Author of

• 11301

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  MO07 - NSCLC - Targeted Therapies II (ID 114)

  • Event: WCLC 2013
  • Type: Mini Oral Abstract Session
  • Track: Medical Oncology
  • Presentations: 1
  • Moderators:T. John, J.W. Riess
  • Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium B, Level 1

  • 11307

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    MO07.06 - Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies (ID 2400)

    16:45 - 16:50  |  Author(s): F.G. Haluska
    • Abstract
    • Presentation
    • Slides

    Background
    AP26113 is a novel tyrosine kinase inhibitor (TKI) that exhibits pan-ALK inhibitory activity against all 9 clinically-identified crizotinib-resistant mutants, including the L1196M gatekeeper, in preclinical experiments. AP26113 also inhibits ROS1 and selectively inhibits mutant EGFR (EGFRm) in preclinical experiments, including the T790M resistance mutation, without affecting the native receptor.

    Methods
    We report data from the dose finding component (3+3 design) of a phase 1/2 open-label, multicenter study in patients with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Dosing was once daily (QD) or twice daily.

    Results
    As of 17 April 2013, 55 patients were enrolled: 30mg (daily dose) n=3, 60mg n=3, 90mg n=8, 120 mg n=15, 180mg n=15, 240mg n=9, 300mg n=2; 62% female, median age 58 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=47), other (n=8). 33 patients discontinued: 22 disease progression, 6 adverse event (AE), 4 deaths (2 possibly related: sudden death, hypoxia), 1 withdrawal by subject. The most common AEs included fatigue (40%), nausea (36%), and diarrhea (33%), which were generally grade 1/2 in severity. The most common grade 3/4 AE was pneumonia (5%). Two patients experienced dose limiting toxicities: grade 3 ALT increase in 1 patient (240mg QD); grade 4 dyspnea and grade 3 hypoxia in 1 patient (300mg QD). Twenty-eight patients had ALK+ history (24 NSCLC, 4 other). Among 24 evaluable ALK+ patients, 15 responded. Responses were observed in 2/4 (50%) ALK+ TKI-naïve patients and 13/17 (76%) ALK+ patients with prior crizotinib therapy and no other ALK inhibitor exposure. Among ALK+ NSCLC patients with prior crizotinib only, 12/16 (75%) responded. The longest response is 40+ weeks (ongoing). 4 of 5 ALK+ patients with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 patient resistant to crizotinib and LDK378 (overall response = stable disease). CNS lesion improvements in all 4 patients are ongoing, with durations ranging from 15+ to 28+ weeks. Twenty patients had EGFRm history (19 NSCLC, 1 SCLC); 18 had ≥1 prior EGFR TKI. Of 18 evaluable EGFRm patients, 1 patient (prior erlotinib) responded at 120mg QD (duration 26+ weeks, ongoing), 7 patients had stable disease, including 4 with T790M by history (1 ongoing at 240mg QD, duration 16+ weeks). The maximum tolerated dose has not been defined; however, based on safety, efficacy, and pharmacokinetics, the recommended phase 2 dose (RP2D) is 180mg QD. Updated data will be presented.

    Conclusion
    AP26113 has promising anti-tumor activity in patients with ALK+ NSCLC and other ALK+ tumors, with initial evidence of activity in EGFRm patients, and is generally well tolerated. Five phase 2 cohorts are enrolling at the RP2D (180mg QD): 1) ALK inhibitor-naïve ALK+ NSCLC, 2) crizotinib-resistant ALK+ NSCLC, 3) single EGFR TKI-resistant NSCLC with documented T790M, 4) other tumors with AP26113 targets, 5) crizotinib-naïve or –resistant ALK+ NSCLC with active CNS metastases. Further phase 1 testing at 240mg QD will occur in EGFRm patients with documented T790M. NCT01449461

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