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Isamu Okamoto



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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-34 - Docetaxel Plus Ramucirumab with Prophylactic PEG-G-CSF Support for Chemo-NaïVe Elderly NSCLC Patients: A Phase II Study (WJOG9416L) (ID 12400)

      16:45 - 18:00  |  Author(s): Isamu Okamoto

      • Abstract

      Background

      Docetaxel monotherapy is the standard of care for chemo-naïve Japanese elderly patients with advanced non-small cell lung cancer (NSCLC), according to our results of phase III trial comparing docetaxel and vinorelbine monotherapies (WJTOG9904). In a pivotal phase III study (REVEL), docetaxel plus ramucirumab demonstrated superior response rate (RR) and progression-free survival (PFS) over docetaxel monotherapy in second-line setting for advanced NSCLC. These differences in RR and PFS were translated into overall survival (OS) benefit. This evidence prompted us to investigate docetaxel plus ramucirumab for chemo-naïve elderly patients. However, in a similarly designed Japanese randomized phase II trial (JVCG trial), febrile neutropenia (FN) was observed in 34.2% of docetaxel plus ramucirumab arm. This high incidence of FN is a clinical concern when using docetaxel plus ramucirumab for elderly patients. The ASCO practice guideline recommends primary prophylactic granulocyte-colony stimulating factor (G-CSF) when the risk of FN is 20% or higher. PEGylated-G-CSF (pegfilgrastim) administered once a cycle demonstrated reduction of FN incidence in many types of cancers. Based on the above background, we considered that primary prophylactic PEG-G-CSF would be beneficial for elderly NSCLC patients who received docetaxel plus ramucirumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a prospective multicenter, single-arm, phase II study conducted by West Japan Oncology Group (WJOG). Main inclusion criteria includes: chemo-naïve; aged ≥75; histologically or cytologically confirmed NSCLC; ECOG PS 0/1; adequate organ functions; with measurable disease; without contraindication of ramucirumab; written informed consent; and estimated life expectancy of at least 3 months. Intravenous docetaxel (60 mg/m2, day 1) plus ramucirumab (10 mg/kg, day 1) with subcutaneous PEG-G-CSF (3.6 mg, day 2) every 3 weeks is administered until progression. Continuous docetaxel or ramucirumab monotherapy is permitted when intolerable toxicities occur but clinical benefit is obtained by each drug. The primary endpoint is objective response rate (ORR). Secondary endpoints are PFS, OS, disease control rate, and safety. We assumed that the threshold and expected ORR were 20% and 35%, respectively. Based on this, the number of patients was calculated to be 59 to provide a power of 80% with probability of one-sided type I error being 0.05. Taking ineligible patients into account, the sample size was set at 65. When the study results are promising, we plan to conduct a phase III trial to compare docetaxel plus ramucirumab with PEG-G-CSF support vs. docetaxel monotherapy for chemo-naïve elderly NSCLC patients. Clinical trial information: UMIN000030598.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion


      Section not applicable

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    P1.14 - Thymoma/Other Thoracic Malignancies (Not CME Accredited Session) (ID 946)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.14-03 - Phase II Trial of Amrubicin and Cisplatin Chemotherapy for Invasive Thymoma: WJOG5509L (ID 11706)

      16:45 - 18:00  |  Author(s): Isamu Okamoto

      • Abstract

      Background

      Background: Platinum and anthracycline combination chemotherapy has been considered as the standard treatment for invasive thymoma for a long time. The clinical activity of amrubicin (AMR)—an anthracycline agent—has been previously reported in the treatment of small cell lung cancer (SCLC). The aim of this study was to evaluate the efficacy and safety of the combination of AMR and cisplatin (CDDP) in patients with advanced or recurrent invasive thymoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Methods: Patients were eligible for inclusion in the study if they met the following criteria: were chemo-naive; not amenable to curative surgery or radiotherapy; and presented with histologically confirmed invasive thymoma in each site. The patients received AMR (35 mg/m2, on days 1–3) and CDDP (60 mg/m2, on day 1) every 3 weeks, for up to 4 cycles. The primary endpoint was the objective response rate (ORR) assessed by an independent review, and the secondary endpoints were overall survival (OS) and toxicity profile of the patients. Based on the SWOG 2-stage design, the planned sample size of 40 patients was determined to reject the ORR of 60% under the expectation of 80% with a power of 0.85 and a type I error of 0.05. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000003933.

