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N. Yamamoto
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MA06 - Locally Advanced NSCLC: Risk Groups, Biological Factors and Treatment Choices (ID 379)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:P. Van Houtte, M. Zemanová
- Coordinates: 12/05/2016, 16:00 - 17:30, Strauss 2
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MA06.11 - Phase II Study of Nimotuzumab + Concurrent Chemoradiotherapy (CRT) for Stage III Non-Small Cell Lung Cancer (NSCLC): 5-Year Follow-Up Results (ID 3868)
16:00 - 17:30 | Author(s): N. Yamamoto
- Abstract
- Presentation
Background:
Nimotuzumab, a humanized IgG~1~ monoclonal anti-EGFR antibody, is approved and widely used in patients (pts) with head and neck cancer or malignant glioma in combination with radiotherapy (RT) in several countries. On in-vitro and in-vivo experiments using NSCLC cell lines, nimotuzumab showed a radio-sensitizing effect.
Methods:
This phase II study evaluated the tolerability and efficacy of nimotuzumab in combination with concurrent CRT in pts with unresectable locally advanced NSCLC. All eligible pts received concurrent thoracic RT (60 Gy, 2 Gy/day, 6 weeks from day 1) and 4 cycles of chemotherapy (cisplatin 80 mg/m[2] on day 1, vinorelbine 20 mg/m[2] on days 1 and 8) once every 4 weeks as scheduled. Nimotuzumab (200 mg) was administrated once a week from cycle 1 to 4. The primary endpoint was tolerability in combination with concurrent CRT, which was measured by the percentage of pts who completed 60 Gy of RT within 8 weeks, completed 2 cycles of chemotherapy and received more than 75% of nimotuzumab.
Results:
Of 40 pts enrolled between June 2009 and May 2010, 39 eligible pts received the study treatment. The pts characteristics were as follows: 62 years (median); male/female, 34/5; stage IIIA/B, 21/18; PS0/1, 25/14. Thirty-four pts met the criteria for treatment tolerability, and 38 pts completed 60 Gy of RT within 8 weeks. Infusion reaction, >grade 3 skin rash, >grade 3 radiation pneumonitis, or >grade 4 nonhematological toxicity were not observed. The 3-year and 5-year overall survival rates for the 39 pts were 66.4% and 58.4%, respectively. The median PFS was 16.9 months, and the 5-year PFS rate for pts with squamous cell carcinoma (Sq; n = 16) was 50%, while that for pts with non-squamous cell carcinoma (non-Sq; n = 23) was 13.7%. In terms of the first relapse site, in-field relapse rates were low for both Sq (4/16; 25%) and non-Sq (4/23; 17%). However, the distant relapse rate was significantly higher for non-Sq (15/23; 65%) than that for Sq (4/16; 25%). Cytologic or histologic specimens were examined for the expression of EGFR protein/mutations using the EGFR IHC/FISH methods in 20 pts. EGFR 2+/3+ expression was shown more frequently in sq (8/10) than non-sq (4/10). EGFR mutation was observed in only 2 pts with non-sq.
Conclusion:
Addition of nimotuzumab to the concurrent CRT in this setting was well tolerated with clinical benefit to the patients. The low in field relapse rates may be attributed to the radio-sensitizing effect of nimotuzumab.
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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)
11:00 - 12:30 | Author(s): N. Yamamoto
- 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)
11:00 - 12:30 | Author(s): N. Yamamoto
- 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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OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
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OA23.06 - Overall Survival (OS) of EGFR Mutation Positive Non-Small Cell Lung Cancer Patients: Real-World Treatment Patterns of 1,660 Japanese Patients (ID 5915)
14:20 - 15:50 | Author(s): N. Yamamoto
- Abstract
- Presentation
Background:
Since the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) was launched in Japan, the survival periods of advanced/recurrent EGFR mutation positive (EGFR m+) non-small cell lung cancer (NSCLC) patients have been getting longer. However, clinical factors which contributed to the extension of survival periods of these patients remain unclear. We investigated overall survival, prognostic factors and treatments patterns of EGFR m+ NSCLC patients in real-world clinical practice.
