TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first-line treatment of metastatic colorectal cancer: A randomized phase 1b/2 trial.

BACKGROUND: In patients with previously untreated metastatic colorectal cancer (mCRC), we conducted a phase 1b/randomized phase 2 trial to define the safety, tolerability, and efficacy of mFOLFOX6 plus bevacizumab (mFOLFOX6/bev) with conatumumab, an investigational, fully human monoclonal IgG1 antibody that specifically activates death receptor 5 (DR5). METHODS: Twelve patients were enrolled in a phase 1b open-label dose-escalation trial of conatumumab with mFOLFOX6/bev; thereafter, 190 patients were randomized 1:1:1 to receive mFOLFOX6/bev in combination with 2 mg/kg conatumumab, 10 mg/kg conatumumab, or placebo. Therapy cycles were repeated every 2 weeks until disease progression or the occurrence of unacceptable toxicity. RESULTS: In phase 1b, conatumumab with mFOLFOX6/bev was tolerated without apparent added toxicity over mFOLFOX6/bev alone. In phase 2, conatumumab with mFOLFOX6/bev did not confer a benefit in progression-free survival when compared with placebo with mFOLFOX6/bev. Toxicity was similar in all treatment arms. Following treatment, similar increases in circulating caspase-3 levels were observed in all arms. CONCLUSIONS: Conatumumab with mFOLFOX6/bev did not offer improved efficacy over the same chemotherapy with placebo in first-line treatment of patients with mCRC. These data do not support further development of conatumumab in advanced CRC.

The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors.

BACKGROUND: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS: Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary "sludge" in Arms A/B/C was 39%/36%/27%. CONCLUSIONS: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00448786.

Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study.

BACKGROUND: Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. METHODS: Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m(2) on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681. FINDINGS: ORRs for the motesanib group and the placebo group did not differ significantly (49%vs 41%; absolute difference 8% [95% CI -6 to 22]; p=0.31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature. INTERPRETATION: Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population. FUNDING: Amgen.

Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer.

PURPOSE: To evaluate the relative prognostic value for specific markers of osteoblast and osteoclast activity while controlling for previously reported prognostic variables among men with hormone-refractory metastatic prostate cancer. EXPERIMENTAL DESIGN: The 643 subjects in this report were participants in multicenter randomized controlled trial of zoledronic acid in men with metastatic prostate cancer. All subjects had bone metastases and disease progression despite medical or surgical castration. Relationships between baseline covariates and overall survival were examined by Cox proportional hazard model. Serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide were assessed as representative specific markers of osteoblast and osteoclast activity, respectively. Other covariates in the model were age, log prostate-specific antigen, hemoglobin, lactate dehydrogenase, albumin, analgesic use, and Eastern Cooperative Oncology Group performance status. RESULTS: Serum BAP was significantly correlated with urinary N-telopeptide (correlation coefficient = 0.674; 95% confidence interval, 0.628-0.715; P < 0.0001). In univariate analyses, higher levels of serum BAP and urinary N-telopeptide levels were significantly associated with shorter overall survival. After controlling for the other variables, including N-telopeptide, in multivariate models, higher serum BAP levels were consistently associated with shorter survival. In contrast, urinary N-telopeptide levels were not significantly associated with survival in multivariate analyses. Variables retained in the reduced multivariate model were age, log prostate-specific antigen, hemoglobin, lactate dehydrogenase, analgesic use, and BAP. CONCLUSIONS: Serum BAP significantly correlates with urinary N-telopeptide in men with androgen-independent prostate cancer and bone metastases. In multivariate models, higher levels of serum BAP but not urinary N-telopeptide are associated with shorter overall survival.

Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.

PURPOSE: Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. PATIENTS AND METHODS: Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. RESULTS: Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. CONCLUSION: The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.

