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Y. Wu
Moderator of
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JCHS - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 239)
- Event: WCLC 2015
- Type: Joint Chinese/ English Session
- Track: Other
- Presentations: 13
- Moderators:C. Bai, Y. Wu
- Coordinates: 9/06/2015, 07:30 - 10:30, Mile High Ballroom 1a-1f
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- Abstract
Abstract not provided
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JCHS.02 - Molecular Epidemiology of Lung Cancer in China (ID 3452)
07:35 - 07:55 | Author(s): B. Han
- Abstract
- Presentation
Abstract not provided
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JCHS.03 - Development of New Drugs by Chinese Pharmaceutical Companies (ID 3453)
07:55 - 08:15 | Author(s): Q. Zhou
- Abstract
- Presentation
Abstract not provided
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JCHS.04 - Current Status of Molecular Testing in China: Application and Technology (ID 3454)
08:15 - 08:35 | Author(s): S. Lu
- Abstract
- Presentation
Abstract not provided
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JCHS.05 - Asian Contributions to Global Drug Development (ID 3455)
08:35 - 08:55 | Author(s): T. Mok
- Abstract
- Presentation
Abstract not provided
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JCHS.06 - New Diagnostic Techniques for Lung Cancer (ID 3456)
08:55 - 09:15 | Author(s): C. Bai
- Abstract
- Presentation
Abstract not provided
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JCHS.07 - First-Line Icotinib Versus Cisplatine/Pemetrexed plus Pemetrexed Maintenance in Advanced NSCLC Patients with EGFR Mutation (ID 3524)
09:15 - 09:25 | Author(s): Y. Shi, L. Wang, B. Han, W. Li, P. Yu, Y. Liu, C. Ding, X. Song, Z. Ma, X. Ren, H. Zhang, G. Chen, N. Wu, C. Yao, Y. Song, S. Zhang, L. Ding, F. Tan, J. Feng
- Abstract
- Presentation
Background:
Clinical studies with anti-EGFR agents demonstrate that EGFR TKIs play critical roles in the treatment of non-small cell lung cancer, especially in patients with positive EGFR mutation. Icotinib is an oral, selective EGFR TKIs. Phase 3 study showed that icotinib is non-inferior to gefitinib in treating unselected or EGFR-mutated advanced NSCLC patients as second-line therapy but better safety profile, which provide a rationale to examine icotinib in first-line setting. The objective of this study is to evaluate progression-free survival (PFS), overall survival (OS) and safety of icotinib in chemotherapy naïve NSCLC patients with EGFR mutation.
Methods:
In this phase 3, open-label, randomized study (CONVINCE, NCT01719536), 285 patients (pathologically confirmed NSCLC, positive 19/21 EGFR mutation, treatment naive) will be 1:1 randomized to receive oral icotinib (125 mg, three times daily) or cisplatine (intravenous [IV], 75 mg/m2, day 1) plus pemetrexed (IV, 500 mg/m2, day 1), patients achieving disease control after 4-cycle chemotherapy continue to receive single pemetrexed (IV, 500 mg/m2, day 1) as maintenance therapy until progression. Randomization will be stratified by performance status (0-1/2), smoking status (smoker/non-smoker), disease stage (IIIB/IV), and mutation type (19/21). A total of 228 events would provide 90% power to detect an HR for PFS of 1 at 2-sided significance level of 0.05. Response will be reviewed by both investigator and independent data monitoring committee. Patient enrollment was completed in June 2014, and the results are expected in June, 2015.
Results:
Not applicable
Conclusion:
Not applicable.
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- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) exon 20 T790M mutation may have a predictive role before EGFR-tyrosine kinase inhibitors (TKIs) treatment and it also might have a prognostic role after acquired resistance to EGFR-TKIs. However, its role in EGFR-TKI rechallenge after failure of initial EGFR-TKIs in EGFR-mutant advanced non-small cell lung cancer (NSCLC) remains unknown.
Methods:
We retrospectively evaluated the clinical course of 515 EGFR-mutant advanced NSCLC patients who received first generation EGFR-TKIs (gefitinib or erlotinib) from December 2009 to November 2014 at Guangdong General Hospital. Of these 515 patients, 65 patients recieved same EGFR-TKI rechallenge, including 51 patients who underwent rebiopsy and secondary EGFR mutation detection after failure of initial EGFR-TKIs. EGFR detection was performed by Sanger sequencing or Amplification Refractory Mutation System (ARMS) methods. Progression-free survival (PFS) and overall survival (OS) were both calculated from commencement of EGFR-TKI rechallenge. Survival data were analyzed using the Kaplan-Meier method and log-rank test.
Results:
EGFR activating mutations still existed in all the 51 patients who received rebiopsy and 18 patients were with T790M mutation while 33 patients were without T790M. The median PFS for the T790M+ and T790M- groups were 1.8 months (95%CI 1.180~2.420) and 2.0 months (95%CI 1.100~2.900), respectively (P=0.261). The median OS for the two groups were 7.7 months (95%CI 6.548~8.852) and 6.8 months (95%CI 4.730~8.870), respectively (P=0.565). No statistical difference was found in PFS or OS between two groups(Figure 1). Fig 1. Kaplan-Meier curves of patients in two groups. (A)Progression-free survival. (B) Overall survival.
Conclusion:
EGFR T790M mutation is neither a predictive nor a prognostic factor for first generation EGFR-TKI rechallenge in EGFR-mutant advanced NSCLC patients, indicating that whether T790M occurs or not, same EGFR-TKI rechallenge could not be recommended as a good strategy to overcome the resistance to first generation EGFR-TKIs.
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- Abstract
- Presentation
Background:
Targeted therapies have considerably improved the prognosis of patients with non-small cell lung cancer (NSCLC).Although not precision enough, RESIST criteria was still the most often used response assessment method to reflecting the clinical benefits. We propose a non-invasive, folate receptor (FR)–based circulating tumor cell (CTC) detection approach to interpret treatment response of targeted therapy between baseline and follow-up CTC values in EGFR mutation/ALK translocation advanced NSCLC.
Methods:
One hundred and thirty eight patients were enrolled in our study. Peripheral blood was analyzed for CTCs enumeration on negative enrichment by immunomagnetic beads. Changes of CTCs levels were correlated with radiological response. Sequential analyses were conducted to monitor CTC signals during therapy and correlate radiological effects with treatment outcome.
Results:
CTCs were detected (≥8.7CTC) in 84.8% of patients. Pretreatment and pro-treatment blood samples from all 118 EGFR-mutant (19deltion:56, L858R:57, G719x:3, L861Q:1, 19 deletion + L858R:1), 14 ALK translocation lung cancer patients and 6 EGFR wild type patients were collected. Of 89 eligible and evaluable patients, baseline CTC counts were not associated with response to treatment by RECIST (P=0.353). There is no difference between exon 19 deletion and L858R of baseline CTC values. (19deletion:19.4 CTCs, L858R:20.9 CTCs,P=0.222) The change of CTCs values increased correlation with radiological response (P=0.042) after treatment of targeted therapy. There is no significant difference between exon 19 deletion and L858R of CTCs values pre and pro EGFR-TKI treatment.(3.32 vs.12.1, P=0.783)
Conclusion:
This study confirms the predictive significance of CTCs in patients with EGFR mutation/ALK translocation NSCLC receiving targeted therapy. The change of CTCs value correlated significantly with radiological response. This strategy may enable non-invasive, specific biomarker assessment method for using CTC decreases as an early indication of response to targeted therapy and monitoring in patients undergoing targeted cancer therapies.
