- Email: [email protected]
Ramucirumab in the treatment of refractory metastatic gastric cancer: Results from the RamSelGa trial
abstracts
795P
A prospective observational study on the optimal maintenance strategy in HER2-positive advanced gastric cancer treated with trastuzumab based therapy
Q. Li, M. Lu, H. Jiang, Y. Wang, S. Yu, Y. Yu, T. Liu Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China Background: Trastuzumab plus chemotherapy is an effective therapy in HER2 positive advanced gastric cancer (AGC). However, the optimal maintenance treatment in patients benefited from the initial therapy remains unclear. Methods: This was a prospective observational study in patients with untreated HER2 positive AGC. After 6 cycles of trastuzumab combined with chemotherapy, patients who had not progression disease were divided into two arms: trastuzumab monotherapy (arm A) and trastuzumab plus single chemo-agent derived from the initial chemotherapy (arm B). Patients received CT/MRI for response evaluation every 8 weeks or anytime suspected treatment failure. Adverse effects and costs were recorded every cycles. The primary end point was overall survival (OS), secondary end points included progression free survival (PFS), cost-effectiveness ratio per progression-free life-year saved (PF-LYS) and safety. Results: In total, 115 HER2 positive AGC treated with trastuzumab based first line chemotherapy were registered. After 6 cycles, 78 patients (6 CR, 46 PR, 26 SD) were eligible: 30 patients were in arm A accepted trastuzumab monotherapy as their maintenance therapy, 48 were in arm B. The clinicalpathological characteristics of two arms were well balanced. There was no significant differences of median OS (16.5 vs 20.0 months, P ¼ 0.169) or PFS (7.9 vs 11.0, P ¼ 0.892) between two arms. Adverse effects were also similar including cardiac safety. Subgroup analysis showed chemotherapy additional to trastuzumab benefited on OS in patients who had stable disease (SD) of response (HR: 0.084, P ¼ 0.004), without liver metastasis (HR:0.271, P ¼ 0.008) or less than 2 organs of distance metastatic (HR: 0.263, P ¼ 0.005). The average cost per patients in arm A was 153,137 RMB and 165,195 RMB in arm B. While, PF-LYS in arm A was 1.29 times higher than arm B (19,384 vs 15,018 RMB). Conclusions: Both maintenance therapy strategies are optional for patients who benefit from the initial 6 cycles of therapy. However, there is an advantage on PF-LYS in patients treated with trastuaumab plus single chemotherapy agent. Furthermore, continual single-chemotherapy agent was beneficial in Patients with certain characterisitic. Legal entity responsible for the study: Zhongshan Hospital, Fudan University. Funding: Shanghai Science and Technology Funds 1741195400. Disclosure: All authors have declared no conflicts of interest.
796P
Randomised phase II trial of first-line docetaxel, carboplatin, capecitabine (CTX) and epirubicin, oxaliplatin, capecitabine (EOX) in advanced esophagogastric adenocarcinoma (SEED)
P.C. Petersen, L. Noergaard Petersen, I.R. Vogelius, J.K. Bjerregaard, L. Baeksgaard Department of Oncology, Rigshospitalet, Copenhagen, Denmark Background: Chemotherapy is associated with a survival benefit in advanced gastric cancer. Several options exist, including EOX. The regimen docetaxel, cisplatin and 5fluorouracil (DCF) is toxic and modifications have been developed. In our institution CTX was a standard treatment from 2004 to 2012 when it was replaced by EOX. Afterwards, a randomised trial with CTX was conducted. Methods: SEED was a prospective, single-center, phase 2 trial in unresectable HER2negative esophagogastric adenocarcinoma. Patients were randomised to either docetaxel 60 mg/m2, carboplatin AUC5 and capecitabine 1000 mg/m2 bd for 14 days q4w (CTX) or epirubicin 50 mg/m2, oxaliplatin 130 mg/m2 and capecitabine 625 mg/m2 bd for 21 days q3w (EOX). Treatment continued until progression, intolerance or a
v306 | Gastrointestinal Tumours, Non-Colorectal
