Virtual Library
Start Your Search
Thanyanan Reungwetwattana
Moderator of
-
+
OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 8
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
-
+
OA 09.01 - Characterizing the Genomic Landscape of EGFR C797S in Lung Cancer Using ctDNA Next-Generation Sequencing (ID 10213)
11:00 - 11:10 | Presenting Author(s): Zofia Piotrowska | Author(s): R.J. Nagy, S. Fairclough, R.B. Lanman, N. Marcoux, Scott N. Gettinger, Taofeek K Owonikoko, Suresh S Ramalingam, Lecia V Sequist
- Abstract
- Presentation
Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in T790M-positive lung cancer. Acquired resistance to osimertinib is driven by EGFR C797S in ~20-30% of cases. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) can be used to identify resistance mechanisms. The allelic configuration (cis vs. trans) of C797S with respect to T790M has therapeutic implications, but the relative frequency of each and other co-occurring genomic alterations are not well defined in clinical samples.
Method:
We queried the Guardant Health database for lung adenocarcinoma patients and an EGFR C797S mutation. All patients had comprehensive ctDNA testing using the Guardant360 NGS assay between June 2015 and June 2017. Cis/trans configuration for T790M and C797S was determined using Integrated Genomics Viewer software.
Result:
We identified 50 unique patients with a total of 66 samples which were C797S positive. All had a co-existent EGFR activating mutation (del19 74%, L858R 24%, other 2%). 60/66 (91%) C797S+ samples were also T790M+. In the 6 samples with C797S but without T790M in ctDNA, 4 were from patients who were T790M+ on a prior Guardant360 assay, 1 never had T790M in blood or tissue and developed C797S while on 1[st]-line afatinib, and 1 had no further clinical details available. T790M and C797S were on the same allele (cis configuration) in 44/46 evaluable patients (98%); 1 (2%) was in trans. One sample had two different C797S mutations, one cis and one trans to T790M. 13 C797S+/T790M+ samples (22%) had multiple C797X mutations detected and 12 samples carried other mutations in or adjacent to the EGFR ATP-binding pocket (e.g. L792, F795, G796, etc). The most common non-EGFR mutations co-occurring with C797S were BRAF amplification/mutation (20%), MET amplification (17%), PIK3CA mutation/amplification (15%), CCNE1 amplification 14% and MYC amplification (14%).
Conclusion:
Understanding EGFR TKI resistance mechanisms is critical to developing more effective therapies. ctDNA offers a non-invasive method to characterize the resistance landscape. Our data suggests C797S most commonly occurs with T790M in cis (98%), a state associated with resistance to all currently available EGFR TKIs. The trans configuration, which may respond to combined 1[st]/3[rd]-gen EGFR TKIs, is rare (2%). Moreover, C797S is frequently detected along with other resistance mechanisms in ctDNA, underscoring the heterogeneity of resistant cancers. New treatments targeting C797S/T790M are needed, as is a deeper understanding of therapeutic targeting of heterogeneity in resistant cancers.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA 09.02 - Osimertinib Resistance Mediated by Loss of EGFR T790M Is Associated with Early Resistance and Competing Resistance Mechanisms (ID 9000)
11:10 - 11:20 | Presenting Author(s): Geoffrey R. Oxnard | Author(s): Y. Hu, K.F. Mileham, P. Tracy, N. Feeney, L.M. Sholl, C.P. Paweletz, K.S. Thress, Pasi A Jänne
- Abstract
- Presentation
Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in EGFR-mutant NSCLC with resistance to prior TKI. Improved understanding of the clinical and molecular characteristics of acquired resistance to osimertinib is needed.
Method:
We initially studied resistance biopsies and plasma specimens from an institutional cohort of 119 patients treated with osimertinib for T790M-positive NSCLC with resistance to prior TKI. For validation, we studied plasma from 157 patients treated with osimertinib on the AURA trial (NCT01802632).