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JCHS.10 - Discussant Special Issue on Tobacco Related Lung Cancer in China- Professors Yi-long Wu and ChunXue Bai guest editors for the Journal Cancer(ISSN:1097-0142) Chair: Prof. Fadlo R. Khuri (editor in chief, Cancer) (ID 3457)
09:45 - 10:00 | Author(s): Y. Wu
- Abstract
- Presentation
Abstract not provided
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JCHS.11 - Overview the Publishing of Cancer Special Issue (ID 3458)
10:00 - 10:05 | Author(s): C. Bai
- Abstract
- Presentation
Abstract not provided
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JCHS.12 - Challenges of Tobacco Related Lung Cancer in China (ID 3460)
10:05 - 10:15 | Author(s): S.S. Ramalingam
- Abstract
- Presentation
Abstract not provided
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JCHS.13 - Progress of Management for Lung Cancer: Focus on China (ID 3461)
10:15 - 10:25 | Author(s): J. Hu
- Abstract
- Presentation
Abstract not provided
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PC 02 - Pro vs Con: Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? / Pro vs Con: Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) (ID 48)
- Event: WCLC 2015
- Type: Pro Con
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
- Moderators:S. Thongprasert, Y. Wu, P. Meldgaard, K. Syrigos
- Coordinates: 9/08/2015, 14:15 - 15:45, 205+207
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PC02.01 - Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? - Pro (ID 2030)
14:20 - 14:40 | Author(s): S.A. Laurie
- Abstract
- Presentation
Abstract:
With the dramatic clinical benefit that can be observed using tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) harbouring activating mutations in EGFR, there has understandably been a focus on the use of these agents in this subset of NSCLC. However, EGFR mutation positive NSCLC represents only approximately 10 – 15 % of all non-squamous NSCLC in non-East Asian patients, and a substantial proportion of East Asian patients do not harbour this mutation. Thus, world-wide, the vast majority of those with NSCLC are so-called “wild-type” for EGFR. For these patients, it is clear from randomized clinical trials that the treatment of choice in the first-line metastatic setting is platinum-doublet chemotherapy. Increasing data suggest that chemotherapy may be preferred in the second-line setting. Is there any role for the use of EGFR TKIs in the wild-type population? Randomized data in which an EGFR TKI is compared to placebo in both the maintenance and refractory settings suggest that there may be. NCIC Clinical Trials Group study BR21 [1] which randomized 731 unselected patients to either erlotinib or matching placebo, was designed and conducted prior to the discovery of activating mutations. Patients had received 1 (50 %) or > 2 (50 %) lines of prior therapy; > 90 % had received a platinum-doublet. An improvement in median survival (6.7 versus 4.7 months [HR 0.70, p < 0.001]) was also associated with a quality of life benefit. This benefit was consistent across subgroups, including in the 50 % of patients with non-adenocarcinoma histology. In a separate analysis of ever-smokers with squamous histology, patients highly unlikely to harbour an EGFR mutation, the magnitude of survival benefit was the same as in the overall study population (median 5.6 versus 3.5 months [HR 0.66, p=0.009])[2]. The SATURN trial [3] randomized 889 patients who had not progressed after 4 cycles of platinum-doublet chemotherapy to either erlotinib or placebo. While of debatable clinical relevance, there was a statistically significant one month prolongation of median survival with the use of erlotinib (HR 0.81, p=0.009). A similar effect was observed in the 44 % of patients with known EGFR wild-type status (HR 0.77, p=0.02). In a pre-planned subgroup analysis [4], a greater magnitude of benefit was observed in those patients whose best response to induction chemotherapy was stable disease (median overall survival 11.9 versus 9.6 months [HR 0.72, p=0.002]), with a similar effect noted in those patients with squamous histology (HR 0.67, p=0.01), and those known to be EGFR wild-type (HR 0.65, p=0.004). Maintenance erlotinib has been shown to not negatively impact quality of life [5], and when used in those with stable disease, to be cost effective [6]. Meta-analyses of placebo-controlled trials of EGFR TKIs in the maintenance setting have confirmed a modest progression-free survival benefit in squamous [7] and known wild-type [8] patients. Multiple trials have compared an EGFR TKI to either docetaxel or pemetrexed in the second-line setting. The TAILOR trial [9], the only trial to prospectively determine and enrol only wild-type patients, showed a clear PFS advantage to docetaxel, and a trend towards improved overall survival. However several other trials that enrolled patients who were unselected with regard to EGFR status had a substantial number of wild type patients, and none of these trials demonstrated a difference in overall survival in wild-type patients between an EGFR TKI and chemotherapy. While these were retrospective analyses on only a subset of enrolled patients with available tissue, wild-type patient numbers in many trials approached (and in one exceeded) the number of patients enrolled to TAILOR. Further, unlike other trials, TAILOR prohibited crossover, which may have impacted survival results, particularly for patients with squamous carcinoma in the erlotinib arm. Taken together these trials suggest that a treatment strategy that includes both chemotherapy and an EGFR TKI sequentially, irrespective of order, will lead to a similar length of survival provided patients receive both lines of therapy. In platinum-pretreated patients who are fit it is likely preferred to use chemotherapy and then at progression move on to an EGFR TKI, as the chance of patients receiving both treatments is higher. Additional data to suggest that EGFR TKIs may have activity in wild-type patients comes from several small, randomized phase II trials comparing second-line chemotherapy with the same chemotherapy with intercalated EGFR TKIs. These studies have shown prolonged PFS in patients treated with the combination. What these trials demonstrate is that EGFR TKIs appear to have a modest treatment effect in EGFR wild-type patients. In these days of targeted therapies leading to substantial treatment effects in a variety of tumours with oncogenic drivers, is this magnitude of benefit sufficient? In lung cancer, many other treatments have been adopted for a similar magnitude of benefit. Although objective response rates to EGFR TKIs are low in wild-type patients, they are also low to standard cytotoxic chemotherapies beyond first-line, and it seems possible that there is a larger proportion of patients with stabilization of disease and / or slowing of progression that is clinically relevant. Not all oncologists or patients will feel that a trial is warranted, but an EGFR TKI is a reasonable choice as last-line therapy when the option is no further treatment, or as maintenance treatment in patients with squamous histology following a best response of stable disease to induction platinum-based chemotherapy. EGFR “wild-type” is a heterogeneous, not homogeneous, population, and as with any therapy, only a subgroup of patients will benefit from treatment. However a consistent reproducible biomarker for benefit in the wild-type subgroup has not yet been discovered. EGFR protein expression, gene copy number, Kras status and serum proteomics have all been evaluated with at times conflicting results, due to limited samples and the retrospective nature of the analyses. The development of rash may be a pharmacodynamic predictor of greater efficacy [10]. Additional work is required to determine which wild-type patients may derive benefit from an EGFR TKI, to avoid needless toxicity and improve cost-effectiveness. References 1. Shepherd et al. N Engl J Med 353: 123-132, 2005 2. Clark et al. Clin Lung Cancer 7:389-394, 2006 3. Cappuzzo et al. Lancet Oncol 11:521-529, 2010 4. Coudert et al. Ann Oncol 23:388-394, 2012 5. Juhasz et al. Eur J Cancer 49:1205-1215, 2013 6. Walleser et al. Clinicoeconomics Outcomes Res 4:269-275, 2012 7. Ameratunga et al. Asia-Pacific J Clin Oncol. 10:273-278, 2014 8. Vale et al. Clin Lung Cancer 16:173-182, 2015 9. Garassino et al. Lancet Oncol 14:981-988, 2013 10. Ding et al. Contemp Clin Trials 29:527-536, 2008
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PC02.02 - Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? - Con (ID 2031)
14:40 - 15:00 | Author(s): L.V. Sequist
- Abstract
- Presentation
Abstract not provided
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PC02.03 - Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) - Pro (ID 2032)
15:00 - 15:20 | Author(s): I.I. Wistuba
- Abstract
- Presentation
Abstract not provided
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PC02.04 - Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) - Con (ID 2033)
15:20 - 15:40 | Author(s): Y. Yatabe
- Abstract
- Presentation
Abstract:
Great advantages of next generation sequencing have been published so far, and many new genetic alterations were found with whole genome sequencing. Targeted sequencing using next generation sequencing technique can analyze FFPE small biopsy specimens, but may be equivalent or less than the current selected testing, such as EGFR and ALK testing. Although the targeted sequencing can actually analyze multiple genes, most diagnostic panels include the genes that are frequently altered in cancer generally, thus practically useful genes are limited in terms of lung cancer, such as EGFR, ALK, ROS1, and RET. In contrast, whole exome sequencing is potentially useful, as it can comprehensively examine mRNA expression on tumor cells. In general, mRNA in clinical samples well represents tumor genetic status even with significant dilution with the normal cells, which are less active in transcription. However, it is difficult to perserve high quality RNA with clinical samples, and it is unclear that the whole exome sequencing is constantly clinically applicable for small biopsy specimens. Furthremore, there are some cases that show discrepant results between DNA and RNA based assays. As EGFR transcript is suppressed in SCLC, EGFR mutation cannot be detected with the exome sequencing in SCLC transformed as a resistant mechanism to EGFR-TKI treatment. On the other hand, current selected testing for EGFR and ALK has been confirmed with clinical trials and are adjusted to clinical demands, e.g., short turnaround time and high sensitivity.
