Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer

M Nishio, T Horai, A Horiike, H Nokihara, N Yamamoto, T Takahashi, H Murakami, N Yamamoto, F Koizumi, K Nishio, W Yusa, N Koyama, T Tamura, M Nishio, T Horai, A Horiike, H Nokihara, N Yamamoto, T Takahashi, H Murakami, N Yamamoto, F Koizumi, K Nishio, W Yusa, N Koyama, T Tamura

Abstract

Background: This dose-finding study evaluated lenvatinib, an oral multitargeted receptor tyrosine kinase inhibitor, in combination with carboplatin/paclitaxel in chemotherapy-naïve non-small-cell lung cancer (NSCLC) patients.

Patients and methods: Patients received lenvatinib twice daily (BID) with carboplatin (area under the curve 6 mg ml(-1) min(-1), day 1)/paclitaxel (200 mg m(-2), day 1) every 3 weeks. The initial dose of lenvatinib was 6 mg BID. The primary end point was maximum tolerated dose (MTD) of lenvatinib. At the MTD, the cohort was expanded by 16 patients. Safety, pharmacokinetics, pharmacodynamics, and antitumor effects were evaluated.

Results: Twenty-eight patients were treated. At 6 mg BID, dose-limiting toxicities (DLTs) included febrile neutropenia/gingival infection (n=2). No DLTs occurred with 4 mg BID, the recommended MTD for the expansion. Common grade 3/4 toxicities included neutropenia, leukopenia, hypertension, and thrombocytopenia. The combination had no significant impact on individual drug pharmacokinetics. Response rate and median progression-free survival were 68% and 9.0 months, respectively, with 4 mg BID. In the plasma biomarker analysis, stromal cell-derived factor 1α, stem cell factor, and granulocyte colony-stimulating factor correlated with antitumor activity.

Conclusion: The MTD for lenvatinib with carboplatin/paclitaxel is 4 mg BID in advanced NSCLC patients. This regimen demonstrated manageable tolerability and encouraging antitumor activity.

Trial registration: ClinicalTrials.gov NCT00832819.

Figures

Figure 1
Figure 1
Waterfall plot of per cent change in sum of the longest diameters of target lesion from baseline to the nadir (n=26). CR=complete response; NE=not evaluable; PD=progressive disease; SD=stable disease.

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