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- E. Van Cutsem
- Y. Kang
LBA27_PR - Docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) for resectable esophagogastric cancer: Updated results from multicenter, randomized phase 3 FLOT4-AIO trial (German Gastric Group at AIO) (ID 2275)
- S. Al-Batran
Abstract
Background
FLOT4 is the first study to show improvement of outcome over another well-established bimodality therapy in patients with esophagogastric cancer. To consolidate initial results, we performed multivariate, subgroup and sensitivity analyses.
Methods
In the FLOT4, pts with resectable gastric or GEJ adenocarcinoma of stage ≥cT2 and/or cN + (n=716) were randomized to either 3 pre-operative and 3 post-operative 3-week cycles of ECF/ECX (epirubicin 50 mg/m2 i.v., cisplatin 60 mg/m2 i.v., both on day 1, and 5-FU 200 mg/m2 as continuous i.v. infusion or capecitabine 1250 mg/m2 orally on days 1 to 21) or 4 pre-operative and 4 post-operative 2-week cycles of FLOT (docetaxel 50 mg/m2 i.v., oxaliplatin 85 mg/m2 i.v., leucovorin 200 mg/m2 i.v., and 5-FU 2600 mg/m2 as 24-hour i.v, infusion, all on day 1). The primary endpoint was overall survival.
Results
Compared to ECF, FLOT was associated with less progressive disease cases during/after preoperative therapy (1% vs. 5%; p < 0.001), more R0-resections (84% vs. 77%; p = 0.011), higher number of pT0/pT1 tumors (25% vs. 15%; p = 0.001), longer progression-free (30 vs. 18 months; HR 0.75; p = 0.001) and overall survival (50 vs. 35 months; HR0.77; p = 0.012). The relative effect from FLOT was observed in all subgroups, including elderly and signet cell tumors, and was numerically pronounced in Siewert type 1 esophageal tumors (HR 0.60), Barrett tumors (HR 0.62), small tumors T1/2 (HR 0.66) or nodal negative tumors (HR 0.64). In multivariate analyses, parameters associated with favorable survival were FLOT therapy (HR 0.75, p = 0.006); stomach as the primary (HR 0.74; p = 0.005), and nodal negativity (HR 0.72, p = 0.022). ECOG PS of 0 showed a trend (HR 0.82; p = 0.078). Age and Lauren’s type of histology had no impact on survival. Post-hoc analyses of relapse-free survival (PFS excluding pts without R0-resection) still favored FLOT (HR 0.8; p = 0.049). 87% of relapses were systemic or both systemic and locoregional. The most frequent sites of relapse were peritoneal (31%) followed by lymphatic (26%), and liver (19%). Further analysis will be presented at the meeting.
Conclusions
Updated analysis confirmed the superiority of FLOT. Pts derived benefit from FLOT even if they were old ( > =70), had small tumors, a nodal negative status, or a signet cell component. The presence of one of these factors should no longer be a reason for not considering perioperative therapy in daily practice.
Clinical trial identification
FLOT4: NCT01216644
Legal entity responsible for the study
Krankenhaus Nordwest GmbH
Funding
Deutsche Krebshilfe, Sanofi
Disclosure
S-E. Al-Batran: Advisory role: Merck, Roche, Celgene, Lilly, Nordic Pharma Speaker: Roche, Celgene, Lilly, Nordic Pharma Research grants: Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly. N. Homann: Consulting or Advisory Role: Sanofi, Roche, Amgen, Cellgene, Lilly. H. Schmalenberg: Consulting or Advisory Role: Lilly, Baxalter; Research Funding: Sanofi; Travel, Accomodations, expenses: Merck. G.M. Haag: Consulting or Advisory Role: Sanofi, Roche, Taiho, Lilly, Pfizer, Nordic; Research Funding: Taiho, Nordic; Travel, Accomodations, expenses: Amgen, Ipsen, Celgene. K. Luley: Travel, accomodations, expenses: Ipsen, Novartis, Sanofi. P. Thuss-Patience: Consulting or Advisory Role: Roche, Lilly, BMS, MSD, Nordic, Pfizer; Research Funding: Novartis; Travel, Accomodations, expenses: Roche, Merck, Teva. M. Koenigsmann: Honoraria: Novartis, Celgene; Consulting or Advisory Role: Novartis, Celgene; Travel, Accomodations, expenses: Novartis. M. Pohl: Research Funding: Amgen, Baxalta, Celgene, Lilly. T. Goetze: Honoraria: MSD, Celgene Advisory board: BMS, Baxalta- Shire. M. Schuler: Honoraria: AstraZeneca, Alexion, Boehringer Ingelheim, Celgene, Lilly, MSD, Novartis, Roche; Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Celgene, Lilly, Novartis, Roche; Research Funding: Boehringer Ingelheim, BMS, Novartis. All other authors have declared no conflicts of interest.
