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1.
Drug Saf ; 45(1): 45-64, 2022 01.
Article in English | MEDLINE | ID: mdl-34928484

ABSTRACT

INTRODUCTION: RELAY was a global, double-blind, placebo-controlled phase III study that demonstrated superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus placebo plus erlotinib (PBO + ERL) in the first-line treatment of patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) mutation-positive, metastatic non-small-cell lung cancer (NSCLC). OBJECTIVE: This article provides an in-depth analysis of the safety profile of RAM + ERL versus PBO + ERL observed in RELAY. METHODS: Eligible patients met these criteria: stage IV NSCLC; EGFR exon 19 deletion or exon 21 substitution (L858R) mutation; Eastern Cooperative Oncology Group performance status 0 or 1; and no central nervous system metastases. Patients were randomized (1:1) to receive erlotinib 150 mg/day orally plus either ramucirumab 10 mg/kg intravenously or matching placebo once every 2 weeks, until disease progression or unacceptable toxicity. The primary endpoint was PFS. Safety was evaluated based on reported treatment-emergent adverse events (AEs) and clinical laboratory assessments. RESULTS: The safety population comprised 446 patients (221 in RAM+ERL arm; 225 in PBO + ERL arm) who received at least one dose of study drug between January 2016 and February 2018. The overall incidence of grade ≥ 3 AEs was higher with RAM + ERL than with PBO + ERL, primarily driven by grade 3 hypertension. Grade ≥ 3 dermatitis acneiform and diarrhea were also reported more frequently in the RAM + ERL arm. The increased incidence of AEs with RAM + ERL was easily detected through routine monitoring and managed through dose adjustments and appropriate supportive care. CONCLUSION: This in-depth safety analysis from RELAY supports that RAM + ERL, irrespective of the increased incidence of AEs, does not affect a patient's ability to benefit from treatment. CLINICAL TRIAL REGISTRATION NUMBER: NCT02411448.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Erlotinib Hydrochloride/adverse effects , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Ramucirumab
2.
JTO Clin Res Rep ; 2(6): 100171, 2021 Jun.
Article in English | MEDLINE | ID: mdl-34590023

ABSTRACT

INTRODUCTION: The phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46-0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan. METHODS: Patients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing. RESULTS: The Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431-0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424-1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317-0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients). CONCLUSIONS: Clinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression.

3.
Clin Cancer Res ; 27(19): 5258-5271, 2021 10 01.
Article in English | MEDLINE | ID: mdl-34301751

ABSTRACT

PURPOSE: In EGFR-mutated metastatic non-small cell lung cancer (NSCLC), outcomes from EGFR tyrosine kinase inhibitors have differed historically by mutation type present, with lower benefit reported in patients with ex21L858R versus ex19del mutations. We investigated if EGFR-activating mutation subtypes impact treatment outcomes in the phase III RELAY study. Associations between EGFR mutation type and preexisting co-occurring and treatment-emergent genetic alterations were also explored. PATIENTS AND METHODS: Patients with metastatic NSCLC, an EGFR ex19del or ex21L858R mutation, and no central nervous system metastases were randomized (1:1) to erlotinib (150 mg/day) with either ramucirumab (10 mg/kg; RAM+ERL) or placebo (PBO+ERL), every 2 weeks, until RECIST v1.1-defined progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary and exploratory endpoints included overall response rate (ORR), duration of response (DOR), PFS2, time-to-chemotherapy (TTCT), safety, and next-generation sequencing analyses. RESULTS: Patients with ex19del and ex21L858R mutations had similar clinical characteristics and comutational profiles. One-year PFS rates for ex19del patients were 74% for RAM+ERL versus 54% for PBO+ERL; for ex21L858R rates were 70% (RAM+ERL) versus 47% (PBO+ERL). Similar treatment benefits (ORR, DOR, PFS2, and TTCT) were observed in RAM+ERL-treated patients with ex19del and ex21L858R. Baseline TP53 comutation was associated with superior outcomes for RAM+ERL in both ex19del and ex21L858R subgroups. EGFR T790M mutation rate at progression was similar between treatment arms and by mutation type. CONCLUSIONS: RAM+ERL provided significant clinical benefit for both EGFR ex19del and ex21L858R NSCLC, supporting this regimen as suitable for patients with either of these EGFR mutation types.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , Erlotinib Hydrochloride , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Protein Kinase Inhibitors/therapeutic use , Ramucirumab
4.
J Thorac Oncol ; 16(2): 205-215, 2021 02.
Article in English | MEDLINE | ID: mdl-33096270