maximum of 9 cycles. The primary endpoint was 1-year-survival for patients treated with CTX. The trial sought to accept (lower boundary 55%) or reject (higher boundary 40%) CTX for further study without making direct comparisons to EOX. Secondary endpoints included OS, PFS and grade 3/4 toxicities. Results: From 2014 to 2019 a total of 98 patients were randomised (49 in each arm). The median age was 63 (36 - 79). Male/female: 79/19; ECOG PS (0/1): 46/52; oesophageal/GEJ/gastric: 29/44/25; metastatic/non-metastatic: 96/2. As of 26 April 2019, 85 patients had died. The estimated 1-year survival was 32% (95% CI 19 - 46) for CTX and 39% (95% CI 25 - 52) for EOX. The median PFS and OS was 6.2 months (95% CI 5.2 7.2) and 9.2 months (95% CI 7.2 - 11.2), respectively, for CTX, and 5.2 months (95% CI 3.5 - 7.0) and 10.2 months (95% CI 7.9 - 12.4), respectively, for EOX. Grade 3/4 related toxicities in > 5% were neutropenia (78%), febrile neutropenia (25%), diarrhoea (8%) and fatigue (6%) for CTX, and neutropenia (49%), febrile neutropenia (10%), peripheral neuropathy (8%) and nausea (8%) for EOX. There were no treatment-related deaths. Conclusions: CTX resulted in a 1-year-survival rate of 32% and so is rejected for further study. Also, CTX had a high rate of febrile neutropenia. CTX is not recommended for patients with esophagogastric cancer, except selected patients intolerant of other standard therapies, and then only with G-CSF support. Clinical trial identification: NCT02177552. Legal entity responsible for the study: Lene Baeksgaard. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
797P
Ramucirumab in the treatment of refractory metastatic gastric cancer: Results from the RamSelGa trial
A. Tryakin1, E. Perminova2, D. Stroyakovsky2, T. Titova3, D. Yukalchuk4, D. Ponomarenko5, N. Beliak6, G.M. Teletaeva7, E. Ratner8, A. Mochalova9, O.O. Gordeeva10, A. Meshcheryakov10, A.S. Zhabina11, S. Gamayunov12, A. Smolin13, A. Povyshev14, M. Andrievsckih15, M. Fedyanin1, I. Tsimafeyeu16, N. Besova3 1 Clinical Pharmacology and Chemotherapy, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation, 2Chemotherapy, Moscow City Oncologic Hospital 62, Moscow, Russian Federation, 3Chemotherapy, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation, 4 Chemotherapy, Regional Oncology Dispensary, Irkutck, Russian Federation, 5 Chemotherapy, Irkutsk Regional Oncology dispensary, Irkutck, Russian Federation, 6 Chemotherapy, St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russian Federation, 7Chemotherapy, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation, 8Chemotherapy, Republican Clinical Oncological Dispensary, Kazan, Russian Federation, 9Chemotherapy, Clinical Hospital 1 Medsi, Moscow, Russian Federation, 10Chemotherapy and Combined Treatments Modalities, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation, 11Chemotherapy, City Cancer Center, St. Petersburg, Russian Federation, 12Department of Radiotherapy and Surgical Treatment of Thoracic Diseases, National Medical Research Radiological Center of the Ministry of Health of the Russian Federation. A. Tsyb Medical Radiological Research Center, Obninsk, Russian Federation, 13Chemotherapy, N.N. Burdenko Main Military Clinical Hospital-Ministry of Defence of Russian Federation, Moscow, Russian Federation, 14Chemotherapy, KhantyMansiysk Regional Oncology dispensary, Khanty-Mansiysk, Russian Federation, 15 Chemotherapy, Chelyabinsk Regional Oncology Dispensary, Chelyabinsk, Russian Federation, 16Moscow Office, Russian Society of Clinical Oncology, Moscow, Russian Federation Background: Ramucirumab is a preferred second-line treatment option for patients with chemorefractory metastatic gastric cancer (mGC). RamSelGa study was conducted by the Russian Society of Clinical Oncology and assessed real-world data on the use of ramucirumab in this population. Methods: To be included in the study patients had to progress on previous platinum and fluoropyrimidine-based chemotherapy and receive ramucirumab-based therapy in second or later lines. Primary end-point was overall survival (OS). Secondary endpoints included progression-free survival (PFS) and safety. Results: One hundred forty-five pts with mGA were enrolled in 14 centers. ECOG performance status 0, 1 and 2 had 19 (13%), 102 (70%) and 24 (17%) patients. Ramucirumab was used in second- and later-lines in 126 and 19 patients, respectively. Ramucirumab was combined with weekly paclitaxel in 109 (75%) patients or irinotecan-based chemotherapy (mostly FOLFIRI) in 24 (17%) patients. Median duration of second-line ramucirumab was 4.7 (range, 0.5-34.1) months, 17 (13%) patients received therapy for 12 months. Median OS was 9.2 months in patients treated with ramucirumab in the second-line setting. OS and PFS data are summarized in the table. VEGFrelated toxicity (all grades) included epistaxis (36%), proteinuria >1g/day (4.2%), and arterial hypertension (30%); grade 3-5 toxicity was bleeding (4.1%) and brain ischemia (0.7%, grade 5). Three patients (2%) discontinued therapy due to toxicity.
