Abstract 736: RTOG 0320:A phase III trial comparing whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) alone versus WBRT with temozolomide (TMZ) or erlotinib for non-small cell lung cancer (NSCLC) and 1-3 brain metastases
Authors: Sperduto Paul W. , Wang Meihua , Robins H. Ian , Schell Michael C. , Werner-Wasik Maria , Komaki Ritsuko U. , Souhami Luis , Buyyounouski@fccc.edu Mark K. , Khuntia Deepak , Demas William F. , Shah Sunjay A. , Nedzi Lucien A. , Perry G A. , Suh John H. , Mehta Minesh P. 
Published: August 2012

Abstract
Background: A previous phase III RTOG study subset analysis demonstrated improvement in overall survival (OS) with the addition of SRS to WBRT in NSCLC patients with 1 to 3 brain metastases. As both TMZ and erlotinib are known to cross the blood brain barrier (potentially providing radiosensitization), and have documented activity in NSCLC, a phase III study was designed to test whether either of these drugs would improve outcome of WBRT/SRS. Methods: NSCLC patients (n=126) with 1-3 brain metastases were randomized (10/2005 to 8/2009; study closed prematurely due to slow accrual) to receive WBRT (2.5 Gy x 15 to 37.5Gy) + SRS alone, vs. WBRT/SRS with TMZ (75mg/m2/D x 21) or erlotinib (150mg/D). Erlotinib or TMZ (150-200 mg/m2/D x 5/mo) could be given in the drug arms post-WBRT/SRS at the discretion of the investigator. The primary endpoint was overall survival (OS). Results: Arms were stratified by RTOG recursive partitioning analysis (RPA) class and balanced for prognostic variables including the Graded Prognostic Assessment (GPA) score. Neither the addition of erlotinib nor TMZ to WBRT/SRS resulted in an improvement in OS, or time to CNS progression compared to WBRT/SRS alone. Patients in the WBRT/SRS arm had longer MST (Median Survival Time) (13.4 mo, 95% CI = 6.5-20.8 mo.) compared to the WBRT+SRS+ erlotinib (6.1 mo, 95% CI = 3.6-12.1 mo)[Hazard ratio (≥2 / α1) and 95% CI; 1.47 (0.92 to 2.36)], or TMZ (6.3 mo, 95% CI= 3.4-10.1 mo.) [Hazard ratio (β3 / α1) and 95% CI; 1.43 (0.89 to 2.31)]. This surprising result was not related to excess toxicity. In fact, patients experiencing grade 3+ Adverse Events (AE) appear to have longer OS than those patients without grade 3+ AE for both drug arms. The WBRT/SRS arm had significantly less deterioration in performance status at 6 mo. There were no significant differences between arms for steroid dependence at 6 mo, or causes of death. Conclusion: The addition of either TMZ or erlotinib to WBRT/SRS in this unselected population of NSCLC patients with 1-3 brain metastases provided no clinical advantage. Treatment with WBRT/SRS alone appeared to result in superior outcome data (compared to the addition of TMZ or erlotinib) relative to OS in this limited data set. Detailed analysis to date provides no obvious explanation for these unexpected results. Support: RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 736. doi:1538-7445.AM2012-736