ABSTRACT

The VEGF pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptors have been developed and approved for use in NSCLCs. Preclinical studies have found that the VEGF and EGFR pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs considerably improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improved progression-free survival in patients with TKI-naive EGFR-mutant NSCLC. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Drug Resistance, Neoplasm , ErbB Receptors/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Vascular Endothelial Growth Factor A
5.
Cancer Sci ; 111(12): 4510-4525, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32954593

ABSTRACT

In the global phase III RELAY study, ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) to placebo plus erlotinib (PL + ERL) in untreated patients with epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small-cell lung cancer (NSCLC) (hazard ratio (HR) [95% CI]: 0.59 [0.46-0.76]). This prespecified analysis assessed RAM + ERL efficacy and safety in the RELAY subset enrolled in East Asia (Japan, Taiwan, South Korea, Hong Kong). Randomized (1:1) patients received oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL Q2W. Primary endpoint was PFS (investigator-assessed). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety. Exploratory endpoints included biomarker analyses and time to second progression (PFS2). Median PFS was 19.4 vs 12.5 mo for RAM + ERL (n = 166) vs PL + ERL (n = 170) (HR: 0.636 [0.485-0.833]; P = .0009). The 1-y PFS rate was 72.4% vs 52.2%, respectively. PFS benefit was consistent in most subgroups, including by EGFR mutation (Ex19del, Ex21.L858R). ORR and DCR were similar in both arms, but median DoR was longer with RAM + ERL. OS and PFS2 were immature at data cut-off (censoring rates, 81.2%-84.3% and 64.1%-70.5%, respectively). Grade ≥ 3 treatment-emergent adverse events were more frequent with RAM + ERL (70.7%) than PL + ERL (49.4%). Adverse events leading to treatment discontinuation were similar in both arms (RAM + ERL, 13.3%; PL + ERL, 12.9%), as were post-progression EGFR T790M mutation rates (43%; 50%). With superior PFS over PL + ERL and safety consistent with the overall RELAY population, RAM + ERL is a viable treatment option for EGFR-mutated metastatic NSCLC in East Asia.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Erlotinib Hydrochloride/therapeutic use , Genes, erbB-1 , Lung Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain Neoplasms/secondary , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/secondary , Erlotinib Hydrochloride/adverse effects , Female , Hong Kong , Humans , Injections, Intravenous , Japan , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Male , Middle Aged , Mutation , Placebos/therapeutic use , Progression-Free Survival , Republic of Korea , Taiwan , Treatment Outcome , Ramucirumab
6.
Curr Med Res Opin ; 36(10): 1667-1675, 2020 10.
Article in English | MEDLINE | ID: mdl-32780643

ABSTRACT

OBJECTIVE: In the phase 3 RELAY trial, ramucirumab/erlotinib demonstrated superior progression-free survival (PFS) over placebo/erlotinib in patients with EGFR-mutated metastatic NSCLC (median PFS 19.4 versus 12.4 months; HR = 0.59, 95% CI = 0.46-0.76; p < .0001). Safety was consistent with established profiles for ramucirumab and erlotinib in NSCLC. Here, we present patient-reported outcomes. METHODS: Patients received oral erlotinib (150 mg daily) plus intravenous ramucirumab (10 mg/kg) or placebo Q2W until progressive disease or unacceptable toxicity. Patients completed the Lung Cancer Symptom Scale (LCSS) and EQ-5D questionnaires at baseline and every other cycle. Analyses included time to deterioration (TtD) for LCSS via Kaplan-Meier method and Cox models and changes from baseline using mixed-model repeated-measures regression analysis. RESULTS: Overall patient compliance for LCSS and EQ-5D was >95%. TtD did not differ between treatment arms for LCSS Total Score (HR = 0.962, 95% CI = 0.690-1.343) and Average Symptom Burden Index (HR = 1.012, 95% CI = 0.732-1.400). TtD of individual LCSS items (appetite loss, fatigue, cough, shortness of breath, pain, symptom distress, difficulties with daily activities, quality of life) indicated no difference between arms; however, patient-reported blood in sputum was worse for ramucirumab/erlotinib (HR = 1.987, 95% CI = 1.206-3.275). Results of LCSS mean changes from baseline were consistent with TtD, indicating no significant differences between treatment arms except for blood in sputum. Mean changes from baseline in EQ-5D index score (p = .94) and visual analogue scale (p = .95) revealed no overall differences in health status between treatment arms. CONCLUSIONS: Patients' overall quality of life and symptom burden did not differ with the addition of ramucirumab to erlotinib compared to placebo/erlotinib. These data support the clinical benefit of ramucirumab/erlotinib in untreated EGFR-mutated metastatic NSCLC.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Erlotinib Hydrochloride/therapeutic use , Lung Neoplasms/drug therapy , Mutation , Patient Reported Outcome Measures , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , Erlotinib Hydrochloride/administration & dosage , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Progression-Free Survival , Proportional Hazards Models , Quality of Life , Ramucirumab
7.
Lancet Oncol ; 20(12): 1655-1669, 2019 12.
Article in English | MEDLINE | ID: mdl-31591063