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Author of
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HOD 01 - Highlights of the Previous Day: Treatment of Advanced, Localized and LocoRegional Disease and Small Cell, Thymoma, Mesothelioma (ID 240)
- Event: WCLC 2015
- Type: Highlights of the Day
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 07:00 - 08:00, Four Seasons Ballroom F1+F2
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HOD01.01 - Treatment of Advanced Disease (ID 3392)
07:00 - 07:15 | Author(s): Y. Wu
- Abstract
- Presentation
Abstract not provided
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JCHS - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 239)
- Event: WCLC 2015
- Type: Joint Chinese/ English Session
- Track: Other
- Presentations: 3
- Moderators:C. Bai, Y. Wu
- Coordinates: 9/06/2015, 07:30 - 10:30, Mile High Ballroom 1a-1f
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JCHS.01 - Introduction (ID 3451)
07:30 - 07:35 | Author(s): Y. Wu
- Abstract
Abstract not provided
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JCHS.08 - Role of T790M Mutation in EGFR-TKI Rechallenge for Patients with EGFR-Mutant Advanced Non-Small Cell Lung Cancer (ID 3525)
09:25 - 09:35 | Author(s): Y. Wu
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) exon 20 T790M mutation may have a predictive role before EGFR-tyrosine kinase inhibitors (TKIs) treatment and it also might have a prognostic role after acquired resistance to EGFR-TKIs. However, its role in EGFR-TKI rechallenge after failure of initial EGFR-TKIs in EGFR-mutant advanced non-small cell lung cancer (NSCLC) remains unknown.
Methods:
We retrospectively evaluated the clinical course of 515 EGFR-mutant advanced NSCLC patients who received first generation EGFR-TKIs (gefitinib or erlotinib) from December 2009 to November 2014 at Guangdong General Hospital. Of these 515 patients, 65 patients recieved same EGFR-TKI rechallenge, including 51 patients who underwent rebiopsy and secondary EGFR mutation detection after failure of initial EGFR-TKIs. EGFR detection was performed by Sanger sequencing or Amplification Refractory Mutation System (ARMS) methods. Progression-free survival (PFS) and overall survival (OS) were both calculated from commencement of EGFR-TKI rechallenge. Survival data were analyzed using the Kaplan-Meier method and log-rank test.
Results:
EGFR activating mutations still existed in all the 51 patients who received rebiopsy and 18 patients were with T790M mutation while 33 patients were without T790M. The median PFS for the T790M+ and T790M- groups were 1.8 months (95%CI 1.180~2.420) and 2.0 months (95%CI 1.100~2.900), respectively (P=0.261). The median OS for the two groups were 7.7 months (95%CI 6.548~8.852) and 6.8 months (95%CI 4.730~8.870), respectively (P=0.565). No statistical difference was found in PFS or OS between two groups(Figure 1). Fig 1. Kaplan-Meier curves of patients in two groups. (A)Progression-free survival. (B) Overall survival.
Conclusion:
EGFR T790M mutation is neither a predictive nor a prognostic factor for first generation EGFR-TKI rechallenge in EGFR-mutant advanced NSCLC patients, indicating that whether T790M occurs or not, same EGFR-TKI rechallenge could not be recommended as a good strategy to overcome the resistance to first generation EGFR-TKIs.
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JCHS.10 - Discussant Special Issue on Tobacco Related Lung Cancer in China- Professors Yi-long Wu and ChunXue Bai guest editors for the Journal Cancer(ISSN:1097-0142) Chair: Prof. Fadlo R. Khuri (editor in chief, Cancer) (ID 3457)
09:45 - 10:00 | Author(s): Y. Wu
- Abstract
- Presentation
Abstract not provided
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.13 - A Randomized Controlled Trial of Erlotinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations (CTONG0901) (ID 2762)
17:55 - 18:00 | Author(s): Y. Wu
- Abstract
- Presentation
Background:
For non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, preclinical data showed the superiority of exon 19 mutations to exon 21 mutations in both response to EGFR tyrosine kinase inhibitors (TKIs) and survival. Meanwhile, retrospective studies demonstrated that erlotinib was significantly superior to gefitinib in progression-free survival (PFS) for advanced NSCLC patients with EGFR mutations. However, no randomized controlled trials compared erlotinib to gefitinib in advanced NSCLC patients with EGFR exon 19 or 21 mutations.
Methods:
We conducted a randomized controlled trial (CTONG 0901；NCT01024413) comparing erlotinib to gefitinib in advanced NSCLC harboring EGFR exon 19 or 21 mutations from July 2009 to July 2014. Eligible patients were randomized to receive erlotinib (150 mg, qd) or gefitinib (250 mg, qd) at the ratio of 1:1 in any line settings. The primary endpoint was PFS, and the secondary endpoints included overall survival (OS), objective response rate (ORR), post-progression survival (PPS), and toxicities.
Results:
The last follow-up was on March 30, 2015. Totally, 256 patients (148 with exon 19 mutations and 108 with exon 21 mutations), of whom 165, 83 and 9 were in the first, second or further-line settings respectively, were randomized to receive erlotinib or gefitinib. Median PFS was 12.4 (95%CI: 10.6~14.1) months in erlotinib arm and 10.4 (95%CI: 8.8~11.9) months in gefitinib arm, HR=0.80 (0.61~1.05), p=0.100; ORR, median PPS and OS were 56.3% versus 52.3% (p=0.530), 6.9 (95%CI: 4.3~9.5) versus 6.9 (95%CI: 4.5~9.2) months (p=0.784), and 22.4 (95%CI: 17.9~27.0) versus 20.5 (95%CI: 17.1~23.8) months (HR=0.90 [0.67~1.22]; p=0.496) respectively. There were no significant differences in toxicities between the two arms, p＞0.05. In the four subgroups (the first-line, second or further-line setting, exon 19 and 21 mutations), except for median PFS being 11.4 versus 7.9 months (HR=0.58 [0.37~0.90], p=0.015) in the second or further-line setting, no significant differencs were observed in median PFS and OS respectively between the two arms, p＞0.05. Receiving erlotinib or gefitinib treatment, EGFR exon 19 mutant patients were superior to those with exon 21 mutations in terms of ORR (62.2% versus 43.5%, p=0.003), median PPS (9.1 [95%CI: 7.0~11.2] versus 4.6 [95%CI: 3.4~5.8] months, p=0.011 ) and OS (24.8 [95%CI: 20.9~28.8] versus 17.7 [95%CI: 15.1~20.3] months, HR=0.66 [0.48~0.89], p=0.006) respectively, even though there was no significantly difference in median PFS (11.4 [95%CI: 9.6~13.2] versus 11.1 [95%CI: 9.4~12.9] months, HR=0.80 [0.60~1.05], p=0.101). Multivariant Cox regression analysis showed that subsequent EGFR TKIs, combination of subsequent EGFR TKIs and local treatment, as well as subsequent chemotherapy were prognostic factors for OS, p＜0.05.
Conclusion:
Erlotinib was not significantly superior to gefitinib in advanced NSCLC with either exon 19 or 21 mutations in response and survival, with similar toxicities. However, EGFR exon 19 mutant patients had remarkably increased ORR, PPS and OS than those with exon 21 mutations after taking erlotinib or gefitinib. Subsequent treatments after failure to EGFR TKIs were significantly prognostic factors for OS.
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MINI 31 - ALK (ID 158)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Malik, I. Ou
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 1a-1f
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MINI31.04 - Intracranial Efficacy of First-Line Crizotinib vs. Chemotherapy in ALK-Positive NSCLC (ID 1238)
18:45 - 18:50 | Author(s): Y. Wu
- Abstract
- Presentation
Background:
The ongoing multicenter, randomized, open-label phase III study PROFILE 1014 recently demonstrated superior efficacy of crizotinib compared with chemotherapy in patients with previously untreated advanced ALK-positive NSCLC (Solomon et al, N Engl J Med 2014). Intracranial efficacy of crizotinib vs. chemotherapy was compared prospectively in this trial.
Methods:
Patients with previously untreated advanced non-squamous ALK-positive NSCLC (N=343) were randomized 1:1 to receive crizotinib 250 mg orally BID (n=172) or intravenous chemotherapy (pemetrexed 500 mg/m[2 ]+ cisplatin 75 mg/m[2] or carboplatin at AUC 5–6; all q3w for ≤6 cycles; n=171). Patients with treated brain metastases that were stable for ≥2 weeks with no ongoing requirement for corticosteroids were eligible. Treatment was continued until PD. Continuation of, or crossover to, crizotinib after PD (per independent radiology review [IRR]) was allowed for patients randomized to crizotinib or chemotherapy, respectively. Brain scanning was performed every 6 weeks in patients with baseline brain metastases and every 12 weeks in those without baseline brain metastases. Protocol-specified efficacy endpoints included PFS (primary endpoint), ORR, OS, and 12- and 18-month OS, as well as intracranial TTP. Intracranial DCR at 12 and 24 weeks was also evaluated. Efficacy was evaluated in the ITT population and in two subgroups of patients: those with and without baseline brain metastases.