Result:
45 of 119 patients underwent a resistance biopsy and 33 had resistance tumor genotyping available. 11 patients maintained T790M at resistance: 7 acquired EGFR C797S, 1 had a PIK3CA mutation. 22 patients had loss of T790M at resistance: 14 harbored a competing resistance mechanism, including histologic transformation to SCLC, MET amplification, mutations in BRAF, PIK3CA, or KRAS, or fusions in RET or FGFR. Median time to treatment failure (TTF) on osimertinib was 3 months in patients with loss of T790M and 15 months in patients with maintained T790M. In the validation cohort, 110 of 157 patients had detectable tumor DNA in plasma and were eligible for analysis. 58 patients (53%) maintained T790M at resistance; 24 (22%) also acquired a C797S mutation. 52 patients (47%) had loss of T790M at resistance and no C797S. Median TTF was shorter in patients with loss of T790M than in those with maintained T790M at resistance (5.7 vs 12.5 months). 50 patients had both pre- and post-osimertinib plasma genotyping. Studying the relative allelic fraction (AF) of T790M compared to driver EGFR mutation, patients with T790M loss had only slightly lower relative T790M AF pretreatment (29% vs. 38% median, p = 0.06). The ability of plasma response to predict subsequent resistance was studied in 19 patients from the initial cohort with baseline and follow-up plasma genotyping after 1-3 weeks on osimertinib. Studying the difference between the relative change in plasma levels of T790M and the EGFR driver, patients with T790M loss at time of resistance consistently had a greater T790M response than driver response (median difference 16%), suggesting incomplete suppression of the driver due to competing resistance mechanisms.
Conclusion:
In patients with acquired resistance to osimertinib, repeat testing for T790M could offer key insights into disease biology. Patients with early resistance on osimertinib are at risk of T790M loss with emergence of a complex variety of competing resistance mechanisms, and represent intuitive candidates for combination approaches such as combined EGFR & MET inhibition.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA 09.03 - TATTON Ph Ib Expansion Cohort: Osimertinib plus Savolitinib for Pts with EGFR-Mutant MET-Amplified NSCLC after Progression on Prior EGFR-TKI (ID 8985)
11:20 - 11:30 | Presenting Author(s): Myung-Ju Ahn | Author(s): Ji-Youn Han, Lecia V Sequist, Byoung Chul Cho, J.S. Lee, Sang-We Kim, W. Su, C. Tsai, James Chih-Hsin Yang, Helena Yu, L. Horn, K. Lee, V. Haddad, M.M. Frigault, G. Ahmed, L. Yang, D. Ghiorghiu, Geoffrey R. Oxnard
- Abstract
- Presentation
Background:
MET amplification is a well described mechanism of acquired resistance to EGFR inhibition in EGFR-mutant NSCLC, making combined MET/EGFR inhibition a compelling therapeutic approach. We previously reported tolerability of the oral, CNS active, third-generation EGFR-TKI osimertinib, which is selective for both EGFR-TKI sensitizing and EGFR T790M resistance mutations, combined with the highly selective MET-TKI savolitinib (volitinib, HMPL-504, AZD6094). Here we assess safety and preliminary activity of this combination in a cohort of patients (pts) with EGFR-mutant NSCLC and MET-positive acquired resistance in the multi-arm, Phase Ib TATTON study (NCT02143466).
Method:
Eligible pts were aged ≥18 years (WHO performance status 0/1) with locally advanced or metastatic EGFR-mutant NSCLC who progressed on at least one prior EGFR-TKI with centrally confirmed MET-amplification (fluorescence in-situ hybridisation, MET gene copy ≥5 or MET/CEP7 ratio ≥2). Pts received osimertinib 80 mg QD plus savolitinib 600 mg QD. Primary objective was safety and tolerability; secondary objectives included preliminary assessment of anti-tumour activity and pharmacokinetics.
Result:
As of data-cut off (15 April 2017), 45 pts with centrally confirmed MET-amplification (FISH) were enrolled and received treatment, including 25 pts previously treated with a third-generation EGFR-TKI and 20 without prior third-generation EGFR-TKI treatment (T790M negative n=13; T790M positive n=7). At baseline, median age was 58 years (range 38–76), 24 (53%) were female, 36 (80%) were Asian. The most frequent adverse events (AEs) were nausea (n=21, 47%), decreased appetite (n=15, 33%), fatigue (n=13, 29%) vomiting (n=13, 29%), rash (n=11, 24%), myalgia (n=8, 18%), pyrexia (n=7, 16%), ALT/AST increased (n=6, 13%), and WBC decreased (n=6, 13%), consistent with the known safety profiles. Serious AEs were reported in 15 (33%) pts; events reported in >1 patient were pneumonia, dyspnoea, acute kidney injury and pyrexia (all n=2). Four pts died due to AEs, none were considered related to study drugs. At data cut-off, confirmed partial responses were reported in 5/25 (20%) pts previously treated with a third-generation EGFR-TKI; 5/12 (42%) T790M negative pts without prior third-generation EGFR-TKI and 3/7 (43%) T790M positive pts without prior third-generation EGFR‑TKI. Twenty-eight (62%) pts are ongoing treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and osimertinib were consistent with historical data.
