Motexafin gadolinium (MGd) combined with prompt whole brain radiation therapy (RT) prolongs time to neurologic progression in non-small cell lung cancer (NSCLC) patients with brain metastases: Results of a phase III trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7014-7014 ◽  
Author(s):  
M. P. Mehta ◽  
R. Gervais ◽  
P. Chabot ◽  
W. R. Shapiro ◽  
R. A. Patchell ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Randomized Study ◽  
Phase Iii ◽  
Phase 3 ◽  
Motexafin Gadolinium ◽  
Whole Brain Radiation ◽  
Significant Prolongation ◽  
Clinically Significant ◽  
Grade 3 ◽  
Nsclc Patients

7014 Background: In a previous randomized study, RT plus MGd prolonged time to neurologic progression (TNP) in NSCLC patients (pts) with brain metastases (BM) (p=0.048). Methods: This Phase 3 trial randomized pts with BM from NSCLC and KPS ≥70 to RT (30 Gy) or RT+MGd, 5 mg/kg qd x 10. A sample size of 550 was based on α=0.001, β=0.8, hazard ratio (HR)=0.65, with a primary endpoint of TNP determined by a blinded events review committee. Results: 554 pts received RT (N=275) or RT+MGd (N=279), 348 in North America (NA), 206 in Europe and Australia (EA). Treatment arms were balanced for factors of known prognostic importance. Most pts had multiple BM (81%), extracranial metastases (51%) and presented with neurologic deficits (84%). Treatment with MGd was well tolerated, with >92% of intended doses administered. Most common MGd-related grade 3+ adverse events were hypertension (4%), ALT increase (3%), and fatigue (3%). TNP improved from 10 months (mo) for RT to 15.4 mo for RT+MGd, p=0.12, HR=0.78. Time to neurocognitive progression was also improved, p=0.089, HR=0.79. More RT pts required salvage brain surgery or radiosurgery than RT+MGd pts (41 RT, 19 RT+MGd). In NA pts, statistically significant prolongation of both TNP, from 8.8 mo for RT to 24.2 mo for RT+MGd, p=0.004, HR=0.53, and time to neurocognitive progression, p=0.04, HR=0.69, were observed. In NA, RT was started sooner after the diagnosis of BM than in EA (median/mean 1.6/2.2 weeks NA vs. 3.0/6.5 weeks EA). There was a significant interaction between earlier RT and MGd benefit, p=0.017. When RT was initiated within 3 weeks of BM diagnosis, regardless of region, TNP was significantly prolonged by addition of MGd (N=378, p=0.006, HR=0.59). When initiation of RT was delayed beyond 3 weeks after BM diagnosis (N=176, 21% of NA pts, 50% of EA pts), MGd benefit was lost. A major reason for RT delay was use of chemotherapy as initial treatment for BM in 41 pts, 17% NA, 83% EA. Conclusions: MGd significantly prolonged TNP in NSCLC patients with BM receiving prompt RT in this randomized Phase 3 trial. The majority of patients in NA received prompt RT (79%), leading to a statistically and clinically significant benefit when combined with MGd. [Table: see text]

Motexafin gadolinium (MGd) combined with whole brain radiation therapy prolongs time to neurologic progression in non- small cell lung cancer (NSCLC) patients with brain metastases: Pooled analysis of two randomized phase III trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2010-2010
Author(s):  
W. R. Shapiro ◽  
M. P. Mehta ◽  
C. Langer ◽  
A. Bezjak ◽  
R. Timmerman ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Brain Metastases ◽  
Pooled Analysis ◽  
Whole Brain Radiation Therapy ◽  
Phase Iii ◽  
Whole Brain ◽  
Motexafin Gadolinium ◽  
Whole Brain Radiation ◽  
Nsclc Patients ◽  
Brain Radiation