Volume 30 | Supplement 5 | October 2019
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and 11.5 m (8.4-15.1) in arm B with HR of 0.954 (0.629-1.448). The OS was 11.5% (3.8-24.0) in arm A and 21.2% (11.0-33.6) in arm B at 3-year. In cohort-6M, the MST was 13.8 m (9.8-22.1) in arm A and 10.9 m (6.6-16.6) in arm B with HR of 0.860 (0.535-1.383). The OS was 13.2% (4.3-27.0) in arm A and 26.0% (13.1-41.0) in arm B at 3-year. Conclusions: Among pts having certain period of chemotherapy, there seem to be more long survivors in arm B than the arm A. Reduction surgery may still be promising if chemotherapy compliance after surgery could be improved. Clinical trial identification: UMIN000001012, Feb 2008. Legal entity responsible for the study: Japan Clinical Oncology Group (JCOG). Funding: The Ministry of Health, Labour and Welfare of Japan and the Korean Gastric Cancer Association. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
abstracts
Annals of Oncology
Table: 797P Second- Median Median Later- Median Median OS, lines, PFS, OS, PFS, line, n ¼ 126 months months n ¼ 19 months months
ramucirumab þ paclitaxel ramucirumab þ irinotecan-based others þ ramucirumab ramucirumab alone
95
5.5
9.2
14
3.1
5.5
24
7.0
10.3
0
-
-
4 3
5.5 2.4
10.1 2.5
3 2
5.2 -
5.6 -
799P
Conclusions: These "real-life" efficacy data of ramucirumab in patients with mGC are in line with previous randomized trials. Ramucirumab is well tolerated in daily clinical practice. Irinotecan-based regimens could be effective and warrant further investigation. Clinical trial identification: russco25072017. Legal entity responsible for the study: Russian Society of Clinical Oncology (RUSSCO). Funding: Has not received any funding. Disclosure: A. Tryakin: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eli Lilly and Company. All other authors have declared no conflicts of interest.
798P
Regorafenib in combination with paclitaxel for beyond first-line treatment of advanced esophagogastric cancer (REPEAT): A phase Ib trial with expansion cohort
M. Khurshed1, C.I. Stroes2, S. Schokker2, S. van der Woude2, R. Mathoˆt3, M. Slingerland4, J. de Vos-Geelen5, M. van Oijen2, O. van Delden6, M. Weterman2, C.J.A. Punt2, M. Bijlsma7, H.W.M. van Laarhoven2 1 Medical Biology, Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 2Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 3Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 4Medical Oncology, Leids Universitair Medisch Centrum (LUMC), Leiden, Netherlands, 5Medical Oncology, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands, 6Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 7Medical Oncology, Amsterdam UMC, University of Amsterdam and Oncode Institute, Amsterdam, Netherlands Background: Advanced esophagogastric cancer (EGC) has a dismal prognosis of less than one year. Survival has improved with second line therapies, such as the combination of the angiogenesis inhibitor Ramucirumab and Paclitaxel (PTX). Monotherapy with Regorafenib (Reg), a multikinase inhibitor of angiogenic, stromal, and oncogenic kinases, demonstrated an improved progression-free survival (PFS) in advanced gastric cancer. In the REPEAT trial, we assessed the tolerability of Reg in combination with PTX for beyond first-line treatment of patients (pts) with advanced EGC. Methods: Pts with metastatic EGC who progressed after first-line treatment, received PTX 80 mg/m2 i.v. on day 1, 8, and 15 of a 28-day cycle, and 120 mg Reg on day 1-21 of a 28-day cycle, as determined in phase Ib. Toxicity was assessed using CTCAE version 4, and Kaplan-Meier estimates of overall survival (OS) and PFS were done. In tumour biopsies, the effect of Reg on PTX uptake and Reg targets will be assessed, and the effect of Reg on PTX pharmacokinetics will be evaluated. Results: Reg 120 mg on day 1-21 combined with PTX was well tolerated in the Ib phase (N ¼ 14), and 33 pts were enrolled in the expansion cohort (total 47 pts, 81% received 120 mg). The majority of pts received treatment as second-line (60%); the remainder as third line or beyond. Most common grade 1/2 toxicities included fatigue (11%), peripheral sensory neuropathy (9%), diarrhea (5%), and alopecia (5%). Hypertension (10%), diarrhea (7%), and peripheral sensory neuropathy (5%) were the most common grade 3/4 toxicities. Median number of cycles was 4 (IQR 2-6), with 5 pts still on treatment (median follow-up 6.9 months). Best responses achieved were partial response (26%), stable disease (51%), and progressive disease (15%), with 4 patients not evaluable. Reasons for treatment discontinuation were progression (n ¼ 36), toxicity (n ¼ 5), or patient decision (n ¼ 1). Median PFS and median OS were 4.1 months and 7.8 months, respectively. Conclusions: The combined treatment of Reg with PTX is tolerable and shows promising effects on survival in beyond first-line treatment of advanced EGC. PK analyses and biomarker analyses on biopsies of metastatic lesions are ongoing. Clinical trial identification: 2014-005433-31 Release date: 10th December 2014. Legal entity responsible for the study: The authors. Funding: Bayer. Disclosure: J. de Vos-Geelen: Non-remunerated activity/ies: BTG; Research grant / Funding (institution), Non-remunerated activity/ies, Outside submitted work: Servier; Advisory / Consultancy: Shire. M. van Oijen: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution):
Volume 30 | Supplement 5 | October 2019
The relationship between the survival and fixed dosing of S-1 in advanced gastric cancer patients by pooled analysis using individual data from four Japanese randomized phase III trials
