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S. Yokoyama



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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      O16.06 - A phase 1 dose escalation study of a new ALK inhibitor, CH5424802/RO5424802, in ALK+ Non-Small Cell Lung Cancer (NSCLC) patients who have failed crizotinib (AF-002JG/NP28761, NCT01588028). (ID 1661)

      11:25 - 11:35  |  Author(s): S. Yokoyama

      • Abstract
      • Presentation
      • Slides

      Background
      Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitutively activated following chromosomal translocation in 3-7% of non-small cell lung cancer (NSCLC). These patients usually respond to the ALK inhibitor crizotinib with a median duration of response around 10 months. CH5424802 is a more potent and specific ALK inhibitor that is being studied as a treatment for NSCLC patients with ALK gene rearrangement.

      Methods
      A phase 1 dose escalation study of CH5424802 was performed using 3+3 study design in NSCLC patients who failed crizotinib. The primary endpoint was dose limiting toxicity, and the secondary endpoints were efficacy, safety and pharmacokinetic (PK) analyses. Key eligibility criteria include prior progression on crizotinib, ECOG 0-2, adequate organ functions, confirmed ALK-rearrangement by an FDA approved test. Patients with symptomatic CNS metastases required treatment before participating. CH5424802 was administered orally at doses of 300, 460, 600, 760 and 900 mg BID until lack of clinical benefits. Intensive PK sampling was performed. Efficacy was assessed by RECIST criteria v1.1. Toxicities were evaluated by CTCAE v4.0.

      Results
      37 NSCLC patients who have failed crizotinib and chemotherapy were enrolled in the study from 6 US sites from May 2012 to May 2013. No DLTs were observed up to the highest dose tested (900 mg BID). Only 1 patient required dose modification due to grade 2 fatigue. The most common AEs were fatigue, CPK increase, myalgia, cough, ALT increased, peripheral edema and rash. Grade 3/4 AEs include GGT increase (n=3), neutrophil decrease (n=2), hypophosphatemia, hyperglycemia, syncope, renal failure and pericardial effusion (n=1 each), but no grade 3 nausea, vomit, diarrhea, edema were reported. Preliminary efficacy was observed with PR 48% and SD 34% by investigator assessment amongst the 30 evaluable patients (See Figure of Waterfall plot). Median progression-free survival has not been reached with 27 patients (73%) remaining on study as of June 10, 2013 (median duration 85 days, range 39-347+ days). CNS activity was observed and described in the companion abstract by Ou et al. CH5424802 single dose half-life was approximately 22 hr, AUC was dose-dependent from 300 to 600 mg BID following multiple doses with a potential plateau at doses higher than 600 mg BID based on available data.Figure 1

      Conclusion
      CH5424802 is a well-tolerated ALK inhibitor with no DLTs observed up to the highest dose tested in this study. Promising anti-tumor activity was observed in patients who have failed crizotinib.

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      O16.07 - Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer (NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761, NCT01588028). (ID 1668)

      11:35 - 11:45  |  Author(s): S. Yokoyama

      • Abstract
      • Presentation
      • Slides

      Background
      Disease progression in brain occurs in ~50% ALK-rearranged NSCLC patients treated with crizotinib. This is likely due in part to low penetration of crizotinib into CNS. CH5424802 is a new ALK inhibitor that is effective in patients who have ALK re-arrangement. Preclinical studies in CNS implantation models suggest a promising anti-tumor activity of CH5424802 against CNS lesions. This report describes CNS activity observed in an ongoing phase I/II clinical trial.

      Methods
      A phase I dose escalation study of CH5424802 was performed in ALK-rearranged NSCLC who have failed crizotinib. Patients received oral CH5424802 doses ranging from 300 to 900 mg BID. All patients had head CT/MRI and body CT scans at baseline, and every 6 weeks after initiation of treatment if baseline scans are positive for brain metastasis. Brain lesions without prior radiation were used to assess CNS response based on modified RECIST criteria. Simultaneous collection of cerebrospinal fluid (CSF) and plasma PK samples in selective patients is ongoing to evaluate CSF/plasma CH5424802 ratios to correlate with clinical activity in brain metastasis.

