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Young-Chul Kim
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-014 - Feasibility of Liquid Biopsy Using Plasma and Platelets for Detection of ALK Rearrangements in Non-Small Cell Lung Cancer (ID 9301)
09:30 - 16:00 | Author(s): Young-Chul Kim
- Abstract
Background:
Fluorescence in situ hybridization (FISH) using tissue biopsy specimen is the gold standard for detection and confirmation of ALK rearrangement in non-small cell lung cancers (NSCLC), but it is time-consuming and labor-dependent procedure. Liquid biopsy using reverse-transcriptase polymerase chain reaction (RT-PCR) is expected to overcome these limitations, and provide an easy accessibility and frequent assessment of biomarkers. The aim of this study is to investigate the feasibility of liquid biopsy using plasma and platelets for detection of ALK rearrangement.
Method:
FISH was performed in 664 patients between January 2015 and May 2017. We retrospectively analyzed the formalin-fixed paraffin-embedded (FFPE) tissue and blood sample to detect ALK rearrangement using multiplex RT-PCR from 30 advanced NSCLC patients who had available tissue specimen and agreed with venous sampling. Total RNA were extracted from FFPE cell blocks, plasma and platelets, respectively. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK, the most common translocation, fusion RNA was detected using PANAqPCR[TM] EML4-ALK fusion gene detection kit.
Result:
Twenty-eight patients were FISH positive and two were negative. In a validation data compared with FISH, RT-PCR using FFPE tissue demonstrated 57.1% sensitivity and 69.2% accuracy. Liquid biopsy (plasma or platelets-positive) had higher sensitivity (96.4%) and accuracy (93.3%). Among the specimen of liquid biopsy, platelets showed slightly higher sensitivity and accuracy than plasma (82.1 and 83.3% vs 78.6 and 76.7%). Compared with FFPE tissue using RT-PCR, liquid biopsy showed 100% sensitivity, 20.0% specificity and 69.2% accuracy. Median proportion of positive cells in FISH was higher in subgroups of liquid biopsy with positive result (Plasma, 30.0 vs 15.0%; Platelets 30.0 vs 20.0%), but it was not statistically significant (p=0.062 and 0.104). In 18 patients with crizotinib treatment, platelets-positive subgroup showed a tendency of longer duration of treatment (7.2 vs 1.5 months) and higher response rate (57.1 vs 0.0 %), but the difference was not significant (p=0.071 and 0.100). However, platelets-positive subgroup showed significantly higher disease control rate than platelets-negative subgroup when they were treated with crizotinib (85.7 vs 25.0%, p=0.044).
Conclusion:
Plasma and platelets are a valuable source for liquid biopsy using RT-PCR technique in detection of ALK rearrangement, and they could play a supplementary role in diagnosis of ALK-positive NSCLC. Furthermore, platelets, especially, may be useful for predicting the treatment outcome of crizotinib.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-024 - Phase II Trial of AZD9291 in Second-Line Treatment after Acquired Resistance with T790M Mutation Detected From Circulating Tumor DNA (ID 8736)
09:30 - 16:00 | Presenting Author(s): Young-Chul Kim
- Abstract
Background:
Administering the best treatment after acquiring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) requires the knowledge of the resistance status. In this trial, the treatment efficacy of osimertinib (AZD9291) was assessed in patients with non-small-cell lung carcinoma (NSCLC) harboring T790M resistance mutation, which was detected in the circulating tumor DNA (CtDNA) without re-biopsy of the tumor tissue.
Method:
To prove 60% response rate of osimertinib compared to 30% as null hypothesis, and considering 10% drop out rate, 19 subjects were recruited. To extract CtDNA, 15 mL of peripheral blood was withdrawn and centrifuged immediately before storage. Cobas® v2 RUO (Roche diagnostics) and PANA mutyper® (Pangene, Korea) were used to detect the EGFR mutations from CtDNA. Osimertinib was prescribed as an 80 mg tablet once in a day irrespective of the food intake.
Result:
Eighty patients with acquired resistance to prior EGFR TKIs were screened for T790M resistance mutation, and the CtDNA of 21 subjects (26.3%) showed T790M mutation. T790M mutation was detected by both PANA mutyper® and Cobas® in 13 cases, T790M was detected only by PANA mutyper® in 4 cases, and only by Cobas® in 4 cases. Nineteen subjects (age: 64.4 ± 11.6 years old, 14 women, 5 men) were enrolled in this prospective single arm trial from September 2016 to April 2017. Prior EGFR TKIs were afatinib (n=3), erlotinib (n=4), gefitinib (n=10), erlotinib and afatinib (n=1), and gefitinib and afatinib (n=1). Twelve subjects had exon 19 deletion of EGFR gene, 4 had L858R point mutation, one showed exon 19 deletion and L858R, 1 had G719X, and 1 case showed no activating mutation. The response to osimertinib was evaluable in 15 subjects; 4 subjects dropped out from this trial before response evaluation. Among the 15 subjects (efficacy analysis set), partial remission was observed in 10 cases (66.7%).
