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- P. Pfeiffer
- D. Arnold
474O - Treatment outcome according to tumor RAS mutation status in TRICOLORE trial: A randomized phase 3 trial of S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment for metastatic colorectal cancer (ID 2652)
- Y. Komatsu
Abstract
Background
Combination therapy with oral fluoropyrimidine and irinotecan (CPT-11) has not yet been established as first-line treatment for metastatic colorectal cancer (mCRC). However, several studies of S-1 and CPT-11 plus bevacizumab (Bmab) combination therapy have shown promising efficacy in mCRC, suggesting the potential to replace mFOLFOX6 or CapeOX plus Bmab. We performed a randomized phase 3 trial to determine whether S-1 and CPT-11 plus Bmab is non-inferior or superior to mFOLFOX6 or CapeOX plus Bmab in terms of progression-free survival (PFS).
Methods
The TRICOLORE trial was a randomized, open-label, phase 3 trial. Chemotherapy-naïve patients with mCRC were randomized to receive either mFOLFOX6 or CapeOX plus Bmab (group A) or S-1 and CPT-11 plus Bmab (group B; 3-week regimen: 7.5 mg/kg Bmab, 150 mg/m2 CPT-11 on day 1, and 40 − 60 mg S-1 twice daily for 2 weeks, followed by a 1-week rest; or 4-week regimen: 5 mg/kg Bmab, 100 mg/m2 CPT-11 on days 1 and 15, and 40 − 60 mg S-1 twice daily for 2 weeks, followed by a 2-week rest). The primary endpoint was PFS. The non-inferiority margin was a hazard ratio (HR) of 1.25 based on the assumption of a median PFS of 11/12 months in group A/group B (power 0.85, 1-sided alpha 0.025). The primary tumor RAS status of patients consented to submit tissue sample were centrally analyzed.
Results
A total of 487 patients were enrolled from June 2012 to September 2014. Data were analyzed after confirming >374 events as planned. All demographic factors were well balanced. Median PFS was 10.8 months in group A and 14.0 months in group B (HR 0.85, 95% CI: 0.70–1.03, p < 0.001 for non-inferiority, p = 0.087 for superiority). The RAS mutation status was evaluable in 67.6%. In the RAS wild-type subgroup, median PFS was 11.6 months in group A and 15.9 months in group B. In the RAS mutant-type subgroup, median PFS was 9.3 months in group A and 11.3 months in group B.
Conclusions
S-1 and CPT-11 plus Bmab was non-inferior to mFOLFOX6 or CapeOX plus Bmab with respect to PFS and has now become a recommended 1st-line treatment for mCRC irrespective of RAS status.
Clinical trial identification
UMIN000007834 2012/05/11
Legal entity responsible for the study
The Tokyo Cooprative Oncology Group
Funding
The Tokyo Cooprative Oncology Group (with funding from Taiho)
Disclosure
Y. Komatsu: Other substantive relationships: Taiho Pharmaceutical, Lilly, MSD, Ono Pharmaceutical, Novartis, Chugai Pharma, Yakult, Merck Serono, Pfizer, Bayer. A. Takashima: Corporate-sponsored research: Taiho Pharmaceutical, Gilead Sciences, Merck Serono. M. Gamoh: Corporate-sponsored research: Taiho Pharmaceutical, Gilead Sciences, Merck Serono. H. Shimodaira: Corporate-sponsored research: Taiho, Eisai, Bayer. H. Baba: Advisory board or Board of directors: Taiho Pharmaceutical Co., Ltd.; corporate-sponsored research: Taiho Pharmaceutical Co., Ltd. C. Ishioka: Mochida, Kyowa-K, Eisai, Chugai, Tsumura, Novartis, Merck Serono, Daiichi Sankyo, Takeda, Nihon-Kayaku, Yakult, Taiho, Ono, Astellas, Asahi Kasei, Kissei, Bristol-Myers Squibb, Mochida, Chugai, Novartis, Lilly, Bayer. A. Sato: Advisory board or Board of directors: Taiho Pharmaceutical Co., Ltd. Chugai Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.; corporate-sponsored research: Taiho Pharmaceutical Co., Ltd.Chugai Pharma Co., Ltd. S. Yuki: Speakers’ bureau: Chugai Pharmaceutical, Eli Lilly Japan, Bayer Yakuhin, Takeda Pharmaceutical, Taiho Pharmaceutical, Merck Serono. S. Morita: Corporate-sponsored research: Taiho; honorarium: Taiho. All other authors have declared no conflicts of interest.