2010 Background: In 2 randomized trials, whole brain radiation therapy (RT) plus MGd prolonged time to neurologic progression (TNP) in NSCLC patients (pts) with brain metastases (BM). In this report, results of a pooled analysis from both trials are presented. Methods: In trial 9801, 401 pts with BM from solid tumors were randomized to RT (30 Gy) or RT+MGd, 5 mg/kg qd x 10 days. The subgroup of 251 pts with NSCLC is included in this analysis. In trial 0211, 554 pts with BM from NSCLC were randomized to the same treatments. In both trials, eligibility included a KPS = 70, no liver metastases, and = 1 site of extracranial metastasis. In both trials, a primary endpoint was time to neurologic progression determined by a blinded events review committee (ERC), incorporating data from neurologic exams, neurologic symptom collection, and neurocognitive tests. Results: 805 pts received RT (N=403) or RT+MGd (N=402). Most pts had multiple BM (80%), extracranial metastases (47%) and presented with neurologic deficits (84%). Treatment with MGd was well tolerated, with 93.3% of intended doses administered. Most common MGd-related grade 3+ adverse events were hypertension (4.6%), and fatigue (2.8%). TNP in the RT+MGd group was 15.4 mo, significantly longer than the 9.0 mo for the RT alone group, p=0.016, HR=0.74 (95% CI 0.57–0.95). The results of both studies are consistent, as shown in the table below. Similar results were observed in time to investigator-determined neurologic progression (p=0.015, HR=0.76) and time to neurocognitive progression (memory: HR=0.80, p=0.047, executive function: HR=0.74, p=0.028, all tests combined: HR=0.78, p=0.020). Conclusions: Motexafin gadolinium significantly prolonged time to neurologic progression and neurocognitive progression in NSCLC patients with brain metastases undergoing whole brain radiation therapy in a pooled analysis of 2 randomized phase III trials. [Table: see text] No significant financial relationships to disclose.

Safety of bevacizumab (B) and erlotinib (E) therapy in patients (pts) with treated brain metastases (mets) in the phase III, placebo (P)-controlled, randomized BeTa trial for pts with advanced non-small cell lung cancer (NSCLC) after failure of standard first-line chemotherapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19025-e19025
Author(s):  
G. A. Otterson ◽  
P. G. O’Connor ◽  
M. Lin ◽  
R. S. Herbst ◽  
Keyword(s):  
Brain Metastases ◽  
Growth Factor Receptor ◽  
Toxic Encephalopathy ◽  
Phase Iii ◽  
First Line ◽  
Bleeding Events ◽  
Whole Brain Radiation ◽  
Fda Approval ◽  
Previously Treated ◽  
Nsclc Patients

e19025 Background: Bevacizumab (B) + carboplatin/paclitaxel received FDA approval in 10/06 for improving survival in first-line treatment of advanced NSCLC patients (pts). In the past, pts with brain mets had been excluded from trials of B due to concerns about the possibility of CNS hemorrhage. We report on the safety of B therapy in combination with E in a subset of pts with treated brain mets who enrolled in the BETA lung study for NSCLC. Methods: Pts in the subset had recurrent advanced stage NSCLC. Their disease at enrollment included brain mets previously treated with whole brain radiation therapy. Neurosurgery and stereotactic radiosurgery were permissible in addition to WBRT. Patients with an ongoing requirement for dexamethasone treatment and those who had previously been treated with anti-angiogenesis or epidermal growth factor receptor-targeted therapy were not eligible. Pts were treated with E+B or E+P. E dosing was at 150 mg daily; B/P dosing was 15mg/kg intravenous every (q) 3 weeks. Responses were evaluated q 6 wks until wk 24 and every 12 wks thereafter. Treatment continued until disease progression. Results: 68 pts with brain metastases were enrolled between June 2005 and April 2008. 37 pts received E+B and 31, E +P, with median treatment durations of 2.6 and 2.7 months respectively. No CNS hemorrhages or Gr 3+ bleeding events were reported among these pts. 3 Gr 3–4 nervous system adverse events (AE) were reported in each arm. One convulsion, one case of memory impairment and one case of toxic encephalopathy was reported in the E+P arm and a case of ataxia, headache, and cerebral ischemia were reported in the E+B arm. Conclusions: 37 pts with previously treated brain mets were treated with E+B in the BETA study. No CNS hemorrhages were reported in this subset and no new safety signals identified. The treatment duration for subjects with metastasis was equivalent in the E+B and E+ P arms. These data suggest an acceptable safety profile for the subset of patients with brain mets treated with B in the BETA lung study. [Table: see text]

