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Yasushi Goto
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- 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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P1.13-06 - First-Line Lorlatinib Versus Crizotinib for Advanced Anaplastic Lymphoma Kinase-Positive (ALK<sup>+</sup>) Non-Small Cell Lung Cancer (ID 12773)
16:45 - 18:00 | Author(s): Yasushi Goto
- Abstract
Background
Lorlatinib and crizotinib are oral tyrosine kinase inhibitors with activity against ALK and ROS1 fusion proteins. Crizotinib is well tolerated and has superior efficacy compared to chemotherapy for treatment of patients with advanced ALK+ non-small-cell lung cancer (NSCLC). However, resistance to crizotinib can develop, and the central nervous system (CNS) is often a site of disease relapse. Second-generation ALK inhibitors, ceritinib and alectinib, have demonstrated activity in crizotinib-naive or resistant treatment settings, and alectinib has been shown to have superior progression-free survival (PFS) compared to crizotinib as first-line therapy. Lorlatinib is a selective, CNS-penetrant ALK inhibitor that has potent activity against ALK and kinase domain resistance mutations, including the difficult-to-treat G1202R mutation.Lorlatinib has shown clinical activity in patients previously treated with crizotinib and other ALK inhibitors, including patients with progressive CNS metastases. This study aims to determine if lorlatinib is superior to crizotinib in prolonging PFS in treatment-naïve patients and to identify candidate biomarkers predictive of clinical efficacy or treatment resistance.
a9ded1e5ce5d75814730bb4caaf49419 Method
Trial Design
This global, multicenter, open-label phase 3 study will enroll ~280 treatment-naïve patients. Eligible patients must be aged ≥18 years, have Eastern Cooperative Oncology Group performance status of 0–2 and ≥1 measurable extracranial target lesion not previously treated with radiotherapy. Patients with asymptomatic brain metastases are eligible. Patients will be randomized (1:1) to lorlatinib 100 mg once daily or crizotinib 250 mg twice daily and stratified by presence of brain metastases (yes/no) and ethnicity (Asian/non-Asian). Treatment will continue until disease progression, patient refusal, or unacceptable toxicity. Crossover between treatment arms will not be permitted. The primary endpoint is PFS based on blinded independent central review (BICR) using RECIST v1.1. Secondary endpoints include PFS based on investigator assessment, overall survival, objective response (OR) by BICR and investigator assessment; intracranial (IC) OR (periodic magnetic resonance imaging will be performed for central nervous system evaluation), IC time to progression, duration of response and time to response all by BICR; tumor tissue and peripheral blood circulating free DNA biomarker assessment, adverse events and patient-reported health-related outcomes as assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 EORTC (QLQ-C30) and EORTC Lung Cancer Module (QLQ-LC13), and the 5-level EuroQol 5-dimension questionnaire (EQ-5D-5L). The first patient was screened on April 14, 2017. This study is registered with ClinicalTrials.gov as NCT03052608.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
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P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)
- 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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P2.06-11 - A Phase I/II Study of Intrapleural Ad-SGE-REIC Administration in Patients with Refractory Malignant Pleural Mesothelioma (ID 11328)
16:45 - 18:00 | Presenting Author(s): Yasushi Goto
- Abstract
Background
Reduced expression in immortalized cell (REIC)/Dickkopf-3 (Dkk-3) is a tumor-suppressor gene and REIC/Dkk-3 expression was markedly downregulated in various human cancer cells. REIC/Dkk-3 protein is also known as a key player, namely an antagonist of the Wnt signaling pathway. Ad-SGE-REIC is an adenoviral vector carrying REIC/Dkk-3 that mediates cancer cell death induction and anti-cancer immunity augmentation.
a9ded1e5ce5d75814730bb4caaf49419 Method
We conducted a phase I/II, 3+3 design, dose escalation study in malignant pleural mesothelioma (MPM) patients (pts) with measurable lesions. Pts with refractory to or unsuitable for standard chemotherapy received 2 intrapleural administrations of Ad-SGE-REIC on days1 and 4. Three escalating doses of level (DL) 1: 3.0×1011, DL2: 1.0×1012 and DL3: 3.0×1012 viral particles were employed. This dosage and regimen were set by considering the reason of manufacturing and neutralizing anti-body for adenovirus. The safety and dose-limiting toxicities (DLTs) of Ad-SGE-REIC were evaluated for 32 days. Continuous safety and efficacy were assessed for 172 days using modified RECIST (mRECIST). The concentrations of REIC/Dkk-3 in pleural fluid also were measured as indirect indication of targeted gene expressions.
4c3880bb027f159e801041b1021e88e8 Result
From 07/2015 to 09/2017, a total of 13 pts have been treated at DL1 (n=4 included one fatal case within 32 days), DL2 (n=3) and DL3 (n=6). Male: 100%; median age 70; PS 0: 23%, 1: 69%, 2: 8%; epithelial/biphasic histology: 69%/15%; Stage III-IV: 77%; previous chemotherapy use with platinum-pemetrexed: 92%. Treatment-related AEs (TRAEs) were all Grade 1-2 and no DLTs occurred. The most frequent TRAEs were fever and CRP increase based on adenovirus infection. Tumor responses assessed by independent central review showed that there was no objective response and DCR was 62% (8/13 pts). Median PFS was 3.4 months at all groups and 5.7 months at DL3. A remarkable increase of REIC/Dkk-3 concentration in pleural fluid was determined (6/13 pts, prominently high in DL3).
