Author of

• 10801

  +

  P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Medical Oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10808

    +

    P1.11-007 - Phase I study of the ALK inhibitor LDK378 in Japanese patients with advanced, ALK-rearranged NSCLC and other tumors harboring genetic ALK alterations (ID 736)

    09:30 - 09:30  |  Author(s): N. Suenaga
    • Abstract

    Background
    Genetic alterations in anaplastic lymphoma kinase (ALK), including ALK rearrangements, occur in 3–7% of NSCLC. ALK-rearranged (ALK+) NSCLC is sensitive to the tyrosine kinase inhibitor (TKI) crizotinib, but acquired resistance inevitably develops. LDK378 is a novel, potent ALK TKI, with significant preclinical antitumor activity, even in crizotinib-resistant models. An ongoing pivotal Phase I study in Western patients established the MTD as 750 mg/day, with overall response rates (ORRs) of 58% in all patients (n=114) and 57% in crizotinib-resistant patients (n=79), treated at ≥400 mg/day (Shaw, et al. ASCO 2013, Abstr 8010). The primary objective of the present study was to estimate the MTD and/or recommended dose in Japanese patients with tumors harboring ALK alterations; secondary objectives included safety, PK, and preliminary antitumor activity.

    Methods
    In this multicenter, open-label, dose-escalation study, patients with ALK alterations were enrolled. Japanese patients (ECOG PS 0–2) with locally advanced or metastatic disease that had progressed on standard therapy, or for which no standard therapy exists, were eligible. LDK378 was administered orally at doses of 300–750 mg once daily (21-day cycles, with a PK run-in period). Adaptive dose escalations were guided by a Bayesian logistic regression model with overdose control. Patients were treated until disease progression, unacceptable toxicity, or consent withdrawal.

    Results
    As of April 29, 2013, the dose-escalation part had enrolled 19 patients (median age 45 years; 11 female), including 18 patients with ALK+ NSCLC (by FISH assay) and one patient with inflammatory myofibroblastic tumor (IMT) harboring an ALK alteration. Fourteen patients with NSCLC had received prior ALK inhibitors (crizotinib, n=9; others [ASP3026 and CH5424802], n=5) and 4 patients with NSCLC were ALK inhibitor-naïve. Patients were treated at 300 mg (n=3), 450 mg (n=6), 600 mg (n=4), and 750 mg (n=6). Two DLTs occurred, at 600 mg (Grade 3 lipase increase) and 750 mg (Grade 3 drug-induced liver injury); the MTD was 750 mg. The most common AEs regardless of drug relationship were nausea (n=18, 95%), diarrhea (n=14, 74%), vomiting (n=14, 74%), blood creatinine increase (n=12, 63%), decreased appetite (n=10, 53%), and fatigue (n=7, 37%). The most common Grade 3/4 AEs were hepatic enzyme increase (n=3) and drug-induced liver injury/abnormal hepatic function (n=2). Among 18 patients with NSCLC (all doses), the ORR (confirmed responses) was 50% (95%CI 26.0─74.0; partial responses [PRs], n=9). PRs were observed in 7/9 crizotinib-pretreated patients (2 unconfirmed). In patients pretreated with other ALK inhibitors, 3/5 had a PR (including 1 who also received crizotinib, and 2/4 who received CH5424802). The patient with IMT also achieved a PR. The preliminary PK profile was similar to that seen in Western patients.

    Conclusion
    The MTD was 750 mg once daily in Japanese patients. The safety profile was tolerable and comparable to that of Western patients; gastrointestinal toxicities were most common, and the most frequent Grade ≥3 AEs were liver toxicities. LDK378 exhibited antitumor activity against ALK+ NSCLC, in both crizotinib-resistant and other ALK inhibitor-resistant patients. An expansion part will further evaluate oral LDK378 750 mg. ClinicalTrials.gov identifier NCT01634763.