W. Ichikawa1, M. Takeuchi2, Y. Sunakawa3, K. Shitara4, K. Oba5, Y. Yamada6, W. Koizumi7, Y. Sakata8, H. Furukawa9, M. Takeuchi10, M. Fujii11 1 Department of Medical Oncology, Showa University Fujigaoka Hospital, Yokohama, Japan, 2Faculty of Environment and Information Studies, Keio University, Fujisawa, Japan, 3Clinical Oncology Department, St.Marianna University School of Medicine, Sagamihara, Japan, 4Department of Gastrointestinal Oncology, National Cancer Center Hospital East Kashiwa City, Chiba, Japan, 5Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 6 Department of Medical Oncology, Hamamatsu University School of Medicine, Hamamatsu, Japan, 7Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan, 8Misawa City Hospital, Misawa, Japan, 9Department of Sugery, Kindai University Faculty of Medicine, Osaka-sayama, Japan, 10Department of Clinical Medicine (Biostatics), Kitasato University, Tokyo, Japan, 11Digestive Surgery, Nihon University School of Dentistry Medecine, Tokyo, Japan Background: S-1 is a commonly used agent in first line therapy of advanced gastric cancer in Japan. The recommended initial dose of S-1 is 120 mg/day for patients (pts) with a body surface area (BSA) of 1.5 m2 in Japan. Systemic exposure to 5-FU is significantly lower in Japanese cancer pts with a large BSA of 1.75 m2 who received the recommended fixed dose of S-1, as compared with those with a BSA of 1.50 m2 and <1.75 m2 (Ann Oncol 20: 946-949, 2009). However, there has been little knowledge of the relationship between survival and fixed dosing of S-1 in pts with large BSA. Methods: Actual data from four randomized Japanese Phase III trials [START (S-1 vs S-1/docetaxel), SPIRITS (S-1 vs S-1/cisplatin), GC0301/TOP-002 (S-1 vs S-1/irinotecan), G-SOX (S-1þcisplatin vs S-1/oxaliplatin)] were combined to evaluate the effect of BSA on survival (OS) in terms of S-1 monotherapy and S-1 combination therapy. The pts were divided into two categories: those with BSA of 1.50 m2 and <1.75 m2 and those with a BSA of 1.75m2. The prognostic relevance of BSA was assessed using a multivariate proportional hazards model adjusted for the established clinical prognostic factors including age, performance status, tumor status, primary tumor, hematogenous metastasis, and peritoneal metastasis. Results: A total of 1,246 pts were available in this analysis (S-1 monotherapy, n ¼ 395; S-1 combination therapy, n ¼ 851). The median OS for S-1 monotherapy and S-1 combination therapy was 11.7 and 13.6 months, respectively. In pts treated with S-1 monotherapy, OS was significantly shorter in those with a BSA of 1.75 m2, compared with those with a BSA of 1.5 m2 and <1.75m2 (HR 1.39; 95% CI 1.05-1.84; p ¼ 0.02). However, OS was comparable in the two BSA categories for pts treated with S-1 combination (HR 1.09; 95% CI 0.90-1.34; p ¼ 0.349). BSA was an independent prognostic factor in S-1 monotherapy (HR 1.33; 95% CI 0.999-1.77; p ¼ 0.05) but not in S-1 combination therapy (HR 1.05; 95% CI 0.85-1.29; p ¼ 0.65). Conclusions: Although the fixed dosing of S-1 monotherapy affects the survival in pts with large BSA, combination therapy might overcome the worse prognosis even in those with large BSA. Clinical trial identification: UMIN000019519. Legal entity responsible for the study: Japan Clinical Cancer Research Organization. Funding: Has not received any funding. Disclosure: W. Ichikawa: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd.; Honoraria (institution): Takeda Pharmaceutical Co.; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Bayer Yakuhin Ltd.; Research grant / Funding (institution): Ono Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Shionogi Pharmaceutical Co. Ltd. Y. Sunakawa: Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Honoraria (institution): Taiho Pharmaceutical Co. Ltd; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Yakult Honsha Co. Ltd.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Bayer Yakuhin Ltd; Honoraria (self), Research grant / Funding (institution): Sanofi K.K.; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan; Research grant / Funding (institution): Daiichi Sankyo Pharmaceutical Co. Ltd.; Research grant / Funding (institution): MSD K.K.; Research grant / Funding (institution): Dainippon Sumitomo Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Solasia Pharma K.K. K. Shitara: Honoraria (self): Novartis; Honoraria (self): AbbVie; Honoraria (self): Yakult; Honoraria (institution), Advisory / Consultancy: Astellas Pharma; Honoraria (institution), Advisory / Consultancy: Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution): Dainippon Sumitomo Pharma; Honoraria (institution): Daiichi Sankyo; Honoraria (institution): Taiho Pharmaceutical; Honoraria (institution): Chugai Pharma; Honoraria (institution): Medi Science. K. Oba: Honoraria (self): Eisai Co., Ltd.; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria
doi:10.1093/annonc/mdz247 | v307
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Regimens
Merck; Research grant / Funding (institution): Nordic. M. Bijlsma: Research grant / Funding (institution), Outside submitted work: Celgene; Research grant / Funding (institution), Outside submitted work: Servier. H.W.M. van Laarhoven: Honoraria (self), Advisory / Consultancy: Lilly/ImClone; Advisory / Consultancy, Research grant / Funding (institution): Nordic Group; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): Bayer Schering Pharma; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Philips Healthcare; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Merck Sharp & Dohme. All other authors have declared no conflicts of interest.
