- Email: [email protected]
tipiracil in elderly patients with previously untreated metastatic colorectal cancer (KSCC 1602): A single-arm, phase II study
abstracts Oncology, University Hospital Utrecht, Utrecht, Netherlands, 16Clinical Trial Department, Netherlands Comprehensive Cancer Organisation, Nijmegen, Netherlands
Pharma; Advisory / Consultancy, Research grant / Funding (institution): Servier. R. van Alphen: Advisory / Consultancy: Nordic Pharma; Travel / Accommodation / Expenses: Roche. C.J.A. Punt: Advisory / Consultancy: Nordic Pharma; Advisory / Consultancy: Servier. All other authors have declared no conflicts of interest.
Results: From Jan to Sep 2018, 102 pts were enrolled, and 98 pts fulfilled the eligibility (49 pts in each). Baseline characteristics of RAS wild-type vs. mutant were follows; median age, 65 vs. 64 years: male, 51% vs. 59%: ECOG PS 0, 69% vs. 59%: left-sided primary, 84% vs. 67%: number of metastasis of > 2, 71% vs. 74%: median time from diagnosis of metastasis, 32.9 vs 21.2 months. The DCR in RAS wild-type was 65.3% (90% CI: 52.6-76.5%, p ¼ 0.0022), while that in RAS mutant was 55.1% (90% CI: 42.467.3%, p ¼ 0.0780). There was not a statistically significant difference in DCR between RAS wild-type and mutant after adjustment of baseline characteristics (adjusted odds ratio¼0.48, 90% CI: 0.21-1.10, p ¼ 0.1435). Partial response was observed only in three pts with RAS wild-type. There were neither unexpected safety signals nor treatment related death. Conclusions: FTD/TPI plus BEV showed a promising activity with an acceptable safety profile for previously treated mCRC harboring either RAS wild-type or mutant. Survival outcome will be presented at the meeting. Legal entity responsible for the study: Japanese Fondation for Multidisciplinary Treatment of Cancer (JFMC). Funding: Japanese Fondation for Multidisciplinary Treatment of Cancer (JFMC). Disclosure: M. Nakamura: Honoraria (self): Taiho Yakuhin; Honoraria (self): Daiichi Sankyo; Honoraria (self): Chugai Seiyaku; Honoraria (self): Merck. A. Makiyama: Advisory / Consultancy: Eli Lily Pharm; Speaker Bureau / Expert testimony: Chugai Pharm; Speaker Bureau / Expert testimony: Eli Lily Pharm; Speaker Bureau / Expert testimony: Taiho Pharm; Speaker Bureau / Expert testimony: Takeda Pharm. K. Oba: Honoraria (self): Chugai Pharm; Honoraria (self): Novartis Pharm; Honoraria (self): Takeda Pharm; Honoraria (self): BMS; Honoraria (self): Pfizer; Honoraria (self): Tsumura Pharm. T. Yoshino: Research grant / Funding (self): Novartis Pharma; Research grant / Funding (self): MSD; Research grant / Funding (self): Sumitomo Dainippon Pharma; Research grant / Funding (self): Chugai Pharmaceutical; Research grant / Funding (self): Sanofi; Research grant / Funding (self): Daiichi Sankyo Company; Research grant / Funding (self): Parexel; Research grant / Funding (self): Ono Pharmaceutical. K. Yoshida: Research grant / Funding (self): Chugai Pharma; Research grant / Funding (self): Lilly; Research grant / Funding (self): MSD; Research grant / Funding (self): Ono Pharma; Honoraria (self): EA Pharma; Honoraria (self): Johnson & Johnson; Honoraria (self): SBI Pharma; Honoraria (self): Olympus; Honoraria (self): Covidien; Honoraria (self): Sanofi; Honoraria (self): TERUMO; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Tsumura; Honoraria (self): Asahi Kasei; Honoraria (self): Pharma International Osaka; Honoraria (self): Daiichi Sankyo; Honoraria (self): Chugai; Honoraria (self): Lilly; Honoraria (self): Takeda; Honoraria (self): Yakult Honsha. K. Yamazaki: Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Chugai. E. Oki: Speaker Bureau / Expert testimony: Taiho Pharm; Speaker Bureau / Expert testimony: Chugai Pharm. T. Takahashi: Speaker Bureau / Expert testimony: Taiho Pharm; Speaker Bureau / Expert testimony: Chugai Pharm. All other authors have declared no conflicts of interest.
