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T. Hida
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.03 - Alectinib (ALC) versus Crizotinib (CRZ) in ALK-Positive Non-Small Cell Lung Cancer (ALK+ NSCLC): Primary Results from Phase III Study (J-ALEX) (ID 5597)
11:12 - 11:18 | Author(s): T. Hida
- Abstract
- Presentation
Background:
ALK inhibitors are the standard treatment for ALK+ NSCLC and the comparison between 2 ALK inhibitors will be valuable in determining therapeutic strategy for ALK+ NSCLC patients (pts). We conducted the randomized open-label Phase III trial designed to prove the superior PFS of ALC to CRZ in ALK-inhibitor naïve ALK+ NSCLC.
Methods:
ALK+ NSCLC pts were randomized 1:1 either to receive ALC (300 mg b.i.d.) or CRZ (250 mg b.i.d.) and stratified by ECOG PS (0/1 vs 2), treatment line (1[st] vs 2[nd]), and clinical stage (IIIB/IV vs recurrence). Primary endpoint was PFS according to the blinded independent review board. Secondary endpoints included overall survival, objective response rate, and safety. Under an assumption of expected hazard ratio (HR) of 0.643, 164 events were required to have 80% power with 2-sided alpha of 0.05. Three interim analyses (IA) for early stopping due to efficacy were planned after 33%, 50%, and 75% of required PFS events occurred.
Results:
207 pts were enrolled at 41 centers in Japan between November 2013 and August 2015. Independent data monitoring committee recommended the release of study data because the superiority in PFS had been demonstrated for ALC based on second IA. The PFS HR of ALC arm to CRZ arm was 0.34 (99.6826% CI: 0.17-0.70, stratified log-rank p<0.0001). Median PFS was not reached (95% CI: 20.3-Not Reached (NR)) in ALC arm while it was 10.2 months (95%CI: 8.2-12.0) in CRZ arm. ALC demonstrated favorable result of PFS in each sub-group for instance, treatment line (1[st] line: HR = 0.30, ALC: NR vs CRZ: 10.2 months, 2[nd] line: HR = 0.39, ALC: 20.3 months vs CRZ: 8.2 months), brain metastases at baseline (yes: HR = 0.08, ALC: NR vs CRZ: 10.2 months, no: HR = 0.39, ALC: 20.3 moths vs CRZ: 10.0 months) and clinical stage (stage IIIb/IV: HR = 0.31 ALC: 20.3 months vs CRZ: 8.3 months, recurrence: HR = 0.49, ALC: NR vs CRZ: 11.6 months). Grade 3-4 AEs (ALC: 26% vs CRZ: 52%), discontinuation of study drug due to AEs (ALC: 9% vs CRZ: 20%) and dose interruptions due to AEs (ALC: 29% vs CRZ: 74%) occurred with lower rate in the ALC arm. There were no treatment-related deaths in either arm.
Conclusion:
ALC demonstrated prolonged PFS compared with CRZ in all sub-groups with a favorable AE profile representing a potential new standard treatment for 1[st] line ALK+ NSCLC pts.
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.10 - Detection of the T790M Mutation of EGFR in Plasma of Advanced NSCLC Patients with Acquired Resistance to EGFR-TKI (WJOG8014LTR) (ID 5377)
12:06 - 12:12 | Author(s): T. Hida
- Abstract
- Presentation
Background:
NSCLC patients with activating mutations of the EGFR initially respond well to TKIs, but about half such patients develop TKI resistance through acquisition of a secondary T790M mutation. Whereas next-generation EGFR-TKIs have been developed to overcome T790M-mediated resistance, performance of a second tumor biopsy to assess T790M mutation status can be problematic.
Methods:
We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation–positive patients with acquired EGFR-TKI resistance.
Results:
A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M.
Conclusion:
Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.
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P1.03 - Poster Session with Presenters Present (ID 455)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.03-044 - EUS-Guided Sampling of Mediastinal Lymph Nodes and Abdominal Lesions in Lung Cancer (ID 5147)
14:30 - 14:30 | Author(s): T. Hida
- Abstract
Background:
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS–TBNA) was introduced to provide access to mediastinal and hilar lymph nodes. However, it is difficult to use EBUS to approach the aortopulmonary window and paraesophagaeal stations. Transesophageal endoscopic ultrasound (EUS) was introduced to provide access to this area. In addition, transgastroduodenal endoscopic ultrasound can evaluate abdominal lesions.