ABSTRACT

BACKGROUND: Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC. METHODS: This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up. FINDINGS: Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p<0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group. INTERPRETATION: Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC. FUNDING: Eli Lilly.


Subject(s)
Adenocarcinoma of Lung/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Mutation , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Aged , Antibodies, Monoclonal, Humanized , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Double-Blind Method , ErbB Receptors/genetics , Erlotinib Hydrochloride , Female , Follow-Up Studies , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Prognosis , Survival Rate , Ramucirumab
8.
Lung Cancer ; 137: 136-143, 2019 11.
Article in English | MEDLINE | ID: mdl-31586771

ABSTRACT

OBJECTIVES: Necitumumab, an anti-EGFR antibody, and abemaciclib, a CDK4/6 inhibitor, have shown activity in patients with non-small cell lung cancer (NSCLC) and have non-overlapping toxicities. A 2-part, single-arm, multicenter, phase 1b trial was conducted to test the safety and efficacy of necitumumab plus abemaciclib in patients with advanced NSCLC who had received ≤2 lines of chemotherapy, including a platinum-based one. MATERIALS AND METHODS: Part A was a dose-escalation phase for abemaciclib (100, 150, 200 mg, Q12 H) in combination with necitumumab 800 mg D1D8 Q3W to determine the recommended dose for the expansion cohort, Part B. The primary endpoint was progression-free survival (PFS) rate at 3 months. RESULTS: Sixty-six patients entered the study: 71% male, 41% squamous histology, 15% never-smokers. In Part A (n = 15), the maximum tolerated dose of abemaciclib was 150 mg Q12H in combination with necitumumab 800 mg. In 57 patients treated at this dose level, the 3-month PFS rate was 32.3% (95% CI: 20.4-44.8); median PFS was 2.14 months (1.41-2.76). The overall response rate (ORR) was 5.3% (1.1-14.6). The median OS was 6.93 months (4.96-12.85). In the exploratory subgroup analysis of EGFR expression-negative patients (n = 10), both the 3-month PFS and ORR were 0.0%. The most common grade 3 treatment-emergent adverse events were fatigue (14%), dyspnea (9%), diarrhea (7%), vomiting (7%), and hypokalemia (7%). CONCLUSIONS: Abemaciclib 150 mg Q12H with necitumumab 800 mg did not produce an additive effect over single-agent activity in patients with Stage IV NSCLC. The safety profile was consistent with the individual study drugs.


Subject(s)
Adenocarcinoma of Lung/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Lung Neoplasms/drug therapy , Adenocarcinoma of Lung/pathology , Adult , Aged , Aged, 80 and over , Aminopyridines/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Benzimidazoles/administration & dosage , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Female , Follow-Up Studies , Humans , Lung Neoplasms/pathology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Survival Rate , Tissue Distribution , Treatment Outcome
9.
J Clin Oncol ; 31(34): 4349-57, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24145346