620P 619P
JFMC51-1702-C7: Phase II study investigating efficacy and safety of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) in patients (pts) with metastatic colorectal cancer (mCRC) refractory or intolerant to standard chemotherapies
K. Kazama1, M. Nakamura2, R. Tanaka3, H. Ojima4, A. Makiyama5, N. Matsuhashi6, Y. Kagawa7, H. Okuda8, M. Asayama9, Y. Yuasa10, Y. Negoro11, H. Mushiake12, D. Manaka13, K. Oba14, T. Yoshino15, K. Yoshida16, Y. Maehara17, K. Yamazaki18, E. Oki19, T. Takahashi16 1 Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan, 2 Gastroenterology, Sapporo City General Hospital, Sapporo, Japan, 3Medical Oncology, Hamanomachi Hospital, Fukuoka, Japan, 4Gastroenterological Surgery, Gunma Prefectural Cancer Center, Ota, Japan, 5Hematology/Oncology, National Kyushu Cancer Center, Fukuoka, Japan, 6Surgical Oncology, Gifu University, Gifu, Japan, 7 Department of Surgery, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan, 8 Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan, 9Gastroenterology Department, Saitama Cancer Center, Ina, Japan, 10Gastrointestinal Surgery, Tokushima Red Cross Hospital, Tokushima, Japan, 11Gastroenterological Medicine & Oncology, Kochi Health Sciences Center, Kochi, Japan, 12Gastroenterological Center, Teikyo University School of Medicine, Tokyo, Japan, 13Department of Surgery, Gastro-Intestinal Center, Kyoto-Katsura Hospital, Kyoto, Japan, 14Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 15 Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan, 16Surgical Oncology, Gifu University Hospital, Gifu, Japan, 17Surgical Oncology, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan, 18Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan, 19Surgery and Science, National Kyushu Cancer Center, Fukuoka, Japan Background: Combination treatment of FTD/TPI plus BEV in the C-TASK FORCE showed a promising activity in pts with mCRC refractory or intolerant to standard chemotherapies; however, due to the small sample size, it remains unclear if this combination works in the same way; RAS wild-type or mutant. We investigated the efficacy and safety of this combination in separate cohorts of RAS wild-type and mutant. Methods: mCRC pts refractory or intolerant to prior treatments with fluoropyrimidines, irinotecan, oxaliplatin, an angiogenesis inhibitor, and an anti-EGFR antibody if RAS wild-type, and without FTD/TPI and regorafenib. Pts received FTD/TPI (35 mg/ m2, twice daily, days 1 to 5 and 8 to 12) and BEV (5mg/kg, day1 and 15) every four weeks. The primary endpoint was disease control rate (DCR). A threshold and expected value of the DCR in each wild-type and mutant were set as 44% and 65%, respectively. Assuming a one-sided significance level of 5.0%, each target sample size was estimated to be 49 to achieve a power of 90%.
v234 | Gastrointestinal Tumours, Colorectal
Bevacizumab plus trifluridine/tipiracil in elderly patients with previously untreated metastatic colorectal cancer (KSCC 1602): A single-arm, phase II study
A. Makiyama1, E. Oki2, Y. Miyamoto3, M. Kotaka4, H. Kawanaka5, K. Miwa6, A. Kabashima7, T. Noguchi8, K. Yuge9, T. Kashiwada10, M. Shimokawa11, H. Saeki12, Y. Akagi13, H. Baba14, M. Mori15 1 Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushu, Japan, 2Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 3Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan, 4Surgery, Sano Hospital-Gastrointestinal Cancer Center, Kobe, Japan, 5Clinical Research Institute and Department of Surgery, National Hospital Organization Beppu Medical Center, Beppu, Japan, 6Mutidisciplinary Treatment Cancer Center, Kurume University Hospital, Kurume, Japan, 7Department of Surgery, Oita Medical Center, Oita, Japan, 8Department of Surgery, Imakiire General Hospital, Kagoshima, Japan, 9 Department of Surgery, Social Insurance Tagawa Hospital, Tagawa, Japan, 10Medical Oncology, Saga Univ Facilty of Medicine-Nabeshima, Saga, Japan, 11Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Ube, Japan, 12General Surgical Science, Gunma University, Maebashi, Japan, 13Surgery, Kurume University, Kurume, Japan, 14Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, Kumamoto, Japan, 15Surgery and Science, Kyushu University, Fukuoka, Japan Background: Elderly patients often cannot tolerate the usual combination of two cytotoxic agents. Recently, bevacizumab plus trifluridine/tipiracil (FTD/TPI) was shown to be a good candidate regimen for vulnerable patients. We aimed to assess the efficacy and safety of bevacizumab plus FTD/TPI in elderly patients with metastatic colorectal cancer. Methods: Patients aged 70 years or older, with previously untreated unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were included in this trial. The treatment consisted of FTD/TPI (35 mg/m2, twice daily on Days 1–5 and Days 8–12) with bevacizumab (5mg/kg intravenously on Day 1 and 15), administrated every 4 weeks until disease progression. The primary endpoint was progression-free survival (PFS). Based on a previous report, we estimated the expected PFS as 9 months and the lower limit of interest as 5 months. As this research was designed to have a statistical power of 80% and one-sided type I error of 0.10, we calculated that 32 patients were required and planned enrolling 35 patients. The secondary endpoints were response rate (ORR), overall survival (OS), and adverse events (AEs). Results: Between 2017 January and 2018 March, 39 patients (17 male; 22 female), with a median age of 77.5 years (range: 70–88), ECOG performance status 0 (79.5%) or 1 (20.5%), and RAS WT/MT/Unknown 23.1/41.0/35.9% were enrolled. The median PFS