Results:
Of 343 patients in the ITT population, 79 had brain metastases at baseline identified by IRR (23%) and 263 did not (77%; data not reported for one patient). Baseline characteristics of patients randomized to receive crizotinib or chemotherapy were generally well balanced within these two patient subgroups. Among the patients with baseline brain metastases, a significantly higher proportion achieved intracranial disease control with crizotinib than with chemotherapy at 12 weeks (33/39 [85%] vs. 18/40 [45%], respectively; P=0.0003) and at 24 weeks (22/39 [56%] vs. 10/40 [25%]; P=0.006). There was a numerical improvement in prospectively measured intracranial TTP with crizotinib in the ITT population (HR 0.60, P=0.069), as well as in patients either with baseline brain metastases (HR 0.45, P=0.063) or without baseline brain metastases (HR 0.69, P=0.323). The frequency of progression in the brain was low in the ITT population (15%) and in patients with and without baseline brain metastases (27% and 11%, respectively). Overall PFS was significantly longer with crizotinib than with chemotherapy in both subgroups (brain metastases present: HR 0.40, P=0.0007, median 9.0 vs. 4.0 months; brain metastases absent: HR 0.51, P≤0.0001, median 11.1 vs. 7.2 months), as it was in the ITT population (HR 0.45, P<0.0001, median 10.9 vs. 7.0 months). Twenty-five patients in the crizotinib arm of the study experienced intracranial PD; 22 of these patients received crizotinib for ≥3 weeks beyond PD and 19 also received intracranial radiotherapy.
Conclusion:
In this prospective assessment of intracranial efficacy, crizotinib demonstrated significantly greater intracranial disease control and overall efficacy compared with chemotherapy in patients with baseline brain metastases. These findings provide further confirmation of crizotinib as the standard of care for patients with previously untreated advanced ALK-positive NSCLC, including those patients with brain metastases at baseline.
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ORAL 16 - Clinical Care of Lung Cancer and Advanced Biopsies (ID 115)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:J.W. Neal, Q. Zhou
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2a-3b
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ORAL16.05 - Retrospective Analysis of ctDNA EGFR Mutations in the Phase III, Randomized IMPRESS Study (ID 2106)
11:28 - 11:39 | Author(s): Y. Wu
- Abstract
- Presentation
Background:
The majority of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer respond to first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs, e.g. gefitinib) but nearly all eventually acquire resistance. The most common mechanism of acquired resistance is a second-site mutation in the EGFR kinase domain, T790M. The phase III, double-blind IMPRESS study evaluated the efficacy and safety of continuing gefitinib plus pemetrexed/cisplatin versus placebo plus pemetrexed/cisplatin in patients with acquired resistance to first-line gefitinib. Study results did not support the continuation of gefitinib after disease progression (by RECIST criteria) when platinum-based doublet chemotherapy is used as second-line therapy. Here we report the results of a retrospective biomarker analysis of plasma circulating free, tumor-derived DNA (ctDNA) from patients in IMPRESS, including T790M profiling, to help understand the IMPRESS clinical trial outcome.
Methods:
Plasma samples for ctDNA isolation were collected at baseline and discontinuation from 151 randomized, non-Chinese patients in IMPRESS (58% of overall IMPRESS population). ctDNA levels of T790M, L858R, and Exon19 deletions were detected using both a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) and a qualitative QIAGEN[®] Therascreen ARMS assay (baseline only). Local EGFR tumor tissue (diagnostic) results were available for 133/151 patients. Mutation concordance rates between tissue and baseline plasma results, and comparisons between the two plasma detection methods, were calculated.
Results:
Baseline ctDNA EGFR mutation results were obtained for >99% (150/151) of patients. Using BEAMing, sensitivity and specificity between baseline plasma EGFR sensitizing mutations and local EGFR tumor tests were 78% (69/89) and 98% (42/43), respectively, for Exon19 deletions, and 82% (31/38) and 97% (91/94) for L858R. The T790M detection rate in baseline plasma samples using BEAMing was 56% (84/150). The Therascreen ARMS assay demonstrated a significantly reduced T790M detection rate of 13% (20/150). Likewise, the sensitivity of the Therascreen ARMS assay with respect to tissue for EGFR sensitizing mutations was also reduced compared with BEAMing: Exon 19: 54% (48/89), L858R: 47% (18/38), though the specificity remained near 100%. In the 97 evaluable plasma samples collected at discontinuation, T790M was detected by BEAMing in 52% (50/97) of patients. When compared with matched baseline plasma, 11 patients had newly acquired T790M mutation at discontinuation while T790M reverted to undetectable in 14 patients. Full plasma profiling data from the complete IMPRESS clinical study population (including 108 patients from China) and correlative analyses of plasma EGFR mutation status with clinical outcome (progression-free survival, overall survival, objective response rate) will be presented.
Conclusion:
In IMPRESS, T790M was detectable with BEAMing digital PCR in the baseline ctDNA samples of 56% of evaluable patients, a rate comparable to similar mutation analyses in this same second-line, EGFR-TKI-failed setting. EGFR mutation detection in plasma using the Therascreen ARMS assay demonstrated comparable specificity to BEAMing but reduced sensitivity. The T790M detection rate afforded by the BEAMing technology will allow for a comprehensive assessment of correlations between clinical outcome in IMPRESS and EGFR mutational status.
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ORAL 17 - EGFR Mutant Lung Cancer (ID 116)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:P. Meldgaard, E. Felip
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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ORAL17.08 - Gefitinib/Chemotherapy vs Chemotherapy in EGFR Mutation-Positive NSCLC Resistant to First-Line Gefitinib: IMPRESS T790M Subgroup Analysis (ID 3287)
12:01 - 12:12 | Author(s): Y. Wu
- Abstract
- Presentation
Background:
Exon 20 T790M mutation is the most common cause of acquired resistance to first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). The IMPRESS study (NCT01544179; Phase III, double-blind IRESSA[TM ]Mutation Positive Multicentre Treatment Beyond ProgRESsion Study; Lancet Oncology: in press) reported no statistically significant difference in progression-free survival (PFS; primary endpoint) between gefitinib plus cisplatin/pemetrexed (cis/pem) (G) vs placebo plus cis/pem (P) in patients with acquired resistance to first-line gefitinib (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.65–1.13; p=0.273; median PFS 5.4 months in both arms) and other secondary endpoints. Among the subgroup analyses performed for IMPRESS, the most noticeable difference was observed by T790M status as tested via plasma circulating free tumor-derived DNA (ctDNA).
Methods:
Patients (age ≥18 years [Japan ≥20 years], chemotherapy-naïve, locally advanced/metastatic NSCLC with an activating EGFR mutation, prior disease progression on first-line gefitinib) from 71 centers (Europe/Asia Pacific) were randomized to G or P (gefitinib 250 mg/day or placebo, plus cis 75 mg/m[2]/pem 500 mg/m[2]). For biomarker analysis, consenting randomized patients provided 10-mL blood samples (at Visit 1 [baseline], 4, 6; then every 6 weeks and at discontinuation) from which to obtain ctDNA. ctDNA levels of EGFR mutations, including T790M, were detected using a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) conducted at a central laboratory (positivity defined as ≥0.02% mutant DNA fraction).
Results:
Data are reported for plasma samples from baseline visits (serial data will be available in the future). Blood samples were available for all 261 randomized patients, of whom T790M status was known for 247 (93.2%): T790M mutation-positive n=142 (57.5%; G=81, P=61) and T790M mutation negative n=105 (42.5%; G=46, P=59). Median PFS for the T790M mutation-positive subgroup was 4.6 vs 5.3 months for G and P, respectively (HR 0.97, 95% CI 0.67 to 1.42, p=0.8829). Median PFS for the T790M mutation-negative subgroup was 6.7 vs 5.4 months for G and P, respectively (HR 0.67, 95% CI 0.43 to 1.03, p=0.0745). See Table for additional study endpoints.