ABSTRACT

PURPOSE: PointBreak (A Study of Pemetrexed, Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer) compared the efficacy and safety of pemetrexed (Pem) plus carboplatin (C) plus bevacizumab (Bev) followed by pemetrexed plus bevacizumab (PemCBev) with paclitaxel (Pac) plus carboplatin (C) plus bevacizumab (Bev) followed by bevacizumab (PacCBev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were randomly assigned to receive pemetrexed 500 mg/m(2) or paclitaxel 200 mg/m(2) combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles. Eligible patients received maintenance until disease progression: pemetrexed plus bevacizumab (for the PemCBev group) or bevacizumab (for the PacCBev group). The primary end point of this superiority study was overall survival (OS). RESULTS: Patients were randomly assigned to PemCBev (n = 472) or PacCBev (n = 467). For PemCBev versus PacCBev, OS hazard ratio (HR) was 1.00 (median OS, 12.6 v 13.4 months; P = .949); progression-free survival (PFS) HR was 0.83 (median PFS, 6.0 v 5.6 months; P = .012); overall response rate was 34.1% versus 33.0%; and disease control rate was 65.9% versus 69.8%. Significantly more study drug-related grade 3 or 4 anemia (14.5% v 2.7%), thrombocytopenia (23.3% v 5.6%), and fatigue (10.9% v 5.0%) occurred with PemCBev; significantly more grade 3 or 4 neutropenia (40.6% v 25.8%), febrile neutropenia (4.1% v 1.4%), sensory neuropathy (4.1% v 0%), and alopecia (grade 1 or 2; 36.8% v 6.6%) occurred with PacCBev. CONCLUSION: OS did not improve with the PemCBev regimen compared with the PacCBev regimen, although PFS was significantly improved with PemCBev. Toxicity profiles differed; both regimens demonstrated tolerability.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Drug Administration Schedule , Female , Glutamates/administration & dosage , Guanine/administration & dosage , Guanine/analogs & derivatives , Humans , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Pemetrexed , Proportional Hazards Models , Time Factors , Treatment Outcome , United States
10.
Lung Cancer ; 81(3): 428-434, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23790468

ABSTRACT

OBJECTIVES: The aim was to determine if combined pemetrexed, cisplatin, and cetuximab was efficacious and safe as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In this single-arm, multicenter clinical trial, patients with Stage IIIB/IV nonsquamous NSCLC received first-line therapy consisting of pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on Day 1 (21-day cycles) plus weekly cetuximab (400 mg/m(2) loading dose, then 250 mg/m(2)) for 4-6 cycles. Non-progressing patients received maintenance therapy consisting of pemetrexed and cetuximab as above until disease progression. All patients received vitamin supplementation, dexamethasone, and antihistamine prophylaxis. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), 1-year survival rate, translational research (TR) and safety. RESULTS: Of the 113 patients receiving study drug, 109 were protocol-qualified. All patients completed ≥1 cycle of induction, and 51 (45%) and 49 (43%) patients completed ≥1 cycle of maintenance with pemetrexed and cetuximab, respectively. The ORR (n = 109) was 38.5% (80% confidence interval [CI], 32.3-45.1%), all partial responses. Median PFS was 5.8 (80% CI, 4.4-6.7) months. One-year survival rate was 45% (80% CI, 39-51%). In exploratory analyses, there was some preliminary evidence of potential prognostic relationships with efficacy outcomes for epidermal growth factor receptor and thyroid transcription factor-1 protein expression, but not for KRAS mutation or for thymidylate synthase or folate receptor-alpha protein expression. Seventy-three (64.6%) patients had study drug-related Grade 3/4 adverse events (AEs). Drug-related serious AEs were reported in 31 (27.4%) patients. There were 3 (2.7%) potentially drug-related deaths on-study or within 30 days of follow up. CONCLUSION: Pemetrexed, cisplatin, and cetuximab appeared efficacious and tolerable in advanced nonsquamous NSCLC patients. The TR outcomes are hypothesis-generating given the study's size and nonrandomized nature.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/mortality , Cetuximab , Cisplatin/administration & dosage , Female , Glutamates/administration & dosage , Guanine/administration & dosage , Guanine/analogs & derivatives , Humans , Induction Chemotherapy , Lung Neoplasms/mortality , Maintenance Chemotherapy , Male , Middle Aged , Neoplasm Staging , Pemetrexed , Translational Research, Biomedical , Treatment Outcome
11.
PLoS One ; 8(6): e65371, 2013.
Article in English | MEDLINE | ID: mdl-23785422