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Background: SALTO is a multi-center, open-label phase III trial in which 161 Western patients with metastatic colorectal cancer (mCRC) were randomized between capecitabine and S-1. The primary endpoint, a lower incidence of hand-foot syndrome (HFS) for S-1, was met (all grade 73% for capecitabine versus 45% for S-1, odds ratio 0.31 [95% confidence interval (CI) 0.16-0.60], p ¼ 0.0005; grade 3 21% for capecitabine versus 4% for S-1, p ¼ 0.003). There was no significant difference in median progressionfree survival (PFS), data on overall survival (OS) were immature. We here present updated results on survival. Methods: mCRC patients in whom first-line fluoropyrimidine monochemotherapy was indicated were randomized between capecitabine twice-daily on day 1 to 14 at a dose of 1250 mg/m2 for patients <70 years or 1000 mg/m2 for patients 70 years of age, or S-1 twice-daily on day 1 to 14 at a dose of 30 mg/m2, irrespective of age. Co-treatment with bevacizumab, 7.5 mg/kg intravenously on day 1, was optional. Cycles were repeated every 3 weeks. The primary endpoint was the incidence of HFS, secondary endpoints included PFS and OS. Results: A total of 161 patients were randomized between January 2014 - July 2015, 81 in the capecitabine group and 80 in the S-1 group. Bevacizumab was administered to 59% of patients in both arms. At data cut-off (6 August 2018, median follow-up 40.3 months), 71 (88%) patients in the capecitabine group and 68 (85%) patients in the S-1 group had died. Median PFS was 8.2 months (95% CI 6.4-10.3) for capecitabine and 8.4 months (95% CI 6.4-10.6) for S-1 (HR 1.02, 95% CI 0.75-1.40, p ¼ 0.89). Median OS was 17.1 months (95% CI 14.3-23.5) and 17.0 months (13.0-20.1), respectively (HR 1.07, 95% CI 0.76-1.49, p ¼ 0.70). Conclusions: This study demonstrated a significantly lower incidence of HFS for S-1 compared to capecitabine in Western mCRC patients. Although the study was not powered to demonstrate non-inferiority, these data suggest comparable efficacy of S-1 and capecitabine in terms of PFS and OS. Clinical trial identification: NCT01918852. Legal entity responsible for the study: Dutch Colorectal Cancer Group. Funding: Nordic Pharma. Disclosure: J.J. Kwakman: Honoraria (self), Research grant / Funding (institution): Nordic
Annals of Oncology
abstracts
Annals of Oncology
Pharmaceutical; Speaker Bureau / Expert testimony: Chugai Pharmaceutical; Speaker Bureau / Expert testimony: Taiho Pharmaceutical; Speaker Bureau / Expert testimony: Takeda Pharmaceutical. M. Kotaka: Honoraria (self): Yakult Honsya; Honoraria (self): Chugai pharmaceutical. H. Baba: Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): Chugai pharmaceutical. M. Mori: Research grant / Funding (institution): Taiho Pharmaceutical Co, Ltd. All other authors have declared no conflicts of interest.
621P
Biweekly TAS-102 and bevacizumab as a third-line chemotherapy for metastatic colorectal cancer: A phase II multicenter clinical trial (TASCC4 study)
Y. Yoshida1, T. Yamada2, H. Matsuoka3, K. Hirata4, H. Kuramochi5, C. Kosugi6, M. Takahashi7, A. Fukazawa8, H. Sonoda9, A. Matsuda10, T. Watanabe11, M. Koizumi12, N. Aisu1, S. Hasegawa1, H. Yoshida2, K. Sakamoto7, H. Ishida13, K. Koda6 1 Gastroenterological Surgery, Fukuoka University School of Medicine, Fukuoka, Japan, 2 Department of Gastroenterological Surgery, Nippon Medical University, Tokyo, Japan, 3 Surgery, Fujita Health University, Toyoake, Japan, 4Department of Surgery 1, University of Occupational & Environmental Health, Fukuoka, Japan, 5Department of Chemotherapy and Palliative Care, Tokyo Women’s Medical University Yachiyo Medical Center, Chiba, Japan, 6Department of Surgery, Teikyo University Chiba Comprehensive Medical Center, Chiba, Japan, 7Department of Coloproctological Surgery, Juntendo University School of Medicine, Tokyo, Japan, 8Gastroenterological Surgery, Iwata City Hospital, Shizuoka, Japan, 9Department of Gastroenterological Surgery, Shiga Medical University, Shiga, Japan, 10Surgery, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan, 11Third Department of Internal Medicine, University of Occupational & Environmental Health, Fukuoka, Japan, 12Digestive Surgery, Nippon Medical School Hospital, Tokyo, Japan, 13Department of Digestive Tract and General Surgery, Saitama Medical University, Saitama, Japan Background: TAS-102 improved overall survival of metastatic colorectal cancer (mCRC) patients with median progression-free survival (PFS) of 2.0 months (RECOURSE trial). Subsequently, the combination of TAS-102 and bevacizumab (BV) has been shown to extend median PFS to 3.7 months (C-TASK FORCE). However, this study included patients with 2nd line and 3rd line chemotherapy. Furthermore, combination chemotherapy of TAS-102 plus BV was reportedly associated with grade 3 neutropenia in 72% of treated patients. This study was designed for patients being treated as 3rd line chemotherapy to investigate the clinical impact of this combination and whether neutropenia could be suppressed by altering the TAS-102 administration protocol (biweekly method). Methods: This phase II study was conducted in investigator-initiated, open-label, single-arm, multicenter manner in Japan. Eligible patients were 20-80 years old and had to have an ECOG performance status of 0 or 1; had confirmed unresectable mCRC with