PURPOSE: To describe the natural history of nonmetastatic prostate cancer and rising prostate-specific antigen (PSA) despite androgen deprivation therapy. PATIENTS AND METHODS: The 201 patients in this report were the placebo control group from an aborted randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising PSA despite androgen deprivation therapy. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were baseline PSA, Gleason sum, history of bilateral orchiectomies, regional lymph node metastases at diagnosis, prior prostatectomy, time from androgen deprivation therapy to random assignment, time from diagnosis to random assignment, and PSA velocity. RESULTS: At 2 years, 33% of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastases and overall survival were not reached. Baseline PSA level greater than 10 ng/mL (relative risk, 3.18; 95% CI, 1.74 to 5.80; P < .001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI, 2.30 to 8.21; P < .001) independently predicted shorter time to first bone metastasis. Baseline PSA and PSA velocity also independently predicted overall survival and metastasis-free survival. Other covariates did not consistently predict clinical outcomes. CONCLUSION: Men with nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy have a relatively indolent natural history. Baseline PSA and PSA velocity independently predict time to first bone metastasis and survival.

Tumor MET Expression and Gene Amplification in Chinese Patients with Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer.

MET and its sole ligand, hepatocyte growth factor (HGF), are promising targets in gastric and gastroesophageal junction cancer. We evaluated whether MET protein expression or MET gene amplification is prognostic for overall survival (OS) in Chinese patients with advanced gastric or gastroesophageal junction cancer. Archival formalin-fixed, paraffin-embedded tumor samples from patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancer enrolled in clinical trials at Peking University Cancer Hospital from 2008 to 2010 were assessed for MET and phospho-MET (p-MET) expression by immunohistochemistry and MET amplification by FISH. MET-positive expression was defined as membrane protein staining in ≥25% of tumor cells. MET amplification was defined as MET:centromere 7 ratio >2.0. We tested the association of MET status with clinical characteristics and OS, and also evaluated the association between expression and amplification. One hundred sixty-eight patients were eligible. Of the evaluable samples, 53 of 137 (39%) were MET positive, eight of 134 (6%) were p-MET positive, and eight of 113 (7%) were MET amplified. Neither MET expression nor MET amplification were associated with clinical characteristics, except Lauren classification (P = 0.04); MET amplification was associated with diffuse type. No significant OS difference was observed between MET-positive and MET-negative populations, regardless of first-line chemotherapy received. In 95 evaluable patients, MET expression was significantly associated with MET amplification (P < 0.001); all MET-amplified tumor samples showed some MET expression. In 96 evaluable patients, p-MET positivity was significantly associated with MET amplification (P < 0.001). Further evaluation in larger and independent sample sets is warranted to confirm our findings.

Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications.

The results of a retrospective exploratory analysis of a phase III trial of zoledronic acid in patients with bone metastases secondary to lung cancer or other solid tumors are reported herein to assess the risk of skeletal-related events (SREs) and the efficacy of 4 mg zoledronic acid compared with placebo. The study is based on patient SRE history before study entry. Patients were stratified based on SRE history (eg, pathologic fracture, spinal cord compression, radiation therapy or surgery to bone, or hypercalcemia) before study entry, and SRE incidence over 21 months was analyzed. Of 507 patients randomized to 4 mg zoledronic acid or placebo, 131 completed the 9-month core phase and 69 entered the 12-month extension phase. Before study entry, 347 of 503 patients who were evaluable for efficacy (69%) experienced >/= 1 SRE; these patients had a higher risk of developing an SRE on study than patients with no prior SRE (odds ratio, 1.41). Among patients with an SRE before study entry, zoledronic acid reduced the risk of SREs by 31% (P = 0.009), reduced the mean skeletal morbidity rate (1.96 vs. 2.81 SREs per year for placebo; P = 0.030), and prolonged the median time to first SRE by nearly 4 months (215 days vs. 106 days for placebo; P = 0.011). Among patients with no SRE before study entry (n = 156), zoledronic acid reduced the risk of SREs by 23% (P = 0.308), reduced the mean skeletal morbidity rate (1.34 vs. 2.53 SREs per year for placebo; P = 0.332), and prolonged the median time to first SRE by 2.5 months (P = 0.534). This exploratory analysis demonstrates that patients with a history of SREs are at high risk for subsequent SREs, but zoledronic acid reduces skeletal morbidity regardless of SRE history.