615O_PR - Hybrid minimally invasive vs. open esophagectomy for patients with esophageal cancer: Long-term outcomes of a multicenter, open-label, randomized phase III controlled trial, the MIRO trial (ID 3249)
- G. Piessen
Abstract
Background
Postoperative morbidity, especially pulmonary complications, affects more than half of patients after open esophagectomy (OE). We assessed whether hybrid minimally invasive esophagectomy (HMIE) reduces morbidity compared with OE.
Methods
We performed a multicentre, open-label, randomised controlled trial at 13 study centres between October 2009 and April 2012. Patients aged 18-75 years old with resectable cancers of the middle or lower third of the oesophagus were assigned by randomisation to undergo either transthoracic OE or HMIE. Surgical quality assurance was implemented through credentialing surgeons before enrolment, standardisation of technique and monitoring of performance during the trial. HMIE comprised an Ivor Lewis procedure with laparoscopic gastric mobilisation and open right thoracotomy. The primary outcome was 30-day grade II-IV postoperative morbidity as defined by the Clavien-Dindo classification. Secondary outcomes were 30-day postoperative mortality, overall and disease free-survivals. Analysis was done by intention to treat.
Results
We randomly assigned 104 patients to the OE group and 103 to the HMIE group. Sixty-seven (64.4%) patients in the OE group had major postoperative morbidity compared with 37 (35.9%) in the HMIE group (OR 0.31, 95%CI 0.18-0.55; p < 0·001). Thirty-one (30.1%) patients in the OE had major pulmonary complications compared with 18 (17.7%) in the HMIE group (p = 0·037). After of follow up of at least 3 years for each patient (median 48.8 months), the overall survival was improved in the HMIE group and at 3 years was 67.0% (95% CI 57% to 75.2%) compared with 54.8% (95% CI 44.8% to 63.8%) for OE (median not reached, p = 0.054).
Conclusions
These findings show that hybrid minimally invasive esophagectomy is an oncologically sound procedure, and reduces the incidence of major morbidity specifically pulmonary following esophagectomy for cancer.
Clinical trial identification
NCT00937456
Legal entity responsible for the study
Lille University Hospital
Funding
The French National Cancer Institute INCa
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant LBA27_PR and 615O_PR (ID 5740)
- A. Roth
616O - Pertuzumab (P) + trastuzumab (H) + chemotherapy (CT) for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (mGC/GEJC): Final analysis of a Phase III study (JACOB) (ID 2289)
- J. Tabernero
Abstract
Background
Targeting HER2 with H + CT significantly improves overall survival (OS) vs CT alone in patients (pts) with HER2-positive mGC/GEJC. In HER2-positive metastatic breast cancer, P + H + docetaxel significantly improves progression-free survival (PFS) and OS vs placebo (PLA) + H + docetaxel. We therefore assessed the efficacy and safety of adding P to H + CT in pts with HER2-positive mGC/GEJC.