ABSTRACT

Alterations in function of the neurotrophin BDNF are associated with neurodegeneration, cognitive decline, and psychiatric disorders. BDNF promotes axonal outgrowth and branching, regulates dendritic tree morphology and is important for axonal regeneration after injury, responses that largely result from activation of its tyrosine kinase receptor TrkB. Although intracellular neurotrophin (NT) signaling presumably reflects the combined action of kinases and phosphatases, little is known about the contributions of the latter to TrkB regulation. The issue is complicated by the fact that phosphatases belong to multiple independently evolved families, which are rarely studied together. We undertook a loss-of-function RNA-interference-based screen of virtually all known (254) human phosphatases to understand their function in BDNF/TrkB-mediated neurite outgrowth in differentiated SH-SY5Y cells. This approach identified phosphatases from diverse families, which either positively or negatively modulate BDNF-TrkB-mediated neurite outgrowth, and most of which have little or no previously established function related to NT signaling. "Classical" protein tyrosine phosphatases (PTPs) accounted for 13% of the candidate regulatory phosphatases. The top classical PTP identified as a negative regulator of BDNF-TrkB-mediated neurite outgrowth was PTPN12 (also called PTP-PEST). Validation and follow-up studies showed that endogenous PTPN12 antagonizes tyrosine phosphorylation of TrkB itself, and the downstream activation of ERK1/2. We also found PTPN12 to negatively regulate phosphorylation of p130cas and FAK, proteins with previously described functions related to cell motility and growth cone behavior. Our data provide the first comprehensive survey of phosphatase function in NT signaling and neurite outgrowth. They reveal the complexity of phosphatase control, with several evolutionarily unrelated phosphatase families cooperating to affect this biological response, and hence the relevance of considering all phosphatase families when mining for potentially druggable targets.


Subject(s)
Neurites/physiology , Phosphoric Monoester Hydrolases/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 12/metabolism , Receptor, trkB/metabolism , Brain-Derived Neurotrophic Factor/pharmacology , Cell Differentiation/drug effects , Cell Line , Crk-Associated Substrate Protein/metabolism , Drug Evaluation, Preclinical/methods , Focal Adhesion Kinase 1/metabolism , Gene Knockdown Techniques , Humans , Neurites/drug effects , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Phenotype , Phosphoric Monoester Hydrolases/genetics , Phosphorylation , Protein Tyrosine Phosphatase, Non-Receptor Type 12/genetics , RNA Interference , Reproducibility of Results , Signal Transduction , Tretinoin/pharmacology
12.
Cancer Invest ; 30(4): 309-16, 2012 May.
Article in English | MEDLINE | ID: mdl-22468806

ABSTRACT

Pemetrexed/cyclophosphamide was evaluated as first-line treatment for patients with locally advanced/metastatic breast cancer. In this randomized phase II study (NCT00190671), therapy consisted of either 600 mg/m(2) (P600) or 1,800 mg/m(2) (P1800) pemetrexed, followed by 600 mg/m(2) cyclophosphamide, every 21 days; 103 females (42 P600; 61 P1800) were enrolled. P600 was discontinued, as response rate (19.1%) was lower than targeted. In the P1800 arm, 20 patients had partial response (32.8%; 95% CI: 21.0-44.6) and 26 (42.6%) had stable disease. Median progression-free survival was 6.3 months (range: 0.3-31.1). P1800 plus cyclophosphamide 600 represents a regimen of reasonable efficacy and acceptable tolerability.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Cyclophosphamide/pharmacokinetics , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Glutamates/administration & dosage , Glutamates/adverse effects , Glutamates/pharmacokinetics , Guanine/administration & dosage , Guanine/adverse effects , Guanine/analogs & derivatives , Guanine/pharmacokinetics , Humans , Kaplan-Meier Estimate , Middle Aged , Pemetrexed , Spectrometry, Mass, Electrospray Ionization
13.
Cancer ; 118(19): 4694-705, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22434360