795P
A prospective observational study on the optimal maintenance strategy in HER2-positive advanced gastric cancer treated with trastuzumab based therapy
Q. Li, M. Lu, H. Jiang, Y. Wang, S. Yu, Y. Yu, T. Liu Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China Background: Trastuzumab plus chemotherapy is an effective therapy in HER2 positive advanced gastric cancer (AGC). However, the optimal maintenance treatment in patients benefited from the initial therapy remains unclear. Methods: This was a prospective observational study in patients with untreated HER2 positive AGC. After 6 cycles of trastuzumab combined with chemotherapy, patients who had not progression disease were divided into two arms: trastuzumab monotherapy (arm A) and trastuzumab plus single chemo-agent derived from the initial chemotherapy (arm B). Patients received CT/MRI for response evaluation every 8 weeks or anytime suspected treatment failure. Adverse effects and costs were recorded every cycles. The primary end point was overall survival (OS), secondary end points included progression free survival (PFS), cost-effectiveness ratio per progression-free life-year saved (PF-LYS) and safety. Results: In total, 115 HER2 positive AGC treated with trastuzumab based first line chemotherapy were registered. After 6 cycles, 78 patients (6 CR, 46 PR, 26 SD) were eligible: 30 patients were in arm A accepted trastuzumab monotherapy as their maintenance therapy, 48 were in arm B. The clinicalpathological characteristics of two arms were well balanced. There was no significant differences of median OS (16.5 vs 20.0 months, P ¼ 0.169) or PFS (7.9 vs 11.0, P ¼ 0.892) between two arms. Adverse effects were also similar including cardiac safety. Subgroup analysis showed chemotherapy additional to trastuzumab benefited on OS in patients who had stable disease (SD) of response (HR: 0.084, P ¼ 0.004), without liver metastasis (HR:0.271, P ¼ 0.008) or less than 2 organs of distance metastatic (HR: 0.263, P ¼ 0.005). The average cost per patients in arm A was 153,137 RMB and 165,195 RMB in arm B. While, PF-LYS in arm A was 1.29 times higher than arm B (19,384 vs 15,018 RMB). Conclusions: Both maintenance therapy strategies are optional for patients who benefit from the initial 6 cycles of therapy. However, there is an advantage on PF-LYS in patients treated with trastuaumab plus single chemotherapy agent. Furthermore, continual single-chemotherapy agent was beneficial in Patients with certain characterisitic. Legal entity responsible for the study: Zhongshan Hospital, Fudan University. Funding: Shanghai Science and Technology Funds 1741195400. Disclosure: All authors have declared no conflicts of interest.
796P
Randomised phase II trial of first-line docetaxel, carboplatin, capecitabine (CTX) and epirubicin, oxaliplatin, capecitabine (EOX) in advanced esophagogastric adenocarcinoma (SEED)
P.C. Petersen, L. Noergaard Petersen, I.R. Vogelius, J.K. Bjerregaard, L. Baeksgaard Department of Oncology, Rigshospitalet, Copenhagen, Denmark Background: Chemotherapy is associated with a survival benefit in advanced gastric cancer. Several options exist, including EOX. The regimen docetaxel, cisplatin and 5fluorouracil (DCF) is toxic and modifications have been developed. In our institution CTX was a standard treatment from 2004 to 2012 when it was replaced by EOX. Afterwards, a randomised trial with CTX was conducted. Methods: SEED was a prospective, single-center, phase 2 trial in unresectable HER2negative esophagogastric adenocarcinoma. Patients were randomised to either docetaxel 60 mg/m2, carboplatin AUC5 and capecitabine 1000 mg/m2 bd for 14 days q4w (CTX) or epirubicin 50 mg/m2, oxaliplatin 130 mg/m2 and capecitabine 625 mg/m2 bd for 21 days q3w (EOX). Treatment continued until progression, intolerance or a
v306 | Gastrointestinal Tumours, Non-Colorectal
