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

Abstract

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]