ABSTRACT

BACKGROUND: Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum-based chemotherapy is often a first-line treatment. Pemetrexed has shown single-agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed-cisplatin for SCCHN. METHODS: In a double-blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m(2) ) plus cisplatin (75 mg/m(2) ; n = 398) or placebo plus cisplatin (75 mg/m(2) ; n = 397) to assess overall survival (OS) and secondary endpoints. RESULTS: Median OS was 7.3 months in the pemetrexed-cisplatin arm and 6.3 months in the placebo-cisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75-1.02; P = .082). Median progression-free survival (PFS, months) was similar in both treatment arms (pemetrexed-cisplatin, 3.6; placebo-cisplatin, 2.8; HR, 0.88; 95% CI, 0.76-1.03; P = .166). Among patients with performance status 0 or 1, pemetrexed-cisplatin (n = 347) led to longer OS and PFS than placebo-cisplatin (n = 343; 8.4 vs 6.7 months; HR, 0.83; P = .026; 4.0 vs 3.0 months; HR, 0.84; P = .044, respectively). Among patients with oropharyngeal cancers, pemetrexed-cisplatin (n = 86) resulted in longer OS and PFS than placebo-cisplatin (n = 106; 9.9 vs 6.1 months; HR, 0.59; P = .002; 4.0 vs 3.4 months; HR, 0.73; P = .047, respectively). Pemetrexed-cisplatin toxicity was consistent with studies in other tumors. CONCLUSIONS: Pemetrexed-cisplatin compared with placebo-cisplatin did not significantly improve survival for the intent-to-treat population. However, in a prespecified subgroup analysis, pemetrexed-cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Cisplatin/therapeutic use , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/pathology , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Double-Blind Method , Female , Glutamates/administration & dosage , Guanine/administration & dosage , Guanine/analogs & derivatives , Humans , Male , Middle Aged , Pemetrexed , Treatment Outcome
14.
Food Nutr Res ; 552011.
Article in English | MEDLINE | ID: mdl-21866221

ABSTRACT

BACKGROUND: Appetite measures are often recorded by visual analogue scales (VAS), and are assumed to reflect central nervous system (CNS) perceptions and sensations. However, little is known about how physiological, psychological, social, and cultural factors influence VAS. OBJECTIVE: To investigate whether age, gender, body mass index (BMI), smoking habits, physical activity, diet behaviour, and menstruation cycle are determinants of appetite ratings. DESIGN: We investigated appetite ratings in different groups of a population during a single meal test, including 178 healthy women (98) and men (80), aged 20-60 years with a BMI of 18.5-35.0 kg/m(2). Subjects consumed an evening meal composed to meet individual requirements of energy content and recommendations regarding macronutrient composition. Before and every half hour until 3 hours after the meal, subjects filled out VAS for satiety, fullness, hunger, and prospective food intake. They also filled in a questionnaire on eating/slimming behaviour. RESULTS: Multiple linear regression analyses showed that gender and age were the most powerful predictors of postprandial satiety (p<0.001, adj. R(2)=0.19) and hunger (p<0.001, adj. R(2)=0.15). Repeated measures general linear model (GLM) analyses revealed that women felt more satisfied than men (p<0.001) and older subjects felt more satisfied than younger (p<0.01). Furthermore, light/no exercisers felt more satisfied and less hungry than hard/moderate exercisers (p<0.05), but these differences disappeared after adjusting for age and gender. Smokers rated their prospective consumption lower than non-smokers (p<005) and women in the ovulation phase felt less hungry than women in the menstruation phase (p<005). Neither BMI nor diet/weight concern were significantly associated with appetite ratings. CONCLUSIONS: Appetite ratings differed according to age, gender, and physical activity and to a lesser degree for smoking habits and menstruation cycle. Appetite ratings were not influenced by BMI and diet/weight concern. These factors should be considered when planning studies and analysing data concerning appetite sensations.

15.
Food Nutr Res ; 552011.
Article in English | MEDLINE | ID: mdl-21799667

ABSTRACT

BACKGROUND: The importance of exchanging sucrose for artificial sweeteners on risk factors for developing diabetes and cardiovascular diseases is not yet clear. OBJECTIVE: To investigate the effects of a diet high in sucrose versus a diet high in artificial sweeteners on fasting and postprandial metabolic profiles after 10 weeks. DESIGN: Healthy overweight subjects were randomised to consume drinks and foods sweetened with either sucrose (∼2 g/kg body weight) (n = 12) or artificial sweeteners (n = 11) as supplements to their usual diet. Supplements were similar on the two diets and consisted of beverages (∼80 weight%) and solid foods (yoghurts, marmalade, ice cream, stewed fruits). The rest of the diet was free of choice and ad libitum. Before (week 0) and after the intervention (week 10) fasting blood samples were drawn and in week 10, postprandial blood was sampled during an 8-hour meal test (breakfast and lunch). RESULTS: After 10 weeks postprandial glucose, insulin, lactate, triglyceride, leptin, glucagon, and GLP-1 were all significantly higher in the sucrose compared with the sweetener group. After adjusting for differences in body weight changes and fasting values (week 10), postprandial glucose, lactate, insulin, GIP, and GLP-1 were significantly higher and after further adjusting for differences in energy and sucrose intake, postprandial lactate, insulin, GIP, and GLP-1 levels were still significantly higher on the sucrose-rich diet. CONCLUSION: A sucrose-rich diet consumed for 10 weeks resulted in significant elevations of postprandial glycaemia, insulinemia, and lipidemia compared to a diet rich in artificial sweeteners in slightly overweight healthy subjects.