Challenges in developing a validated biomarker for angiogenesis inhibitors: the motesanib experience.

PURPOSE: We sought to develop placental growth factor as a predictive pharmacodynamic biomarker for motesanib efficacy as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer. EXPERIMENTAL DESIGN: Placental growth factor was evaluated at baseline and study week 4 (after 3 weeks treatment) in an exploratory analysis of data from a randomized phase 2 study of motesanib 125 mg once daily plus carboplatin/paclitaxel and in a prespecified analysis of data from a randomized, double-blind phase 3 study of motesanib 125 mg once daily plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel (MONET1). Associations between fold-change from baseline in placental growth factor and overall survival were evaluated using Cox proportional hazards models. RESULTS: In the phase 2 study, serum placental growth factor increased from baseline a mean 2.8-fold at study week 4. Patients with ≥2.2-fold change from baseline in placental growth factor (n = 18) had significantly longer overall survival than those with <2.2-fold change (n = 19; 22.9 vs 7.9 months; hazard ratio, 0.30; 95% CI, 0.12-0.74; P = 0.009). Consequently, placental growth factor was investigated as a pharmacodynamic biomarker in the phase 3 MONET1 study. There was no association between log-transformed placental growth factor fold-change from baseline to week 4 (continuous variable) and overall survival (hazard ratio, 0.98; 95% CI, 0.79-1.22; P = 0.868). MONET1 did not meet its primary endpoint of overall survival. Likewise, median overall survival was similar among patients with ≥2.0-fold change in placental growth factor (n = 229) compared with <2.0-fold change (n = 127; 14.8 vs 13.8 months; hazard ratio, 0.88; 95% CI, 0.67-1.15, P = 0.340). CONCLUSIONS: Our results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00460317, NCT00369070.

Motesanib plus carboplatin/paclitaxel in patients with advanced squamous non-small-cell lung cancer: results from the randomized controlled MONET1 study.

INTRODUCTION: The phase 3 MONET1 study evaluated motesanib (a small-molecule inhibitor of vascular endothelial growth factor receptors) plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC). Treatment and enrollment of patients with squamous histology were permanently discontinued following higher early mortality and gross hemoptysis in those with squamous NSCLC who received motesanib. Enrollment of patients with nonsquamous histology was temporarily halted, but resumed following a protocol amendment (Scagliotti et al. J Clin Oncol. 2012;30:2829-2836). Herein, we report data from the squamous cohort. METHODS: Patients with stage IIIB/IV or recurrent squamous NSCLC (without prior systemic therapy for advanced disease) received up to six 3-week cycles of chemotherapy (carboplatin, area under the curve 6 mg/mL•min/paclitaxel, 200 mg/m) and were randomized 1:1 to receive motesanib 125 mg (Arm A) or placebo (Arm B) once daily. The primary end point was overall survival. RESULTS: Three-hundred and sixty patients with squamous NSCLC were randomized (Arm A, n = 182; Arm B, n = 178) between July 2007 and November 2008. Twenty-three patients (13%) in Arm A and 10 (6%) in Arm B had fatal adverse events within the first 60 days of treatment. Among these, six patients in Arm A, but none in Arm B, had fatal bleeding events. At final analysis, serious adverse events had occurred in 47% of patients in Arm A and 29% of patients in Arm B. Median overall survival was similar in Arms A and B (11.1 versus 10.7 months). CONCLUSIONS: Motesanib plus carboplatin/paclitaxel had unacceptable toxicity compared with carboplatin/paclitaxel alone in patients with advanced squamous NSCLC.

A randomized phase 2 study of paclitaxel and carboplatin with or without conatumumab for first-line treatment of advanced non-small-cell lung cancer.

