Expanded
mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC), and low mutant allele frequency (MAF) mutations are of unclear significance. ...We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive beads, emulsion, amplification, and magnetics (BEAMing) analysis, capable of detecting alterations below standard clinical assays.
CO.17 trial compared cetuximab versus best supportive care (BSC) in
-unselected mCRC. We performed
analysis on microdissected tissue of 242 patients in CO.17 trial using BEAMing for
(codons 12/13/59/61/117/146) and
V600E. Patients without BEAMing but with previous Sanger sequencing-detected mutations were included.
, and
mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival OS; HR, 0.51; 95% confidence interval (CI), 0.32-0.81;
= 0.004 and progression-free survival (PFS; HR, 0.25; 95% CI, 0.15-0.41;
< 0.0001) compared with BSC in
wild-type patients. Cetuximab did not improve OS/PFS for
, or
mutated tumors, and tests of interaction confirmed expanded
(
= 0.0002) and
(
= 0.006) as predictive, while
mutations were not (
= 0.089). BEAMing identified 14% more tumors as
mutant than Sanger sequencing, and cetuximab lacked activity in these patients. Mutations at MAF < 5% were noted in 6 of 242 patients (2%). One patient with a
A59T mutation (MAF = 2%) responded to cetuximab. More
than
mutations were low MAF (OR, 20.50; 95% CI, 3.88-96.85;
= 0.0038).
We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal
alterations are uncommon and remain of indeterminate significance.
FOLFIRINOX has been shown to significantly increase both overall survival (OS) and progression-free survival (PFS) in metastatic pancreas cancer. There is limited data regarding the treatment of ...locally advanced pancreatic cancer. We present a retrospective study of patients with both locally advanced and metastatic pancreas cancer using FOLFIRINOX as first-line therapy in our centre.
This is a retrospective review of patients treated with FOLFIRINOX for pancreatic cancer at Princess Margaret Cancer Centre, between December 2011 and July 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications.
One hundred two patients were identified; 66 metastatic and 36 locally advanced. Sixty-eight per cent of patients initiated treatment with a dose reduction. The median (95% CI) OS in the metastatic group was 13.1 (6.3-16.1) months with full dose and 12.9 (10.3-30.1) months with modified dose. The median (95% CI) OS in the locally advanced group was 11.1 (6.1-not reached) months with full dose and 23 (not reached-not reached) months with modified dose. The median (95% CI) PFS in the metastatic group was 6.2 (4.9-15.2) months with full dose and 8.7 (5.7-12.9) months with modified dose. The median (95% CI) PFS in the locally advanced group was 11.1 (3.1-not reached) months with full dose and 10.4 (6.8-not reached) months with modified dose. Grade 3/4 haematologic adverse events were observed in 43% of patients. Grade 3/4 non-haematologic adverse events were observed in 28% of patients. Patient well-being significantly improved from baseline to cycle 4 (P=0.002).
Efficacy was achievable with dose-modified FOLFIRINOX in daily setting. The safety of FOLFIRINOX remains a concern with a high rate of grades 3 and 4 neutropaenia despite dose reduction.
The time spent in pursuing treatments for advanced cancer can be substantial. We have previously proposed a pragmatic and patient-centered metric of these time costs-which we term time toxicity-as ...any day with physical health care system contact. This includes outpatient visits (eg, bloodwork, scans, etc), emergency department visits, and overnight stays in a health care facility. Herein, we sought to assess time toxicity in a completed randomized controlled trial (RCT).
We conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions versus supportive care alone in 572 patients with advanced colorectal cancer. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1
4.6 months). Subsequent analyses reported that benefit was restricted to patients with
wild-type tumors. We calculated patient-level time toxicity by analyzing trial forms. We considered days without health care contact as home days. We compared medians of time measures across arms and stratified results by
status.
In the overall population, median time toxic days were higher in the cetuximab arm (28
10,
< .001) although median home days were not statistically different between arms (140
121,
= .09). In patients with
-mutated tumors, cetuximab was associated with almost numerically equal home days (114 days
112 days,
= .571) and higher time toxicity (23 days
11 days,
< .001). In patients with
wild-type tumors, cetuximab was associated with more home days (186
132,
< .001).