histologically diagnosed adenocarcinoma; had previously administrated first- and second-line chemotherapy for mCRC and whose tumors were diagnosed as progression of disease (PD). TAS-102 (35 mg/ m2) was given orally twice daily on days 1 -5 and 15 -19 in a 4-weeks cycle, and BV (5 mg/ kg) was administered by intravenous infusion for 30 min in every 2 weeks. The primary endpoint was PFS, and the secondary endpoints were response rate (RR), disease control rate (DCR), overall survival (OS), and safety. This study was registered at the University Hospital Medical Information Network, as UMIN#000030030. Results: Between January 1, 2018, and March 31, 2019, 45 patients with mCRC were enrolled in this study (median age, 63; male, 51%). The median PFS was 121 days. The RR and DCR were 4.4% and 73.3%, respectively. Grade 3 or higher adverse events were hypertension (20.0%), neutropenia (15.5 %), leukopenia (6.7 %), fatigue (6.7 %), anemia (4.4 %), anorexia (2.2 %), nausea (2.2 %), creatinine increased (2.2 %) and proteinuria (2.2 %). No treatment-related deaths occurred. Conclusions: Biweekly administration of TAS-102 and BV prevents neutropenia and could be one of the treatment options for 3rd line chemotherapy for mCRC. Clinical trial identification: UMIN000030030. 2018/March/01. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
622P
Liquid biopsy concordance based on clonality and timing of testing in patients with metastatic colorectal cancer
P.M. Kasi1, S. Kamatham2, F. Shahjehan2, Z. Li3, P.W. Johnson3, A. Merchea4, D.T. Colibaseanu4 1 Hematology/Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA, 2Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA, 3 Biostatistics, Mayo Clinic, Jacksonville, FL, USA, 4Colorectal Surgery, Mayo Clinic, Jacksonville, FL, USA Background: The most recent consensus statement on the use of liquid biopsies (circulating tumor DNA – ctDNA testing) has been that it is not yet ready for prime time. However, in patients with metastatic colorectal cancer (mCRC), there is significantly more ‘shedding’ of DNA detectable in blood allowing this test to be of value. We aimed at reporting the concordance of liquid biopsies based on clonality and timing of testing in patients with mCRC. Methods: A total of 92 mCRC patients were identified who had both a commercially available liquid and tissue next generation sequencing assay done from December 2016 to February 2019. Arbitrarily, mutations were classified as clonal or subclonal based on the 50% cutoff of the highest variant allele frequency (VAF) reported. Concordance rates, including clonal (BRAF-V600E/ RAS), subclonal and amplification concordance were calculated separately for patients for whom the liquid biopsy testing was done before initiation of treatment (n ¼ 27) and after initiation of treatment (n ¼ 65). Results: Clonal concordance rates were 96.3% for patients when the liquid biopsy was done before initiation of treatment versus 64.6% for patients when the test was obtained after they were already on some systemic therapy (p value: 0.001). Similarly, subclonal and amplification concordance rates for patients in the test before treatment and test after treatment groups are summarized in the table. Moreover, the median of highest VAF% was noted to be 3.1% and 1.1% in test before treatment and test after treatment groups respectively (p value: 0.092). Conclusions: Liquid biopsies show a very high concordance rate in patients with metastatic colorectal cancer. It is important to take the timing of the assay into consideration alongside relevant clonal mutations while assessing the concordance of liquid biopsies, not just for mCRC but for other malignancies.
Table: 622P Summary of concordance rates by timing of liquid biopsy test
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was 8.0 months (80% CI 6.7–11.2), and the median OS was not reached. The best response was 40.5% (15/37; 95% CI: 24.8–57.9), and the disease control rate was 86.5% (32/37; 95% CI: 71.2–95.5). The most frequently occurring grade 3 or 4 AEs were neutropenia (71.8%), leucopenia (48.7%), hypertension (20.5%), anemia (17.9%), anorexia (12.8%), febrile neutropenia (10.3%), and fatigue (10.3%). No treatment-related deaths occurred. Conclusions: In this Phase 2 KSCC 1602 trial of bevacizumab plus FTD/TPI, the primary endpoint of PFS was achieved. This combination therapy showed favorable survival outcomes with an acceptable safety profile for elderly patients with previously untreated metastatic colorectal cancer. Clinical trial identification: UMIN000025241. Legal entity responsible for the study: Kyushu Study group of Clinical Cancer. Funding: Taho Pharmaceutical. Disclosure: A. Makiyama: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lily
Pharma; Advisory / Consultancy, Research grant / Funding (institution): Servier. R. van Alphen: Advisory / Consultancy: Nordic Pharma; Travel / Accommodation / Expenses: Roche. C.J.A. Punt: Advisory / Consultancy: Nordic Pharma; Advisory / Consultancy: Servier. All other authors have declared no conflicts of interest.