Methods:
This is a multi-center, observational, retrospective study. Histologically or cytologically diagnosed EGFR m+ NSCLC patients who were started first-line treatment from 1/1/2008 to 31/12/2012 were enrolled. The primary objective was the estimated OS. The secondary objectives were to determine prognostic factors, real-world treatment patterns.
Results:
1,660 EGFR m+ NSCLC patients were enrolled from 17 hospitals in Japan (median age 67.0 years, female 64.8%, 38.9% had smoking history, ECOG-performance status 0, 1, 2, 3, 4 were 39.5%, 41.1%, 7.1%, 4.9%, 0.7%, respectively, adenocarcinoma 95.2%, 50.1% exon 19 deletion, 66.7% at stage IV). Median estimated OS was 29.7 months. Cox regression analysis revealed age, smoking history, performance status, histological diagnosis, EGFR mutation type and clinical stage were independently associated with OS. Five year survival rate of stage IV patients was 13.8%. The median number of treatment regimens was two. EGFR-TKI and platinum-doublet chemotherapy were most frequently used as first- and second-line treatments.
Conclusion:
Real world treatment of the large data-set of 1,660 EGFR m+ NSCLC patients was retrospectively investigated. Median OS was 29.7 months and EGFR-TKIs are major components of the treatment regimens for these patients in Japan. (NCT0247520)
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-060 - Comparative Analysis of PD-L1 Expression between Circulating Tumor Cells and Tumor Tissues in Patients with Lung Cancer (ID 5402)
14:30 - 15:45 | Author(s): N. Yamamoto
- Abstract
Background:
Blockade of programmed death receptor-1 (PD-1) pathway has been shown to be effective against solid tumors including lung cancer. Although PD-ligand 1 (PD-L1) expression on tumor tissue is expected as a potential predictive biomarker, its detection remains challenging due to its dynamic and unstable status. Here, we evaluated the PD-L1 expression on circulating tumor cells (CTCs) in patients with lung cancer and investigated its concordance with that on tumor tissues.
Methods:
CTCs were captured and immune-stained using microcavity array system. CTCs were defined as those positive for DAPI and cytokeratin (CK) and negative for CD45. PD-L1 expression on CTCs was evaluated by addition of the process of PD-L1 immunocytochemistry. For CTCs detection, 3 ml of peripheral whole blood was collected from the patients who consented in written form and PD-L1 immunohistochemistry was performed using corresponding tumor tissues.
Results:
Sixty-seven lung cancer patients were enrolled in the study between July 2015 and April 2016 at Wakayama Medical University. Patient characteristics were as follows: median age 71 (range, 39 to 86); male 72%; stage II-III/IV, 15/85%; non-small cell lung cancer (NSCLC)/small cell lung cancer (SCLC)/Other, 73/21/6%. CTCs were detected in 66 out of 67 patients (median 19; range, 0 to 115) and more than 5 CTCs were detected in 78% of patients. PD-L1 expressing CTCs were detected in 73% of patients and the proportion score (PS) of PD-L1 expressing CTCs ranged from 3% to 100%, suggesting intra-patient heterogeneity of PD-L1 expression on CTCs. Significantly more PD-L1 expressing CTCs were detected in patients without EGFR mutations than those with EGFR mutations (P = 0.0385). Tumor tissues were available from 27 patients and were immune-stained for PD-L1. No positive correlation was observed on PD-L1 expression between tumor tissues and CTCs based on PS (R[2 ]= 0.0103). Three adenocarcinoma cases with PD-L1-positive tumor tissue did not harbor any PD-L1 expressing CTCs and conversely, three adenocarcinoma cases with PD-L1-negative tumor tissue harbored PD-L1 expressing CTCs, showing the total discrepancy between tumor tissues and CTCs. It is also noteworthy that SCLC patients had perfect agreement on PD-L1 expression between tumor tissues and CTCs.
