOG PS 2, safety J Tabenero et al. WGIC 2018, Arkenau H, et al. ESMO 2018

35 LBA25: TAGS: a phase 3, randomised, double-blind study of trifluridine/ tipiracil (TAS-102) versus placebo in patients with refractory mgc OS TFD/TPI (n=337) a Placebo (n=170) a Events, n (%) 244 (72) 140 (82) mos, months OS, % HR (95%CI) 0.69 (0.56, 0.85) One-sided p-value b Two-sided p-value b month OS: 13% 12-month OS: 21% Time, months No. at risk TFD/TPI Placebo a ITT population; b stratified log-rank test Arkenau H, et al. Ann Oncol 2018;29(suppl 5):abstr LBA25

36 Phase III study of intraperitoneal paclitaxel plus S- 1/paclitaxel compared with S-1/cisplatin in GC pts with peritoneal metastasis: PHOENIX-GC trial Gastric cancer with peritoneal metastasis R 2 1 IP PTX + S-1/PTX S-1/CDDP Key Eligibility Criteria No or <2mo prior chemo. No other distant metastasis No prior gastrectomy No frequent ascites drainage Stratification Institution Prior chemo. +/- Peritoneal meta. P1/P2-3 Primary Endpoint Overall survival Secondary Endpoints Response rate Safety Hironori Ishigami Japan intraperitoneal chemotherapy study group (JIPG), Cancer 2013, ASCO 2016

37 Efficacy Median OS, months (95% CI) Survival Rate IP : 17.7 ( ) SP : 15.2 ( ) HR=0.72 (95% CI: ) P=0.081 Time (Months) Evaluation of ascites by CT Disappeared Decreased No change Increased IP (n=38) 15 (39%) 18 (47%) 3 (8%) 2 (5%) SP (n=7) 0 (0%) 2 (29%) 3 (43%) 2 (29%) Mantel test P=0.001 Slightly increased neutropenia, diarrhea and neuropathy

38 Summary Cytotoxic chemotherapy has a significant role in treatment of mgc, including combination partner with MTA or IOs Proper subgroup selection might increase risk/benefit ratio: clinical or molecular subgroups not yet No homogeneous Tx: Ethnicity-based diverse strategy More understanding of host characteristics (PK/TME) for personalized treatment

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