maximum of 9 cycles. The primary endpoint was 1-year-survival for patients treated with CTX. The trial sought to accept (lower boundary 55%) or reject (higher boundary 40%) CTX for further study without making direct comparisons to EOX. Secondary endpoints included OS, PFS and grade 3/4 toxicities. Results: From 2014 to 2019 a total of 98 patients were randomised (49 in each arm). The median age was 63 (36 - 79). Male/female: 79/19; ECOG PS (0/1): 46/52; oesophageal/GEJ/gastric: 29/44/25; metastatic/non-metastatic: 96/2. As of 26 April 2019, 85 patients had died. The estimated 1-year survival was 32% (95% CI 19 - 46) for CTX and 39% (95% CI 25 - 52) for EOX. The median PFS and OS was 6.2 months (95% CI 5.2 7.2) and 9.2 months (95% CI 7.2 - 11.2), respectively, for CTX, and 5.2 months (95% CI 3.5 - 7.0) and 10.2 months (95% CI 7.9 - 12.4), respectively, for EOX. Grade 3/4 related toxicities in > 5% were neutropenia (78%), febrile neutropenia (25%), diarrhoea (8%) and fatigue (6%) for CTX, and neutropenia (49%), febrile neutropenia (10%), peripheral neuropathy (8%) and nausea (8%) for EOX. There were no treatment-related deaths. Conclusions: CTX resulted in a 1-year-survival rate of 32% and so is rejected for further study. Also, CTX had a high rate of febrile neutropenia. CTX is not recommended for patients with esophagogastric cancer, except selected patients intolerant of other standard therapies, and then only with G-CSF support. Clinical trial identification: NCT02177552. Legal entity responsible for the study: Lene Baeksgaard. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
797P
Ramucirumab in the treatment of refractory metastatic gastric cancer: Results from the RamSelGa trial
A. Tryakin1, E. Perminova2, D. Stroyakovsky2, T. Titova3, D. Yukalchuk4, D. Ponomarenko5, N. Beliak6, G.M. Teletaeva7, E. Ratner8, A. Mochalova9, O.O. Gordeeva10, A. Meshcheryakov10, A.S. Zhabina11, S. Gamayunov12, A. Smolin13, A. Povyshev14, M. Andrievsckih15, M. Fedyanin1, I. Tsimafeyeu16, N. Besova3 1 Clinical Pharmacology and Chemotherapy, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation, 2Chemotherapy, Moscow City Oncologic Hospital 62, Moscow, Russian Federation, 3Chemotherapy, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation, 4 Chemotherapy, Regional Oncology Dispensary, Irkutck, Russian Federation, 5 Chemotherapy, Irkutsk Regional Oncology dispensary, Irkutck, Russian Federation, 6 Chemotherapy, St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russian Federation, 7Chemotherapy, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation, 8Chemotherapy, Republican Clinical Oncological Dispensary, Kazan, Russian Federation, 9Chemotherapy, Clinical Hospital 1 Medsi, Moscow, Russian Federation, 10Chemotherapy and Combined Treatments Modalities, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation, 11Chemotherapy, City Cancer Center, St. Petersburg, Russian Federation, 12Department of Radiotherapy and Surgical Treatment of Thoracic Diseases, National Medical Research Radiological Center of the Ministry of Health of the Russian Federation. A. Tsyb Medical Radiological Research Center, Obninsk, Russian Federation, 13Chemotherapy, N.N. Burdenko Main Military Clinical Hospital-Ministry of Defence of Russian Federation, Moscow, Russian Federation, 14Chemotherapy, KhantyMansiysk Regional Oncology dispensary, Khanty-Mansiysk, Russian Federation, 15 Chemotherapy, Chelyabinsk Regional Oncology Dispensary, Chelyabinsk, Russian Federation, 16Moscow Office, Russian Society of Clinical Oncology, Moscow, Russian Federation Background: Ramucirumab is a preferred second-line treatment option for patients with chemorefractory metastatic gastric cancer (mGC). RamSelGa study was conducted by the Russian Society of Clinical Oncology and assessed real-world data on the use of ramucirumab in this population. Methods: To be included in the study patients had to progress on previous platinum and fluoropyrimidine-based chemotherapy and receive ramucirumab-based therapy in second or later lines. Primary end-point was overall survival (OS). Secondary endpoints included progression-free survival (PFS) and safety. Results: One hundred forty-five pts with mGA were enrolled in 14 centers. ECOG performance status 0, 1 and 2 had 19 (13%), 102 (70%) and 24 (17%) patients. Ramucirumab was used in second- and later-lines in 126 and 19 patients, respectively. Ramucirumab was combined with weekly paclitaxel in 109 (75%) patients or irinotecan-based chemotherapy (mostly FOLFIRI) in 24 (17%) patients. Median duration of second-line ramucirumab was 4.7 (range, 0.5-34.1) months, 17 (13%) patients received therapy for 12 months. Median OS was 9.2 months in patients treated with ramucirumab in the second-line setting. OS and PFS data are summarized in the table. VEGFrelated toxicity (all grades) included epistaxis (36%), proteinuria >1g/day (4.2%), and arterial hypertension (30%); grade 3-5 toxicity was bleeding (4.1%) and brain ischemia (0.7%, grade 5). Three patients (2%) discontinued therapy due to toxicity.