Conclusion:
PD-L1 expression was detectable on CTCs in lung cancer patients and intra-patient heterogeneity of its expression was observed. There was no agreement between tumor tissues and CTCs on PD-L1 expression though it may differ among tumor histologies. Further investigation is warranted to better understand the clinical significance of PD-L1 expressing CTCs.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-015 - The NICE Salvage Study: A Phase II Trial of Weekly Nab-Paclitaxel in the Salvage Setting for Advanced Non-Small Cell Lung Cancer (ID 4566)
14:30 - 15:45 | Author(s): N. Yamamoto
- Abstract
Background:
The standard chemotherapy for advanced NSCLC after the failing of second or third line chemotherapy has yet to be established. In these salvage setting patients the acceptable safety and efficacy of solvent-based paclitaxel (sb-P) monotherapy have been previously reported as one possible treatment option (Anticancer Res 2005). Compared with sb-P, nab-paclitaxel(nab-P) yielded a higher mean maximal circulating concentration of free paclitaxel and delivered higher drug concentration to tumors in preclinical xenograft models (Clin. Cancer Res. 2006). Moreover, a large multicenter international phase III study (CA031) of nab-P + carboplatin (C) vs sb-P + C, nab-P + C produced a significantly higher overall response rate (ORR) compared with sb-P + C, and had an acceptable safety profile as a first line chemotherapy (J. Clin. Oncol. 2012) .These results suggest that nab-P monotherapy have possibility to be more efficacious and tolerable compared to sb-P monotherapy. KTOSG trial 1301 has recently revealed weekly nab-P as a second line chemotherapy is associated with acceptable toxicity and a favorable ORR in patients with advanced NSCLC (Lung Cancer 2016). However, there are no reports of nab-P monotherapy after the failing of second or third line chemotherapy. We therefore planned this study aiming to assess the efficacy and safety of nab-P monotherapy for patients in the salvage setting.
Methods:
This multicenter single arm phase II study assesses the efficacy of nab-P in pts with PS 0-2 and aged < 75 years with advanced non-small cell lung cancer. Pts must have failed two or three prior lines of therapy including at least a platinum- containing chemotherapy. Pts pretreated with sb-P or nab-P, or tumors harboring EGFR mutation or ALK fusion gene are excluded. Pts receive nab-P 80 mg/m2 on days 1,8 and 15 of a 28-days cycle. The primary endpoint of the trial is progression-free survival in an intent-to-treat analysis using the Kaplan-Meier method and log-rank test. Secondary endpoints include overall survival, ORR, disease control rate, efficacy according to prior docetaxel, quality of life, and safety. The study is powered to detect a 1.5-month improvement in median PFS in this investigational arm beyond the 2.0-month median PFS estimated from historical data. Assuming a one-sided 0.10 level of Type I error and 80% power, the sample size was calculated to be 35 pts based on the Brookmeyer-Crowley method. The target sample size is established as 38 pts. As of June 2016, 14 pts were registered and recruitment is ongoing (UMIN000016173).
Results:
Section not applicable
Conclusion:
Section not applicable
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P2.06-023 - A Phase III Study Comparing Gefitinib and Inserted Cisplatin plus Pemetrexed with Gefitinib for EGFR-Mutated Advanced Non-Squamous NSCLC (ID 4587)
14:30 - 15:45 | Author(s): N. Yamamoto
- Abstract
Background:
Overcoming and prevention of acquired resistance to EGFR-TKIs in the treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC) is a critical issue. Although third-generation EGFR-TKIs, such as osimertinib, which are potent against EGFR carrying the T790M mutation, have been developed, they are insufficient to overcome other resistance mechanisms. We hypothesized that the insertion of platinum-doublet chemotherapy with EGFR-TKIs might prevent the emergence of acquired resistance to EGFR-TKIs and prolong the patient survival. An early phase II study of inserted cisplatin and docetaxel with gefitinib showed promising outcomes, including a median progression-free survival of 19.5 months and median survival time of 48.0 months.