Conclusion:
These findings demonstrate promising safety, tolerability, and preliminary activity of osimertinib plus savolitinib and support further investigation of this combination for the treatment of pts with locally advanced or metastatic EGFR-mutant NSCLC and MET-amplification. Updated data will be presented.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA 09.04 - Discussant - OA 09.01, OA 09.02, OA 09.03 (ID 10797)
11:30 - 11:45 | Presenting Author(s): Hatim Husain
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA 09.05 - Identification of Novel Potentially Targetable Genomic Alterations in Paired Tumors with Acquired EGFR TKI Resistance by NGS (ID 9088)
11:45 - 11:55 | Presenting Author(s): Jacqulyne Ponville Robichaux | Author(s): Y.Y. Elamin, Jianjun Zhang, A. Futreal, E. Roarty, W. Rinsurongkawong, J. Lewis, H.T. Tran, Stephen Swisher, John V Heymach
- Abstract
- Presentation
Background:
While previous reports have established MET and HER2 amplification as two mechanisms of non-T790M driven EGFR TKI resistance in EGFR mutant NSCLC, resistance occurs in the absence of these modifications in a significant number of patients. Therefore, there exists an unmet need to define additional mechanisms of resistance to EGFR TKIs. We hypothesized that targeted next-generation sequencing could detect additional targetable activating mutations in paired tumor samples from patients with acquired resistance to first or second generation EGFR TKIs.
Method:
We conducted an analysis of clinical and molecular data prospectively collected from 285 EGFR-mutant NSCLC patients enrolled into the MD Anderson Lung Cancer GEMINI database. Of 157 patients treated with first-line therapy (erlotinib, gefitinib, or afatinib), we identified 75 patients with TKI-acquired resistance with matched pre/post-TKI tumor samples. Matched tumor samples were analyzed with targeted gene sequencing. Recurrent alterations were defined as an alteration occurring more than 2 times. Recurrent acquired mutations were expressed in Ba/F3 and EGFR mutant (T790M+/-) NSCLC cells. Mutation expressing Ba/F3 cell lines were assayed for IL-3 independence, and mutation expressing NSCLC cell were screened against combination targeted TKIs.
Result:
EGFR mutant NSCLC patients treated with first-line therapy had a median PFS of 14 months; and, of the patients with pre/post-TKI tumor molecular data, 47% of patients were T790M negative. There were 30 recurrent acquired alterations identified in 13 different genes. Genes included ARAF, BRAF, EGFR, FGFR, GNAS, JAK2, MCL1, PDGFRα, PIK3CA, RAF1, RB1, SMAD4, and TP53. Of the alterations identified, most occurred in 1 of 4 targetable genes: BRAF (N=3), FGFR (N=5), PDGFRα (N=3), or PIK3CA (N=2). Both previously reported and novel mutations were identified, and preliminary screening of mutant expressing Ba/F3 cell lines found that of the mutations tested (BRAF WT & G469H, FGFR2 A371G, PDGFRα WT & L682F, and PIK3Ca E545K) all grew independent of IL-3. HCC827 and H1975 cell lines expressing acquired mutations in BRAF, FGFR, PDGFRα, or PIK3CA were more sensitive to combination targeted therapy compared to EGFR TKIs or mutation specific TKIs alone unlike control cell lines, supporting the possibility that targeting these mutations would be of therapeutic benefit.