      4c3880bb027f159e801041b1021e88e8 Result

      Results: From August 2010 to November 2014, a total of 26 patients were enrolled at 14 institutions in Japan. During the planned interim analysis in April 2014, the ORR of the 20 patients who had been enrolled so far, was assessed via independent review and found to be 55.6% (11/20), resulting in the early termination of this study because of its futility. In the final assessment, the ORR was 54.2% (95% confidence interval, 32.8–74.4) and the disease control rate was 95.8%. The OS did not reach the median value. The major grade 3 or 4 toxicities noted were neutropenia (96.2%), anemia (26.9%), anorexia (11.5%) and febrile neutropenia (26.9%), albeit these were transient and manageable. There was one treatment-related death.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusions: The combination of AMR with CDDP had minimal activity on invasive thymoma. Thus, we do not recommend further study of this regimen.

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    P1.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 948)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.16-21 - Phase I / II Study of Carboplatin, Nab-Paclitaxel, and Concurrent Radiotherapy for Patients with Locally Advanced NSCLC (ID 12112)

      16:45 - 18:00  |  Author(s): Isamu Okamoto

      • Abstract

      Background

      We performed an open-label, multicenter phase I/II study (UMIN ID 000012719) to prospectively evaluate the efficacy and safety of the combination of nab-paclitaxel plus carboplatin (nab-P/C) with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the phase I study (standard 3+3 design), escalating doses of weekly nab-paclitaxel were given along with weekly carboplatin area under the plasma concentration time curve (AUC) 2 and concurrent radiotherapy 60 Gy in 30 fractions, followed by 2 cycles of nab-paclitaxel (100 mg/m2 on Days 1, 8 and 15) plus carboplatin (AUC 6 on Day 1). In the phase II study, nab-P/C at recommend dose (RD) was administered.

      4c3880bb027f159e801041b1021e88e8 Result

      In the Phase I study, 11 patients were enrolled with 9 evaluable for dose limiting toxicity (DLT). At level 1 (nab-paclitaxel 40mg/m2), none of 3 patients experienced DLT. At level 2 (nab-paclitaxel 50mg/ m2), 1 of 6 patients experienced DLT: grade 3 leukopenia requiring a second consecutive skip in the administration of weekly nab-P/C. Level 2 was defined as the RD. A total of 56 patients including 6 patients who received at dose of RD, were evaluable for the efficacy and safety. Of the 56 patients for safety analysis, common toxicities in the concurrent phase included grade 3/4 leukopenia (60.7 %), neutropenia (26.8 %), anemia (7.1 %), anorexia (7.1 %), esophagitis (5.4 %) and febrile neutropenia (1.8 %). In one patient, grade 3 pneumonitis was observed. There were no treatment-related deaths. The objective response rate was 76.8 % (95% confidence interval (CI), 64.2 to 85.9 %). The median progression-free survival was 11.8 months (60% CI, 10.6 to 16.2 months, 95% CI, 8.2 to 20.8 months), and the median overall survival was not reached.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the first study to demonstrate encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel 50 mg/m2 and CBDCA AUC 2 in patients with locally advanced NSCLC.

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-18 - A Multicenter Prospective Biomarker Study to Explore Mechanisms of Afatinib Resistance Based on Digita PCR and Next-Generation Sequencing (ID 12187)

      16:45 - 18:00  |  Author(s): Isamu Okamoto

      • Abstract

      Background

      Afatinib is an oral irreversible blocker of ErbB-family kinases and shows a pronounced anti-tumor efficacy for advanced non–small cell lung cancer (NSCLC) positive for activating mutations of EGFR. We applied digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) to explore mechanisms of afatinib resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations. Tumor and plasma samples were collected before afatinib treatment and after treatment failure with disease progression (systemic progressive disease, SPD). DNA from the samples was analyzed by dPCR and NGS.