Conclusion:
Following acquired resistance to first-line gefitinib, these data suggest there were two distinct patient populations defined by T790M genotype. For plasma T790M-positive, gefitinib should not be continued when platinum-based doublet chemotherapy is used as second-line therapy. For plasma T790M-negative, continuation of gefitinib in combination with platinum-based doublet chemotherapy may offer clinical benefit, which would require further confirmation in a prospective randomized study.IMPRESS subgroup populations (plasma) T790M mutation-positive N=142 T790M mutation-negative N=105 ORR, % (G vs P) 28.4 vs 39.3 p=0.282 37.0 vs 27.1 p=0.171 DCR, % (G vs P) 81.5 vs 77.0 p=0.5175 93.5 vs 83.1 p=0.0895 OS, HR (95% CI)* 2.16 (1.26, 3.82) p=0.0067 0.83 (0.36, 1.85) p=0.6644 Plasma BEAMing PCR (compared with tumor), % (n/N) Exon 19 Deletions L858R Sensitivity 73.8 (124/168) 81.6 (62/76) Specificity 96.7 (89/92) 95.3 (161/169) Concordance 81.9 (213/260) 91.0 (224/247) *OS immature, follow up ongoing G: gefitinib plus cisplatin/pemetrexed; P: placebo plus cisplatin/pemetrexed ORR, objective response rate; DCR, disease control rate; OS, overall survival
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ORAL 20 - Chemoradiotherapy (ID 124)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:G. Blumenschein, J.Y. Chang
- Coordinates: 9/08/2015, 10:45 - 12:15, 201+203
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ORAL20.02 - Safety Results of the Consolidation Phase of a Phase III (PROCLAIM): Pemetrexed, Cisplatin or Etoposide, Cisplatin plus Thoracic Radiation Therapy followed by Consolidation Cytotoxic Chemotherapy in Locally Advanced Nonsquamous Non-Small Cell Lung Cancer (ID 645)
10:56 - 11:07 | Author(s): Y. Wu
- Abstract
- Presentation
Background:
Standard treatment for inoperable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy. However, many patients die from recurrent disease, indicating that new treatment strategies are needed.
Methods:
PROCLAIM is a phase III trial comparing overall survival in patients with unresectable stage III nonsquamous NSCLC receiving pemetrexed+cisplatin (PemCis) and concurrent radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation (Arm A) versus etoposide+cisplatin (EtoCis) and concurrent radiotherapy for 2 cycles followed by consolidation with a platinum-based doublet of choice for up to 2 cycles (Arm B). Possible consolidation therapies in Arm B were EtoCis, vinorelbine+cisplatin (VinCis), and paclitaxel+carboplatin (PacCarb). Overall efficacy and safety results for the intent-to-treat population will be presented in a separate disclosure. Safety was a secondary objective. Interim safety results for the concurrent phase were previously presented. Here we present safety results for the consolidation phase. Treatment-emergent adverse events (TEAEs) were assessed according to the Common Terminology Criteria for Adverse Events (v3.0, CTCAE). TEAE incidences were compared using Fisher’s exact test (two-sided α=0.05).
Results:
Of 598 randomized patients, 555 were treated in the concurrent phase (Arm A: N=283; Arm B: N=272), most of whom (Arm A: n=229 [80.9%]; Arm B: n=202 [74.3%]) continued on to the consolidation phase (Arm B patients: EtoCis [33.5%], PacCarb [26.8%], VinCis [14.0%]). Baseline characteristics, including age, gender, performance status, smoking status, stage, and origin, were well-balanced across arms. Percentages of patients in Arm A completing ≥2, ≥3, and 4 consolidation cycles were 95.2%, 84.3%, and 73.4%, respectively. Percentages of patients in Arm B completing 2 consolidation cycles (maximum) were EtoCis (89.0%), PacCarb (93.2%), and VinCis (86.8%). Mean dose intensities for pemetrexed, etoposide, vinorelbine, cisplatin, paclitaxel, and carboplatin were 95.4%, 94.0%, 84.2%, 91.2%, 88.7%, and 92.7%, respectively. More patients in Arm B, compared to Arm A, experienced dose reductions, dose omissions, and cycle delays. Patients in Arm B reported more grade 3/4/5 drug-related TEAEs than Arm A (51.0% versus 31.0%, p<0.001; Table). Rates of drug-related serious AEs were similar between groups (Arm A: 14.4%; Arm B: 13.4%).Drug-related Grade 3/4/5 TEAEs Occurring in ≥2% of Patients (or of Clinical Relevance) in the Consolidation Phase
CTCAE Arm A (N=229) n (%) Arm B (N=202) n (%) Neutrophils 27 (11.8) 76 (37.6)* Leukocytes 19 (8.3) 29 (14.4) Hemoglobin 6 (2.6) 9 (4.5) Platelets 5 (2.2) 10 (5.0) Febrile neutropenia 7 (3.1) 7 (3.5) Lymphopenia 8 (3.5) 5 (2.5) Pneumonitis/pulmonary infiltrates 5 (2.2) 2 (1.0) Fatigue 2 (0.9) 4 (2.0) Pneumonia 5 (2.2) 0 Esophagitis 0 3 (1.5) *p<0.001, Fisher’s exact test. Note: Of the TEAEs listed here, only one case (0.4%, Arm A, pneumonia) was grade 5.
Conclusion:
During the PROCLAIM consolidation phase, most patients were able to complete the planned number of cycles in either arm, with the highest dose intensity corresponding to pemetrexed. Pemetrexed consolidation had a significantly lower incidence of drug-related grade 3/4/5 TEAEs than the platinum doublets in Arm B. A more detailed analysis of Arm B (by treatment regimen) is underway.
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ORAL 32 - EGFR WT and MT Targeting (ID 144)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K.J. O'Byrne, D.R. Gandara
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL32.04 - Discussant for ORAL32.01, ORAL32.02, ORAL32.03 (ID 3369)
17:18 - 17:28 | Author(s): Y. Wu
- Abstract
- Presentation
Abstract not provided
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ORAL 35 - Surgical Approaches in Localized Lung Cancer (ID 155)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:M. de Perrot, J. Mitchell
- Coordinates: 9/09/2015, 16:45 - 18:15, 601+603
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ORAL35.01 - Surgical Approach and Disease Recurrence in NSCLC Patients in the MAGRIT Study (ID 318)
16:45 - 16:56 | Author(s): Y. Wu
- Abstract
- Presentation
Background:
Surgical resection is the standard treatment for early stage Non-Small Cell Lung Cancer (NSCLC). Anatomical resection with lymphadenectomy is recommended in surgically treated patients with Stage I-IIIA NSCLC. Whether mediastinal lymph node dissection (MLND) or mediastinal lymph node sampling (MLNS) should be performed remains controversial, and there is currently no consensus within the literature. We describe surgical approaches and patterns of disease recurrence in patients enrolled in MAGRIT: a large global randomized study of the MAGE-A3 Cancer Immunotherapeutic versus placebo after complete tumor resection (Phase III trial, MAGRIT, NCT00480025).
Methods:
Study participants were aged ≥18 years, with histologically-proven, MAGE-A3-positive Stage IB, II or IIIA NSCLC (AJCC 6.0) who had undergone R0 anatomic resection of their tumor (lobectomy or pneumonectomy) with mediastinal lymphadenectomy. Patients were randomized to MAGE-A3 or placebo in a 2:1 ratio. A total of 2,272 patients were treated at 556 centers in 34 countries. Because MAGRIT did not demonstrate efficacy overall, and because the number of recurrences in the placebo arm was small (n=271), recurrence patterns by surgical technique are presented in the overall population. An analysis of the placebo population was also conducted as the overall population results are subject to potential bias (a limited treatment effect in small sub-groups cannot be excluded). Cox regression models were used to explore whether lymphadenectomy procedure could be prognostic for disease-free survival (DFS) or overall survival (OS).
Results:
In the total treated population, 76% were men, 52% had squamous cell carcinoma, and 52% received adjuvant chemotherapy. More than half (57%) of patients were enrolled in Europe, with 23% in East Asia, 16% in North America and 4% in other countries. 47% of patients had Stage IB, 6.5% IIA, 30% IIB, and 17% IIIA disease. Lobectomy (including bi- and sleeve-lobectomy) was performed in 85% of patients, and 14% required pneumonectomy. MLNS was performed in 53% and MLND in 47% of patients. MLNS and MLND patients had a similar disease stage distribution. By region, the percentage of patients who underwent MLNS was: 36% in Europe, 65% in East Asia, 94% in North America and 59% in other countries. Among patients who had undergone MLNS or MLND, 37% (n=447/1202) and 36% (379/1067) developed recurrent disease, respectively. Loco-regional recurrence was observed in 40% (177/447) of patients after MLNS and 31% (118/379) after MLND, with distant recurrence observed in 55% (244/447) and 64% (244/379), respectively. There was no difference in the pattern of distant metastases between patients who had MLNS or MLND. Cox modeling showed no impact of the extent of lymphadenectomy on either DFS or OS. A separate analysis of patients in the placebo arm demonstrated similar trends to those of the total study population.
Conclusion:
Lobectomy (including bi- and sleeve-lobectomy) was the most frequently used treatment for patients who participated in the MAGRIT study. Important regional differences in lymphadenectomy were observed. Although the patterns of recurrence varied to some extent with the type of lymphadenectomy, our study did not demonstrate any prognostic impact related to the type of lymphadenectomy performed.