Conclusion:
Analysis of patient data identified 30 recurrent genomic alterations in 13 different genes including novel alterations in BRAF, EGFR, FGFR, PDGFRα, RB1, and SMAD4, many of which were found to be activating mutations. Our analysis identified potentially targetable mutations of BRAF, FGFR, PDGFRα, and PIK3CA which merits further pre-clinical and clinical investigation.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA 09.06 - A Phase Ib Trial of Savolitinib plus Gefitinib for Chinese Patients with EGFR-Mutant MET-Amplified Advanced NSCLC (ID 8995)
11:55 - 12:05 | Presenting Author(s): Jin -Ji Yang | Author(s): Jian Fang, Y. Shu, J. Chang, G. Chen, J. He, W. Li, X. Liu, N. Yang, Caicun Zhou, J. Huang, L. Yang, A.A. Handzel, M.M. Frigault, G. Ahmed, C. Egile, S. Morgan, Yi-Long Wu
- Abstract
- Presentation
Background:
EGFR-tyrosine kinase inhibitor (TKI) treatment failure has been attributed to innate and/or acquired MET-amplification in patients with advanced EGFR-mutant NSCLC. Savolitinib (volitinib, HMPL-504, AZD6094), a highly selective small molecule MET-TKI, demonstrated greater efficacy combined with gefitinib than either compound alone in preclinical EGFR-mutant NSCLC models (D’Cruz et al. AACR, 2015).
Method:
This open-label, multi-centre, Phase Ib study (NCT02374645) assessed savolitinib plus gefitinib in patients enrolled in China with EGFR-mutant advanced NSCLC who progressed on prior EGFR-TKI. Primary objective was safety, tolerability, and identification of recommended Phase II dose (RP2D). Secondary objectives included preliminary anti-tumour activity (RECIST 1.1), pharmacokinetics, and ctDNA analysis for EGFR T790M mutation status. Eligible patients (≥18 years) had measurable disease, radiological disease progression on treatment, ECOG performance status 0/1, and adequate organ function. Patients had central evaluation of EGFR mutation (plasma based BEAMing digital PCR) and central screening for MET-amplification (MET/CEP7 ratio ≥2 or MET gene number ≥5, defined by tumour tissue FISH). Patients received gefitinib 250 mg once daily (QD) plus savolitinib 600 mg QD.
Result:
As of data-cut off (March 2017), 44 patients received study treatment. Median age was 61 years, 64% of patients were female; 6 patients were EGFR T790M positive and 5 were T790M negative (interim readout). The most common (≥20% patients) all causality adverse events (AEs), were vomiting (n=18, 41%), nausea (n=17, 39%), rash (n=16, 36%), increased ALT (n=14, 32%), increased AST (n=13, 30%), hypoalbuminaemia and gamma‑glutamyl transpeptidase increase (both n=11, 25%), and increased blood alkaline phosphatase (n=9, 21%). Grade ≥3 all causality AEs were reported in 14 (32%) patients; increased AST and increased ALT (both n=3, 7%) were most frequent. Three (7%) patients died due to an AE (respiratory failure [n=1], lung neoplasm [n=2]); none were considered treatment related. Anti-tumour activity was observed; confirmed partial responses were reported in 11/44 (25%) patients and a further 4 patients are awaiting confirmation of response (confirmed and unconfirmed response rate 15/44 [34%]). At the time of the scheduled 12 week study assessment, 20 (46%) patients remained on study treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and gefitinib were consistent with historical data.
Conclusion:
These encouraging findings warrant further assessment of savolitinib plus gefitinib for patients with EGFR-mutant, MET-amplified NSCLC who progressed on prior EGFR-TKI. The RP2D was confirmed as savolitinib 600 mg QD plus gefitinib 250 mg QD. This study is ongoing; updated safety and efficacy including anti-tumour activity by T790M status will be presented.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA 09.07 - Clonality of c-MET Copy Number Gain as a Determinant of Primary TKI Resistance in EGFR-Mutant NSCLC (ID 8887)
12:05 - 12:15 | Presenting Author(s): Gillianne Lai | Author(s): R. Nahar, T. Lim, X. Kwang, P.J.R. Liew, J. Lim, Z.W. Aung, A. Takano, Wan-Teck Lim, D.P. Lau, Wan Ling Tan, M. Ang, C.K. Toh, B.S. Tan, A. Devanand, C.W. Too, A. Gogna, B.H. Ong, Tina Koh, R. Kanesvaran, Q.S. Ng, A. Jain, J. Yuan, T.K. Lim, A.S. Lim, A. Hillmer, W. Zhai, G. Iyer, E.H. Tan, W. Tam, Daniel SW Tan
- Abstract
- Presentation
Background:
cMET activation is a valid mechanism of secondary TKI resistance in EGFR mutation-positive (EGFR-M+) NSCLC. However, its role in the treatment-naïve setting remains unclear. We sought to ascertain the prevalence and clinical impact of co-existing cMET copy number gain(CNG) in TKI-naïve early-stage and metastatic EGFR-M+ NSCLC.
