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H. Murakami



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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): H. Murakami

      • 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): H. Murakami

      • 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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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-021 - The effect of gefitinib in patients with postoperative recurrent non-small cell lung cancer harbouring mutations of the epidermal growth factor receptor. (ID 1367)

      09:30 - 09:30  |  Author(s): H. Murakami

      • Abstract

      Background
      For patients with postoperative recurrent non-small cell lung cancer (NSCLC) harbouring mutations of the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitor, such as gefitinib, is frequently used in clinical practice, in accordance with the treatment for patients with stage IV NSCLC. However, it is unclear whether there is a difference in effect of gefitinib between patients with postoperative recurrent NSCLC and patients with stage IV NSCLC, harbouring EGFR mutations.

      Methods
      We reviewed consecutive patients with postoperative recurrent or stage IV (at diagnosis) NSCLC harbouring EGFR mutations, who were treated with gefitinib at the Shizuoka Cancer Center between September 2002 and March 2012. The clinical data of the patients were obtained from their medical records, and retrospectively reviewed. The baseline patient characteristics, response to gefitinib, and survival were compared between patients with postoperative recurrent NSCLC (postoperative group) and patients with stage IV NSCLC at diagnosis (stage IV group). Patients were not included if they had received other EGFR tyrosine kinase inhibitors before administration of gefitinib.

      Results
      A total of 169 patients met the eligibility criteria for this study (postoperative group; 50, stage IV group; 119). The baseline characteristics (sex, age, histology, EGFR mutations status, prior cytotoxic chemotherapy) were well balanced between both groups, with the exception of performance status (PS). Patients in postoperative group had better PS than those in stage IV group (p = 0.044). At the start of treatment with gefitinib, bone and liver metastases were more common in stage IV group (p = 0.002 and p = 0.032), and pulmonary metastases were more common in postoperative group (p = 0.004). There was no significant difference in number of metastatic sites between two groups. The response rate of gefitinib in postoperative group was similar to that in stage IV group (58 vs 61%, p = 0.685). In contrast, progression free survival (PFS) (median PFS 16.7 vs 9.8 months, p < 0.001) and overall survival (OS) (median OS 63.3 vs 23.9 months, p < 0.001) were significantly longer in postoperative group than in stage IV group. Additionally, postoperative recurrent disease, PS (0-1) and single metastatic site were independent prognostic factors in the multivariate analysis of survival.

      Conclusion
      PFS and OS were superior in patients with postoperative recurrent NSCLC harbouring EGFR mutations treated by gefitinib than in those with stage IV disease. These results suggest, postoperative recurrent disease may be considered to be a stratification factor in clinical trial for NSCLC with EGFR mutations.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-012 - Pharmacogenetic study of Japanese patients with advanced non-squamous non-small cell lung cancer treated with pemetrexed plus cisplatin (ID 1407)

      09:30 - 09:30  |  Author(s): H. Murakami

      • Abstract

      Background
      Pemetrexed (PEM) inhibits multiple enzymes in the folate (F) pathway. Several studies show that genetic polymorphisms in these enzymes influence the efficacy and toxicity of PEM. We aimed to investigate the relationship between genetic polymorphisms associated with the F pathway and clinical outcomes of Japanese patients with advanced non-squamous non-small cell lung cancer (NSQ-NSCLC) treated with PEM plus cisplatin (CIS).

      Methods
      We analyzed 34 polymorphisms in 14 genes associated with the F pathway in NSQ-NSCLC patients treated with PEM plus CIS: ABCC11, ADA, ATIC, DHFR, ERCC1, FPGS, GGH, MTHFD1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, and TYMS. These polymorphisms were compared with clinical outcomes such as response, toxicity, and progression-free survival (PFS) using Pearson’s χ[2] test and the log-rank test.

      Results
      All 56 patients were Japanese, with a median age of 62 years; 57.1% were male, 96.4% had an Eastern Cooperative Oncology Group Performance Status of 0–1, 96.4% had stage IV disease, and 94.6% had adenocarcinoma. The response rate, disease control rate, and median PFS were 32.2%, 78.6%, and 4.7 months, respectively. Of the 38 polymorphisms tested, none were associated with response or toxicity, but 2 single nucleotide polymorphisms (SNPs) (in the gamma-glutamyl hydrolase [GGH 452C>T] and methionine synthase [MTR 2756A>G] genes) were significantly associated with PFS. Patients harboring the GGH-C452C variant had significantly longer PFS (5.6 vs 2.8 months; p < 0.0001) than those with the C452T or T452T variants. Further, patients harboring the MTR-A2756A variant had significantly longer PFS (5.3 vs 3.7 months; p = 0.036) than those with the A2756G variant. In addition, among patients with the GGH-C452C variant, those harboring the MTR-A2756A variant had significantly longer PFS (5.9 vs 4.3 months; p = 0.044) than those with the A2756G variant.

      Conclusion
      SNPs in GGH and MTR seem to predict differences in PFS in NSQ-NSCLC patients treated with PEM plus CIS, and a combination of these 2 SNPs may predict differences in PFS more accurately. These results should be validated in larger, adequately designed prospective studies.

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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): H. Murakami

      • 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.