INTRODUCTION: This study evaluated the efficacy, safety, and pharmacokinetics of conatumumab combined with paclitaxel-carboplatin (PC) as first-line treatment for advanced non-small-cell lung cancer (NSCLC). METHODS: Patients (aged >18 years) with previously untreated advanced or recurrent NSCLC were randomized 1:1:1 (stratified by Eastern Cooperative Oncology Group performance status and disease stage) to receive up to six 3-week cycles of PC combined with conatumumab (arm 1, 3 mg/kg; arm 2, 15 mg/kg) or placebo (arm 3) every 3 weeks. The primary endpoint was progression-free survival (PFS). This study is registered with ClinicalTrials.gov (NCT00534027). RESULTS: Between August 8, 2007 and April 9, 2009, 172 patients were randomized (arm 1, n = 57; arm 2, n = 56; arm 3, n = 59). Median PFS was 5.4 months (95% confidence interval [CI] 4.1-6.3) in arm 1 (hazard ratio [HR] 0.84 [95% CI 0.57-1.24]; p = 0.41), 4.8 months (95% CI 3.2-6.5) in arm 2 (HR 0.93 [0.64-1.35]; p = 0.57), and 5.5 months (95% CI 4.3-5.7) in arm 3. There was an interaction between tumor histology and the effect of conatumumab on PFS (squamous HR 0.47 [0.23-0.94]; nonsquamous HR 1.08 [0.74-1.57]; interaction p = 0.039).The most common grade of three or more adverse events were neutropenia, anemia, and thrombocytopenia. There was no evidence of pharmacokinetic interactions between conatumumab and PC. Of 158 patients assessable for FCGR3A polymorphisms, conatumumab treatment was associated with a trend toward longer overall survival (HR 0.72 [0.43-1.23]) among V-allele carriers (V/V or F/V; n = 54) but not among F-allele homozygotes (n = 34; HR 1.37 [0.66-2.86]). CONCLUSION: Although well tolerated, the addition of conatumumab to PC did not improve outcomes in unselected patients with previously untreated advanced NSCLC.

First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: a phase I/II open-label and double-blind study.

BACKGROUND: Conatumumab is a fully human monoclonal agonist antibody that binds to death receptor 5 and induces apoptosis in sensitive cells. This study evaluated the safety and efficacy of doxorubicin ± conatumumab as first-line systemic therapy for metastatic or locally advanced/unresectable soft-tissue sarcoma. METHODS: In Phase I, six patients received doxorubicin (75 mg/m2) with conatumumab (15 mg/kg) every 3 weeks. In Phase II, patients were randomised (2:1) to receive doxorubicin with either double-blind conatumumab 15 mg/kg (conatumumab-doxorubicin; n=86) or placebo (placebo-doxorubicin; n=42). Patients who progressed on placebo-doxorubicin could receive open-label conatumumab monotherapy post-chemotherapy (n=21). FINDINGS: The expected histopathologic subtypes (e.g. leiomyosarcoma, liposarcoma, others) were represented in this trial. No unexpected adverse events were noted in either Phase I or II. Median progression-free survival in Phase II was 5.6 and 6.4 months in the conatumumab-doxorubicin and placebo-doxorubicin arms, respectively (stratified HR: 1.00; p=0.973), with more early progressions noted in the first 3.5 months in the conatumumab-doxorubicin arm. Median overall survival was not reached after 8.6 months median follow-up in either arm. Common adverse events were nausea (conatumumab-doxorubicin: 66%; placebo-doxorubicin: 80%), alopecia (55%; 63%), fatigue (60%; 38%) and neutropenia (32%; 50%). Post-chemotherapy results were not notably improved by conatumumab dosing. INTERPRETATION: Addition of conatumumab to doxorubicin appeared to be safe but did not improve disease control in a heterogeneous unselected group of patients with soft tissue sarcomas. The results of this trial are very useful for estimating the outcomes of first-line therapy of sarcoma patients treated with standard doxorubicin.

International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1.