Neurocognitive Function and Progression in Patients With Brain Metastases Treated With Whole-Brain Radiation and Motexafin Gadolinium: Results of a Randomized Phase III Trial

2004 ◽  
Vol 22 (1) ◽  
pp. 157-165 ◽  
Author(s):  
Christina A. Meyers ◽  
Jennifer A. Smith ◽  
Andrea Bezjak ◽  
Minesh P. Mehta ◽  
James Liebmann ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Executive Function ◽  
Brain Metastases ◽  
Phase Iii ◽  
Fine Motor ◽  
Whole Brain ◽  
Motexafin Gadolinium ◽  
Whole Brain Radiation ◽  
Neurocognitive Tests ◽  
Brain Radiation

Purpose To report the neurocognitive findings in a phase III randomized trial evaluating survival and neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). Patients and Methods Patients were randomly assigned to receive WBRT 30 Gy in 10 fractions with or without MGd 5 mg/kg/d. Monthly neurocognitive testing for memory, executive function, and fine motor skill was performed. Results Four hundred one patients were enrolled (251 with non–small-cell lung cancer, 75 with breast cancer, and 75 with other cancers); 90.5% patients had impairment of one or more neurocognitive tests at baseline. Neurocognitive test scores of memory, fine motor speed, executive function, and global neurocognitive impairment at baseline were correlated with brain tumor volume and predictive of survival. There was no statistically significant difference between treatment arms in time to neurocognitive progression. Patients with lung cancer (but not other types of cancer) who were treated with MGd tended to have improved memory and executive function (P = .062) and improved neurologic function as assessed by a blinded events review committee (P = .048). Conclusion Neurocognitive tests are a relatively sensitive measure of brain functioning; a combination of tumor prognostic variables and brain function assessments seems to predict survival better than tumor variables alone. Although the addition of MGd to WBRT did not produce a significant overall improvement between treatment arms, MGd may improve memory and executive function and prolong time to neurocognitive and neurologic progression in patients with brain metastases from lung cancer.

Phase III randomized study of oral vinorelbine (oV) and gemcitabine (G) (oVG) versus docetaxel (D) and gemcitabine (DG) as first-line treatment of patients with advanced non-small cell lung cancer (NSCLC): A preliminary report

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7538-7538 ◽  
Author(s):  
S. Agelaki ◽  
N. Androulakis ◽  
A. Agelidou ◽  
M. Agelidou ◽  
A. Kotsakis ◽  
...  
Keyword(s):  
Randomized Study ◽  
Age Groups ◽  
Stage Iv ◽  
Phase Iii ◽  
Disease Stage ◽  
Oral Vinorelbine ◽  
Secondary Endpoints ◽  
Adequate Organ Function ◽  
Grade 3 ◽  
Nsclc Patients

7538 Background: Non-platinum based doublets are effective treatments for advanced NSCLC. We performed a multicenter phase III trial to compare the efficacy and tolerance of oVG and DG in NSCLC patients (pts). Methods: Chemotherapy-naive pts with stage IIIB/IV NSCLC and PS (WHO) 0–2 and adequate organ function were eligible. Pts received oV 70 mg/m2 combined with G 900 mg/m2 on days 1, 15 of a 4-week cycle or D 75 mg/m2 on day 1 combined with G 1,000 mg/m2 on days 1, 8 of a 3-week cycle. Primary endpoint was OS and secondary endpoints were response rate (RR), time to progression (TTP) and toxicity. Stratification was done for age, stage and PS. Results: 254 pts received oVG (n=121) or DG (n=133). Median age was 64 and 63 years, and PS was 0–1 in 94.2% and 94%, for oVG and DG, respectively. Most patients had disease stage IV and were =70 years (80.9% vs 74.4% and 74% vs 77%, in oVG and DG, respectively). After a median follow-up time of 6.1 months, median OS was 9.0 vs 10.7 months and 1-yr survival was 38% vs 46% for oVG and DG, respectively (p=0.486). Significantly more responders were observed in the DG arm (11% vs 23%, p=0.018). Median TTP was 3.1 vs 3.9 for oVG and DG, respectively (p=0.335). A similar toxicity profile was observed except for a trend for higher neutropenia grade 3–4 in DG compared to oVG (p= 0.066). There was no difference with respect to neutropenic infections (p= 0.124). An analysis of the influence of age (=70 and = 70) on OS and toxicity revealed that OS was similar for both arms in the two age groups but grade 3–4 neutropenia was lower in the oVG arm for pts =70 years. Conclusions: A higher RR that was not translated to a survival benefit was recorded for the DG arm. Both regimens were well tolerated without significant differences in toxicity. No significant financial relationships to disclose.