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P1.12 - Poster Session/ Community Practice (ID 232)
- Event: WCLC 2015
- Type: Poster
- Track: Community Practice
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.12-002 - International Online Tool for Therapeutic Decision Making in NSCLC (V2.0) (ID 2160)
09:30 - 09:30 | Author(s): Y. Wu
- Abstract
Background:
Practice guidelines in non-small-cell lung cancer (NSCLC) list multiple therapy choices based on levels of evidence but cannot account for variability in patient (pt)-tumor characteristics between individual patient cases. To provide oncologists with expert guidance and feedback on choice of treatment (Tx) for specific pt scenarios, we previously implemented an interactive Web-based decision support tool in 2012, in which oncologist users input specific pt characteristics and selected among treatment options, then compared their selection with that of an NSCLC expert panel for that scenario. (Chow JTO 2015). Here we report data from version 2.0 of this tool, capturing current Tx trends for advanced NSCLC and investigating the impact of this online tool on oncology practitioners.
Methods:
V2.0 was developed based on input from 6 international NSCLC experts who provided Tx recommendations for 1st-line treatment in 96 pt case variations based on histology (nonsquamous vs squamous), EGFR mutational status (positive [+] vs negative [-]), ALK rearrangement (+ vs -), age (< 70 vs ≥ 70 years), performance status (0, 1 vs 2), smoking history (never/former light vs former heavy/current), and pt primary Tx goal (response and survival vs quality of life and low adverse events). As in V1.0, oncologist users input specific pt scenarios, then were prompted for their treatment choice. Once completed, recommendations for that scenario from each of the experts were displayed, and users were prompted to indicate whether the expert recommendations changed their treatment choice. Statistical methods: as previously described (Chow JTO 2015).
Results:
V2.0 oncologist users (N = 218 unique users) contributing 314 unique cases were 87% non-USA, 13% USA. As in V1.0, experts agreed on selection of targeted therapies (TKIs) for cases with actionable EGFR mutations and ALK translocations. Choice of a specific EGFR inhibitor by experts varied depending on region and clinical factors. By comparison, among online users of V2.0, an EGFR inhibitor was selected for 67% of EGFR-mutated cases (n = 78), while an ALK inhibitor was selected for 61% of ALK cases (n = 31). For nonsquamous histology cases without actionable mutations, use of pemetrexed was more common among experts compared with oncologist users (91% vs 48% of case scenarios). In 182 cases entered by users who reported on the impact of expert recommendations, treatment choice was affected in 86% of cases (confirmed in 71%); 5.5% disagreed with expert recommendations and 8% indicated barriers to implementing the recommendations. In comparing overall results from V1.0 (2012) to V2.0 (2014), more oncologist users were likely to select TKIs in both EGFR mutation (49% vs 67%) and ALK translocation (35% vs 61%), with a corresponding decrease in use of chemotherapy. A detailed analysis of expert vs user data will be presented, comparing V1.0 (2012) and V2.0 (2014).
Conclusion:
Expert opinions were largely unchanged between V1.0 and V2.0, while oncologist users increased use of TKIs. Most oncologist users of V2.0 either confirmed or changed treatment choices based on expert recommendations. This online tool can aid decision making, serve an educational purpose, and capture practice trends.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-024 - An ENSURE Extension Study to Evaluate 2<sup>nd</sup> Line Erlotinib and Gemcitabine/Cisplatin Cross-Over Treatment for EGFR-Mutant Chinese NSCLC Patients (ID 1747)
09:30 - 09:30 | Author(s): Y. Wu
- Abstract
Background:
ENSURE study shows that 1[st] line treatment with erlotinib provides longer PFS over gemcitabine/cisplatin (GP) for stage IIIB/IV NSCLC patients with EGFR mutations. Cross-over treatments after progression of disease (PD) was allowed in ENSURE study. However, post-study treatments might have significant impact on patient survival or other clinical benefits, which is insufficiently investigated. This trial in an extension of the ENSURE study, intended to evaluate PFS in 2[nd] line progression after cross-over treatments in ENSURE.
Methods:
Chinese patients who had PD after 1[st] line treatment in ENSURE were enrolled. Enrolled patients received cross-over treatment as 2[nd] line treatment after 1[st] line PD. The primary endpoint was PFS, defined as the time of randomization in ENSURE to disease progression or death while on 2[nd] line treatment. For patients who had already progressed after 2[nd] line therapy prior to entering this extension study, relevant information would be collected retrospectively. PFS from 1[st] line PD to 2[nd] line PD was also calculated. The study was approved by IRB and all patients signed informed consent. This study was registered in clinicalgrials.gov (NCT02000531). We also retrospectively analyzed the time to 2[nd] line treatment failure (TTF) defined as the time from randomization to discontinuation of 2[nd] line treatment for any reason.
Results:
Forty-five patients (21 from erlotinib arm and 24 from GP arm) were enrolled in the final analysis in this ENSURE extension study. Limited recruitment was mainly due to later initiation of this study (from January to December of 2014), many deaths at the beginning of this study, or unwillingness to sign informed consent by some patients. Age, sex, and ECOG at baseline in erlotinib group and GP group were balanced. Among 45 enrolled subjects, 33 (73.3%) subjects completed the study. There was no significant difference in median PFS from the date of randomization in ENSURE study to 2[nd] line PD for both arms 26.3 (95%CI: 19.8 , 34.0 ) months vs 23.4 (95%CI: 17.8, 39.0 ) months, HR=1.26 (95%CI: 0.61, 2.62), p=0.529). For 2[nd] line cross-over treatment, ORR in erlotinib and GP arms was 33.3% (7PR/21) and 66.7% (16PR/24) respectively (p=0.0377). In a retrospective analysis of 175 patients from the whole ENSURE study, 63.2% patients in erlotinib arm (n=87) received 2[nd] line chemotherapy and 86.4% patients in GP arm (n=88) received 2[nd] line targeted therapy. The median TTF in erlotinib and GP arm were 29.4 (95%CI: 24.7, 34.2) and 24.7 (95%CI: 21.9, 28.4) months respectively (HR=0.74(95%CI: 0.47, 1.17), p=0.192).The subgroup analysis (mutation type, ECOG performance status, gender) for TTF between erlotinib and GP arm showed similar trend to the primary analysis.
Conclusion:
Despite limitations, both median PFS (in prospective analysis) and TTF (in retrospective analysis) for erlotinib patients were numerically larger than that in GP arm. This first cross-over treatment ENSURE extension study further confirms benefits of erlotinib as standard 1[st] line treatment for EGFR mutant NSCLC. It also supports the importance of 1[st] and 2[nd] line treatment sequence of erlotinib and platinum-based chemotherapy for the treatment of EGFR mutant NSCLC.
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P2.01-063 - Dynamic Change of Fatigue for East-Asian Patients in the JMEN Trial (ID 843)
09:30 - 09:30 | Author(s): Y. Wu
- Abstract
Background:
In the JMEN trial (Ciuleanu et al., Lancet 374:1432-1440, 2009), patients with advanced non-squamous non-small cell lung cancer (NSCLC) derived a benefit from pemetrexed maintenance therapy after platinum-based initial therapy by extending survival, delaying disease progression, and maintaining overall quality of life (QoL). However, fatigue was the most common physician-reported toxic effect in the pemetrexed treated group. We conducted a post-hoc analysis to investigate the dynamic change of fatigue in overall population and East-Asian (EA) patients treated on the JMEN trial.
Methods:
This analysis was performed in the overall safety population (N=656) and the EA subgroup safety population (N=152) mainly from China, Taiwan, and Korea including squamous and non-squamous NSCLC patients. The Common Terminology Criteria for Adverse Events (version 3.0) was used for summary of the AE incidence rates by cycle and AE severity reported by investigator. The Lung Cancer Symptom Scale (LCSS) was used to evaluate patients’ QoL. Worsening of fatigue was defined as an increase of 15 mm or more from baseline on a 100 mm scale in LCSS reported by the patients. The percentage of patients with worsening fatigue was also summarized by cycle. The time to worsening of fatigue symptom was analyzed using Kaplan-Meier method and Cox proportional model.