Volume 30 | Supplement 5 | October 2019
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and 11.5 m (8.4-15.1) in arm B with HR of 0.954 (0.629-1.448). The OS was 11.5% (3.8-24.0) in arm A and 21.2% (11.0-33.6) in arm B at 3-year. In cohort-6M, the MST was 13.8 m (9.8-22.1) in arm A and 10.9 m (6.6-16.6) in arm B with HR of 0.860 (0.535-1.383). The OS was 13.2% (4.3-27.0) in arm A and 26.0% (13.1-41.0) in arm B at 3-year. Conclusions: Among pts having certain period of chemotherapy, there seem to be more long survivors in arm B than the arm A. Reduction surgery may still be promising if chemotherapy compliance after surgery could be improved. Clinical trial identification: UMIN000001012, Feb 2008. Legal entity responsible for the study: Japan Clinical Oncology Group (JCOG). Funding: The Ministry of Health, Labour and Welfare of Japan and the Korean Gastric Cancer Association. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
abstracts
Annals of Oncology
Table: 797P Second- Median Median Later- Median Median OS, lines, PFS, OS, PFS, line, n ¼ 126 months months n ¼ 19 months months
ramucirumab þ paclitaxel ramucirumab þ irinotecan-based others þ ramucirumab ramucirumab alone
95
5.5
9.2
14
3.1
5.5
24
7.0
10.3
0
-
-
4 3
5.5 2.4
10.1 2.5
3 2
5.2 -
5.6 -
799P
Conclusions: These "real-life" efficacy data of ramucirumab in patients with mGC are in line with previous randomized trials. Ramucirumab is well tolerated in daily clinical practice. Irinotecan-based regimens could be effective and warrant further investigation. Clinical trial identification: russco25072017. Legal entity responsible for the study: Russian Society of Clinical Oncology (RUSSCO). Funding: Has not received any funding. Disclosure: A. Tryakin: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eli Lilly and Company. All other authors have declared no conflicts of interest.
798P
Regorafenib in combination with paclitaxel for beyond first-line treatment of advanced esophagogastric cancer (REPEAT): A phase Ib trial with expansion cohort
M. Khurshed1, C.I. Stroes2, S. Schokker2, S. van der Woude2, R. Mathoˆt3, M. Slingerland4, J. de Vos-Geelen5, M. van Oijen2, O. van Delden6, M. Weterman2, C.J.A. Punt2, M. Bijlsma7, H.W.M. van Laarhoven2 1 Medical Biology, Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 2Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 3Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 4Medical Oncology, Leids Universitair Medisch Centrum (LUMC), Leiden, Netherlands, 5Medical Oncology, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands, 6Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 7Medical Oncology, Amsterdam UMC, University of Amsterdam and Oncode Institute, Amsterdam, Netherlands Background: Advanced esophagogastric cancer (EGC) has a dismal prognosis of less than one year. Survival has improved with second line therapies, such as the combination of the angiogenesis inhibitor Ramucirumab and Paclitaxel (PTX). Monotherapy with Regorafenib (Reg), a multikinase inhibitor of angiogenic, stromal, and oncogenic kinases, demonstrated an improved progression-free survival (PFS) in advanced gastric cancer. In the REPEAT trial, we assessed the tolerability of Reg in combination with PTX for beyond first-line treatment of patients (pts) with advanced EGC. Methods: Pts with metastatic EGC who progressed after first-line treatment, received PTX 80 mg/m2 i.v. on day 1, 8, and 15 of a 28-day cycle, and 120 mg Reg on day 1-21 of a 28-day cycle, as determined in phase Ib. Toxicity was assessed using CTCAE version 4, and Kaplan-Meier estimates of overall survival (OS) and PFS were done. In tumour biopsies, the effect of Reg on PTX uptake and Reg targets will be assessed, and the effect of Reg on PTX pharmacokinetics will be evaluated. Results: Reg 120 mg on day 1-21 combined with PTX was well tolerated in the Ib phase (N ¼ 14), and 33 pts were enrolled in the expansion cohort (total 47 pts, 81% received 120 mg). The majority of pts received treatment as second-line (60%); the remainder as third line or beyond. Most common grade 1/2 toxicities included fatigue (11%), peripheral sensory neuropathy (9%), diarrhea (5%), and alopecia (5%). Hypertension (10%), diarrhea (7%), and peripheral sensory neuropathy (5%) were the most common grade 3/4 toxicities. Median number of cycles was 4 (IQR 2-6), with 5 pts still on treatment (median follow-up 6.9 months). Best responses achieved were partial response (26%), stable disease (51%), and progressive disease (15%), with 4 patients not evaluable. Reasons for treatment discontinuation were progression (n ¼ 36), toxicity (n ¼ 5), or patient decision (n ¼ 1). Median PFS and median OS were 4.1 months and 7.8 months, respectively. Conclusions: The combined treatment of Reg with PTX is tolerable and shows promising effects on survival in beyond first-line treatment of advanced EGC. PK analyses and biomarker analyses on biopsies of metastatic lesions are ongoing. Clinical trial identification: 2014-005433-31 Release date: 10th December 2014. Legal entity responsible for the study: The authors. Funding: Bayer. Disclosure: J. de Vos-Geelen: Non-remunerated activity/ies: BTG; Research grant / Funding (institution), Non-remunerated activity/ies, Outside submitted work: Servier; Advisory / Consultancy: Shire. M. van Oijen: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution):
Volume 30 | Supplement 5 | October 2019
The relationship between the survival and fixed dosing of S-1 in advanced gastric cancer patients by pooled analysis using individual data from four Japanese randomized phase III trials
