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A. Horiike



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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      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): A. Horiike

      • 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.

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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-006 - Long-term results of a phase II trial of S-1 and cisplatin with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (ID 1371)

      09:30 - 09:30  |  Author(s): A. Horiike

      • Abstract

      Background
      Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). S-1 has been shown to be significant efficacious for treating advanced NSCLC. Our previous phase II study reported short-term outcomes of cisplatin (CDDP)/S-1 chemoradiotherapy. Because CDDP/S-1 chemoradiotherapy is considered to have advantages over others in overall survival (OS) and toxicity, we analyzed its long-term outcomes by following up patients included in the phase II study.

      Methods
      Forty-eight patients (aged <75 years) with unresectable stage III NSCLC were evaluated. They were treated with CDDP (60 mg/m[2] on day 1) intravenously and oral S-1 (40 mg/m[2] twice daily on days 1–14); this regimen was repeated every 4 weeks for four cycles. A 60-Gy thoracic radiation dose was delivered in 30 fractions beginning on day 2.

      Results
      After a median follow-up of 6.3 years (range, 5.7–7.4 years), the median OS was 2.8 years [95% confidence interval (CI); 1.04–4.63 years], and the 3- and 5-year OS rates were 49.7% (95% CI: 35.6%–63.8%) and 33.0% (95% CI: 20.0%–46.6%), respectively. Out of the several variables evaluated as predictors of OS, including gender, age, stage, histology, and performance status (PS), only PS proved to be a statistically significant predictor in both univariate and multivariate analyses.

      Conclusion
      CDDP/S-1 concurrent thoracic radiotherapy is clinically feasible and highly efficacious. Despite our relatively small sample size, the benefits of this regimen revealed in this study warrant further research.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-020 - Sorafenib in patients with RET fusion-positive non-small cell lung cancer (ID 1717)

      09:30 - 09:30  |  Author(s): A. Horiike

      • Abstract

      Background
      RET fusions were recently identified in non-small cell lung cancer (NSCLC) and considered to be a druggable target of NSCLC. There are several small molecules which can potentially inhibit RET kinase activity. Among them, sorafenib, sunitinib and vandetanib are clinically available, and sorafenib is the most promising agent which showed potent anti-RET activity (the IC50 against RET is 0.0059-0.047 μM) in preclinical studies. However, it is difficult to evaluate the efficacy of this agent in RET-positive NSCLC in large clinical trials, because RET-positive NSCLC makes up only 1% to 2% of NSCLC cases. Therefore, we conducted a pilot study to evaluate the efficacy and feasibility of sorafenib treatment in a small number of patients with RET fusion-positive NSCLC.

      Methods
      Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an ECOG performance status (PS) 0–2, adequate organ function and provided informed consent. The RET fusion gene was confirmed by a split FISH assay. Patients received 400 mg of sorafenib orally twice daily. The treatment was continued until disease progression or unacceptable toxicity.

      Results
      From March 2012 to April 2013, three patients were enrolled. The first patient was a 62-year-old female who had stage IV NSCLC and had received three prior chemotherapy regimens (pemetrexed with cisplatin, docetaxel and erlotinib) and two courses of palliative radiation (thorax and whole brain) before being enrolled this study. The second patient was a 38-year-old male who had recurrence after thoracic surgery and had received two prior chemotherapy regimens (pemetrexed with cisplatin and docetaxel) and whole brain radiation before enrolling this study. The third patient was a 75-year-old female who had recurrence after thoracic surgery and had received one prior chemotherapy regimen (Docetaxel). The pathological diagnoses were adenocarcinoma in two patients and NSCLC not otherwise specified in one patient. Their tumors did not demonstrate any EGFR mutations or ALK fusion. The RET partner genes were KIF5B in two patients and unknown in one patient. All three patients were treated with sorafenib at 400 mg orally twice daily. Unfortunately, there was no response. The best responses to sorafenib in the patients were PD, SD and SD. In the third patient, sorafenib treatment was continued for over seven weeks. The most common toxicities were hand-foot syndrome, hypertension and diarrhea. The third patient needed a dose reduction to 400 mg once daily due to grade 3 hand-foot syndrome.

      Conclusion
      Sorafenib seems to have some efficacy for the RET fusion-positive NSCLC, but no dramatic response was observed.

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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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      P3.11-010 - Patterns of relapse and prognosis after crizotinib therapy failure in ALK+ Non-small cell lung cancer (ID 983)

      09:30 - 09:30  |  Author(s): A. Horiike

      • Abstract

      Background
      Although crizotinib which is a first-in-class oral ALK inhibitor shows dramatic response and prolonged PFS in patients with ALK(+) NSCLC, most of the patients relapsed within one year. However, patterns of relapse, prognosis, and outcome of further therapy after crizotinib failure have not been well examined.

      Methods
      We identified patients at our hospital with ALK(+) NSCLC who received and failed in crizotinib therapy.

      Results
      There were 20 patients (11 females and 9 males, with a median age 48 years). ALK fusion gene was confirmed by IHC and/or FISH (17 patients IHC+/FISH+, 3 patients FISH+). The median treatment duration of crizotonib was 4.5 months (range, 1.1-18.6 months) and the median overall survival (OS) after discontinued on crizotinib was 4.8 months; 13 patients died. At the time when crizotinib was discontinued, 2 patients (10%) had progressive disease (PD) at the primary site of disease (local recurrence), 18 patients (90%) had PD of distant metastasis and one patient had PD at both the primary site and distant metastasis. PD in CNS was observed in 9 patients. Re-biopsies after failure of criztotinib were performed in 3 patients. Two secondary mutation were identified in 2 of 3 pts (L1196M (n = 1) and G1269A (n = 1). Eleven of 20 patients received additional chemotherapy (7 cytotoxic chemotherapies and 4 ALK-inhibitor). Two of 7 patients who received cytotoxic chemotherapy (included docetaxel, S-1, cisplatin+pemetrexed+bevacizumab and carboplatin+pemetrexed) after crizotinib had PR (28.5%).

      Conclusion
      After crizotinib therapy failure, PD most commonly occurred at distant metastasis especially CNS in ALK+ NSCLC patients. Cytotoxic chemotherapy after crizotinib failure provide only minimum responses. A New effective therapeutic strategy after failure of crizotinib is necessary in ALK+ NSCLC patients.