Results: From Jan to Sep 2018, 102 pts were enrolled, and 98 pts fulfilled the eligibility (49 pts in each). Baseline characteristics of RAS wild-type vs. mutant were follows; median age, 65 vs. 64 years: male, 51% vs. 59%: ECOG PS 0, 69% vs. 59%: left-sided primary, 84% vs. 67%: number of metastasis of > 2, 71% vs. 74%: median time from diagnosis of metastasis, 32.9 vs 21.2 months. The DCR in RAS wild-type was 65.3% (90% CI: 52.6-76.5%, p ¼ 0.0022), while that in RAS mutant was 55.1% (90% CI: 42.467.3%, p ¼ 0.0780). There was not a statistically significant difference in DCR between RAS wild-type and mutant after adjustment of baseline characteristics (adjusted odds ratio¼0.48, 90% CI: 0.21-1.10, p ¼ 0.1435). Partial response was observed only in three pts with RAS wild-type. There were neither unexpected safety signals nor treatment related death. Conclusions: FTD/TPI plus BEV showed a promising activity with an acceptable safety profile for previously treated mCRC harboring either RAS wild-type or mutant. Survival outcome will be presented at the meeting. Legal entity responsible for the study: Japanese Fondation for Multidisciplinary Treatment of Cancer (JFMC). Funding: Japanese Fondation for Multidisciplinary Treatment of Cancer (JFMC). Disclosure: M. Nakamura: Honoraria (self): Taiho Yakuhin; Honoraria (self): Daiichi Sankyo; Honoraria (self): Chugai Seiyaku; Honoraria (self): Merck. A. Makiyama: Advisory / Consultancy: Eli Lily Pharm; Speaker Bureau / Expert testimony: Chugai Pharm; Speaker Bureau / Expert testimony: Eli Lily Pharm; Speaker Bureau / Expert testimony: Taiho Pharm; Speaker Bureau / Expert testimony: Takeda Pharm. K. Oba: Honoraria (self): Chugai Pharm; Honoraria (self): Novartis Pharm; Honoraria (self): Takeda Pharm; Honoraria (self): BMS; Honoraria (self): Pfizer; Honoraria (self): Tsumura Pharm. T. Yoshino: Research grant / Funding (self): Novartis Pharma; Research grant / Funding (self): MSD; Research grant / Funding (self): Sumitomo Dainippon Pharma; Research grant / Funding (self): Chugai Pharmaceutical; Research grant / Funding (self): Sanofi; Research grant / Funding (self): Daiichi Sankyo Company; Research grant / Funding (self): Parexel; Research grant / Funding (self): Ono Pharmaceutical. K. Yoshida: Research grant / Funding (self): Chugai Pharma; Research grant / Funding (self): Lilly; Research grant / Funding (self): MSD; Research grant / Funding (self): Ono Pharma; Honoraria (self): EA Pharma; Honoraria (self): Johnson & Johnson; Honoraria (self): SBI Pharma; Honoraria (self): Olympus; Honoraria (self): Covidien; Honoraria (self): Sanofi; Honoraria (self): TERUMO; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Tsumura; Honoraria (self): Asahi Kasei; Honoraria (self): Pharma International Osaka; Honoraria (self): Daiichi Sankyo; Honoraria (self): Chugai; Honoraria (self): Lilly; Honoraria (self): Takeda; Honoraria (self): Yakult Honsha. K. Yamazaki: Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Chugai. E. Oki: Speaker Bureau / Expert testimony: Taiho Pharm; Speaker Bureau / Expert testimony: Chugai Pharm. T. Takahashi: Speaker Bureau / Expert testimony: Taiho Pharm; Speaker Bureau / Expert testimony: Chugai Pharm. All other authors have declared no conflicts of interest.
