An open-label multicenter phase II study of oral lapatinib (GW572016) as single agent, second-line therapy in patients with metastatic colorectal cancer
Anthony FieldsDavid RinaldiCharles HendersonColin GermondLuis ChuKimberli J. BrillL. LeopoldM. S. Berger
48
Citation
0
Reference
10
Related Paper
Citation Trend
Abstract:
3583 Background: Lapatinib is an orally active, reversible inhibitor of the tyrosine kinase activity of ErbB1 (EGFR) and ErbB2 (HER-2/neu). This multicenter, open-label, phase II study was designed to evaluate the safety and efficacy of single-agent lapatinib in patients with metastatic colorectal carcinoma, whose tumors progressed on first-line therapy with 5-fluorouracil in combination with irinotecan or oxaliplatin. Methods: Eighty-six (86) patients received 1250mg of oral lapatinib daily until disease progression or unacceptable toxicity. Safety and efficacy assessments were performed at 4-week and 8-week intervals respectively. Tumor response was determined by an independent review committee using RECIST guidelines. Results: The median age was 60 years (22–83) and median KPS was 90 (70–100). Patients were not selected based on ErbB expression; however, 54.2% and 44.1% of the patients had positive expression (+1, +2, +3) for ErbB1 and ErbB2, respectively. The most commonly encountered adverse events were: diarrhea (45% grade 1, 2, 5% grade 3), rash (33% grade 1, 2, 2% grade 3), fatigue (27% grade 1, 2, 2% grade 3), nausea (20% grade 1, 2, 1% grade 3), anorexia (16% grade 1, 2, 2% grade 3), and vomiting (14% grade 1, 2). In addition, 3 (3%) patients experienced a drug-related Grade 2 (≥20%) decrease in LVEF. All decreases in LVEF were asymptomatic and resolved within three weeks after discontinuation of lapatinib. One (1%) patient experienced a confirmed partial response; however, five patients experienced a minor response with cytoreduction of 20%, 22.4%, 22.8%, 26.8%, and 34% at week 8. Overall, five patients experienced clinical benefit with stable disease for ≥20 weeks. The median TTP and overall survival were 8 and 42.9 weeks respectively. Conclusions: Lapatinib was well tolerated, but demonstrated limited activity as second-line monotherapy in patients with recurrent metastatic colorectal cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKlineKeywords:
Lapatinib
Discontinuation
Lapatinib
Chordoma
Cite
Citations (137)
Regimen
Cite
Citations (18)
Purpose The standard of care for second-line therapy in patients with advanced pancreatic cancer after gemcitabine-based therapy is not clearly defined. The CONKO-003 phase III study reported a survival benefit with second-line fluorouracil (FU) and oxaliplatin using the oxaliplatin, folinic acid, and FU (OFF) regimen. 1 PANCREOX was a phase III multicenter trial to evaluate the benefit of FU and oxaliplatin administered as modified FOLFOX6 (mFOLFOX6; infusional fluorouracil, leucovorin, and oxaliplatin) versus infusional FU/leucovorin (LV) in this setting. Patients and Methods Patients with confirmed advanced pancreatic cancer who were previously treated with gemcitabine therapy and with an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. A total of 108 patients were randomly assigned to receive biweekly mFOLFOX6 or infusional FU/LV until progression. Progression-free survival (PFS) was the primary end point. Results Baseline patient characteristics were similar in both arms. No difference was observed in PFS (median, 3.1 months v 2.9 months; P = .99). Overall survival (OS) was inferior in patients assigned to mFOLFOX6 (median, 6.1 months v 9.9 months; P = .02). Increased toxicity was observed with the addition of oxaliplatin, with grade 3/4 adverse events occurring in 63% of patients who received mFOLFOX6 and 11% of those who received FU/LV. More patients in the mFOLFOX6 arm withdrew from study due to adverse events than in the FU/LV arm (20% v 2%), whereas the use of postprogression therapy was significantly higher in the FU/LV arm (25% v 7%; P = .015). No significant differences were observed in time to deterioration on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 global health scale. Conclusion No benefit was observed with the addition of oxaliplatin, administered as mFOLFOX6, versus infusional FU/LV in patients with advanced pancreatic cancer previously treated with first-line gemcitabine.
Folinic acid
Regimen
Clinical endpoint
Progression-free survival
Performance status
Cite
Citations (259)
Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35–40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m−2 (level 1) or 130 mg m−2 (level 2) on day 1, and S-1 (80–120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2–14), RR of 50% (1 CR and 13 PR: 95% CI 31–69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access.