This proof-of-concept feasibility study demonstrates that measures of time toxicity can be extracted through secondary analyses of RCTs. In CO.17, despite an overall OS benefit with cetuximab, home days were statistically similar across arms. Such data can supplement traditional survival end points in RCTs. Further work should refine and validate the measure prospectively.Media: see text.
Aims
Type 1 diabetes is characterised by the destruction of pancreatic β‐cells. Significant levels of β‐cells remain at diagnosis. Preserving these cells improves glucose control and protects from ...long‐term complications. We undertook a systematic review and meta‐analyses of all randomised controlled trials (RCTs) of interventions to preserve β‐cell function in people newly diagnosed with type 1 diabetes. This paper reports the results of interventions for improving glucose control to assess whether they preserve β‐cell function.
Methods
Searches for RCTs in MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov and WHO International Clinical Trials Registry. Eligible studies included newly diagnosed patients with type 1 diabetes, any intervention to improve glucose control and at least 1 month of follow‐up. Data were extracted using a pre‐defined data‐extraction sheet with 10% of extractions checked by a second reviewer.
Results
Twenty‐eight studies with 1662 participants were grouped by intervention into six subgroups (alternative insulins, subcutaneous and intravenous insulin delivery, intensive therapy, glucose sensing, adjuncts). Only three studies demonstrated an improvement in glucose control as well as β‐cell function. These interventions included intensive insulin therapy and use of an alternative insulin.
Conclusions
This is the largest comprehensive review of RCTs in this area. It demonstrates a lack of robust evidence that interventions to improve glucose control preserve β‐cell function in new onset type 1 diabetes, although analysis was hampered by low‐quality evidence and inconsistent reporting of studies. Development of guidelines to support the design of trials in this field is a priority.
Aflibercept is a recombinant fusion protein of the VEGF receptor (VEGFR) 1 and VEGFR2 extracellular domains. We assessed the safety and efficacy of aflibercept in patients with metastatic colorectal ...cancer (MCRC) who had received at least one prior palliative regimen.
Seventy-five patients were enrolled onto this two-stage phase II trial in two cohorts, bevacizumab naïve (n = 24) and prior bevacizumab (n = 51). Aflibercept was administered at 4 mg/kg i.v. in two-week cycles. The primary endpoint was a combination of objective response rate and 16-week progression-free survival (PFS).
In the bevacizumab-naïve cohort (n = 24), the best response was stable disease for 16 weeks or more in five of 24 patients. In the prior bevacizumab cohort (n = 50), one patient achieved a partial response and six patients had stable disease for 16 weeks or more. The median PFS in the bevacizumab-naïve and prior bevacizumab cohorts was two months 95% confidence interval (CI): 1.7-8.6 months and 2.4 months (95% CI: 1.9-3.7 months), respectively. Median overall survival (OS) was 10.4 months (95% CI: 7.6-15.5) and 8.5 months (95% CI: 6.2-10.6), respectively. The most common grade 3 or higher treatment-related adverse events were hypertension, proteinuria, fatigue, and headache. Ten patients discontinued study treatment due to toxicity. Mean free to VEGF-bound aflibercept ratio was 1.82, suggesting that free aflibercept was present in sufficient amount to bind endogenous VEGF.
Aflibercept showed limited single-agent activity in patients with pretreated MCRC with moderate toxicity. Further study of aflibercept with chemotherapy is ongoing.
Phase II trials are screening trials that seek to identify agents with sufficient activity to continue development and those for which further evaluation should be halted. Although definitive phase ...III trials use progression-free or overall survival to confirm clinical benefit, earlier endpoints are preferable for phase II trials. Traditionally, tumor shrinkage of a predetermined degree (response) has been used as a surrogate of eventual survival benefit based on the observation that high response rates (RR), and particularly complete responses, in the phase II setting resulted in survival benefit in subsequent phase III trials. Recently, some molecularly targeted agents have shown survival and clinical benefit despite very modest RRs in early clinical trials. These observations provide a major conundrum, with concerns of inappropriate termination of development for active agents with low RRs being balanced by concerns of inactive agents being taken to late-phase development with resultant increases in the failure rate of phase III trials. Numerous alternate or complementary endpoints have been explored, incorporating multinomial endpoints (including progression and response), progression-free survival, biomarkers, and, more recently, evaluation of tumor size as a continuous variable. In this review, we discuss the current status of phase II endpoints and present retrospective analyses of two international gastrointestinal cancer studies showing the potential utility of one novel approach. Alternate endpoints, although promising, require additional evaluation and prospective validation before their use as a primary endpoint for phase II trials.
