Phase I/II study of rilotumumab (R) and erlotinib (E) in previously treated patients (pts) with metastatic NSCLC.

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8092 Background: MET is frequently overexpressed in NSCLC. Amplification of MET and its ligand (HGF), are mechanisms of resistance to EGFR inhibitors. R is an IgG2 human mAb that targets HGF. This phase I/II trial evaluated the safety and recommended phase 2 dose (RP2D) of R combined with E for pts with metastatic previously treated NSCLC (Phase I) and whether efficacy is high enough to warrant further interest (Phase II). Methods: Phase I adopted a dose de-escalation design with R starting at 15 mg/kg IV every 3 weeks and E 150 mg orally daily (dose level 0). If dose de-escalation was needed it would proceed according to Narayana k-in-a-row design where a selected dose was estimated by isotonic regression. RP2D was the maximum below the dose associated with a 25% DLT rate. Phase II intended to test whether disease control rate (stable disease or response, DCR) of 50% for E could be improved by adding R. A Simon 2 stage design was used to select the optimal sample size for type I and II error of .10. Twenty-seven of 45 pts were required to have disease control for evidence of a statistically significant improvement over E alone. Response was assessed by RECIST every 6 weeks. Results: In the absence of need for de-escalation among the first 8 pts, the RP2D was defined as dose level 0. Overall, 45 response-evaluable pts with stage IV were enrolled (13 squamous and 32 adenocarcinoma; 2 EGFR and 7 KRAS mutant). Median age was 65 years. A median of 4 cycles (range 1-18+) were administered. Four pts had partial response (one with EGFR and one KRAS mutation), 23 had SD, and 18 had progression, for a response rate of 8.9% (90% CI, 3.9 - 18.1) and DCR of 60% (90% CI, 47.1 - 71.3). Median PFS 2.6 months (90% CI 1.4- 2.7). At a median follow up of 15 months, median OS was 6.6 months (90% CI, 5.6 - 8.9). Probability of surviving one year was .33 (90% CI, .23 - .47). Among grade 3/4 AEs that were considered at least possibly related were rash (3), oral mucositis (1), elevated alkaline phosphatase (3) and bilirubin (1), thromboembolic event (3), diarrhea (5). Conclusions: The combination of R and E in this study was found to have an acceptable safety profile and the DCR rate met the study’s pre-specified criteria for success. Further investigation of this regimen is warranted. Clinical trial information: NCT01233687.

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