475O - mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer m(CRC): A randomized phase II VOLFI trial of the AIO (AIO-KRK0109) (ID 2996)
- M. Geissler
Abstract
Background
Triple chemotherapy with an anti-EGFR reported promising activity with some safety concerns in single arm phase II trials. The randomized VOLFI trial evaluated activity and safety of mFOLFOXIRI + panitumumab versus FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients.
Background
Triple chemotherapy with an anti-EGFR reported promising activity with some safety concerns in single arm phase II trials. The randomized VOLFI trial evaluated activity and safety of mFOLFOXIRI + panitumumab versus FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients.
Methods
Prospective 2:1 randomized, multi-center, phase II trial comparing mFOLFOXIRI (Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2, 5-FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + Panitumumab 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5-FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Cohort 1: irresectable mCRC; cohort 2: chance of secondary resection of metastatic lesions. Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), DCR, PFS, OS, toxicity, quality of life. Financially supported by an unrestricted grant from Amgen.
Methods
Prospective 2:1 randomized, multi-center, phase II trial comparing mFOLFOXIRI (Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2, 5-FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + Panitumumab 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5-FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Cohort 1: irresectable mCRC; cohort 2: chance of secondary resection of metastatic lesions. Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), DCR, PFS, OS, toxicity, quality of life. Financially supported by an unrestricted grant from Amgen.
Results
A total of 96 patients were randomized (63 arm A, 33 arm B). In arm A and B 20 (31.7%) and 11 (33.3%) patients belonged to cohort 2, respectively. ORR was 85.7% in arm A and 54.5% in arm B (p = 0.0013, OR 5.000; 95%-CI 1.870-13.370). DCR was 96.8% in arm A and 78.8% in arm B (p = 0.0071, OR 8.212). In arm A and B 53 (84,1%) and 25 (75.8%) tumors were left sided, 10 (15.9%) and 6 (18.2%) were located in the right colon, respectively. ORR in Arm A was 90.6% versus 60.0% (p = 0.0288, OR 6.400) and in Arm B 60.0% versus 50% (p=n.s.) for left and right located CRC, respectively. ORR between arms A and B comparing left and right sided CRC was 90.6% versus 60.0% (p = 0.0039, OR 6.400; 95%-CI 1.889-21.679) and 60.0% versus 50.0% (p= n.s.), respectively. Secondary resections in cohort 2 were 60% (n = 12) and 36.4% (n = 4) in arms A and B, respectively. Serious adverse advents grade 3-5 occured in 45.3% and 24.2% in arms A and B, respectively (p = 0.0496).
Conclusions
mFOLFOXIRI plus panitumumab results in significantly higher response rates compared to FOLFOXIRI in RAS wild-type mCRC. Response rates, however, are differential according to tumor sidedness. High secondary resection rates were observed. Toxicity is manageable in younger fit patients with ECOG 0-1. PFS, OS, QL and TR data are still immature and will be presented at the meeting.
Clinical trial identification
NCT01328171
Legal entity responsible for the study
AIO
Funding
Amgen
Disclosure
M. Geissler: Honoraria and advisory board from Amgen All other authors have declared no conflicts of interest.
Invited Discussant 474O and 475O (ID 5757)
- D. Arnold
476O - Neoadjuvant FOLFOX 4 versus FOLFOX 4 plus cetuximab versus immediate surgery for high-risk stage II and III colon cancers: A phase II multicentre randomised controlled trial (PRODIGE 22) (ID 1433)
- M. Karoui
Abstract
Background
Neoadjuvant chemotherapy has proven valuable in several tumors, but not in colon cancer (CC). The present randomized phase II trial addressed this issue in patients (pts) with locally advanced CC.
Methods
Pts with resectable CC deemed as high risk T3 (extramural tumor invasion > 5 mm), T4 and/or N2 (3 or more visible lymph nodes or 1 node >10mm diameter) on initial abdominopelvic CT-scan were randomized to either receive 6 months of adjuvant FOLFOX after colectomy (arm A control), or neoadjuvant FOLFOX for 4 cycles before surgery and 8 cycles after (arm B). In RAS wild-type pts a third arm testing peri-operative FOLFOX + cetuximab has been added prior to colectomy (arm C). The primary endpoint of the study was the rate of major pathological Tumor Regression Grade (TRG) as defined by Ryan centrally assessed by 2 pathologists blinded to the pts treatment. The secondary endpoints included toxicity, perioperative morbidity, carcinologic quality and completeness of the surgery. Analysis was by intention to treat.