Methods:
Endoscopic ultrasound fine needle aspiration (EUS-FNA) was performed under conscious sedation with the administration of intravenous midazolam and pethidine hydrochloride. It was performed with a convex array echoendoscope connected to an ultrasound scanning system. Lymph nodes of paraesophageal, subcarinal, lower paratracheal, subaortic, and upper paratracheal regions were evaluated from esophagus. Left adrenal gland and right adrenal gland were evaluated from stomach and duodenum, respectively. Abdominal lesions were also evaluated from stomach and duodenum. After obtaining tissue via EUS-FNA, the tissue was reviewed immediately (rapid on-site cytopathological evaluation: ROSE) by a cytopathologist. Subsequent punctures in the same patient were not performed before confirming the results of ROSE so as to minimize the complications.
Results:
As to the lymph node level, the lower mediastinum and the aortopulmonary window are particularly important for detection by transesophageal EUS, whereas pretracheal and hilar lymph nodes are out of reach because of the interposition of air from the trachea and bronchi. EUS was chosen to assess the posterior mediastinum nodes (#5, 7, 8, or 9) but not the anterior ones. A final diagnosis was obtained by EUS-FNA in 76 patients. The lesions sampled were mediastinal lymph nodes (n=64; #5, 7, 8, or 9), abdominal lymph nodes (n=8), and adrenal gland (n=4).
Conclusion:
Repeat tumor biopsies from patients with acquired resistance were initially obtained through research efforts to ascertain mechanisms of resistance, but are now recommended to help select second-line therapies. However, such biopsies are associated with both risk and discomfort and may not always supply enough tumor tissue for genetic analyses. Although EUS–FNA does not provide access to pretracheal and hilar lymph nodes, EUS-FNA is an accurate, safe, and minimally invasive modality for evaluating mediastinal lymphadenopathy and abdominal lesions in patients suspected of having lung metastases.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-007 - Clinical Outcomes of Patients with LS-SCLC Treated with Chemoradiotherapy. Can We Find Candidates for Salvage Surgery? (ID 5288)
14:30 - 14:30 | Author(s): T. Hida
- Abstract
Background:
Although small cell lung cancer (SCLC) is generally considered a systemic disease even in patients with limited stage (LS). Selected recurrent LS-SCLC patients after chemoradiation treatment have been reported long survival with receiving salvage surgery. Purpose of this study was to find candidates for salvage surgery.
Methods:
We retrospectively reviewed the charts of 43 consecutive patients who were treated with chemoradiotherapy for LS-SCLC at our hospital from January 2011 to December 2015 to search for the patients with locoregional progression without mediastinal lymph node involvement.
Results:
Of the 43 patients, the median age was 69 (38-83), 91% were male and all of them had ECOG PS 0 or 1. Clinical stage: IIA (12%), IIIA (53%), IIIB (35%). 35 (81%) received hyperfractionated RT (45Gy/30fr/3w). Objective response rate was 95%. One patient died of pneumonia. The median survival time was 1584 days and the median progression free survival was 280 days. 33 (77%) demonstrated disease progression. The first progression site was distant (include pulmonary metastasis and malignant pleural effusion) in 17, locoregional in 11, lymph node metastasis out of the radiation field in 2 and both distant and locoregional in 3. In the locoregional progression patients, 6 developed mediastinal lymph node progression in their clinical courses. Finally, 5 in 33 progressive patients had locoregional progression without mediastinal lymph node progression, and were thought possible candidates for salvage surgery.
Conclusion:
Most of the patients experienced distant metastasis and/or mediastinal lymph node progression. About 15% of patients who presented with apparently localized disease at the primary pulmonary site after chemoradiation might become possible candidates for salvage surgery.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-023 - Quality Assessment of Resampling Specimens in Primary Lung Cancers with Acquired Resistance to the Initial Therapy (ID 5543)
14:30 - 14:30 | Author(s): T. Hida
- Abstract
Background:
Most patients treated against molecular targets eventually develop resistance even after an initial dramatic response. Although rebiopsy of tumors at progression provide information for next-line therapy, it is expected that the tumor tissues would be modified by the therapy.
Methods:
We retrospectively examined histologic features in the resampled specimens in lung cancer patients with resistance to the initial therapy. Furthermore, we also analyzed the differences of tumor cell contents and molecular testing performance according to each biopsy site.
