Background: Cabo inhibits tyrosine kinases including MET, VEGF receptors, AXL, and RET. The primary objective of this phase 1 study was to establish the recommended phase 2 dose (RP2D) of Cabo in Japanese pts; secondary objectives included assessment of safety, pharmacokinetics, and preliminary evidence of anti-tumor activity. Results from the dose escalation (DE) portion of the study have been previously reported. The final results of the study are presented, including data from expansion cohorts (ECs) in NSCLC with defined molecular alterations involving known driver oncogenes.

Methods: Pts with advanced solid malignancies were enrolled in successive cohorts to receive escalating doses of Cabo orally once daily in a 3+3 design using capsule or tablet formulations. The RP2D was previously determined to be 60 mg qd tablet. Based on responses observed in pts with NSCLC, 3 molecularly defined NSCLC ECs were planned at the RP2D: EC1) pts with mutant EGFR and previous treatment with an EGFR inhibitor, EC2) pts with KRAS mutations, and EC3) pts with rearranged ALK (and previous treatment with an ALK inhibitor), RET, or ROS1. Tumor assessments per RECIST were performed on study day 29, and every 8 weeks thereafter until discontinuation of study treatment.

Results: Forty three total pts were enrolled. Twenty three pts were enrolled in the DE cohorts, including 9 pts with NSCLC. Twenty pts were enrolled in the NSCLC ECs: 15 pts in EC1, 2 pts in EC2, and 3 pts in EC3 (n = 1 ALK+, n = 2 RET+). The median duration of treatment was 28.1 (3-156) weeks (wks) in the DE cohorts, and 13.3 (4-49) wks in the NSCLC ECs. Grade 3-4 AEs experienced by ≥3 pts were gamma glutamyl transferase increase (n = 4), hypertension (n = 3), and lymphopenia (n = 3) in the DE cohorts, and hypertension (n = 6), neutropenia (n = 5), alanine aminotransferase increase (n = 3), hand foot syndrome (n = 3), hypophosphatemia (n = 3), and dyspnea (n = 3) in the ECs. Serious AEs in ≥3 pts were dyspnea (n = 3), lung infection/pneumonia (n = 3), and pleural effusion (n = 3). The final PK analysis demonstrated that Cabo plasma exposures in Japanese pts were approximately 34% higher than reported previously in non-Japanese pts at the 60 mg tablet dose, and were within the range of inter-subject variability (%CV: 34% Japanese; 48% non-Japanese). Objective responses were observed in NSCLC pts: 4/9 NSCLC pts enrolled in the DE cohorts had a confirmed partial response (cPR) (2 pts ALK+, 1 pt RET+, 1 pt EGFR+), and 4/20 pts enrolled in the NSCLC EC cohorts had a cPR (all 4 pts were in EC1 [EGFR+]). Best change in sum of longest diameters (SLD) for all NSCLC pts with measureable disease (n = 28) ranged from 0 - 82% decrease (median = 24% decrease). For pts with a cPR, the time to initial response ranged from 4 - 20 wks and time from response to radiographic progression ranged from 4 - 64 wks.

Conclusions: The RP2D of Cabo in Japanese pts was determined to be 60 mg. The safety and pharmacokinetic profiles are consistent with data from studies in non-Japanese pts. Antitumor activity with Cabo has been observed, including in pts with molecularly-defined NSCLC.

Citation Format: Hiroshi Nokihara, Makoto Nishio, Noboru Yamamoto, Yutaka Fujiwawa, Hidehito Horinouchi, Shintaro Kanda, Asushi Horiike, Fumiyoshi Ohyanagi, Yifah Yaron, Anne Borgman, Tomohide Tamura. Final results of a phase 1 study of cabozantinib (Cabo) in Japanese patients (pts) with expansion cohorts in non-small cell lung cancer (NSCLC) with defined molecular alterations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B179.