8eea62084ca7e541d918e823422bd82e Conclusion
The intrapleural administration of Ad-SGE-REIC up to 2 cycles was safe and well tolerated in MPM pts and promising results of efficient REIC/Dkk-3 expression and durable disease control were obtained. We are planning phase II study using repeated intrapleural or intratumoral administration.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- 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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P3.01-30 - Treatment Sequencing in Patients With Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer (NSCLC) in Japan (ID 12786)
12:00 - 13:30 | Presenting Author(s): Yasushi Goto
- Abstract
Background
Limited data are available on real-world treatment patterns and outcomes of ALK inhibitors used sequentially. Access to a large medical records database and availability of multiple ALK inhibitors in Japan, the first country to approve alectinib in 2014, presents a unique opportunity to evaluate real-world treatment sequencing and outcomes in ALK-positive NSCLC patients.
a9ded1e5ce5d75814730bb4caaf49419 Method
This descriptive, retrospective observational study used inpatient/outpatient medical and prescription records, claims and diagnoses from the Japan Medical Data Vision (MDV) Database. Included patients had confirmed diagnosis of lung cancer, an ALK test and first prescription order for an ALK inhibitor (prescription date = index date) on or before March 31, 2017. Descriptive analyses included demographics, baseline characteristics, treatment patterns including ALK inhibitor sequences, non-ALK inhibitor treatments received, and treatment duration.
4c3880bb027f159e801041b1021e88e8 Result
Overall, 378 patients (mean age 61 years; 53% female; 48% no history of smoking) met inclusion criteria. Baseline characteristics were similar among mutually exclusive groups of patients receiving 1, 2, or 3 ALK inhibitors. Similar proportions of patients received crizotinib (52%) and alectinib (48%) as index ALK inhibitor. Prior to the index date, 40% of patients received chemotherapy. ALK inhibitor sequences are shown (Table). In patients who had discontinued all ALK inhibitors, the next treatments were chemotherapy (46%) and immunotherapy (6%). The most common sequence was a crizotinib-led sequence of 2 ALK inhibitors; median duration of treatment was 53 months. Changes in treatment patterns over time and further duration of treatment data will be presented.
8eea62084ca7e541d918e823422bd82e ConclusionSequence Overall Population
N = 378
n (%) 1 ALK inhibitor (n=261) Crizotinib 91 (24.07) Alectinib 170 (44.97) 2 ALK inhibitors (n=98) Crizotinib -> Alectinib 89 (23.54) Crizotinib -> Ceritinib 1 (0.26) Alectinib -> Crizotinib 7 (1.85) Alectinib -> Ceritinib 1 (0.26) 3 ALK inhibitors (n=19) Crizotinib -> Alectinib -> Ceritinib 16 (4.23) Alectinib -> Crizotinib -> Ceritinib 3 (0.79)
Treatment patterns in ALK-positive NSCLC patients have evolved over time. The most common sequence for patients receiving > 1 ALK inhibitor was crizotinib-led. Median duration of treatment with crizotinib-led sequences is consistent with what has been reported previously. Additional research is warranted to evaluate non-crizotinib-led sequences as data mature.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 982)
- 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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P3.16-02 - Phase III Study of Canakinumab (ACZ885) as Adjuvant Therapy in Patients with Surgically Resected NSCLC (ID 12069)
12:00 - 13:30 | Author(s): Yasushi Goto
- Abstract
Background
Preclinical and clinical data suggest that cytokines such as interleukin (IL)-1β can promote angiogenesis and tumor growth, and are essential to tumor invasiveness. Canakinumab (ACZ885) is a high-affinity human IgGκ anti-IL-1β monoclonal antibody approved for patients with various IL-1–driven auto-inflammatory diseases. In the Phase III Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) in patients with atherosclerosis, canakinumab was associated with a significant reduction in the incidence of fatal and non-fatal lung cancer in patients with increased high-sensitivity C-reactive protein levels. ACZ885T2301 (NCT03447769) is evaluating the efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected non-small cell lung cancer (NSCLC).
a9ded1e5ce5d75814730bb4caaf49419 Method
This Phase III, randomized, double-blind, placebo-controlled study is enrolling patients (≥18 years, Eastern Cooperative Oncology Group Performance Status ≤1) with completely resected (R0) American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) v.8 stages II−IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg every 3 weeks [Q3W], subcutaneous [s.c.]) or placebo (Q3W, s.c.) on Day 1 of 21-day cycles for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Following baseline screening, imaging assessment will be performed every 12 weeks for the first year (treatment phase) following Cycle 1 Day 1, then every 26 weeks during Years 2 and 3, and annually during Years 4 and 5 (post-treatment surveillance phase). Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region.
The primary objective is to compare disease-free survival (DFS) in the canakinumab versus placebo arms, as determined by local investigator assessment. Secondary objectives include a comparison of the two treatment groups with respect to overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Exploratory objectives include assessment of the relationship between pharmacokinetics, pharmacodynamics, safety, and efficacy, and evaluation of correlation between cytokines/soluble markers and efficacy endpoints. Enrollment is ongoing.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
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