Results
120 pts from 37 French centres were enrolled, 94% completed preoperative chemotherapy. All but 5 pts (disease progression n = 2, metastatic disease at inclusion n = 1, non resectable tumor n = 1, death n = 1) in the preoperative arms were resected. 95% and 98% of patients underwent R0 resection in the preoperative arms and control arm, respectively. No significant differences in severe postoperative morbidity rates (Dindo Grade >3) were seen between arm A (13.7%), B (8.2%) and C (14.3%) (p = 0.64). Major pathological responses (TRG 1-2) were observed in 7.7%, 44.2%, and 6.3% in arm A, B and C respectively (p < 0.001).
Conclusions
Preoperative FOLFOX for locally advanced resectable CC is feasible with acceptable toxicity/morbidity and high TRG. A phase III trial to establish whether these encouraging results translate into improved long-term oncological outcome is now warranted.
Clinical trial identification
NCT01675999
Legal entity responsible for the study
AP-HP
Funding
Merck, PHRC 2010
Disclosure
O. Bouche: Roche, Merck-Serono, Amgen, Lilly, Boehringer Ingelheim, Bayer J-F. Seitz: Merck, Sanofi. J. Taieb: Abbvie, Amgen, Baxalta, Celgene, Lilly, Merck, Roche. All other authors have declared no conflicts of interest.
477O - Bevacizumab (Bev) or cetuximab (Cet) plus chemotherapy after progression with bevacizumab plus chemotherapy in patients with wild-type (WT) KRAS metastatic colorectal cancer (mCRC): Final analysis of a French randomized, multicenter, phase II study (PRODIGE 18) (ID 893)
- J. Bennouna
Abstract
Background
Second-line treatment with chemotherapy plus Bev or Cet is now established as a valid option in mCRC. The main objective of this French multicenter, randomized open phase II trial, was to evaluate the Progression Free Survival (PFS) rate at 4 months with chemotherapy plus Bev or Cet in patients with disease progression after Bev plus chemotherapy.
Methods
The main eligibility criterion was disease progression after bevacizumab + 5-FU with irinotecan or oxaliplatin in patients with WT KRAS exon 2 mCRC. Patients were randomized in Arm A (FOLFIRI or mFOLFOX6 plus Bev) or in Arm B (FOLFIRI or mFOLFOX6 plus Cet); the chemotherapy doublet was chosen according to the first line (cross over). Analyses were performed in ITT population. They were repeated on the KRAS + NRAS WT population and in the triple negative population (KRAS, NRAS, and BRAF negative).
Results
From October 2010 to May 2015, 133 patients were included in 25 sites (1 patient ineligible): 85 males (64%), PS 0 (74, 56%), 1 (54, 41%), unknown (4, 3%). The 4-month PFS rate was 80.3% [95%CI (68.0% - 88.3%)] in Arm A and 66.7% [95%CI (53.6% - 76.8%)] in Arm B. Median PFS was 7.1 months in Arm A vs 5.6 months in Arm B (p = 0.060). Median OS reached 15.8 months in Arm A vs 10.4 months in Arm B (p = 0.073). Tumors samples were collected by a central laboratory and 95 were analysed using the KRAS/BRAF mutation analysis panel kit (KRAS exon 2,3,4 and BRAF V600E) and NRAS mutation detection kit (exons 2,3,4; Entrogen). On the whole, 81 patients were KRAS and NRAS WT (41 in Arm A and 40 in Arm B). Median PFS was respectively 7.8 months and 5.6 months in Arm A and Arm B (p = 0.076); median OS was 21.0 months in Arm A vs 10.7 months in arm B (p = 0.324). 73 were negative for the 3 genes (n = 36 and 37). Their median PFS were 8.2 months in Arm A) vs 5.7 months in arm B (p = 0.100). Median OS was 21.1 months vs 12.6 months (p = 0.365).
Conclusions
PRODIGE18 study is in favour of bevacizumab continuation beyond progression with chemotherapy cross over in WT RAS mCRC initially treated with first-line Bev plus chemotherapy.
Clinical trial identification
Clinical trial information:
Legal entity responsible for the study
UNICANCER
Funding
Roche
Disclosure
J. Bennouna: Advisory Board for Roche, Boehringer Ingelheim, AstraZeneca, Servier, BMS. S. Hiret: Roche, Boehringer Ingelheim, AstraZeneca. C. Borg: Roche, Sanofi, Servier. O. Bouche: Roche, Merck, Amgen, Lilly, Pierre Fabre, Boehringer Ingelheim, Novartis. E. Francois: Advisory Board: Roche, Merck. F. Ghiringhelli: Roche, Sanofi, Amgen, BMS. J-F. Seitz: Roche, Merck, Sanofi. P. Artru: Roche, Merck, Amgen. A. Adenis: Roche. All other authors have declared no conflicts of interest.
Invited Discussant 476O and 477O (ID 5758)
- R. Adams