      4c3880bb027f159e801041b1021e88e8 Result

      Thirty-five patients were enrolled, with a median follow-up time of 15.8 months. Among 25 patients with SPD, tumor, plasma, or both samples were available for 18, 23, and 16 individuals, respectively. dPCR and NGS detected EGFR T790M mutation in 13 (56.5%) and 11 (47.8%) of 23 plasma samples at SPD, with sensitivity and specificity compared with tumor samples being 83.3% and 70.0% (dPCR) and 50.0% and 70.0% (NGS), respectively. Applying the ratio of the number of T790M alleles to that of activating mutations (T/A) for determination of the T790M positivity improved the sensitivity and specificity of plasma analysis compared with tumor analysis to 83.3% and 100% (dPCR) and 57.1% and 100% (NGS), respectively. Among 25 patients with SPD, the T790M mutation of EGFR alone (n = 11), copy number gain (CNG) of NRAS (n = 1), CNG of MET (n = 1), CNG of EGFR plus T790M (n = 1), and CNG and E545K of PIK3CA plus T790M of EGFR (n = 1) were identified by NGS as putative resistance mechanisms against afatinib. No tumor showed transformation to small cell carcinoma. Median progression-free survival was longer in patients with than in those without T790M at SPD (15.1 versus 10.9 months, P =0.25). Median time to SPD was much longer in patients with than in those without T790M at SPD (17.9 versus 10.9 months, P =0.18).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Assessment of T/A ratio with dPCR or NGS improved specificity of plasma analysis for determination of T790M positivity compared with tumor analysis. dPCR and NGS analysis in tumor and plasma samples shed light on exploring mechanisms of afatinib resistance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.09 - Pathology (Not CME Accredited Session) (ID 975)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.09-15 - Genetic Profiling of Idiopathic Pulmonary Fibrosis Associated Non-Small Cell Lung Cancer by Targeted Next-Generation Sequencing (ID 13842)

      12:00 - 13:30  |  Author(s): Isamu Okamoto

      • Abstract

      Background

      Little is known about the pathogenesis or genetic profiles of idiopathic pulmonary fibrosis (IPF) associated non-small cell lung cancer (NSCLC). This study was performed to investigate the genetic profiles of IPF associated NSCLC and to explore the possibility of defining potential therapeutic targets by using next-generation sequencing (NGS).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The Oncomine Comprehensive Assay v3 (OCAv3) from Thermo Fisher was used to detect clinically relevant single nucleotide variants (SNVs), insertions/deletions (INDELs), copy number variations (CNVs), and gene fusions from 161 unique cancer-related genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Surgically resected tumor specimens from 18 patients with IPF associated NSCLC (adenocarcinoma, n=9; squamous cell carcinoma, n=9) were collected. A total of 61 gene mutations was identified by targeted NGS and a median number of mutated genes per patient was 5 (range, 2–26). No sensitizing EGFR mutation (exon 19 del, L858R, G719X, L861Q) and fusions genes (ALK, ROS1, RET) were identified. Fourteen samples had one or more mutations in oncogenes including PIK3CA (n=7, 39%), BRAF (n=5, 28%), PTEN (n=4, 22%), EGFR (n=4, 22%), MET (n=3, 17%), KRAS (n=2, 11%), HRAS (n=2, 11%), NRAS (n=1, 6%), ERBB2 (n=1, 6%) and DDR2 (n=1, 6%). In addition to these potentially druggable oncogenes, loss-of-function mutations in ARID1A (n=10, 56%) and TP53 (n=7, 39%), tumor suppressor genes regulating DNA damage checkpoint were frequently identified. Furthermore, loss-of-function deletions (P2415del) in NOTCH1 which plays a role in cell fate determination, growth, and survival was observed in six (33%) patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study demonstrated novel genetic profiles of IPF associated NSCLC using NGS.

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