Axitinib (AG-013736; AG) combined with chemotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) and other solid tumors

Abstract

3559 Background: AG is an oral, potent and selective inhibitor of VEGFRs 1, 2, 3. Anti-VEGF therapies combined with chemotherapy improve survival vs chemotherapy alone in pts with advanced solid tumors, including NSCLC. This phase I trial assessed AG combined with chemotherapy. Methods: Pts with advanced solid tumors without prior treatment with platins or taxanes received paclitaxel/carboplatin (P: 200 mg/m2 / C: AUC 6 mg*min/mL) every 3 weeks + AG at lead-in doses of 1, 3 or 5 mg BID. AG was increased to 5 mg BID post lead-in. Another cohort of pts with any prior chemotherapy for metastatic disease received AG 5 mg BID + gemcitabine/cisplatin (G: 1250 mg/m2 on days 1 and 8 / Cis: 80 mg/m2 on day 1) in 3-week cycles. For all cohorts, cycle 1 consisted of a 3–5-day lead-in period followed by AG for 18 days. On day 19, AG was held and then continued without interruption on day 3, cycle 2. Following determination of the maximum tolerated doses (MTDs) of AG + P/C or G/Cis, pts with squamous NSCLC were enrolled into an expansion cohort (prior anti-VEGF therapy not permitted) and received AG 5 mg BID + P/C. Dose-limiting toxicities (DLTs), adverse events (AEs), objective response rate (ORR), and pharmacokinetics (PK) were evaluated. Results: A total of 47 pts were enrolled; 26 pts were evaluable in the P/C cohort (including 12 pts with squamous NSCLC) and 21 pts in the G/Cis cohort. The MTD for AG in combination with standard doses of P/C and G/Cis was 5 mg BID. DLTs included fatigue, proteinuria and rash (1 each). Treatment-related AEs included hypertension (42%), diarrhea (35%) and fatigue (35%) in the P/C cohort, and headache (29%), hypertension (29%) and fatigue (24%) in the G/Cis cohort. There was no grade ≥3 hemoptysis among 12 pts with squamous NSCLC. The ORR was 29% and 26% for P/C (n = 24) and G/Cis (n = 19) cohorts, respectively. AG, P, C, G and Cis PK parameters and profiles were similar when administered alone and in combination (eg P: mean (%CV) AUCinf 20,822 (21) and 20,596 (21) ng.h/mL, respectively). Conclusions: AG 5 mg BID can be combined with standard P/C and G/Cis regimens with no apparent overlapping toxicities and unaltered PK. Both combinations have antitumor activity. In pts with squamous NSCLC, AG + P/C was well tolerated with no evidence of grade ≥3 hemoptysis. [Table: see text]