Methods
JACOB (NCT01774786) is a double-blind, randomised, PLA-controlled, Phase III study in mGC/GEJC. Pts were randomised 1:1 to PLA + H + CT (standard cisplatin/fluoropyrimidine regimen) or P + H + CT. P and H were given every 3 weeks until disease progression or unacceptable toxicity (P at 840 mg, H: 8 mg/kg loading and 6 mg/kg maintenance doses). CT was given as per standard regimens/doses. Stratification factors were world region, prior gastrectomy and HER2 immunohistochemistry score. Primary endpoint was OS. Secondary endpoints included PFS and safety. JACOB was estimated to have 80% power to detect a significant improvement in OS (hazard ratio [HR] 0.777) at the final efficacy analysis after 502 events (overall two-sided α-level 5%).
Results
From 10 Jun 2013 to 12 Jan 2016, 388 pts were randomised to P + H + CT and 392 to PLA + H + CT. After a median OS follow-up of approx. 2 years, 504 patients had died, 242 in the P + H + CT arm (median OS 17.5 months) and 262 in the PLA + H + CT arm (median OS 14.2 months) (HR 0.84, 95% confidence interval [CI] 0.71–1.00; p = 0.0565). Median PFS was 8.5 months and 7.0 months respectively (HR 0.73, 95% CI 0.62–0.86). The safety profile was generally comparable between treatment arms except for diarrhoea (all grades: 61.6% in P + H + CT vs 35.1% in PLA + H + CT). Incidence of symptomatic and asymptomatic left ventricular systolic dysfunction was low and similar in both arms.
Conclusions
The study failed to demonstrate a statistically significant improvement in OS with the addition of P to H + CT, although a 3.3-month increase in median OS was observed. P was generally well tolerated and no new safety signals were identified. Further analyses will be presented.
Clinical trial identification
Protocol number: BO25114; ClinicalTrials.gov NCT01774786
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
J. Tabernero: Advisory board: Amgen, Bayer, Boehringer-Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda. P.M. Hoff: Corporate-sponsored research: Roche. L. Shen: Advisory board: Hengrui, Merck, Roche, BMS. Corporate-sponsored research: Taiho, Hengrui, Merck, Roche AZ. A. Ohtsu: Corporate-sponsored research: BMS. M.A. Shah: Advisory board: Lilly, Inc. Corporate-sponsored research to institution: Roche, Boston Biomedical, Gilead. K. Cheng: Stock ownership: Genentech. Employee of Genentech. C. Song: Stock ownership: Roche. Corporate-sponsored research: Roche. Employee of Roche. H. Wu: Employee of Roche (China) Holding Ltd. J. Eng-Wong: Employee of Genentech. Y-K. Kang: Advisory board: Roche, Novartis, Ono, Daehwa, LSK Biopharma, Blueprint, Taiho, BMS.
617O - A Phase 3 Study of nivolumab (Nivo) in previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer: Updated results and subset analysis by PD-L1 expression (ATTRACTION-02) (ID 4410)
- N. Boku
Abstract
Background
Nivo monotherapy demonstrated its efficacy with manageable safety for G/GEJ cancer refractory or intolerant to standard chemotherapy at the primary analysis (ATTRACTION-02[ONO-4538-12]: ASCO-GI 2017, Kang YK et al.
Methods
493 patients(pts) aged ≥ 20 years with ECOG PS 0-1 and unresectable advanced or recurrent G/GEJ cancer after failure of two or more previous chemotherapy regimens were randomized in a 2:1 ratio to receive 3 mg/kg Nivo (N = 330) or placebo (N = 163) every 2 weeks until unacceptable toxicity or disease progression. The primary endpoint was overall survival (OS). The PD-L1 expression was assessed by immunohistochemistry (28-8 pharmDx assay). And updated results of the efficacy and safety were based on ≥ 1-year follow-up after last patient enrollment.
Results
As of the data cut-off on February 25th 2017, one year after last patient enrollment, the median OS (mOS) was 5.32 months with Nivo versus 4.14 months with placebo (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.50-0.75; p < 0.0001). The OS rates were 46.4% (95% CI, 40.8-51.8) versus 34.7% (95% CI, 27.4-42.1) at 6 months and 27.6%(95% CI, 22.8-32.6) versus 11.6% (95% CI,7.2-17.1) at 12 months. Immunohistochemistry was performed for exploratory analyses of OS by PD-L1 status on pretreatment tumor biopsies obtained from 197 pts. In pts with PD-L1-positive (expression ≥1%) tumors, the mOS was 5.22 months in the Nivo (16 pts) versus 3.83 months in placebo (10 pts) (HR, 0.58; 95% CI, 0.24-1.38). In pts with PD-L1 negative (<1%) tumors, mOS was 6.05 months (115 pts) versus 4.19 months (52 pts) (HR, 0.70; 95% CI, 0.49-1.00), respectively.