620P 619P
JFMC51-1702-C7: Phase II study investigating efficacy and safety of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) in patients (pts) with metastatic colorectal cancer (mCRC) refractory or intolerant to standard chemotherapies
K. Kazama1, M. Nakamura2, R. Tanaka3, H. Ojima4, A. Makiyama5, N. Matsuhashi6, Y. Kagawa7, H. Okuda8, M. Asayama9, Y. Yuasa10, Y. Negoro11, H. Mushiake12, D. Manaka13, K. Oba14, T. Yoshino15, K. Yoshida16, Y. Maehara17, K. Yamazaki18, E. Oki19, T. Takahashi16 1 Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan, 2 Gastroenterology, Sapporo City General Hospital, Sapporo, Japan, 3Medical Oncology, Hamanomachi Hospital, Fukuoka, Japan, 4Gastroenterological Surgery, Gunma Prefectural Cancer Center, Ota, Japan, 5Hematology/Oncology, National Kyushu Cancer Center, Fukuoka, Japan, 6Surgical Oncology, Gifu University, Gifu, Japan, 7 Department of Surgery, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan, 8 Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan, 9Gastroenterology Department, Saitama Cancer Center, Ina, Japan, 10Gastrointestinal Surgery, Tokushima Red Cross Hospital, Tokushima, Japan, 11Gastroenterological Medicine & Oncology, Kochi Health Sciences Center, Kochi, Japan, 12Gastroenterological Center, Teikyo University School of Medicine, Tokyo, Japan, 13Department of Surgery, Gastro-Intestinal Center, Kyoto-Katsura Hospital, Kyoto, Japan, 14Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 15 Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan, 16Surgical Oncology, Gifu University Hospital, Gifu, Japan, 17Surgical Oncology, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan, 18Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan, 19Surgery and Science, National Kyushu Cancer Center, Fukuoka, Japan Background: Combination treatment of FTD/TPI plus BEV in the C-TASK FORCE showed a promising activity in pts with mCRC refractory or intolerant to standard chemotherapies; however, due to the small sample size, it remains unclear if this combination works in the same way; RAS wild-type or mutant. We investigated the efficacy and safety of this combination in separate cohorts of RAS wild-type and mutant. Methods: mCRC pts refractory or intolerant to prior treatments with fluoropyrimidines, irinotecan, oxaliplatin, an angiogenesis inhibitor, and an anti-EGFR antibody if RAS wild-type, and without FTD/TPI and regorafenib. Pts received FTD/TPI (35 mg/ m2, twice daily, days 1 to 5 and 8 to 12) and BEV (5mg/kg, day1 and 15) every four weeks. The primary endpoint was disease control rate (DCR). A threshold and expected value of the DCR in each wild-type and mutant were set as 44% and 65%, respectively. Assuming a one-sided significance level of 5.0%, each target sample size was estimated to be 49 to achieve a power of 90%.
v234 | Gastrointestinal Tumours, Colorectal
Bevacizumab plus trifluridine/tipiracil in elderly patients with previously untreated metastatic colorectal cancer (KSCC 1602): A single-arm, phase II study
A. Makiyama1, E. Oki2, Y. Miyamoto3, M. Kotaka4, H. Kawanaka5, K. Miwa6, A. Kabashima7, T. Noguchi8, K. Yuge9, T. Kashiwada10, M. Shimokawa11, H. Saeki12, Y. Akagi13, H. Baba14, M. Mori15 1 Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushu, Japan, 2Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 3Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan, 4Surgery, Sano Hospital-Gastrointestinal Cancer Center, Kobe, Japan, 5Clinical Research Institute and Department of Surgery, National Hospital Organization Beppu Medical Center, Beppu, Japan, 6Mutidisciplinary Treatment Cancer Center, Kurume University Hospital, Kurume, Japan, 7Department of Surgery, Oita Medical Center, Oita, Japan, 8Department of Surgery, Imakiire General Hospital, Kagoshima, Japan, 9 Department of Surgery, Social Insurance Tagawa Hospital, Tagawa, Japan, 10Medical Oncology, Saga Univ Facilty of Medicine-Nabeshima, Saga, Japan, 11Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Ube, Japan, 12General Surgical Science, Gunma University, Maebashi, Japan, 13Surgery, Kurume University, Kurume, Japan, 14Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, Kumamoto, Japan, 15Surgery and Science, Kyushu University, Fukuoka, Japan Background: Elderly patients often cannot tolerate the usual combination of two cytotoxic agents. Recently, bevacizumab plus trifluridine/tipiracil (FTD/TPI) was shown to be a good candidate regimen for vulnerable patients. We aimed to assess the efficacy and safety of bevacizumab plus FTD/TPI in elderly patients with metastatic colorectal cancer. Methods: Patients aged 70 years or older, with previously untreated unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were included in this trial. The treatment consisted of FTD/TPI (35 mg/m2, twice daily on Days 1–5 and Days 8–12) with bevacizumab (5mg/kg intravenously on Day 1 and 15), administrated every 4 weeks until disease progression. The primary endpoint was progression-free survival (PFS). Based on a previous report, we estimated the expected PFS as 9 months and the lower limit of interest as 5 months. As this research was designed to have a statistical power of 80% and one-sided type I error of 0.10, we calculated that 32 patients were required and planned enrolling 35 patients. The secondary endpoints were response rate (ORR), overall survival (OS), and adverse events (AEs). Results: Between 2017 January and 2018 March, 39 patients (17 male; 22 female), with a median age of 77.5 years (range: 70–88), ECOG performance status 0 (79.5%) or 1 (20.5%), and RAS WT/MT/Unknown 23.1/41.0/35.9% were enrolled. The median PFS