Results:
A total of 315 resampled specimens were submitted to pathology department from 260 patients. Of 315 samples, 116 (37%) were obtained from the lung and 96 (30%) from pleural effusion, 42 (13%) from lymph node, 16 (5%) from liver, 12 (4%) from cerebrospinal fluid (CSF), 10 (3%) from pleura and pericardial effusion, 7 (2%) from bone and 6 (2%) from other biopsy sites. When we compared 48 paired lung tissues between initial and rebiopsies, rebiopsy specimens had significantly less extents of tumor cells and more fibrosis than those in initial biopsy, and these differences were statistically significant with digital quantitation. Resampled sites affect the tumor cell extents and those were high in the order of liver, subcutaneous tissue, lymph node and lung biopsy, whereas pleura and bone samples had a tendency to contain a less number of tumor cells. Molecular testing was performed in 272 samples (from 222 patients). Of 272 samples, 223 (82%) were successfully analyzed, whereas 49 samples were unsuitable for the testing due to low tumor-cell content or complete absence of tumor cells. Higher success rates for molecular testing were seen in the liver and lymph nodes and the value of bone was lowest. Resistant T790M mutations were also differently detected and the higher detection rates were seen in liver, pleura and pericardial effusions.
Conclusion:
Resampled specimens had different property in terms of tumor extents, which differed among the biopsy sites. For molecular testing using resampled specimens, the difference should be taken into account.
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PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)
- Event: WCLC 2016
- Type: Plenary
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:J. Soria, C. Zhou
- Coordinates: 12/07/2016, 08:45 - 09:40, Hall D (Plenary Hall)
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PL04a.02 - OAK, a Randomized Ph III Study of Atezolizumab vs Docetaxel in Patients with Advanced NSCLC: Results from Subgroup Analyses (Abstract under Embargo until December 7, 7:00 CET) (ID 5822)
08:55 - 09:05 | Author(s): T. Hida
- Abstract
- Presentation
Background:
Atezolizumab inhibits PD-L1 binding to its receptors PD-1 and B7.1, thereby restoring tumor-specific T-cell immunity. Primary analysis of the Phase III OAK study in previously-treated NSCLC revealed superior survival for atezolizumab vs docetaxel in the ITT population (mOS, 13.8 vs 9.6 months; HR, 0.73) and in patients expressing ≥1% PD-L1 on TC or IC (TC1/2/3 or IC1/2/3; mOS, 15.7 vs 10.3; HR, 0.74). Here we present further subgroup analyses.
Methods:
OAK evaluated atezolizumab vs docetaxel in an unselected NSCLC population who had failed prior platinum-containing chemotherapy. Patients were stratified by PD-L1 expression, prior chemotherapy regimens and histology, and randomized 1:1 to atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. PD-L1 expression by IHC and mRNA was centrally evaluated by VENTANA SP142 IHC assay and Fluidigm, respectively. Data cutoff, July 7, 2016.
Results:
For the first 850 of 1225 randomized patients (primary study population), OS was improved with atezolizumab vs docetaxel regardless of histology and this benefit was observed across PD-L1 subgroups within each histology (Table). PD-L1 gene expression showed a similar association with OS as PD-L1 IHC. In nonsquamous patients ORR was 14.4% vs 15.2%; in squamous patients ORR was 11.6% vs 8.2% (atezolizumab vs docetaxel). OS benefit vs docetaxel was seen across subgroups including patients with treated baseline brain metastases (n=85; mOS 20.1 vs 11.9 mo; HR 0.54, 95% CI 0.63-0.89) and never smokers (n=156; mOS 16.3 vs 12.6 mo, HR 0.71, 95% CI 0.47-1.08). Further secondary endpoints and exploratory biomarker analyses for these subgroups and by age and EGFR/KRAS status will be presented.
Conclusion:
OAK demonstrated clinically relevant improvements with atezolizumab in the ITT population, including in both histology subgroups regardless of PD-L1 expression (measured by IHC or tumor gene expression), and among other subgroups including never smokers and in patients with baseline brain metastases.OS Atezolizumab Docetaxel HR[a]95% CI n Median, mo n Median, mo Nonsquamous TC3 or IC3 49 22.5 47 8.7 0.35(0.21-0.61) TC2/3 or IC2/3 89 18.7 99 11.3 0.61(0.42-0.88) TC1/2/3 or IC1/2/3 171 17.6 162 11.3 0.72(0.55-0.95) TC0 and IC0 140 14.0 150 11.2 0.75(0.57-1.00) All 313 15.6 315 11.2 0.73(0.60-0.89) Squamous TC3 or IC3 23 17.5 18 11.6 0.57(0.27-1.20) TC2/3 or IC2/3 40 10.4 37 9.7 0.76(0.45-1.29) TC1/2/3 or IC1/2/3 70 9.9 60 8.7 0.71(0.48-1.06) TC0 and IC0 40 7.6 49 7.1 0.82(0.51-1.32) All 112 8.9 110 7.7 0.73(0.54-0.98) [a]Unstratified HRs. TC=tumor cell, IC=tumor-infiltrating immune cell
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