| Summary: | <b>Background:</b> Resistance to chemotherapy in progressive NSCLC is associated with overexpression of antiapoptotic proteins including survivin. Down-regulation of survivin can sensitize NSCLC to DO in vitro and in xenograft studies. On the basis of preclinical/phase I results we examined antitumor activity of DO+LY compared with DO alone. <b>Methods:</b> Key eligibility criteria: ECOG PS 0-1, stage IIIB/IV NSCLC all histologies, progression after first-line platinum regimen. Patients randomized (N=180) 2:1 to receive DO+LY (LY 750 mg IV loading ×3, Q1W maintenance) or DO alone (75 mg/m2 D1Q3W) until progression/toxicities. Antitumor activity was compared using CTS from baseline to end of cycle (C) 2 in each arm. This analysis, which uses tumor measurements as a continuous variable rather than a categorical endpoint based on RECIST, increases statistical efficiency and enables early assessment of clinical benefit. Secondary objectives included assessment of toxicity, PK, PFS and OS. <b>Results:</b> 114 patients received study drug and were included in the analyses. Baseline patient demographics were similar. No statistically significant difference in mean CTS ratio at C2 or in PFS was observed between the 2 arms: CTS was 1.07 with LY+DO (SD, 0.28) and 1.04 with DO (SD, 0.28); median PFS was 2.83 mo (95% CI, 1.84–3.65) with LY+DO and 3.35 mo (95% CI, 2.69–4.57) with DO (log-rank p=0.191). However, Cox regression revealed CTS to be a statistically significant factor for PFS: decreased CTS was associated with increased PFS (HR 0.45; 95% CI, 0.30–0.68, p=0.0001). Median OS was 7.9 mo (90% CI, 6.6–9.7) with LY+DO and 8.8 mo (90% CI, 5.7–13.8) with DO (log-rank p=0.481). There were no differences in toxicities or other secondary parameters. Incidence of grade III/IV toxicities was similar in both arms and was consistent with the known profile of LY+DO as was the PK profile. <b>Conclusions:</b> Addition of LY to DO did not improve the antitumor activity of DO. CTS appears to be a useful endpoint in phase II studies and should be considered further as an endpoint for early decision-making. Clinical trial information: NCT01107444.
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