Volume 30 | Supplement 5 | October 2019
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Background: SALTO is a multi-center, open-label phase III trial in which 161 Western patients with metastatic colorectal cancer (mCRC) were randomized between capecitabine and S-1. The primary endpoint, a lower incidence of hand-foot syndrome (HFS) for S-1, was met (all grade 73% for capecitabine versus 45% for S-1, odds ratio 0.31 [95% confidence interval (CI) 0.16-0.60], p ¼ 0.0005; grade 3 21% for capecitabine versus 4% for S-1, p ¼ 0.003). There was no significant difference in median progressionfree survival (PFS), data on overall survival (OS) were immature. We here present updated results on survival. Methods: mCRC patients in whom first-line fluoropyrimidine monochemotherapy was indicated were randomized between capecitabine twice-daily on day 1 to 14 at a dose of 1250 mg/m2 for patients <70 years or 1000 mg/m2 for patients 70 years of age, or S-1 twice-daily on day 1 to 14 at a dose of 30 mg/m2, irrespective of age. Co-treatment with bevacizumab, 7.5 mg/kg intravenously on day 1, was optional. Cycles were repeated every 3 weeks. The primary endpoint was the incidence of HFS, secondary endpoints included PFS and OS. Results: A total of 161 patients were randomized between January 2014 - July 2015, 81 in the capecitabine group and 80 in the S-1 group. Bevacizumab was administered to 59% of patients in both arms. At data cut-off (6 August 2018, median follow-up 40.3 months), 71 (88%) patients in the capecitabine group and 68 (85%) patients in the S-1 group had died. Median PFS was 8.2 months (95% CI 6.4-10.3) for capecitabine and 8.4 months (95% CI 6.4-10.6) for S-1 (HR 1.02, 95% CI 0.75-1.40, p ¼ 0.89). Median OS was 17.1 months (95% CI 14.3-23.5) and 17.0 months (13.0-20.1), respectively (HR 1.07, 95% CI 0.76-1.49, p ¼ 0.70). Conclusions: This study demonstrated a significantly lower incidence of HFS for S-1 compared to capecitabine in Western mCRC patients. Although the study was not powered to demonstrate non-inferiority, these data suggest comparable efficacy of S-1 and capecitabine in terms of PFS and OS. Clinical trial identification: NCT01918852. Legal entity responsible for the study: Dutch Colorectal Cancer Group. Funding: Nordic Pharma. Disclosure: J.J. Kwakman: Honoraria (self), Research grant / Funding (institution): Nordic
Annals of Oncology
abstracts
Annals of Oncology
Pharmaceutical; Speaker Bureau / Expert testimony: Chugai Pharmaceutical; Speaker Bureau / Expert testimony: Taiho Pharmaceutical; Speaker Bureau / Expert testimony: Takeda Pharmaceutical. M. Kotaka: Honoraria (self): Yakult Honsya; Honoraria (self): Chugai pharmaceutical. H. Baba: Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): Chugai pharmaceutical. M. Mori: Research grant / Funding (institution): Taiho Pharmaceutical Co, Ltd. All other authors have declared no conflicts of interest.
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Biweekly TAS-102 and bevacizumab as a third-line chemotherapy for metastatic colorectal cancer: A phase II multicenter clinical trial (TASCC4 study)
Y. Yoshida1, T. Yamada2, H. Matsuoka3, K. Hirata4, H. Kuramochi5, C. Kosugi6, M. Takahashi7, A. Fukazawa8, H. Sonoda9, A. Matsuda10, T. Watanabe11, M. Koizumi12, N. Aisu1, S. Hasegawa1, H. Yoshida2, K. Sakamoto7, H. Ishida13, K. Koda6 1 Gastroenterological Surgery, Fukuoka University School of Medicine, Fukuoka, Japan, 2 Department of Gastroenterological Surgery, Nippon Medical University, Tokyo, Japan, 3 Surgery, Fujita Health University, Toyoake, Japan, 4Department of Surgery 1, University of Occupational & Environmental Health, Fukuoka, Japan, 5Department of Chemotherapy and Palliative Care, Tokyo Women’s Medical University Yachiyo Medical Center, Chiba, Japan, 6Department of Surgery, Teikyo University Chiba Comprehensive Medical Center, Chiba, Japan, 7Department of Coloproctological Surgery, Juntendo University School of Medicine, Tokyo, Japan, 8Gastroenterological Surgery, Iwata City Hospital, Shizuoka, Japan, 9Department of Gastroenterological Surgery, Shiga Medical University, Shiga, Japan, 10Surgery, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan, 11Third Department of Internal Medicine, University of Occupational & Environmental Health, Fukuoka, Japan, 12Digestive Surgery, Nippon Medical School Hospital, Tokyo, Japan, 13Department of Digestive Tract and General Surgery, Saitama Medical University, Saitama, Japan Background: TAS-102 improved overall survival of metastatic colorectal cancer (mCRC) patients with median progression-free survival (PFS) of 2.0 months (RECOURSE trial). Subsequently, the combination of TAS-102 and bevacizumab (BV) has been shown to extend median PFS to 3.7 months (C-TASK FORCE). However, this study included patients with 2nd line and 3rd line chemotherapy. Furthermore, combination chemotherapy of TAS-102 plus BV was reportedly associated with grade 3 neutropenia in 72% of treated patients. This study was designed for patients being treated as 3rd line chemotherapy to investigate the clinical impact of this combination and whether neutropenia could be suppressed by altering the TAS-102 administration protocol (biweekly method). Methods: This phase II study was conducted in investigator-initiated, open-label, single-arm, multicenter manner in Japan. Eligible patients were 20-80 years old and had to have an ECOG performance status of 0 or 1; had confirmed unresectable mCRC with