16.
J Clin Oncol ; 27(11): 1753-60, 2009 Apr 10.
Article in English | MEDLINE | ID: mdl-19273714

ABSTRACT

PURPOSE: Patients with metastatic breast cancer who are pretreated with anthracyclines frequently receive taxane-based combinations. This phase III study compared the efficacy and safety of gemcitabine-docetaxel (GD) with capecitabine-docetaxel (CD) in advanced breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to GD (G 1,000 mg/m(2) days 1 and 8; D 75 mg/m(2) day 1) or CD (C 1,250 mg/m(2) twice daily days 1 through 14; D 75 mg/m(2) day 1) every 21 days. Comparison of progression-free survival (PFS) was the primary objective. RESULTS: Patient characteristics were balanced between arms (N = 305). Median PFS was 8.05 months (95% CI, 6.60 to 8.71) for GD and 7.98 (95% CI, 6.93 to 8.77) for CD (log-rank P = .121). Overall response rate (ORR) was 32% in both arms, and overall survival (OS) was not different between arms (P = .983). Time to treatment failure (TTF; defined as discontinuation, progressive disease, death as a result of any cause, or the start of a new anticancer therapy) was superior in the GD arm (P = .059). Hematologic toxicity was similar in both arms, except for grades 3 to 4 leukopenia (GD, 78%; CD, 66%; P = .025) and transfusions (GD, 17%; CD, 7%; P = .0051). Grades 3 to 4 diarrhea, mucositis, and hand-and-foot syndrome were significantly higher in the CD arm. Fewer patients in the GD arm discontinued because of drug-related adverse events (13% v 27% in CD; P = .002). CONCLUSION: No difference was observed between GD and CD arms in PFS, ORR, and OS. TTF was longer in the GD arm. These findings, combined with a nonhematologic toxicity profile that favors GD over approved doses of CD, suggest that gemcitabine may be a better option than capecitabine in combination with docetaxel in this clinical setting.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Adult , Aged , Anthracyclines/administration & dosage , Breast Neoplasms/secondary , Capecitabine , Combined Modality Therapy , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Docetaxel , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Humans , Middle Aged , Survival Analysis , Taxoids/administration & dosage , Gemcitabine
17.
J Biol Chem ; 283(51): 35815-24, 2008 Dec 19.
Article in English | MEDLINE | ID: mdl-18948260

ABSTRACT

Src family tyrosine kinases (SFKs) function in multiple signaling pathways, raising the question of how appropriate regulation and substrate choice are achieved. SFK activity is modulated by several protein-tyrosine phosphatases, among which RPTPalpha and SHP2 are the best established. We studied how RPTPalpha affects substrate specificity and regulation of c-Src and Fyn in response to epidermal growth factor and platelet-derived growth factor. We find that RPTPalpha, in a growth factor-specific manner, directs the specificity of these kinases toward a specific subset of SFK substrates, particularly the focal adhesion protein Paxillin and the lipid raft scaffolding protein Cbp/PAG. A significant fraction of RPTPalpha is present in lipid rafts, where its targets Fyn and Cbp/PAG reside, and growth factor-mediated SFK activation within this compartment is strictly dependent on RPTPalpha. Forced concentration of RPTPalpha into lipid rafts is compatible with activation of Fyn. Finally, RPTPalpha-induced phosphorylation of Paxillin and Cbp/PAG induces recruitment of the SFK inhibitory kinase Csk, indicative of negative feedback loops limiting SFK activation by RPTPalpha. Our findings indicate that individual SFK-controlling PTPs play important and specific roles in dictating SFK substrate specificity and regulatory mechanism.