Conclusions
With minimum 1-year of follow-up, long-term survival benefit of nivolumab was confirmed for patients with advanced G/GEJ cancer. Although tumor samples were available only in 40% of all enrolled patients, Nivo demonstrated benefit irrespective of PD-L1 expression in the exploratory analysis.
Clinical trial identification
NCT02267343
Legal entity responsible for the study
Ono Pharmaceutical Co., Ltd
Funding
Ono Pharmaceutical Co., Ltd, Bristol-Myers Squibb
Disclosure
N. Boku: Ono, Taiho, Chugai, Eli-Lilly. Y-K. Kang: Ono, Bristol-Myers Squibb, Lilly/ImClone, Taiho Pharmaceutical, Roche/Genentech, Novartis, Bayer. T. Satoh: Ono. K. Kato: Ono, Shionogi, MSD. H.C. Chung: Lilly, GSK, MSD, Merck Serono, BMS, Ono, Taiho, Celltrion, Quintiles, BMS. K. Muro: Shionogi, MSD K.K., Daiichi Sankyo, Kyowa Hakko Kirin, Gilead Sciences, Chugai, Takeda, Eli Lilly Japan K.K., Merck Serono, Taiho, Yakult Honsha. T. Yoshikawa: Taiho, Chugai, Yakult, Ono, MSD. K-W. Lee: Ono. L-T. Chen: Ono, Eli-Lilly, MSD, PharmaEngine, Merrimack, TTY, Syncore, Five Prime, Novartis, GSK, Merck Serono, Polaris, Anti-Alpha Enolase (ENO-1) monoclonal antibody/HuniLife. All other authors have declared no conflicts of interest.
LBA28_PR - KEYNOTE-059 Update: Efficacy and safety of pembrolizumab alone or in combination with chemotherapy in patients with advanced gastric or gastroesophageal (G/GEJ) cancer (ID 5642)
- Z. Wainberg
Abstract
Background
Prior results from the global, phase 2 KEYNOTE-059 study (NCT02335411) demonstrated manageable safety and promising antitumor activity for pembro alone and pembro + chemo in pts with G/GEJ cancer.
Methods
Pts with recurrent or metastatic G/GEJ adenocarcinoma were enrolled. Pts were enrolled in cohorts 1 and 2 regardless of tumor PD-L1 expression; only pts with PD-L1-positive tumors (combined positive score of ≥ 1% using the PD-L1 IHC 22C3 pharmDx assay) were enrolled in cohort 3. Cohort 1 pts received pembro alone after ≥2 prior lines of therapy. Cohort 2 pts received pembro + cisplatin (80 mg/m2 day 1) + 5-fluorouracil (800 mg/m2 days 1-5 Q3W) or capecitabine (in Japan only, 1000 mg/m2 twice daily) as first-line. Cohort 3 pts received pembro alone as first-line. In all cohorts, pembro was given at 200 mg Q3W for up to 2 years. Primary end points were safety (all) and ORR by RECIST v1.1 by central review (cohorts 1 and 3); key secondary end points were ORR (cohort 2) and DOR by RECIST v1.1, PFS, and OS.
