Motexafin Gadolinium Combined With Prompt Whole Brain Radiotherapy Prolongs Time to Neurologic Progression in Non–Small-Cell Lung Cancer Patients With Brain Metastases: Results of a Phase III Trial

doi:10.1016/j.ijrobp.2008.05.068

International Journal of Radiation OncologyBiologyPhysics

Volume 73, Issue 4, 15 March 2009, Pages 1069-1076

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https://doi.org/10.1016/j.ijrobp.2008.05.068 Get rights and content

Purpose

To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non–small-cell lung cancer.

Methods and Materials

In an international, randomized, Phase III study, patients with brain metastases from non–small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received.

Results

Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed.

Conclusion

In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non–small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.

Introduction

Brain metastases from non–small-cell lung cancer (NSCLC) are a major cause of morbidity (1). Up to 50% of NSCLC patients may develop brain metastases (2). Whole brain radiotherapy (WBRT) is the standard of care for patients with multiple lesions. No approved drugs are available for the treatment of brain metastases. Nearly one-half of patients develop progressive neurologic problems, and only 10–15% survive 1 year.

The prevention and palliation of neurologic problems due to progression are important goals of treatment. Improvement in survival might not be an ideal measure of the benefit of a local therapy, because overall survival is commonly determined by extracranial disease. Tumor size, number, location, extracranial disease, comorbidities, steroid use, and previous therapies complicate the evaluation of clinical benefit. In a previous Phase III trial (PCI-P120-9801, termed 9801) of WBRT with or without motexafin gadolinium (MGd) for patients with brain metastases, the interval to neurologic progression was determined by an Events Review Committee (ERC), unaware of the treatment received, that reviewed the standardized neurologic examination data, neurologic symptoms, and neurocognitive test results 3, 4, 5. The trial demonstrated that standardized neurologic and neurocognitive assessments and the ERC-determined neurologic progression endpoint could be used effectively in an international trial. The ERC-determined neurologic progression endpoint is sensitive to change, objective, clinically relevant, and validated against conventional endpoints such as survival and radiologic progression (6). This endpoint captures data indicating severe neurologic decline that is related to brain metastasis progression.

Motexafin gadolinium is a novel drug that disrupts redox-dependent pathways by targeting oxidative stress-related proteins such as thioredoxin reductase and metallothioneins 7, 8, 9. Thioredoxin reductase is overexpressed in lung cancer and is associated with a poor prognosis (10). Clinical trials have shown that MGd concentrates in tumor cells and is visible on magnetic resonance imaging 11, 12, 13. In preclinical studies, MGd enhanced the effects of ionizing radiation (14). The purpose of the present trial, PCYC-0211, was to confirm the results from the 9801 study that demonstrated a benefit of MGd in patients with brain metastases from NSCLC (4).

Section snippets

Patients

The institutional review board at each center approved the study, and all patients provided informed consent in accordance with the Helsinki Declaration (15). Adults with brain metastases from NSCLC and a Karnofsky performance status (KPS) of ≥70 were eligible. Patients were excluded if they had liver metastases, two or more sites of extracranial metastases, leptomeningeal metastases, or had undergone previous resection of a single brain metastasis, previous WBRT, previous stereotactic

Patient characteristics

Of the 554 patients, 275 were randomized between December 2002 and March 2005 to WBRT and 279 to MGd at 94 sites in the United States (n = 185, 33.4%), Canada (n = 163, 29.4%), France (n = 117, 21.1%), Germany (n = 47, 8.5%), Australia (n = 14, 2.5%), Belgium (n = 11, 2.0%), The Netherlands (n = 11, 2.0%), and Austria (n = 6, 1.1%). All patients had advanced lung cancer: 61.6% had Stage IV at presentation, 47% had brain metastases as their initial presentation of lung cancer, 81% had multiple

Discussion

In this trial, adaptive randomization resulted in well-balanced treatment groups. Patient compliance with respect to the neurologic assessments and treatment was excellent. The safety profile of MGd was acceptable, consisting primarily of Grade 1 and 2 adverse events and minor laboratory test abnormalities.

In the present trial, an improvement (median, 10.0 vs. 15.4 months) in the primary endpoint of the interval to ERC-determined neurologic progression was seen, although it did not reach

Conclusion

In the present study, a trend in favor of the MGd group was observed in the intent-to-treat analysis of the primary endpoint of the interval to neurologic progression that did not reach statistical significance (p = 0.12). The magnitude of the observed benefit was large, with a 5.4-month improvement in the median time to neurologic progression (10.0 months for the WBRT group vs. 15.4 months for the MGd group; HR = 0.78). In a subgroup analysis of promptly treated patients (WBRT initiated within

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: Supported by Pharmacyclics, Inc., Sunnyvale, CA.

: Conflict of interest: the study was sponsored by Pharmacyclics, Inc.; the following authors are (or were during the study period) employees and shareholders of Pharmacyclics, Inc.: See-Chun Phan, M.D., Jennifer Smith, Ph.D., Richard Miller, M.D., and Markus Renschler, M.D.

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International Journal of Radiation OncologyBiologyPhysics

Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Patients

Patient characteristics

Discussion

Conclusion

References (19)

Motexafin gadolinium, a tumor-selective drug targeting thioredoxin reductase and ribonucleotide reductase and ribonucleotide reducatase

J Biol Chem

Effects of motexafin gadolinium on tumor metabolism and radiation sensitivity

Int J Radiat Oncol Biol Phys

Properties of the urn randomization in clinical trials [published erratum appears in Control Clin Trials 1989;10; following 126]

Control Clin Trials

Oncologic emergencies: Diagnosis and treatment

Mayo Clin Proc

Result of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Francais de Pneumo-Cancerologie (GFPC) Protocol 95-1

Ann Oncol

Current management of brain metastases, with a focus on systemic options

J Clin Oncol

Neurologic complications of cancer

Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: Centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points

J Clin Oncol

Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases

J Clin Oncol

Cited by (146)

Phytochemicals and mitochondria: Therapeutic allies against gastric cancer

Thioredoxin reductase selenoproteins from different organisms as potential drug targets for treatment of human diseases

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Comparative Efficacy of Treatments for Brain Metastases from Non–Small Cell Lung Cancer without an EGFR-Mutation/ALK-Rearrangement: A Systematic Review and Network Meta-Analysis

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Theranostic AGuIX nanoparticles as radiosensitizer: A phase I, dose-escalation study in patients with multiple brain metastases (NANO-RAD trial)

Clinical InvestigationMotexafin Gadolinium Combined With Prompt Whole Brain Radiotherapy Prolongs Time to Neurologic Progression in Non–Small-Cell Lung Cancer Patients With Brain Metastases: Results of a Phase III Trial

Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Patients

Patient characteristics

Discussion

Conclusion

J Biol Chem

Int J Radiat Oncol Biol Phys

Control Clin Trials

Mayo Clin Proc

Ann Oncol

Current management of brain metastases, with a focus on systemic options

J Clin Oncol

Neurologic complications of cancer

Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: Centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points

J Clin Oncol

Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases

J Clin Oncol

Clinical Investigation
Motexafin Gadolinium Combined With Prompt Whole Brain Radiotherapy Prolongs Time to Neurologic Progression in Non–Small-Cell Lung Cancer Patients With Brain Metastases: Results of a Phase III Trial