Conclusion:
Assuming 40% of screened patients are harboring T790M mutation, sensitivity of CtDNA testing is 65% using both tests, and 53% with either test. Toxicity and survival analyses will be followed. (ClinicalTrials.gov Identifier: NCT02769286)
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P2.03-058 - Tiger-3: A Phase 3 Randomized Study of Rociletinib Vs Chemotherapy in EGFR-mutated Non-small Cell Lung Cancer (NSCLC) (ID 8395)
09:30 - 16:00 | Author(s): Young-Chul Kim
- Abstract
Background:
Rociletinib, an oral, irreversible tyrosine kinase inhibitor (TKI), selectively targets activating mutations in EGFR and the acquired resistance mutation T790M and demonstrated antitumor activity in the phase 1/2 TIGER-X study (NCT01526928). Initial results are reported from the TIGER-3 study (NCT02322281) of rociletinib vs chemotherapy in EGFR TKI-resistant patients with EGFR-mutated NSCLC.
Method:
Eligibility criteria included: metastatic or unresectable, locally advanced, EGFR-mutated NSCLC; radiological progression on most recent TKI therapy; ≥1 line of platinum doublet chemotherapy. Patients were not selected based on T790M status. Patients (N=900) were to be randomized (1:1:1) to rociletinib 500 or 625 mg BID or investigator’s choice of chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). The primary endpoint was investigator-assessed progression-free survival (PFS) (RECIST v1.1); objective response rate (ORR) was a secondary endpoint. The rociletinib dosing groups were combined and compared with chemotherapy in a step-down procedure (patients with a centrally confirmed T790M mutation, followed by all randomized patients).
Result:
TIGER-3 enrollment was halted upon discontinuation of rociletinib development in NSCLC in 2016; therefore, target enrollment was not achieved. TIGER-3 enrolled 75 patients in the rociletinib groups [500 mg BID, n=53; 625 mg BID, n=22] and 74 in the chemotherapy group. Median age was 62 years, 69.1% had ECOG Performance Status of 1, 39.6% were Asian, 58.4% were female, and median number of prior therapies was 3. PFS and ORR data are presented in the Table. The most common adverse events (all grade; grade ≥3) in the rociletinib group were diarrhea (62.7%; 2.7%), hyperglycemia (58.7%; 24.0%), nausea (37.3%; 4.0%), fatigue (37.3%; 8.0%), and decreased appetite (37.3%; 0%) and in the chemotherapy group were nausea (27.4%; 5.5%), anemia (24.7%; 2.7%), and fatigue (24.7%; 9.6%).Outcome Centrally Confirmed T790MPositive Centrally Confirmed T790MNegative Intent-to-Treat Population* Rociletinib[†] (n=25) Chemotherapy (n=20) Rociletinib[†] (n=36) Chemotherapy (n=41) Rociletinib[†] (n=75) Chemotherapy (n=73) Median PFS, mo (95% CI) 6.8 (3.7–12.2) 2.7 (1.3–7.0) 4.1 (2.5–4.6) 1.4 (1.3–2.7) 4.1 (2.8–5.5) 2.5 (1.4–2.9) HR (95% CI) 0.570 (0.285–1.140); P=0.105 0.532 (0.322–0.878); P=0.011 0.609 (0.423–0.875); P=0.006 Confirmed ORR, n (%) [95% CI] 9 (36.0) [18.0%–57.5%] 3 (15.0) [3.2%–37.9%] 3 (8.3) [1.8%–22.5%] 2 (4.9) [0.6%–16.5%] 13 (17.3) [9.6%–27.8%] 6 (8.2) [3.1%–17.0%] *Includes patients with undetermined T790M mutation status. [†]Rociletinib 500 mg BID and 625 mg BID dose groups were pooled for the analysis. CI, confidence interval; HR, hazard ratio.
Conclusion:
Incomplete enrollment precluded hypothesis testing. However, the data show a trend toward longer PFS and higher ORR with rociletinib.
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P2.14 - Radiotherapy (ID 715)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.14-017 - Postoperative Radiotherapy in Completely Resected Stage IIIA-N2 Non-Small Cell Lung Cancer (ID 9641)
09:30 - 16:00 | Author(s): Young-Chul Kim
- Abstract
Background:
Use of postoperative radiotherapy (PORT) in completely resected (R0) pathologic stage IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial. To assess the impact of PORT, we analyzed on the patterns of failure and survival difference in these patients.