PURPOSE: We evaluated whether motesanib (a selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) combined with carboplatin/paclitaxel improved overall survival (OS) versus chemotherapy alone in patients with nonsquamous non-small-cell lung cancer (NSCLC) and in the subset of patients with adenocarcinoma. PATIENTS AND METHODS: Patients with stage IIIB/IV or recurrent nonsquamous NSCLC (no prior systemic therapy for advanced disease) were randomly assigned 1:1 to carboplatin (area under the curve, 6 mg/ml · min) and paclitaxel (200 mg/m(2)) intravenously for up to six 3-week cycles plus either motesanib 125 mg (arm A) or placebo (arm B) once daily orally. OS was the primary end point. Secondary end points included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and association between placental growth factor (PLGF) change and OS. RESULTS: A total of 1,090 patients with nonsquamous NSCLC were randomly assigned (arms A/B, n = 541 of 549); of those, 890 had adenocarcinoma (n = 448 of 442). Median OS in arms A and B was 13.0 and 11.0 months, respectively (hazard ratio [HR], 0.90; 95% CI, 0.78 to 1.04; P = .14); median OS for the adenocarcinoma subset was 13.5 and 11.0 months, respectively (HR, 0.88; 95% CI, 0.75 to 1.03; P = .11). In descriptive analyses (arms A v B), median PFS was 5.6 months versus 5.4 months (P = < .001); ORR was 40% versus 26% (P < .001). There was no association between PLGF change and OS in arm A. The incidence of grade ≥ 3 AEs (arms A and B, 73% and 59%, respectively) and grade 5 AEs (14% and 9%, respectively) was higher with motesanib treatment. CONCLUSION: Motesanib plus carboplatin/paclitaxel did not significantly improve OS over carboplatin/paclitaxel alone in patients with advanced nonsquamous NSCLC or in the adenocarcinoma subset.

Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program.

BACKGROUND: The role of histology in the targeted management of nonsmall cell lung cancer (NSCLC) has garnered renewed attention in recent years. We provide contemporary population-based estimates of survival and an assessment of important prognostic factors in stage IV NSCLC by major histologic subtype. METHODS: Using data from the Surveillance, Epidemiology and End Results (SEER) Program, we stratified 51,749 incident stage IV NSCLC patients (1988-2003 with follow-up through 2006) by major histologic subtype. We used Kaplan-Meier and Cox proportional hazards methods to describe overall survival and the prognostic influence of select patient, tumor, and treatment characteristics for each histologic subgroup. RESULTS: Survival was highest in patients with bronchioloalveolar adenocarcinoma (1-year survival: 29.1%) and lowest in those with large cell tumors (1-year survival: 12.8%). Diagnosis in later years, female gender, younger age, either Asian/Pacific Islander or Hispanic race/ethnicity, lower tumor grade, and surgery or beam radiation as part of first-line treatment were generally independently associated with a decreased risk of death, but the prognostic significance of some of these factors (age, ethnicity, tumor grade) varied according to histologic subtype. CONCLUSION: Findings demonstrate a poor prognosis across histologic subtypes in stage IV NSCLC patients but highlight differences in both absolute survival and the relative importance of select prognostic factors by histologic subclassification. More research using other sources of population-based data could help clarify the role of histology in the presentation, management, and prognosis of late-stage NSCLC.

Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy and safety of dulanermin combined with paclitaxel and carboplatin (PC) and bevacizumab (PCB) as first-line treatment for advanced or recurrent non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with squamous NSCLC and/or CNS metastases received PC every 3 weeks alone (arm 1) or with dulanermin 8 mg/kg for 5 days (arm 2). Patients with nonsquamous NSCLC received PCB alone (arm 3) or with dulanermin 8 mg/kg for 5 days (arm 4) or 20 mg/kg for 2 days (arm 5). The primary end point was the objective response rate (ORR). RESULTS: Overall, 213 patients were randomly assigned (arm 1, n = 41; arm 2, n = 39; arm 3, n = 42; arm 4, n = 40; arm 5, n = 41). The ORR in arms 1 to 5 was 39% (95% CI, 24% to 56%), 38% (95% CI, 24% to 54%), 50% (95% CI, 35% to 65%), 40% (95% CI, 25% to 56%), and 40% (95% CI, 25% to 56%), respectively. The odds ratio for ORR was 1.04 (P = 1.000) for arm 1 versus arm 2, 1.53 (P = .391) for arm 3 and versus arm 4, and 1.53 (P = .391) for arm 3 versus arm 5. The most common grade ≥ 3 adverse events were neutropenia, asthenia, anemia, thrombocytopenia, and hemoptysis. Of 161 available serum samples, a trend toward increased caspase-cleaved cytokeratin-18 was observed after dulanermin treatment in cycles 1 and 2. Among 84 patients evaluated for GalNT14 expression, there was a trend toward favorable progression-free survival and overall survival with dulanermin treatment in those with high GalNT14 expression. CONCLUSION: The addition of dulanermin to PC and PCB did not improve outcomes in unselected patients with previously untreated advanced or recurrent NSCLC.

Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer.

CONTEXT: Antiangiogenic therapies have shown potential in the treatment of advanced thyroid cancer, but it is uncertain which patients are most likely to benefit from therapy. OBJECTIVE: This prespecified exploratory analysis investigated whether baseline levels and/or changes in circulating biomarkers could predict tumor response and/or progression-free survival (PFS) among patients enrolled in a phase 2 study of motesanib in advanced thyroid cancer. DESIGN/SETTING/PATIENTS: Patients with progressive locally advanced or metastatic medullary or differentiated thyroid cancer received motesanib 125 mg once daily for up to 48 wk in a phase 2 interventional study. Samples for assessment of circulating biomarkers of angiogenesis or apoptosis were collected at study wk 1 (baseline), 2, 4, 8, 16, 24, 32, 40, 48, and 4 wk after cessation of motesanib treatment. Tumor response was assessed per Response Evaluation Criteria in Solid Tumors by independent review. RESULTS: Change from baseline in serum placental growth factor (PlGF) after 1 wk of treatment correlated with best tumor response (Kendall rank correlation, 0.28; P < 0.0001). Using a Fisher exact test, the most significant separation between patients who had an objective response and those who did not was at a 4.7-fold increase in PlGF. The response rate among patients with a greater than 4.7-fold increase in PlGF was 30% compared with 3% below this threshold. There was also a significant separation between responders and nonresponders at a 1.6-fold decrease in soluble vascular endothelial growth factor (VEGF) receptor 2 after 3 wk of treatment. Patients with baseline serum VEGF less than 671 pg/ml had significantly longer PFS times than the remainder of patients. CONCLUSIONS: Changes in PlGF and soluble VEGF receptor 2 levels after initiation of therapy predicted response to motesanib in patients with advanced differentiated thyroid cancer or metastatic medullary thyroid cancer. Lower baseline VEGF levels were associated with longer PFS.

Predictors of skeletal complications in men with hormone-refractory metastatic prostate cancer.

OBJECTIVES: Skeletal complications are a major cause of morbidity in men with hormone-refractory metastatic prostate cancer. These analyses were designed to identify the variables associated with a greater risk of skeletal complications. METHODS: The 643 subjects in this report were participants in a randomized placebo-controlled trial to evaluate the effects of zoledronic acid on the incidence of skeletal-related events. All subjects had bone metastases and disease progression despite medical or surgical castration. The relationships between the baseline covariates and the time to the first skeletal-related event were assessed by Cox proportional hazard analyses. The serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide level was assessed as a representative specific marker of osteoblastic and osteoclastic activity, respectively. The other covariates included in the model were age, cancer duration, Eastern Cooperative Oncology Group performance status, analgesic use, and prostate-specific antigen, hemoglobin, and lactate dehydrogenase levels. RESULTS: Elevated BAP levels were consistently associated with a greater risk of adverse skeletal outcomes. Elevated BAP was significantly associated with a shorter time to the first skeletal-related event on multivariate analyses of the entire study population (relative risk 1.84, 95% confidence interval 1.40 to 2.43; P <0.001) and in subset analyses of the placebo and zoledronic acid groups. Elevated BAP levels were also consistently associated with adverse skeletal outcomes on multivariate analyses of the time to radiotherapy and pathologic fracture, the most common types of skeletal-related events in the study population. No other baseline variable was consistently associated with the risk of adverse skeletal outcomes. CONCLUSIONS: The results of our study have shown that elevated serum BAP levels are associated with a greater risk of adverse skeletal outcomes in men with hormone-refractory prostate cancer and bone metastases.

Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors.

