First-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: Updated results.
2013; Lippincott Williams & Wilkins; Volume: 31; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2013.31.15_suppl.8031
ISSN1527-7755
AutoresD. Ross Camidge, Lyudmila Bazhenova, Ravi Salgia, Glen J. Weiss, Corey J. Langer, Alice T. Shaw, Narayana I. Narasimhan, David J. Dorer, Victor M. Rivera, Joshua Zhang, Tim Clackson, Frank G. Haluska, Scott Gettinger,
Tópico(s)Lymphoma Diagnosis and Treatment
Resumo8031 Background: AP26113 is a novel tyrosine kinase inhibitor (TKI) that potently inhibits mutant activated forms of anaplastic lymphoma kinase (ALK+) and epidermal growth factor receptor (EGFRm), and TKI-resistant forms including L1196M (ALK) and T790M (EGFR). AP26113 does not inhibit native EGFR. Methods: The dose finding phase (3+3 design) of this phase I/II open-label, multicenter study is ongoing in pts with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Initial dosing is orally once daily. Results: As of 14 Jan 2013, 44 pts were enrolled: 30 mg n=3, 60 mg n=3, 90 mg n=8, 120 mg n=8, 180 mg n=11, 240 mg n=9, 300 mg n=2; 64% female, median age 60 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=37), other (n=7). 26 pts discontinued: 18 disease progression, 6 adverse event (AE), 2 deaths (sudden death, hypoxia; both possibly related). Most common AEs: nausea (45%), fatigue (39%), diarrhea (27%); most common grade 3/4 treatment-related AE: diarrhea (5%). 2 dose limiting toxicities observed: grade 3 ALT increase, 240 mg; grade 4 dyspnea, 300 mg. Doses <300 mg are being explored further. 21 pts had ALK+ history (18 NSCLC, 3 other). Among 18 evaluable ALK+ pts, 10 responded. 15 ALK+ pts had 0 (n=3) or 1 (n=12) prior ALK TKI (crizotinib); of these, 2/3 and 8/12 pts (67%) responded, including 2 complete responses. The longest response is 40 wks (ongoing). 4 of 5 ALK+ pts with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 pt resistant to crizotinib and LDK378 (overall response = stable disease). 16 pts had EGFRm history (15 NSCLC, 1 SCLC); 14 pts had ≥1 prior EGFR TKI. Of 12 EGFRm pts with a follow-up scan, 1 pt (prior erlotinib) responded at 120 mg (duration 21 wks, ongoing), 6 pts had stable disease (2 ongoing, duration 7-31 wks). Conclusions: AP26113 has promising anti-tumor activity in ALK+ pts, with initial evidence of activity in EGFRm pts, and is generally well tolerated. Phase II will begin after the recommended phase II dose is determined, with 4 cohorts: crizotinib-naïve NSCLC; crizotinib-resistant NSCLC; EGFR TKI-resistant NSCLC; other tumors. NCT01449461. Clinical trial information: NCT01449461.
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