Results:
In the EA population drug-related fatigue (grade 1-4) occurred more frequently in pemetrexed arm compared with placebo arm (30.4% vs 16.0%, p=0.075). The grade 3/4 drug-related fatigue was rare in both arms (1 event reported in each arm). For both overall and EA populations, the fatigue incidence by cycle during the maintenance treatment with pemetrexed did not increase during subsequent cycles (Figure 1A, B). The percentage of patients who experienced worsening of fatigue based on the patients-reported LCSS scores was also comparable between the two arms in the overall and EA populations (Figure 1C, D). EA Patients in the pemetrexed arm experienced a numerically longer median time to worsening of fatigue compared to EA patients in the placebo arm, although the difference is not statistically significant (5.95 months vs. 3.91 months, HR= 0.84, 95% confidence interval [CI]: 0.51-1.37, p= 0.471). Figure 1
Conclusion:
These analyses suggest that despite a higher incidence of grade 1/2 drug-related fatigue compared with placebo, pemetrexed maintenance treatment for EA patients with advanced NSCLC will not impair patient-reported QoL.
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P2.01-094 - Phase II Trial of Tepotinib/Gefitinib vs Cisplatin/Pemetrexed in T790M-/c-Met+ NSCLC (ID 2105)
09:30 - 09:30 | Author(s): Y. Wu
- Abstract
Background:
The recommended phase II dose of the highly selective c-Met inhibitor tepotinib (MSC2156119J) for use in combination with gefitinib was confirmed as 500 mg/day in the phase Ib part of the current trial, in which patients with gefitinib-resistant locally advanced/metastatic c-Met-positive NSCLC were treated with tepotinib plus gefitinib. This trial demonstrated that the combination regimen is well tolerated and has evidence of antitumor activity that may be associated with c-Met-positive tumor status. These observations suggest that c-Met inhibition may have a role in EGFR tyrosine kinase inhibitor-resistant NSCLC and that a phase II trial is warranted.
Methods:
The design of the phase II part of a phase Ib/II trial (NCT01982955) is described. Asian adults with histologically or cytologically confirmed, gefitinib-resistant locally advanced/metastatic NSCLC other than predominantly squamous histology and ECOG PS 0/1 are eligible. Patients must have tumors with documented activating mutations of EGFR. Tumor tissue obtained between documentation of acquired resistance to gefitinib and enrollment must be available. Tumors must be confirmed as being c-Met positive (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]). EGFR mutation status will be assessed centrally using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). Patients will be enrolled into different parts of the trial based on tumor T790M status. Patients with c-Met-positive, T790M-negative NSCLC (n=136) will be randomized to tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w or cisplatin 75 mg/m[2] + pemetrexed 500 mg/m[2] q3w for up to 6 cycles. Patients with c-Met-positive, T790M-positive NSCLC (n=15) will be treated with tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w. The primary objective is to determine whether progression-free survival (PFS) in patients treated with second-line tepotinib combined with gefitinib is superior to that of pemetrexed + cisplatin in patients with c-Met-positive, T790M-negative advanced NSCLC and acquired resistance to first-line gefitinib. The two T790M subgroups will be analyzed separately. An interim analysis of the randomized part of the study is planned when 50% of PFS events have occurred in both arms. Secondary objectives are to evaluate: the safety and tolerability tepotinib combined with gefitinib; the efficacy of tepotinib combined with gefitinib; the antitumor activity of tepotinib combined with gefitinib in patients with c-Met-positive, T790M-positive tumors; and patient-reported outcomes.
Results:
not applicable
Conclusion:
This randomized phase II trial will provide the first evidence regarding whether tepotinib has a role in the treatment of Asian patients with gefitinib-resistant, c-Met-positive, T790M-negative NSCLC.
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P2.01-097 - Phase 3 Study of Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1<sup>+</sup> NSCLC (ID 2182)
09:30 - 09:30 | Author(s): Y. Wu
- Abstract
Background:
Platinum-based chemotherapy with or without maintenance therapy is the standard of care for treatment-naive non-small cell lung carcinoma (NSCLC) that lacks EGFR sensitizing mutations and ALK translocations. The PD-1 pathway is frequently used by tumors to evade an immune response. Pembrolizumab (MK-3475), an anti–PD-1 monoclonal antibody, has demonstrated manageable toxicity and promising antitumor activity in patients with treatment-naive NSCLC enrolled in the phase 1b KEYNOTE-001 study. In this study, a relationship between increased tumor PD-L1 expression and improved pembrolizumab antitumor activity was observed. KEYNOTE-042 (ClinicalTrials.gov identifier NCT02220894) is a randomized, open-label, international, phase 3 study designed to compare the efficacy and safety of pembrolizumab with those of platinum-doublet chemotherapy as first-line therapy for PD-L1–positive advanced NSCLC.
Methods:
Eligibility criteria include age ≥18 years, advanced NSCLC without EGFR sensitizing mutations or ALK translocation, no prior systemic chemotherapy, PD-L1 expression in ≥1% of tumor cells, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1. Patients are randomly assigned in a 1:1 ratio to a 200-mg fixed dose of pembrolizumab every 3 weeks (Q3W) or investigator’s choice of carboplatin AUC 5 or 6 plus paclitaxel 200 mg/m[2] Q3W or carboplatin AUC 5 or 6 plus pemetrexed 500 mg/m[2] Q3W. Randomization is stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), region (East Asia vs non-East Asia), and PD-L1 expression (strong [staining in ≥50% of tumor cells] vs weak [staining in 1%-49% of tumor cells], as assessed by immunohistochemistry at a central laboratory). Pembrolizumab will be continued for 35 cycles or until disease progression, intolerable toxicity, or investigator decision; treatment may be continued beyond initial radiographic disease progression in eligible patients. Discontinuation of pembrolizumab is permitted for patients who experience a complete response confirmed on a follow-up scan performed ≥4 weeks after initial observation. Chemotherapy will be given for a maximum of 6 cycles and may be followed by optional pemetrexed 500 mg/m[2] Q3W maintenance therapy in patients with nonsquamous histology. Adverse events will be collected throughout the study and for 30 days (90 days for serious adverse events) thereafter and graded per NCI CTCAE v4.0. Response will be assessed every 9 weeks per RECIST v1.1 by independent central review. Patients will be followed for survival every 2 months. Primary end point is overall survival in the PD-L1–strong-positive stratum; secondary end points are progression-free survival in the strong-positive stratum and progression-free and overall survival in all patients. Enrollment is ongoing and will continue until approximately 1240 patients have been allocated to study treatment.
Results:
Not applicable.
Conclusion:
Not applicable.
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-031 - Subgroup Analysis of East Asian Patients in the Phase III PROCLAIM Trial (ID 1293)
09:30 - 09:30 | Author(s): Y. Wu
- Abstract
Background:
PROCLAIM is a phase III trial comparing overall survival (OS) in patients with stage III, unresectable, nonsquamous non-small cell lung cancer (NSCLC) receiving pemetrexed (Pem) plus cisplatin (Cis) and concurrent thoracic radiation therapy (TRT) for 3 cycles followed by 4 cycles of Pem consolidation (Pem+Cis arm) versus etoposide (Etop) plus Cis and concurrent TRT for 2 cycles followed by up to 2 cycles of consolidation with a platinum-based doublet of choice (Etop+Cis arm). Overall efficacy and safety results for the intent-to-treat (ITT) population (N=598) will be presented in a separate disclosure. Efficacy and safety results from an East Asia (EA) subgroup analysis are presented here.
Methods:
A subgroup analysis was performed using the EA randomized population (N=97), which consisted of all patients who were randomized to the study from China (n=61), Taiwan (n=25), and The Republic of Korea (n=11). OS and progression-free survival (PFS) were evaluated by the Kaplan-Meier method and hazard ratios (HRs) were calculated using a Cox regression model. The log-rank test was used to compare treatment arms. Objective response rates (ORRs) were compared using an unadjusted, normal distribution approximation for the difference in rates. ClinicalTrials.gov number NCT00686959.
Results:
Baseline characteristics were balanced between treatment arms for EA patients. In the 97 randomized EA patients (n=44 in the Pem+Cis arm; n=53 in the Etop+Cis arm), median PFS was 10.0 months for the Pem+Cis arm and 7.6 months for the Etop+Cis arm (HR: 0.97, 95% confidence interval [CI]: 0.61–1.54, p=0.890). The censoring rate was high for OS (Pem+Cis arm: 43.2%; Etop+Cis arm: 52.8%), and there was no significant difference in OS between the Pem+Cis arm and the Etop+Cis arm (HR: 1.23, 95% CI: 0.70–2.14, p=0.469). The interaction test for region and treatment effect for OS was not significant (p=0.374). The ORRs were 47.7% (95% CI: 32.46–63.31) in the Pem+Cis arm and 34.0% (95% CI: 21.52–48.27) in the Etop+Cis arm. In the 90 treated EA patients (n=44 in the Pem+Cis arm; n=46 in the Etop+Cis arm), the overall incidence of drug-related grade 3/4 treatment-emergent adverse events (TEAEs) was significantly lower in the Pem+Cis arm versus the Etop+Cis arm (61.4% vs. 91.3%; p=0.001). All drug-related grade 3/4 TEAEs occurring in ≥5% of patients had a numerically lower incidence in the Pem+Cis arm than in the Etop+Cis arm except lymphopenia (17 [38.6%] vs. 17 [37.0%]).
