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Jun Sakakibara-Konishi



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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-04 - Neoadjuvant Ceritinib for Locally Advanced Non-Small Cell Lung Cancer with ALK Rearrangement: SAKULA Trial (ID 876)

      09:45 - 18:00  |  Author(s): Jun Sakakibara-Konishi

      • Abstract
      • Slides

      Background

      Ceritinib is a highly selective ALK inhibitor that has been shown potent antitumor activity against ALK-positive non-small cell lung cancer (NSCLC). We conducted a multicenter single-arm phase II study to assess the efficacy and safety of neoadjuvant therapy with ceritinib followed by surgery in patients with ALK-positive resectable locally advanced (LA) NSCLC.

      Method

      Three cycles of ceritinib were administered as induction therapy. The drug was administered orally at the dose 750 mg once daily for 28 days per cycle. The primary endpoint was the major pathological response rate (mpRR). This study required 19 patients, with mpRR of 15% considered non-promising and 45% promising (one-side alpha = 0.025; beta = 0.2). Biomarker analyses using pre- and post-ceritinib through next-generation sequencing (NGS) of plasma and tissue is also planned. (Trial Identifier, UMIN000017906).

      Result

      A total of 395 patients with LA-NSCLC were screened from March 2015 to March 2018 and 15 patients (4%) were identified as ALK-positive. Only 7 patients were enrolled because of slow accrual. The median age of the patients was 50 years and 71% (n=5) were male. All patients had stage IIIA disease and adenocarcinoma. 6 out of 7 patients completed three cycles of neoadjuvant therapy with ceritinib as planned, 71% (n=5) of patients required dose adjustment. One patient was withdrawn from the study because of hepatitis. The objective clinical response rate was 100%. Surgical resection was performed in 6 patients, and complete (R0) resection was achieved in 5 patients. Among the 7 evaluable patients, the mpRR was 57% (95% CI, 18 to 90); 4 patients achieved mpR and 2 patients achieved pathologic complete response. With a median follow-up of 10 (range 8-33) months, 1 patient died of disease progression and 6 patients remain alive, including 4 patients who are recurrence-free. The most common toxicities were gastrointestinal toxicities.

      Conclusion

      Our results showed that neoadjuvant ceritinib is safe and effective, with a high rate of pathologic response, in patients with ALK-positive resectable LA-NSCLC, although the limitation of the data interpretation due to small sample size.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-53 - Immunoproteasome as a Potential Therapeutic Target in Cisplatin-Resistant Small and Non-Small Cell Lung Cancer (ID 365)

      10:15 - 18:15  |  Author(s): Jun Sakakibara-Konishi

      • Abstract
      • Slides

      Background

      Cisplatin resistance remains a major problem in the treatment of both non-small (NSCLC) and small cell lung cancer (SCLC). Cisplatin has been reported to cause DNA damages and oxidative stress leading to numerous changes in cell physiology in transcriptional and protein levels. Thus, cisplatin-resistant (CR) cancer cells could alter the proteasome expression to eliminate abnormal proteins induced by cisplatin. Here, we examined the status of proteasomes in CR lung cancer cells and whether proteasomes could be a therapeutic target to overcome cisplatin resistance in lung cancer.

      Method

      CR variants were established from three NSCLC cell lines (A549, H1299, and H1975) and two SCLC cell lines (SBC3 and SBC5) in our laboratory. The activity of 20S proteasome core enzyme, the expressions of proteasome subunits, and the sensitivity of immunoproteasome inhibitors, Carfilzomib (CFZ) and PR957, were examined in these CR cells.

      Result

      The CR cells showed higher activity of 20S proteasome core enzyme compared with the parent cell counterparts. Quantitative RT-PCR and Western blot analysis revealed that all of the five CR cells had significantly higher expressions of immunoproteasomes, including PSMB8 and PSMB9, while no remarkable changes were observed in the expressions of standard proteasomes. H1299 and SBC3 cells became more sensitive to CFZ and PR957 when acquiring resistance to cisplatin. CFZ induced cell cycle G2/M arrest and apoptosis in CR variants of H1299 and SBC3.

      Conclusion

      Immunoproteasome can be a therapeutic target in a portion of cisplatin-resistant both of NSCLC and SCLC.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Jun Sakakibara-Konishi

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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