Methods:
Figure 1 This study (JCOG1404 / WJOG8214L: AGAIN study) is an intergroup, multicenter, randomized phase III study conducted by the Japan Clinical Oncology Group (JCOG) and the West Japan Oncology Group (WJOG). The objective of this study is to confirm the superiority, in terms of the overall survival, of the study treatment, described below, over gefitinib monotherapy. As the study treatment, gefitinib are administered on days 1-56. Then, after a two-week drug-free period, three cycles of cisplatin and pemetrexed are administered on days 71, 92, and 113. Thereafter, gefitinib is re-started on day 134 and continued until disease progression. The secondary endpoints are progression-free survival, response rate, adverse events, severe adverse events and proportion of EGFR T790M mutation positive in the tumor samples at disease progression. The key eligibility criteria are: patients with advanced or recurrent non-squamous NSCLC harboring EGFR activating mutations (exon 19 deletion or exon21 L858R), age 20 to 74 years, and PS 0 or 1. This study was started in December 2015, and a total of 500 patients will be enrolled over a period of 3 years. This trial has been registered at UMIN-CTR[umin.ac.jp/ctr/] as UMIN000020242.
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-073 - A Phase II, Liquid Biopsy Study Using Digital PCR in EGFR Mutated, Lung Cancer Patients Treated with Afatinib (WJOG 8114LTR) (ID 4754)
14:30 - 15:45 | Author(s): N. Yamamoto
- Abstract
Background:
Liquid biopsy is an ideal strategy to monitor mutation status of cancer repeatedly and less invasively. In chronic myeloid leukemia, early remission of mutated cells was reported as a surrogate of longer efficacy. In epidermal growth factor (EGFR) mutated non-small cell lung cancer (NSCLC), to detect resistant mutation (exon20 T790M) during treatment is clinically important because newer tyrosine kinase inhibitors (TKIs) have been developed. Although some reports have mentioned the utility of liquid biopsy in EGFR mutated NSCLC, most were single-institutional, retrospective studies.
Methods:
West Japan Oncology Group (WJOG) 8114LTR is a multi-institutional, prospective liquid biopsy study in advanced NSCLC. Chemotherapy naïve, advanced NSCLC patients with EGFR-sensitizing mutation will receive afatinib monotherapy (40 mg/body) until progressive disease (PD) or unacceptable toxicity. Plasma DNA will be obtained from patients at baseline, 2, 4, 8, 12, 24, 48 weeks, and at PD. Three types of common EGFR mutations (exon 19 deletion, exon 20 T790M and exon 21 L858R) will be analyzed using plasma DNA with multiplexed, pico-droplet digital PCR assay (RainDrop® system, RainDance Technologies, Billerica, MA). Primary endpoint of this study is the concordance of EGFR mutation status between tissue and plasma at baseline. Secondary endpoints are overall response rate, progression-free survival and safety. This is the first report on the primary endpoint and early remission rate based on mutated cf-DNA. This study was registered at UMIN (ID: 000015847).
Results:
Fifty-seven patients were registered and samples from 55 patients were analyzed. Clinical characteristics were as follows; median age: 69 years, male / female: 25/30, PS 0/1: 23/32, c-stage III / IV / post-operative relapse: 2/37/16, exon 19 deletion / exon 21 L858R: 28/27. Sensitivity of plasma sample was 63.6% among overall, while that was 84.6% in patients with distant metastasis. Eighty-two percent of plasma positive patients at baseline showed molecular response in plasma after two weeks of afatinib treatment. De novo T790M mutation was detected in one patient (2%) from plasma samples.
Conclusion:
Liquid biopsy seemed to be suitable especially in patients with distant metastasis. Early molecular remission (within two weeks) was observed in 70% of patients.