Abstract Background Since 1981 Princess Margaret Hospital has used initial active surveillance (AS) with delayed treatment at relapse as the preferred management for all patients with clinical stage ...I nonseminomatous germ cell tumors (NSGCT). Objective Our aim was to report our overall AS experience and compare outcomes over different periods using this non–risk-adapted approach. Design, setting, and participants Three hundred and seventy-one patients with stage I NSGCT were managed by AS from 1981 to 2005. For analysis by time period, patients were divided into two cohorts by diagnosis date: initial cohort, 1981–1992 ( n = 157), and recent cohort, 1993–2005 ( n = 214). Intervention Patients were followed at regular intervals, and treatment was only given for relapse. Measurements Recurrence rates, time to relapse, risk factors for recurrence, disease-specific survival, and overall survival were determined. Results and limitations With a median follow-up of 6.3 yr, 104 patients (28%) relapsed: 53 of 157 (33.8%) in the initial group and 51 of 214 (23.8%) in the recent group. Median time to relapse was 7 mo. Lymphovascular invasion ( p < 0.0001) and pure embryonal carcinoma ( p = 0.02) were independent predictors of recurrence; 125 patients (33.7%) were designated as high risk based on the presence of one or both factors. In the initial cohort, 66 of 157 patients (42.0%) were high risk and 36 of 66 patients (54.5%) relapsed versus 17 of 91 low-risk patients (18.7%) ( p < 0.0001). In the recent cohort, 59 of 214 patients (27.6%) were high risk and 29 of 59 had a recurrence (49.2%) versus 22 of 155 low-risk patients (14.2%) ( p < 0.0001). Three patients (0.8%) died from testis cancer. The estimated 5-yr disease-specific survival was 99.3% in the initial group and 98.9% in the recent one. Conclusions Non–risk-adapted surveillance is an effective, simple strategy for the management of all stage I NSGCT.
With its potent inhibitory effects against Raf-1 kinase and vascular endothelial growth factor receptor-2, sorafenib is a novel oral anticancer agent targeting signal transduction and angiogenic ...pathways. This study is designed to combine sorafenib and gemcitabine due to their compatibility in preclinical models and nonoverlapping clinical toxicities.
An initial dose-escalation part of the study enrolled patients with advanced solid tumors, followed by an expanded cohort at the recommended dose for patients with advanced unresectable or metastatic pancreatic cancer. Sorafenib is administered continuously, whereas gemcitabine is given at 1,000 mg/m2 weekly x 7 followed by 1 rest week, then weekly x 3 every 4 weeks.
Forty-two patients have been enrolled overall, including 19 in the dose-escalation part and 23 in the extended pancreatic cancer cohort. Demographics were as follows: male-to-female ratio = 26:16; median age = 61 years (range 39-83 years); Eastern Cooperative Oncology Group performance status 0:1:2 ratio = 16:21:5. The recommended dose of this combination is sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2. The most frequent grade 3 or 4 adverse events of all causalities were thrombocytopenia (28.6%), lymphopenia (21.4%), lipase elevation (19%), neutropenia (16.7%), and fatigue (14.3%). Antitumor activity was observed in both groups, with 2 (10.5%) confirmed partial responses in ovarian cancer and 12 patients (63.2%) with disease stabilization in the dose-escalation part; 13 patients (56.5%) achieved disease stabilization in the pancreatic cohort. There was no consistent pharmacokinetic drug-to-drug interaction between sorafenib and gemcitabine.
Sorafenib and gemcitabine are well tolerated in combination; further evaluations in pancreatic and ovarian cancers are warranted.
Learning Objectives
After completing this course, the reader will be able to:
Describe the mechanisms of action of sorafenib.
Discuss the safety and toxicity data from phase I trials of sorafenib.
...Evaluate phase I and II trials of sorafenib with activity data.
Discuss future areas for research in the development of this drug.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single‐agent, dose‐escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum‐tolerated dose of 400 mg twice daily (bid). The most frequently reported drug‐related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand–foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal–related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non‐small cell lung cancer.
Disclosure of potential conflicts of interest is found at the end of this article.
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