Background: Advanced NSCLC pts with Zubrod PS2 are often excluded from clinical trials and platinum-based therapy. In SWOG 0341, ERL in PS 2 pts yielded progression-free (PFS) and overall survival (OS) of 2.1 and 5 months respectively. In a trial of ERL versus C/T in PS2 pts (Lilenbaum, JCO 2008), PFS for ERL and C/T were 1.9 and 3.5 months. Early reports suggested a potential role for serum proteomics in predicting ERL benefit beyond that of EGFR mutational status. We conducted a trial in PS2 pts enriched by serum proteomics (Veristrat-good). Methods: NSCLC pts with PS2 and Veristrat-good status were randomized to either Arm A (ERL 150 mg po QD) or Arm B (ERL 150 mg po QD d2-16 + carbo AUC 5 IV day 1, paclitaxel 200 mg/m2 IV d1 x 4 cycles, then ERL 150 mg QD). Cycles were q3 weeks. Arm B agents were pharmacodynamically separated to mitigate potential antagonism. The arm with superior observed median PFS would be selected for further evaluation, but only if ≥ 3 months. A sample size of 98 pts was based on a variety of assumed PFS probabilities for each arm. The trial prematurely closed after the FDA determined an IDE application was required for VeriStrat; however SWOG had limited resources available for such filing. Results: Of 156 pts screened, 83 (59%) were Veristrat-good, of which 59 (60%) met trial eligibility & were randomized. Treatment-related grade 4 adverse events were seen in 2 pts in Arm A (DVT, hypoMg+); 5 pts in Arm B (neutropenia 5, febrile neutropenia 1, leukopenia 1). Conclusions: In PS2 pts with advanced NSCLC and Veristrat-good status, ERL + C/T (vs. ERL alone) had better observed median PFS/OS and surpassed the protocol-specified benchmark of PFS >= 3 months required for further study. Clinical trial information: NCT00661193

*Subset w/ measurable disease at baseline.