Subject(s)
Genes, src/physiology , Membrane Microdomains/metabolism , Proto-Oncogene Proteins c-fyn/metabolism , Receptor-Like Protein Tyrosine Phosphatases, Class 4/metabolism , Animals , Cell Line , Enzyme Activation/drug effects , Enzyme Activation/physiology , Epidermal Growth Factor/pharmacology , Intercellular Signaling Peptides and Proteins , Membrane Microdomains/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Knockout , Paxillin/genetics , Paxillin/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , Platelet-Derived Growth Factor/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Proto-Oncogene Proteins c-fyn/genetics , Receptor-Like Protein Tyrosine Phosphatases, Class 4/genetics , Substrate Specificity/drug effects , Substrate Specificity/physiology
18.
Br J Nutr ; 98(1): 17-25, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17524176

ABSTRACT

It is unclear whether postprandial blood glucose or insulin exerts a regulatory function in short-term appetite regulation in humans. The aim of this study was to investigate, by use of meta-analysis, the role of blood glucose and insulin in short-term appetite sensation and energy intake (EI) in normal weight and overweight participants. Data from seven test meal studies were used, including 136 healthy participants (ALL) (92 normal weight (NW) and 44 overweight or obese (OW)). All meals were served as breakfasts after an overnight fast, and appetite sensations and blood samples were obtained frequently in the postprandial period. Finally, an ad libitum lunch was served. Data were analysed by fixed effects study level (SL) meta-regression analysis and individual participant data (IPD) regression analysis, using STATA software. In SL analysis, postprandial insulin response was associated with decreased hunger in ALL, NW and OW (P < 0.019), and with increased satiety in NW (P = 0.004) and lower subsequent EI in OW (P = 0.022). Multivariate IPD analysis showed similar associations, but only in NW for hunger, satiety and EI (P < 0.028), and in ALL for EI (P = 0.016). The only association involving blood glucose was the multivariate IPD analysis showing an inverse association between blood glucose and EI in ALL (P = 0.032). Our results suggest that insulin, but not glucose, is associated with short-term appetite regulation in healthy participants, but the relationship is disrupted in the overweight and obese. We conclude that the postprandial insulin response may be an important satiety signal, and that central nervous system insulin resistance in overweight might explain the blunted effect on appetite.


Subject(s)
Appetite Regulation/physiology , Blood Glucose/physiology , Energy Intake/physiology , Insulin/blood , Overweight/physiology , Blood Glucose/metabolism , Food , Humans , Obesity/physiopathology , Postprandial Period , Satiety Response/physiology
19.
Am J Clin Nutr ; 84(6): 1365-73, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17158418

ABSTRACT

BACKGROUND: The importance of the postprandial glycemic and insulinemic responses for appetite and energy intake (EI) is controversial. OBJECTIVE: The aim of the study was to test the hypothesis that postprandial appetite sensations and subsequent EI are determined by postprandial glycemic and insulinemic responses after the intake of a range of breakfast meals. DESIGN: The study was a randomized, crossover meal test including 28 healthy young men, each of whom tested 10 of 14 breakfast meals. Each meal contained 50 g carbohydrate with various glycemic index and energy and macronutrient contents. Blood samples were taken, and appetite sensations were measured 3 h after the meals. Subsequently, EI at lunch (EI(lunch)) was recorded. RESULTS: The glycemic response was unrelated to appetite sensations, whereas the insulinemic response was positively associated with postprandial fullness (R2 = 0.33, P < 0.05). In contrast, the insulinemic response was unrelated to the subsequent EI(lunch), whereas the glycemic response was positively associated with EI(lunch) (R2 = 0.33, P < 0.05). Although no significant difference in EI(lunch) was observed between different breakfast conditions, a low breakfast EI was associated with a high EI(lunch) (R2 = 0.60, P < 0.001). CONCLUSIONS: The current study does not support the contention that the postprandial glycemic response has an important effect on short-term appetite sensations, but a low-glycemic index meal may reduce subsequent EI. In contrast, postprandial insulin seems to affect short-term appetite sensations.


Subject(s)
Appetite Regulation/physiology , Blood Glucose/metabolism , Dietary Carbohydrates/administration & dosage , Energy Intake/physiology , Glycemic Index , Insulin/metabolism , Adult , Appetite Regulation/drug effects , Area Under Curve , Cross-Over Studies , Dietary Carbohydrates/pharmacokinetics , Food Analysis , Humans , Male , Postprandial Period/physiology , Time Factors
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