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

Received 25 March 2008; received in revised form 19 May 2008; accepted 20 May 2008. published online 31 October 2008.

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.

Brain metastases, Non–small-cell lung cancer, Whole brain radiotherapy, Motexafin gadolinium, Neurologic progression, Neurocognitive function

∗ Department of Human Oncology, University of Wisconsin, Madison, WI

† Barrow Neurological Institute, Phoenix, AZ

‡ Clinical Development, Pharmacyclics, Sunnyvale, CA

§ Centre François Baclesse, Caen, France

¶ Centre Léon-Bérard, Lyon, France

‖ Hôpital Maisonneuve-Rosemont, Montreal, QB, Canada

# University of Kentucky, Lexington, KY

∗∗ University of Massachusetts, Hinsdale, MA

†† Stanford University, Palo Alto, CA

‡‡ Fox Chase Cancer Center, Philadelphia, PA

§§ Juravinski Cancer Centre at Hamilton Regional Cancer Centre, Hamilton, ON, Canada

¶¶ Cross Cancer Institute, Edmonton, AB, Canada

‖‖ Centre René Gauducheau, Nantes-St. Herblain, France

## Hotel-Dieu de Québec, Québec, QB, Canada

∗∗∗ Klinikum rechts der Isar der Technischen Universität Műnchen, Munich, Germany

††† University of Texas M. D. Anderson Cancer Center, Houston, TX

Reprint requests to: Minesh P. Mehta, M.D., Department of Human Oncology, Radiation Oncology, University of Wisconsin–Madison, K4/B100, 600 Highland Ave., Madison, WI 53792. Tel: (608) 263-8500; Fax: (608) 263-9167

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.

PII: S0360-3016(08)02953-2

doi:10.1016/j.ijrobp.2008.05.068

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