Conclusion:
For EA patients with nonsquamous NSCLC, Pem+Cis did not improve OS, but did have a good safety profile and numerically improved PFS and ORR compared to Etop+Cis.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-011 - Antitumor Activity of Tepotinib plus Gefitinib in Asian Patients with Met+ EGFRm+ NSCLC (ID 763)
09:30 - 09:30 | Author(s): Y. Wu
- Abstract
Background:
c-Met abnormalities are key in resistance to EGFR TKIs in EGFRm+ NSCLC patients (pts). The highly selective c-Met inhibitor tepotinib (MSC2156119J) had promising activity in a phase I trial in pts with advanced solid tumors. We report phase Ib data from a trial evaluating tepotinib + gefitinib in pts with Met+ NSCLC (NCT01982955).
Methods:
Asian adults with locally advanced/metastatic NSCLC, Met+ status (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]) and ECOG PS 0/1 were eligible. EGFR mutation status was assessed using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). A 3+3 design was used for the phase Ib part; planned recruitment was 15-18 pts, who received tepotinib 300 or 500 mg p.o. + gefitinib 250 mg/d q3w. Primary objective: determine the RP2D of tepotinib for use in combination; secondary objectives: pharmacokinetics, safety, antitumor activity.
Results:
14 pts have been enrolled (median age 65 years; male 43%; ECOG PS 0/1 2/12; median prior therapy regimens including an EGFR TKI 3.5). 3 pts received tepotinib 300 mg + gefitinib and 11 tepotinib 500 mg + gefitinib. No DLTs were observed; 4 pts had grade 3/4 treatment-related adverse events (amylase increase [n=3], lipase increase [2], decreased neutrophil count [1]). Best overall response by c-Met status (cut-off Jan 20, 2015) for the 12 evaluable pts is shown in the table. EGFR mutation status for these 12 pts was T790M and L858R mutation (n=2), L858R mutation alone (4), exon 19 deletion (4), no mutation detected using the therascreen[®] kit (2).Best overall response (n) n=12 Partial response Stable disease Progression IHC 2+ 0 5 2 3+ 4 0 1 FISH c-Met:CEP7 ratio >2 1 0 0 ≥5 copies in >50% of cells 3 1 1 Negative 0 3 2 Not valid 0 1 0
Conclusion:
The RP2D of tepotinib in combination with gefitinib has been confirmed as 500 mg/d in pts with advanced NSCLC. The data show evidence of antitumor activity and that response may be associated with c-Met status. The phase II trial will randomize ≈136 pts with T790M-/c-Met+ tumors who have failed first-line gefitinib to tepotinib 500 mg/d + gefitinib or cisplatin/pemetrexed.
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P3.01-051 - Biomarker Analyses from a Phase II Trial of Nab-Paclitaxel/Carboplatin vs Emcitabine/Carboplatin in Advanced Squamous Cell Lung Cancer (ID 2846)
09:30 - 09:30 | Author(s): Y. Wu
- Abstract
Background:
The administration of nab-paclitaxel/carboplatin (nab-PC) as first-line therapy in patients with advanced non-small-cell lung cancer (NSCLC) was efficacious and resulted in a significantly improved objective overall response rate (ORR) versus solvent-based PC in a phase Ⅲ trial. However, our phase Ⅱ trial (NCT01236716; CTONG1002), which compared the efficacy and safety of first-line nab-PC with gemcitabine/carboplatin (GC) in advanced squamous cell carcinoma of the lung, only showed a marginally improved ORR caused by first-line nab-PC. Meanwhile, the matricellular glycoprotein SPARC (secreted protein acidic and rich in cysteine) and caveolin-1 are potential biomarkers for advanced NSCLC patients receiving nab-PC. Therefore, we retrospectively aimed to explore their predictive and prognostic value using immunohistochemistry (IHC).
Methods:
From November 2010 to June 2013, 127 untreated patients with locally advanced and metastatic squamous cell carcinoma of the lung were randomly assigned 1:1 to receive first-line nab-PC (nab-P, 135 mg/m[2], d1, d8, q3w; C, AUC = 5, d1, q3w ) or GC (G, 1,250 mg/m[2], d1, d8, q3w; C, AUC = 5, d1, q3w). There were 110 patients evaluable for ORR (nab-PC, 54; GC, 56), 119 evaluable for survival (nab-PC, 57; GC, 62) respectively. However, there were 72 patients with sufficient tissue for IHC of both SPARC and caveolin-1 proteins. Different cut-off values of IHC scoring systems were used to explore predictive and prognostic role of both biomarkers.
Results:
The last follow-up was on January 16, 2015. Considering treatment, when the maximum rank method was used for cut-off values, median progression-free survival (PFS) was 7.5 (95%CI: 2.4~12.6) months in higher SPARC-expression arm and 4.3 (95%CI: 2.2~6.3) months in lower SPARC-expression arm for patients treated with GC, HR=0.43 (95%CI: 0.19~0.94), p = 0.030; Median overall survival (OS) was 20.0 (95%CI: 14.7~25.3) months in lower SPARC-expression arm and 10.1 (95%CI: 6.2~14.0) months in higher SPARC-expression arm for patients treated with nab-PC, HR=2.41 (95%CI: 1.08~5.40), p = 0.027. When average method was used for cut-off values, median OS was 18.2 (95%CI: 9.6~26.8) months in lower SPARC-expression arm and 8.4 (95%CI: 5.1~11.7) months in higher SPARC-expression arm for patients treated with nab-PC, HR=2.46 (95%CI: 1.07~5.65), p = 0.029. Regardless of treatment, when the maximum rank method was used for cut-off values, median OS was 14.5 (95%CI: 6.8~22.1) months in lower SPARC-expression arm and 8.4 (95%CI: 5.3~11.5) months in higher SPARC-expression arm, HR=0.47 (95%CI: 0.27~0.83), p = 0.007. When average method was used for cut-off values, median OS was 14.4 (95%CI: 9.2~19.5) months in lower SPARC-expression arm and 8.4 (95%CI: 5.4~11.4) months in higher SPARC-expression arm, HR=0.48 (95%CI: 0.27~0.87), p = 0.013. ORR was not correlated with expression of SPARC, p＞0.05. However, there were no significant differences in ORR, PFS and OS between higher and lower caveolin-1 expression arms, p＞0.05.
Conclusion:
SPARC expression could be a negative prognostic factor for OS of patients with advanced squamous cell carcinoma of the lung, but was not a predictive factor for ORR and PFS, except for patients treated with GC. However, caveolin-1 expression had neither predictive nor prognostic value.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-036 - Rare Discrepancies in a Driving Gene Alteration within Histologically Heterogeneous Primary Lung Cancers (ID 2229)
09:30 - 09:30 | Author(s): Y. Wu
- Abstract
Background:
Most lung adenocarcinomas consist of a mixture of histological subtypes among which driving gene mutations occurred with different frequencies. However, little is known about intratumoral heterogeneity within histologically heterogeneous primary lung cancers. Investigating key driver genes in respective morphological pattern is crucial to clinical practice and personalized treatment.
Methods:
Morphologically different tumor areas within the same surgically resected primary tumors were extracted from tissue sections and the gene status in each growth pattern was analyzed. Driving genes, epidermal growth factor receptor (EGFR), KRAS, and rearrangements in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), were assessed by assays of different sensitivity.
Results:
Seventy-nine consecutive, surgically resected, adenocarcinomas or adeno-squamouse cell carcinomas harboring a driving gene mutation or rearrangement (EGFR, n = 65; KARS, n = 10; EML4-ALK, n = 4) were selected. For EGFR mutations in adenocarcinomas, ITH occurred in 13.3% (8/60) as determined by direct sequencing, but in only 1.7% (1/60) by ARMS(P= 0.016). A consistent intratumoral EGFR mutation status was found within 5 histologically heterogeneous adeno-squamous cell carcinomas, as shown with ARMS. ITH among KRAS mutations were detected in 20% (2/10) of regions examined by direct sequencing ,whereas a consistent status (10/10) was obtained with HRM. There were no discrepancies in EML4-ALK rearrangements according to FISH for four tumors.
Conclusion:
Rare ITHs deriving from EGFR/KRAS/EML4-ALK alterations within histologically heterogeneous primary lung adenocarcinomas were found with methods of high sensitivity. Discrepancies might be due to the abundance of cells harboring driving gene and detection assays.
