Data From Pivotal Phase III SMART Trial Support NDA Filing for Novel Agent

Pharmacyclics, Inc, announced that new data and analyses supporting the company's decision to file a new drug application (NDA) for motexafin gadolinium (Xcytrin) were presented at the 2006 annual meeting of the American Society of Clinical Oncology (ASCO). This abstract was selected by the ASCO Scientific Program Committee to be featured in the "2006 Best of ASCO Meetings" in June.

According to the new data analyses, which adjust for treatment arm imbalances in the company's phase III randomized, controlled

S

tudy of Neurologic Progression With

M

otexafin Gadolinium

A

nd

R

adiation

T

herapy (SMART), motexafin appeared to significantly prolong time to neurologic progression, the primary endpoint of the study, in non-small-cell lung cancer patients with brain metastases.

Combination With Radiation

"In the intent-to-treat analysis corrected for treatment arm imbalance, Xcytrin plus whole-brain radiation therapy (WBRT) significantly prolonged the time to neurologic progression compared to WBRT alone," said presenter Minesh P. Mehta, MD, professor and chairman of human oncology and professor of neurological surgery at the University of Wisconsin Medical School. "This study indicates that prompt treatment of patients with brain metastases favorably affects treatment outcome and that the benefit of Xcytrin is greatest in patients receiving earlier use of WBRT. This study also highlights the differences in treatment practices in different countries and how these factors may affect outcome."

Regional Differences

The SMART trial enrolled 554 patients at 94 centers in North America, Europe, and Australia. The investigation was designed to compare the safety and efficacy of WBRT alone to WBRT plus motexafin. The three largest-enrolling areas were North America (63%), France (21%), and Germany (8%). The primary prespecified endpoint of time to neurologic progression was measured from the date of randomization on the study to the time of neurologic progression as determined by a blinded events review committee.

Results from the trial indicated that there were substantial differences in the management of patients with brain metastases in North America vs Europe, particularly in France. In some centers in France, there was a significant treatment delay between diagnosis and randomization on the trial. Overall, mean time from brain metastases diagnosis to randomization for the motexafin arm was 4.3 weeks vs 3.3 weeks for the control arm, an imbalance that adversely affected outcomes in the motexafin arm of the study.

Key Results

In the intent-to-treat population of 554 patients, the median time to neurologic progression was 15.4 months for those receiving WBRT plus motexafin compared to 10.0 months for patients treated with WBRT alone (P = .12, hazard ratio = 0.78), a trend in favor of the motexafin-treated arm. However, analyses correcting for the imbalance in treatment delay showed that, in the intent-to-treat population, median time to neurologic progression was 15.5 months for those receiving WBRT plus motexafin compared to 10.2 months for the control arm (P = .05).

In North America, 59.8% of patients enrolled in the study received WBRT or WBRT plus motexafin within 2 weeks of brain metastases diagnosis, 90.3% received treatment within 4 weeks of diagnosis, and only 9.8% received treatment beyond 4 weeks from diagnosis. In France, 22% of patients received treatment within 2 weeks of brain metastases diagnosis, 43.6% received treatment within 4 weeks of diagnosis, and 56.4% of patients received treatment beyond 4 weeks from diagnosis. In many cases, randomization was delayed for months. Some of the reasons for these delays were use of chemotherapy as the initial treatment for brain metastases instead of WBRT or logistical delays in gaining access to WBRT.

The time interval between brain metastases diagnosis and use of WBRT or randomization to the protocol was a determinant of treatment outcome. The longer interval resulted in a poorer outcome in the control patients and also abrogated the benefit of motexafin. In the control arm, the median time to neurologic progression (measured from randomization to progression) was 10.0, 8.8, and 8.8 months for patients receiving WBRT within 2, 4, and 8 weeks of diagnosis, respectively. In the motexafin treatment arm, the median time to neurologic progression was 24.2, 24.2, and 15.4 months for patients receiving WBRT plus motexafin within 2, 4, and 8 weeks, respectively.

Median time to neurologic progression in the North American patients (N = 348) was 24.2 months for those receiving WBRT plus motexafin vs just 8.8 months for those receiving WBRT alone (P = .004, hazard ratio = 0.53).