W. Ichikawa1, M. Takeuchi2, Y. Sunakawa3, K. Shitara4, K. Oba5, Y. Yamada6, W. Koizumi7, Y. Sakata8, H. Furukawa9, M. Takeuchi10, M. Fujii11 1 Department of Medical Oncology, Showa University Fujigaoka Hospital, Yokohama, Japan, 2Faculty of Environment and Information Studies, Keio University, Fujisawa, Japan, 3Clinical Oncology Department, St.Marianna University School of Medicine, Sagamihara, Japan, 4Department of Gastrointestinal Oncology, National Cancer Center Hospital East Kashiwa City, Chiba, Japan, 5Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 6 Department of Medical Oncology, Hamamatsu University School of Medicine, Hamamatsu, Japan, 7Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan, 8Misawa City Hospital, Misawa, Japan, 9Department of Sugery, Kindai University Faculty of Medicine, Osaka-sayama, Japan, 10Department of Clinical Medicine (Biostatics), Kitasato University, Tokyo, Japan, 11Digestive Surgery, Nihon University School of Dentistry Medecine, Tokyo, Japan Background: S-1 is a commonly used agent in first line therapy of advanced gastric cancer in Japan. The recommended initial dose of S-1 is 120 mg/day for patients (pts) with a body surface area (BSA) of 1.5 m2 in Japan. Systemic exposure to 5-FU is significantly lower in Japanese cancer pts with a large BSA of 1.75 m2 who received the recommended fixed dose of S-1, as compared with those with a BSA of 1.50 m2 and <1.75 m2 (Ann Oncol 20: 946-949, 2009). However, there has been little knowledge of the relationship between survival and fixed dosing of S-1 in pts with large BSA. Methods: Actual data from four randomized Japanese Phase III trials [START (S-1 vs S-1/docetaxel), SPIRITS (S-1 vs S-1/cisplatin), GC0301/TOP-002 (S-1 vs S-1/irinotecan), G-SOX (S-1þcisplatin vs S-1/oxaliplatin)] were combined to evaluate the effect of BSA on survival (OS) in terms of S-1 monotherapy and S-1 combination therapy. The pts were divided into two categories: those with BSA of 1.50 m2 and <1.75 m2 and those with a BSA of 1.75m2. The prognostic relevance of BSA was assessed using a multivariate proportional hazards model adjusted for the established clinical prognostic factors including age, performance status, tumor status, primary tumor, hematogenous metastasis, and peritoneal metastasis. Results: A total of 1,246 pts were available in this analysis (S-1 monotherapy, n ¼ 395; S-1 combination therapy, n ¼ 851). The median OS for S-1 monotherapy and S-1 combination therapy was 11.7 and 13.6 months, respectively. In pts treated with S-1 monotherapy, OS was significantly shorter in those with a BSA of 1.75 m2, compared with those with a BSA of 1.5 m2 and <1.75m2 (HR 1.39; 95% CI 1.05-1.84; p ¼ 0.02). However, OS was comparable in the two BSA categories for pts treated with S-1 combination (HR 1.09; 95% CI 0.90-1.34; p ¼ 0.349). BSA was an independent prognostic factor in S-1 monotherapy (HR 1.33; 95% CI 0.999-1.77; p ¼ 0.05) but not in S-1 combination therapy (HR 1.05; 95% CI 0.85-1.29; p ¼ 0.65). Conclusions: Although the fixed dosing of S-1 monotherapy affects the survival in pts with large BSA, combination therapy might overcome the worse prognosis even in those with large BSA. Clinical trial identification: UMIN000019519. Legal entity responsible for the study: Japan Clinical Cancer Research Organization. Funding: Has not received any funding. Disclosure: W. Ichikawa: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd.; Honoraria (institution): Takeda Pharmaceutical Co.; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Bayer Yakuhin Ltd.; Research grant / Funding (institution): Ono Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Shionogi Pharmaceutical Co. Ltd. Y. Sunakawa: Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Honoraria (institution): Taiho Pharmaceutical Co. Ltd; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Yakult Honsha Co. Ltd.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Bayer Yakuhin Ltd; Honoraria (self), Research grant / Funding (institution): Sanofi K.K.; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan; Research grant / Funding (institution): Daiichi Sankyo Pharmaceutical Co. Ltd.; Research grant / Funding (institution): MSD K.K.; Research grant / Funding (institution): Dainippon Sumitomo Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Solasia Pharma K.K. K. Shitara: Honoraria (self): Novartis; Honoraria (self): AbbVie; Honoraria (self): Yakult; Honoraria (institution), Advisory / Consultancy: Astellas Pharma; Honoraria (institution), Advisory / Consultancy: Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution): Dainippon Sumitomo Pharma; Honoraria (institution): Daiichi Sankyo; Honoraria (institution): Taiho Pharmaceutical; Honoraria (institution): Chugai Pharma; Honoraria (institution): Medi Science. K. Oba: Honoraria (self): Eisai Co., Ltd.; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria
doi:10.1093/annonc/mdz247 | v307
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Regimens
Merck; Research grant / Funding (institution): Nordic. M. Bijlsma: Research grant / Funding (institution), Outside submitted work: Celgene; Research grant / Funding (institution), Outside submitted work: Servier. H.W.M. van Laarhoven: Honoraria (self), Advisory / Consultancy: Lilly/ImClone; Advisory / Consultancy, Research grant / Funding (institution): Nordic Group; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): Bayer Schering Pharma; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Philips Healthcare; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Merck Sharp & Dohme. All other authors have declared no conflicts of interest.