Tolerability
Regimen
Cite
Citations (73)
Although several evidences have demonstrated a synergistic activity of 5-fluorouracil with irinotecan and oxaliplatin, thus explaining the use of this drug combination in the first-line treatment of advanced colorectal cancer, the need for the reintroduction of 5-FU in the second-line setting is more questionable.We retrospectively evaluated the outcome of patients developing progressive disease while on an infusional 5-FU-based front-line chemotherapy and subsequently treated with one of the four following chemotherapy regimens: irinotecan, oxaliplatin and irinotecan or oxaliplatin both combined with the de Gramont schedule (LV5-FU2).225 patients (137 males and 88 females), were eligible for analysis. Second-line chemotherapy consisted of irinotecan in 79 patients (35%, group A), oxaliplatin in 47 patients (21%, group B), irinotecan with LV5-FU2 in 53 patients (24%, group C) and oxaliplatin with LV5-FU2 in the remaining 46 cases (20%, group D). The response rate to second-line chemotherapy was obtained in 6/79 patients (8%) in group A, in 4/47 patients (9%) in group B, in 11/53 patients (21%) in group C and in 10/46 patients (22%) in group D (p = 0.04).These data suggest that reintroduction of 5-FU could increase irinotecan and oxaliplatin activity in patients progressing during a 5-FU-based first-line chemotherapy.
Refractory (planetary science)
Cite
Citations (4)
TPS189 Background: PD-L1 is frequently overexpressed in esophageal cancer. Pembrolizumab is a humanized monoclonal antibody that targets the PD-1 receptor and blocks interaction with PD-L1 and PD-L2. In the multicohort, phase Ib KEYNOTE-028 trial, pembrolizumab showed manageable toxicity, a 30.4% ORR, and median duration of response of 40 wk in 23 patients (pts) with PD-L1 + advanced esophageal cancer. The single-arm, multicenter phase II KEYNOTE-180 trial is designed to further evaluate pembrolizumab as a monotherapy in pts with previously treated advanced/metastatic esophageal cancer. Methods: Key eligibility criteria include age ≥ 18 y, advanced/metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type I adenocarcinoma of the esophagogastric junction (EGJ), measurable disease, documented progression during or after 2 prior lines of therapy, ECOG PS 0-1, no active autoimmune disease or brain metastases, and provision of a tumor sample for retrospective biomarker analysis. Pts with metastatic Siewert type I EGJ adenocarcinoma must have known HER2 status and, if HER2 + , must have documented progression on treatment containing trastuzumab. Eligible pts will receive pembrolizumab 200 mg Q3W for 35 cycles (~2 y) or until progression, unacceptable toxicity, or investigator or pt decision. Response will be assessed every 9 wk per RECIST v1.1 and RECIST adapted for immunotherapy response patterns. Treatment may be discontinued for pts who have a CR, and eligible pts may continue treatment beyond initial RECIST-defined progression. AEs will be assessed throughout treatment and for 30 d thereafter (up to 90 d for serious AEs) and graded per NCI CTCAE v4.0. Pts will be followed for survival every 9 wk. The primary efficacy end point is ORR per RECIST v1.1 by central review. Secondary end points include PFS, OS, and duration of response. Exploratory analyses include evaluation of immune-related gene expression profiles and PD-L1 expression status as predictors of pembrolizumab efficacy. Enrollment in KEYNOTE-180 is expected to begin in October 2015 and will continue until approximately 100 pts are enrolled.
Cite
Citations (7)
Although oxaliplatin (L-OHP) combined with infusional 5-fluorouracil (5-FU) and leucovorin (LV) is one of the standard chemotherapy regimens for metastatic or recurrent colorectal cancer, its introduction to Japan has been delayed. Phase I studies of L-OHP monotherapy in Japan showed no dose-limiting toxicity at the internationally recommended dose of 130 mg/m2 every 3 weeks, as well as no racial differences in pharmacokinetics as compared with Western subjects. This study aimed to clarify the efficacy and safety of L-OHP monotherapy in patients with metastatic colorectal cancer refractory to fluoropyrimidines.Patients with metastatic colorectal cancer who had failed to respond to fluoropyrimidine-based chemotherapy received L-OHP at a dose of 130 mg/m2 every 3 weeks.Sixty patients were enrolled. Two ineligible patients and one untreated patient were excluded from analysis. The median number of treatment cycles was 4 (range, 1-6). The overall response rate was 9% (5/57, 95% CI: 4-19%). The median time to progression was 2.7 months, and the median survival time was 11.1 months. Grade 3 major toxicity comprised thrombocytopenia (12%) and nausea (11%). There was no grade 4 toxicity. All patients experienced mild to moderate sensory neurotoxicity without functional impairment interfering with activities of daily living.The efficacy and toxicity of L-OHP in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines is apparently similar to those in Western patients.