Survival and Neurologic Outcomes in a Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation Therapy in Brain Metastases

2003 ◽  
Vol 21 (13) ◽  
pp. 2529-2536 ◽  
Author(s):  
Minesh P. Mehta ◽  
Patrick Rodrigus ◽  
C.H.J. Terhaard ◽  
Aroor Rao ◽  
John Suh ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Brain Metastases ◽  
Randomized Trial ◽  
Cancer Patients ◽  
Treatment Benefit ◽  
Motexafin Gadolinium ◽  
Lung Cancer Patients ◽  
Whole Brain Radiation ◽  
Brain Radiation

Purpose: This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). Patients and Methods: Patients were randomly assigned to 30 Gy of WBRT ± 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated. Results: Four hundred one (251 non–small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P = .48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P = .95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P = .048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P = .018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P = .025). MGd improved neurocognitive function in lung cancer patients. Conclusion: The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.

scholarly journals Whole Brain Radiotherapy With and Without Concurrent Erlotinib in NSCLC with Brain Metastases: a multicentre, open-label, randomized, controlled phase 3 Trial

2020 ◽  
Author(s):  
Zhenzhou Yang ◽  
Yan Zhang ◽  
Rongqing Li ◽  
Abulimiti Yisikandaer ◽  
Biyong Ren ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Objective Response ◽  
Whole Brain Radiotherapy ◽  
Combination Group ◽  
Open Label ◽  
Phase 3 ◽  
Whole Brain ◽  
Brain Radiotherapy ◽  
Egfr Mutant ◽  
Nsclc Patients

Abstract Background Erlotinib combined with whole brain radiotherapy (WBRT) demonstrated a favorable objective response rate in a phase 2 single-arm trial of non-small cell lung cancer (NSCLC) patients with brain metastases. We assessed whether concurrent erlotinib with WBRT is safe and benefits patients in a phase 3, randomized trial. Methods NSCLC patients with two or more brain metastases were enrolled and randomly assigned (1:1) to WBRT (n=115) or WBRT combined with erlotinib arms (n=109). The primary endpoint was intracranial progression-free survival (iPFS) and cognitive function (CF) was assessed by Mini–Mental State Examination (MMSE). Results A total of 224 patients from 10 centers across China were randomized to treatments. Median follow-up was 11.2 months. Median iPFS for WBRT concurrent erlotinib was 11.2 months versus 9.2 months for WBRT-alone (p=0.601). Median PFS and overall survival (OS) of combination group were 5.3 versus 4.0 months (p=0.825) and 12.9 versus 10.0 months (p=0.545), respectively, compared with WBRT-alone. In EGFR-mutant patients, iPFS (14.6 versus 12.8 months; p=0.164), PFS (8.8 versus 6.4 months; p=0.702) and OS (17.5 versus 16.9 months; p=0.221) were not significantly improved in combination group over WBRT-alone. Moreover, there were no significant differences in patients experiencing MMSE score change between the treatments. Conclusion Concurrent erlotinib with WBRT didn’t improve iPFS and excessive CF detriment either in the intent-to-treat (ITT) population or in EGFR-mutant patients compared with WBRT-alone, suggesting that while safe for patients already taking the drug, there is no justification for adding concurrent EGFR-TKI with WBRT for the treatment of brain metastases.

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