      Results
      As of June 6, 2013, 37 patients were enrolled in the phase I study, and 31 of them were evaluable for efficacy. Preliminary overall response rate (ORR) is ~48% (15/31) in evaluable patients. 16 had brain metastases at baseline, and 2 had no prior brain irradiation but all had documented CNS progression prior to study treatment. These 16 patients received CH5424802 at 300mg (n=2), 460mg (n=2), 600mg (n=5), 760mg (n=3), and 900mg (n=4) BID. The median duration of follow-up of these 16 patients was 130+ days, with the longest being 347+ days. Activity against CNS lesions was observed as early as the first scan (3[rd] week). The preliminary CNS response is highly promising as shown in the representative scans below. Enrollment is still ongoing and CNS progression-free survival (PFS) will be presented. Currently 2 patients had simultaneous CSF and plasma levels of CH5424802, and the CSF/plasma ratios will be reported to evaluate any correlation between CSF/plasma ratios and the observed clinical activity of CH5424802 in brain metastasis.Figure 1

      Conclusion
      CH5424802 demonstrates consistent and rapid clinical activity in brain metastases in ALK+ NSCLC patients who progressed on crizitinib. Within 3-6 weeks of treatment, CH5424802 dramatically shrinks brain lesions that progressed on crizotinib. CH5424802 could potentially replace or delay the need of brain radiation in ALK-positive NSCLC patients.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-034 - One-year follow-up of a Phase I/II study of a highly selective ALK inhibitor CH5424802/RO5424802 in ALK-rearranged advanced non-small cell lung cancer (NSCLC) (ID 2591)

      09:30 - 09:30  |  Author(s): S. Yokoyama

      • Abstract

      Background
      CH5424802 is a novel tyrosine-kinase inhibitor that selectively inhibits ALK as well as secondary ALK mutations including L1196M. The preliminary results of the Phase I/II study (Lancet Oncol. 2013; 14: 590–8) showed that CH5424802 was active in the CNS and achieved a 93.5% objective response rate by RECIST in crizotinib-naïve NSCLC patients with a median follow-up of 7.6 months (range, 3.4–11.3). Here we report the 1-year follow-up results after the last patient enrolled in the Phase II analysis.

      Methods
      Patients with ALK-rearranged advanced NSCLC, who progressed after ≥1 prior chemotherapy regimens and who were naïve to any ALK inhibitors, received CH5424802 300 mg orally twice daily in the Phase II portion of the study. ALK fusion gene expression was confirmed by IHC and FISH or by RT-PCR at central laboratories. Tumor assessment was performed every cycle (21 days) until Cycle 4 and every 2 cycles thereafter with RECIST ver. 1.1.

      Results
      As of April 18, 2013, 46 patients had been treated with CH5424802 in the Phase II portion: median age, 48 years (range, 26–75); male/female, 22/24; ECOG PS 0/1, 20/26; never-smoker, 59%; ≥2 prior chemotherapy regimens, 52%. The objective response rate remains the same as previously reported, 93.5% (95% CI: 82.1% to 98.6%). At 1-year follow-up, a total of 7 patients (15%) had achieved a complete response. The median progression-free survival had not been achieved, and the 1-year progression-free rate (PFR) was 83% (95% CI: 68% to 92%). 34/46 patients were still on study treatment, and the median treatment duration had passed 14.8 months. CH5424802 also shows promising efficacy in the CNS: of 14 patients with baseline brain metastasis, 9 remained in the study without CNS or systemic progression for >12 months, with 6 of them exceeding 16 months. The other 5 patients with baseline CNS metastasis had no CNS progression during CH5424802 treatment. One of these patients discontinued the study due to AE, and the remaining 4 patients had systemic progression. The safety profile remains similar to that previously reported, with no patient requiring dose reduction.

      Conclusion
      CH5424802 demonstrated a high 1-year PFR of 83% and promising CNS activity. CH5424802 could be a novel therapeutic option for the treatment of ALK-rearranged NSCLC.