BACKGROUND: Whether bone markers have prognostic value in patients with bone metastases is unknown. We investigated this question in patients with bone metastases secondary to prostate cancer and to non-small-cell lung cancer (NSCLC) and other solid tumors assigned to the placebo arms of two phase III trials of zoledronic acid. METHODS: Levels of the urinary bone resorption marker N-telopeptide and the serum bone formation marker bone-specific alkaline phosphatase were assessed every 3 months for patients with prostate cancer (n = 203) or NSCLC or other solid tumors (n = 238) and were categorized as low or high. Patients were monitored for skeletal-related events, bone disease progression, and death. The relative risks (RRs) and 95% confidence intervals (CIs) for these outcomes were estimated for patients with high versus low levels of each marker using intensity-based multiple event and Cox regression models. All statistical tests were two-sided. RESULTS: In each disease group and overall, high levels of each marker at the beginning of the study were statistically significantly associated with an increased risk of negative outcomes. Use of recent marker assessments as time-dependent covariates gave even greater prognostic significance. High N-telopeptide levels were a stronger prognostic indicator of negative outcomes than bone-specific alkaline phosphatase levels. In recent assessments, patients with high N-telopeptide levels had an increased relative risk of skeletal-related events (prostate cancer, RR = 3.25, 95% CI = 2.26 to 4.68, P<.001; NSCLC and other solid tumors, RR = 1.79, 95% CI = 1.15 to 2.79, P = .010), disease progression (prostate cancer, RR = 2.02, 95% CI = 1.48 to 2.74, P<.001; NSCLC and other solid tumors, RR = 1.91, 95% CI = 1.16 to 3.15, P = .011), and death (prostate cancer, RR = 4.59, 95% CI = 2.82 to 7.46, P<.001; NSCLC and other solid tumors, RR = 2.67, 95% CI = 1.85 to 3.85, P<.001) compared with patients with low N-telopeptide levels. CONCLUSIONS: Baseline and recent bone marker levels were predictive of negative clinical outcomes in patients with bone metastases secondary to prostate cancer and to NSCLC and other solid tumors. N-telopeptide levels were more consistent prognostic indicators than bone-specific alkaline phosphatase for all tumor types, reflecting the key role of osteolysis in the development of skeletal complications.

Inhibition of disease progression by a novel retinoid antagonist in animal models of arthritis.

OBJECTIVE: To investigate the usefulness of a novel retinoic acid receptor (RAR) antagonist (BMS-189453) in animal models of arthritis. METHODS: BMS-189453 was tested in HIG-82 rabbit synovial fibroblasts to determine its ability to repress collagenase (matrix metalloproteinase-1, MMP-1) mRNA expression in vitro. Cells were stimulated with phorbol myristate acetate or interleukin 1 beta and mRNA quantified by slot-blot analysis. In vivo, BMS-189453 was evaluated in 2 animal models of arthritis: collagen induced arthritis (CIA) in mice and streptococcal cell wall induced arthritis (SCWA) in rats. Clinical scores for arthritis were recorded weekly. At the end of each study, limbs were evaluated histologically. In CIA, these results were correlated with mRNA levels for collagenase-3 (MMP-13) and stromelysin-1 (MMP-3) as determined by Northern blot. RESULTS: BMS-189453 reduced MMP-1 expression in HIG-82 synovial fibroblasts in culture. BMS-189453 treatment blocked the clinical progression of arthritis beyond soft tissue inflammation in the CIA model. In the SCWA model, BMS-189453 treatment resulted in significantly reduced swelling with no notable progression to joint distortion/destruction. Histological evaluation of the joints from animals in both models confirmed this result. Analysis of mRNA from the CIA paws showed that BMS-189453 prevented the overexpression of MMP-13 and MMP-3 in arthritic joints. CONCLUSION: Improvement in clinical and histologic variables in 2 separate animal models, along with simultaneous reduction in MMP expression in the affected joint, suggests that RAR antagonists such as BMS-189453 may be useful as agents to treat rheumatoid arthritis and for determining the role of MMP in disease progression. This is the first study to show the clinical potential of RAR antagonists in arthritis.