Results
At data cutoff (Apr 21, 2017), median (range) follow-up was 6 (1-25), 14 (2-24), and 18 (2-21) months for cohorts 1 (259 pts), 2 (25 pts) and 3 (31 pts), respectively. Confirmed ORR (95% CI) was 12% (8-17) overall, 16% (11-23) in PD-L1-positive, and 6% (3-13) in PD-L1-negative tumors in cohort 1. Confirmed ORR was 60% (39-79) overall, 73% (45-92) in PD-L1-positive, and 38% (9-76) in PD-L1-negative tumors in cohort 2. In cohort 3, confirmed ORR (95% CI) was 26% (12-45). Median PFS (95% CI) was 2 (2-2), 7 (6-11), and 3 (2-6) months in cohorts 1, 2, and 3, respectively. Median OS (95% CI) in months was 6 (4-7), 14 (9-not estimable), and not reached (9-21) in cohorts 1, 2, and 3, respectively. In cohorts 1, 2 and 3, grade 3-5 treatment-related adverse event (TRAE) incidence was 46 (18%), 19 (76%), and 7 (23%), respectively. In cohort 1, TRAEs led to discontinuation in 7 pts (3%) and death in 2 pts (1%); in cohort 2, TRAEs led to discontinuation in 3 pts (12%); in cohort 3, TRAEs led to death in 1 pt (3%).
Conclusions
These updated results show manageable safety and promising antitumor activity for pembro alone and pembro + chemo in pts with advanced G/GEJ cancer.
Clinical trial identification
NCT02335411
Legal entity responsible for the study
Merck & Co, Inc.
Funding
Merck & Co, Inc.
Disclosure
Z.A. Wainberg: Consultant for Genetech, Array, Sirtex, Novartis, and Five Prime Therapeutics. S. Jalal: Research funding: AstraZeneca. K. Muro: Research funding: Shionogi & Co, MSD K.K., Daiichi Sankyo, Kyowa Hakko Kirin,. Gilead Sciences Honoraria: Chugai Pharmaceutical, Takeda Pharmaceutical, Eli Lilly Japan K.K., Merck Serono, Taiho, Yakult Honsha. T. Doi: Advisory board: Lilly, Chugai Pharma, Kyowa Hakko, Kirin, Novartis, MSD, Daiichi Sankyo, Amgen Research funding: Taiho, Novartis, Merck Serono, Astellas, MSD, Janssen Pharma, Behringer Ingelheim, Takeda, Pfizer, Lilly, Sumitomo Group, Chugai Pharma, Bayer, Kyowa Hakko, Kirin, Daiichi Sankyo, Celegene. D.V. Catenacci: Advisory board: Merck, BMS, Lilly, Genentech Honoraria: Merck, BMS, Lilly, Genentech Travel expenses, including accommodations: Merck, BMS, Lilly, Genentech. R. Geva: Advisory board: Bayer, MSD, Novartis Honoraria: BMS, Lilly, Medison, Roche, Novartis, Janssen Travel expenses: Roche, BMS. G. Ku: Advisory board member: Merck Research funding: Merck (to institution) Travel expenses: Merck J. Bleeker: Travel expenses: Merck & Co., Inc. Consultant fee: BMS. Y-J. Bang: Advisory board: AstraZeneca, Novartis, Roche, Genentech, MSD, Pfizer, Bayer, BMS, Eli Lilly, Merck Serano, FivePrime, Merrimack, Taiho, Ono, ADC Therapeutics, GreenCross, Samyang Biopharm Research funding: AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, GSK, BMS, Pfizer, Eli Lilly, Boeringer-Ingelheim, MacroGenics, Boston Biomedical, FivePrime, CKD, Ono, Otsuka, Taiho, Takeda, BeiGene, Hanmi, Green Cross, Curis. H. Hara: Research funding to institution: AstraZenaca, Chugai Pharma, Merck Serono, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Dainippon Sumitomo Pharma, Daiichi Sankyo, Lilly Honoraria: Chugai Pharma, Taiho Pharmaceuticals, Merck Serono, Yakult Honsha, Lilly. M. Savage, J. Wang, M. Koshiji, R. Dalal: Employment: Merck & Co., Inc. C.S. Fuchs: Advisory board: Eli Lilly, Entrinsic Health, Genentech, Merck, Gilead, Sanofi, Dicerna, Five Prime Therapeutics, Merrimack, Bayer, Agios, Taiho. All other authors have declared no conflicts of interest.
Invited Discussant 616O, 617O and LBA28 (ID 5742)
- E. Van Cutsem