Refractory (planetary science)
Cite
Citations (16)
Purpose:To investigate the efficacy of combined chemotherapy based on Oxaliplatin(OXA),Irinotecan(CPT-11)and fluorouracil(5-Fu),for treatment of relapse and metastatic colorectal cancer and its side-effects. Methods:25 cases of relapse and metastatic colorectal cancer by interventional arterial chemotherapy and iv drip,based on Oxaliplatin,Irinotecan and 5-Fu,CF,then after 2 cycles of treatment,the efficacy and clinical symptoms were evaluated. Results:After treatment,the terventional arterial group 1/15 achieved CR,9/15 achieved PR,the response rate was 66.7%. In the iv drip group 4/10 achieved PR,response rate was 40.0%,there was no significant difference between the two groups(P0.05),the overall response rate was 56.0% .Symptoms(18/25) related to cancer improved and side-reactions were tolerable. Conclusions:Treatment of relapse and metastatic colorectal cancer with combined chemotherapy based on oxaliplatin,irinotecan and 5-Fu by arterial intervention and iv drip is safe and effective,with only slight side-effects. This treatment can improve the symptoms and life quality of patients.
Cite
Citations (0)
Purpose: Five-fluorouracil (5-FU) is the basement drug of chemotherapy in patients with colorectal cancer. Recently, 5-FU and oxaliplatin or irinotecan is to be used by merging. This study investigated the chemosensitivity of 5-FU in patients with colorectal cancer, the additional effects of oxaliplatin or irinotecan to chemosensitivity when they are combined, and the effects of clinicopathologic factors to chemosensitivity. Methods: We performed in vitro chemosensitivity test for the fresh tumor tissue of 48 patients of colorectal cancer and evaluated the chemosensitivity to standard drugs (5-FU, 5-FU plus oxaliplatin: FOx, and 5-FU plus irinotecan: FIri) by using Histoculture drug response assay. Results: The average chemosensitiviy of FOx and FIri were significantly higher than that of 5-FU (32.3% and 36.0% vs. 21.8%, P<0.001). The chemosensitivity of FOx in the lymph node (LN) negative group was higher than LN positive group (35.3% vs. 19.3%, P=0.008). The group of under 70-year-old and the group of negative distant metastasis showed the trends of increased sensitivity to FOx (P=0.052, respectively). The chemosensitivity to FIri in the well or moderately differentiated group was significantly higher than the poorly differentiated goup (35.2% vs. 15.0%, P=0.038). Ki-67 positive group showed significantly increased chemosensitivity to FIri (P=0.021). Conclusion: This study demonstrates that combination of oxaliplatin or irinotecan to 5-FU can be more effective than 5-FU on in vitro chemosensitivity assay in colorectal cancer tissues. Oxaliplatin might be effective in LN negative group, and irinotecan might be effective in well differentiated group and Ki-67 positive group. Keywords: Anticancer drug sensitivity tests, Colorectal neoplasm, Fluorouracil, Oxaliplatin, Irinotecan
Chemosensitivity assay
Cite
Citations (0)
Trans-arterial chemoembolization (TACE) is a promising locoregional therapy for the treatment of primary hepatic tumors and liver metastases. The aim of the study was to define the activity and outcome of using DC Bead, drug-eluting bead, a spherical embolic device capable of being loaded with irinotecan.We conducted a double institutional, single arm, phase II clinical study to evaluate TACE adopting this device in 82 patients presenting with metastatic colorectal carcinoma to the liver after failing chemotherapy. The primary endpoints were tumor shrinkage, safety, feasibility, compliance, and overall survival. RECIST criteria were used to assess responses. Quality of life (QoL) was addressed using Edmonton SAS improvement scale.Out of 103 patients considered, 82 were enrolled and underwent a total of 185 treatments of TACE. The median number of TACE was 2.2 (1-4). A post-embolization syndrome was frequently observed. Adverse observed effects were: right upper quadrant pain (40%), fever (80%), nausea (27%) and increased transaminases (70%). The median follow-up was 29 months. Within one month after treatment, each patient received a computed tomograpic scan. It showed reduction of metastatic contrast enhancement in all patients. Responses were 78% at 3 months. After the first treatment, 75 out 82 patients declared an improvement of their well being lasting more than 18 weeks. The median duration of response was 6 (range 3-10) months; the median follow up was 29 (range 7-48) months. The median survival was 25 (range 6-34) months, with progression free survival at 8 (range 4-16) months.We suggest that TACE adopting DC Bead®, drug-eluting bead loaded with irinotecan could be proposed as palliative therapy for unresectable and chemotherapy resistant liver metastases from CRC.
Cite
Citations (86)