histologically diagnosed adenocarcinoma; had previously administrated first- and second-line chemotherapy for mCRC and whose tumors were diagnosed as progression of disease (PD). TAS-102 (35 mg/ m2) was given orally twice daily on days 1 -5 and 15 -19 in a 4-weeks cycle, and BV (5 mg/ kg) was administered by intravenous infusion for 30 min in every 2 weeks. The primary endpoint was PFS, and the secondary endpoints were response rate (RR), disease control rate (DCR), overall survival (OS), and safety. This study was registered at the University Hospital Medical Information Network, as UMIN#000030030. Results: Between January 1, 2018, and March 31, 2019, 45 patients with mCRC were enrolled in this study (median age, 63; male, 51%). The median PFS was 121 days. The RR and DCR were 4.4% and 73.3%, respectively. Grade 3 or higher adverse events were hypertension (20.0%), neutropenia (15.5 %), leukopenia (6.7 %), fatigue (6.7 %), anemia (4.4 %), anorexia (2.2 %), nausea (2.2 %), creatinine increased (2.2 %) and proteinuria (2.2 %). No treatment-related deaths occurred. Conclusions: Biweekly administration of TAS-102 and BV prevents neutropenia and could be one of the treatment options for 3rd line chemotherapy for mCRC. Clinical trial identification: UMIN000030030. 2018/March/01. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
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Liquid biopsy concordance based on clonality and timing of testing in patients with metastatic colorectal cancer
P.M. Kasi1, S. Kamatham2, F. Shahjehan2, Z. Li3, P.W. Johnson3, A. Merchea4, D.T. Colibaseanu4 1 Hematology/Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA, 2Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA, 3 Biostatistics, Mayo Clinic, Jacksonville, FL, USA, 4Colorectal Surgery, Mayo Clinic, Jacksonville, FL, USA Background: The most recent consensus statement on the use of liquid biopsies (circulating tumor DNA – ctDNA testing) has been that it is not yet ready for prime time. However, in patients with metastatic colorectal cancer (mCRC), there is significantly more ‘shedding’ of DNA detectable in blood allowing this test to be of value. We aimed at reporting the concordance of liquid biopsies based on clonality and timing of testing in patients with mCRC. Methods: A total of 92 mCRC patients were identified who had both a commercially available liquid and tissue next generation sequencing assay done from December 2016 to February 2019. Arbitrarily, mutations were classified as clonal or subclonal based on the 50% cutoff of the highest variant allele frequency (VAF) reported. Concordance rates, including clonal (BRAF-V600E/ RAS), subclonal and amplification concordance were calculated separately for patients for whom the liquid biopsy testing was done before initiation of treatment (n ¼ 27) and after initiation of treatment (n ¼ 65). Results: Clonal concordance rates were 96.3% for patients when the liquid biopsy was done before initiation of treatment versus 64.6% for patients when the test was obtained after they were already on some systemic therapy (p value: 0.001). Similarly, subclonal and amplification concordance rates for patients in the test before treatment and test after treatment groups are summarized in the table. Moreover, the median of highest VAF% was noted to be 3.1% and 1.1% in test before treatment and test after treatment groups respectively (p value: 0.092). Conclusions: Liquid biopsies show a very high concordance rate in patients with metastatic colorectal cancer. It is important to take the timing of the assay into consideration alongside relevant clonal mutations while assessing the concordance of liquid biopsies, not just for mCRC but for other malignancies.
Table: 622P Summary of concordance rates by timing of liquid biopsy test
Volume 30 | Supplement 5 | October 2019
doi:10.1093/annonc/mdz246 | v235
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was 8.0 months (80% CI 6.7–11.2), and the median OS was not reached. The best response was 40.5% (15/37; 95% CI: 24.8–57.9), and the disease control rate was 86.5% (32/37; 95% CI: 71.2–95.5). The most frequently occurring grade 3 or 4 AEs were neutropenia (71.8%), leucopenia (48.7%), hypertension (20.5%), anemia (17.9%), anorexia (12.8%), febrile neutropenia (10.3%), and fatigue (10.3%). No treatment-related deaths occurred. Conclusions: In this Phase 2 KSCC 1602 trial of bevacizumab plus FTD/TPI, the primary endpoint of PFS was achieved. This combination therapy showed favorable survival outcomes with an acceptable safety profile for elderly patients with previously untreated metastatic colorectal cancer. Clinical trial identification: UMIN000025241. Legal entity responsible for the study: Kyushu Study group of Clinical Cancer. Funding: Taho Pharmaceutical. Disclosure: A. Makiyama: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lily