Method:
Consecutive 50 patients with pathologic stage ⅢA-N2 NSCLC who underwent surgery with complete resection (R0) between Apr. 2004 and Dec. 2013 were retrospectively reviewed. Thirty-five(70%) patients were male and median age was 63 years (range, 35 - 82 years). Thirty-nine(78%) patients underwent lobectomy, 7(14%) bilobectomy, and 4(8%) pneumonectomy. Postoperative adjuvant therapy consisted of chemotherapy (ChT) alone in 26(52%) patients, ChT + PORT in 10(20%), PORT alone in 4(8%), and none in 10(20%). Radiation dose was ranged from 34 to 60 Gy with the median 55 Gy. Follow-up period was ranged from 4 to 132 months with median 42 months. Survival was calculated from the date of surgery. Kaplan-Meier method was used for survival calculation and their comparison was done using log-rank test.
Result:
The 3 and 5-year overall survival (OS) rate of all 50 patients was 70% and 58%, respectively and the median survival time was not yet reached. Both univariate and multivariate analysis showed age (> 70 yrs old) and ratio of node positive (LNR > 17%) were correlated with the poor OS. The locoregional recurrence was appeared in 19(38%) patients and distant metastasis in 27(54%). The median time to recurrence was 16 months (range, 1 - 87 months) in locoregional failure and that of distant metastasis was 20 months (range, 6 - 60 months). Lymphovascular space invasion (LVSI) was the only statistically significant factor correlating to the locoregional recurrence-free survival (LRFS) both in univariate and multivariate analysis. PORT did not improve both OS and LRFS. Three and 5-years OS in patients with PORT were 56% and 40%, in a while 76% and 68% in patients without PORT (P=0.166), respectively. Three and 5-years LRFS in patients with or without PORT was 80% and 80% versus 54% and 50% (P=0.105), respectively. We could find that the LNR over 17% (p=0.003), tumor extension (p=0.006), and LVSI (p=0.01) were more prevalent in patients group with PORT.
Conclusion:
In this analysis, the most important prognostic factor in the pathologic stage IIIA-N2 (R0) NSCLC patients was the age and positive lymph node ratio. Risk of locoregional recurrence was decreased with the use of PORT. However, this benefit was not leaded to the overall survival benefit.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-050 - A Real World Treatment Study of Osimertinib: ASTRIS Study Korean Subgroup Analysis (ID 9678)
09:30 - 16:00 | Author(s): Young-Chul Kim
- Abstract
Background:
ASTRIS (NCT02474355) is an open-label, single-arm, multination, real world treatment study, investigating the safety and efficacy of osimertinib in patients with T790M-positive advanced non-small cell lung cancer (NSCLC), who have previously received EGFR-TKI. We report the first results of Korean subset from ASTRIS which is the largest real world treatment study of osimertinib to date.
Method:
Eligible patients had advanced NSCLC harbouring a T790M mutation determined by local validated molecular tests, received prior EGFR-TKI therapy, acceptable organ and bone marrow function and no history of interstitial lung disease (ILD) or QTc prolongation. Enrollment of patients with asymptomatic, stable CNS metastases were permitted. Patients received osimertinib 80 mg once daily. The primary efficacy outcome was overall survival; other outcomes included investigator-assessed response rate (RR), progression-free survival (PFS) and time to treatment discontinuation (TTD). Safety assessment was also conducted. Data cut-off (DCO) was 3 November 2016; results from 1,217 patients in the global study have been presented previously (ASCO 2017 Abstract 9036).
Result:
A total of 371 patients received at least one dose of osimertinib from 30 Korean sites (full analysis set); at DCO, 319 patients (81.4%) were ongoing and median follow-up time was of 3.1 (0–8) months. Baseline patients’ characteristics were median age 61.1 (27–85) years old, female 65.5%, PS 0/1 88%, prior chemotherapy 47%, prior radiotherapy 48%. Tissue was the most common specimen source to test T790M mutation as well as other EGFR mutations (287/371, 77.4%) and plasma was the next (39/371, 13.1%). Fifty two patients (13.3%) had discontinued treatment; median duration of exposure 3.3 (0–7) months, 30 pts (7.7%) had disease progression and 24 patients (6.5%) died. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, the investigator-assessed RR was 72.1% (212/294; 95% CI 66.6 – 77.2). Due to limited follow-up period, OS, PFS, and TTD were immature to analyze. Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 26 patients (7%) and 14 patients (3.8%), respectively. Serious AEs were reported in 50 patients (13.5%) and AEs leading to death in 8 patients (2.2%). ILD/pneumonitis-like events were reported in 9 patients (2.4%), and QTc prolongation (>470ms) in 5 patients (1.3%).
Conclusion:
At DCO for the 1[st] interim analysis of ASTRIS, Korean subgroup results demonstrated similar clinical activities (RR) to that observed in the osimertinib clinical trial program with no new safety signals.