Method:
Multi-region SNP array analysis (n=59 sectors) was performed on 13 early-stage resected EGFR-M+ NSCLC. cMET FISH was performed in a separate cohort of 206 metastatic treatment-naïve EGFR-M+ patients, all of whom were treated with first-line EGFR TKIs. We defined cMET-high as CNG≥5 copies, with an additional criteria of MET:CEP7 ratio >2.0 for amplification. Time-to-treatment failure(TTF) in patients cMET-high/low was estimated by Kaplan-Meier method and compared using log-rank test. A cell line from a cMET-high patient exhibiting primary TKI resistance was established.
Result:
Relative to median ploidy across sectors, 7/13(53.8%) early-stage EGFR-M+ tumors showed cMET CNG in at least one sector, with majority displaying(n=6/7) copy number intra-tumor heterogeneity. In the metastatic cohort, 55/206 patients (26.7%) were found to be cMET-high at diagnosis: 6(10.9%) had MET amplification, 49(89.1%) MET polysomy, with the following distribution: 5-6 copies(n=11), 6-8 copies(n=32), and >8 copies(n=12). We next evaluated clinical outcomes stratified by MET-high v low: median TTF was 14.7m(12.2–NE) vs 14.6m(12.7–16.5), p=0.985 respectively, with no significant difference in response rates(RR) to EGFR TKI (66.7%v73.7%; p=0.940). Further stratification by level of CNG did not reveal any differences in RR (5-6 copies:75.0%, 6-8 copies:63.0%, >8 copies:71.4%; p=0.868). In MET-high amplified group, only 2/6 (33.3%) had a partial response to EGFR TKI. In the cohort with suboptimal TKI response (PFS<6m, n=22), we did not observe significant enrichment for MET-high, relative to rest of the cohort (36.4%v25.5%, p=0.278). Finally, in 6 patients with progressive disease within 4 weeks of initiating EGFR TKI, 2/6(33.3%) were MET-high. In a cell line model derived from a MET-high patient (L858R, cMET:7.3 copies) genomic profiling of cell colonies revealed clonal cMET CNG and subclonal EGFR, with the patient demonstrating clinical response to crizotinib.
Conclusion:
Although up to 26% of TKI-naïve EGFR-M+ NSCLC harbor high cMET CNG by FISH, this occurs on the background of a highly variegated copy number landscape. cMET CNG alone does not significantly impact clinical outcomes to EGFR TKI, with the exception of one patient with a clonal cMET-driven tumor. Our data challenges the utility of arbitrary copy number thresholds to define clinically relevant MET pathway dysregulation and underscores the importance of targeting dominant truncal drivers.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA 09.08 - Discussant - OA 09.05, OA 09.06, OA 09.07 (ID 10798)
12:15 - 12:30 | Presenting Author(s): Howard L West
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
Author of
-
+
OA 11 - Reducing Burden: Patient-Centered Care (ID 682)
- Event: WCLC 2017
- Type: Oral
- Track: Nursing/Palliative Care/Ethics
- Presentations: 1
- Moderators:Beth Ivimey, E. Bernicker
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 313 + 314
-
+
OA 11.04 - Effect of Early Palliative Care on Aggressiveness of Cancer Care near End of Life in Lung Cancer Patient (ID 8294)
11:30 - 11:40 | Author(s): Thanyanan Reungwetwattana
- Abstract
- Presentation
Background:
Aggressive care and chemotherapy worsens quality of life (QoL) of dying cancer patients. Early palliative care (EPC) in patients with metastatic non small cell lung cancer (NSCLC) is associated with improvements in QoL. Thus, we aimed to explore an impact of EPC on the aggressiveness of care at the end of life (EOL).
Method:
An observational cohort enrolled newly diagnosed metastasis NSCLC at Ramathibodi hospital from 31[st] August 2015 to 1[st] September 2016. In EPC group, the consultation of specialized palliative team was performed ≤ 4 weeks of diagnosis and before start chemotherapy treatment, then monthly visits until death and the last visit for bereavement. The palliative consultation in standard of care (SOC) patients performed as their routine practices. The cutoff date for survival analysis was on 31[st] December 2016. The aggressiveness of care in EOL was defined as the composite outcome as any of the followings: last dose of chemotherapy received < 14 days of death, a new chemotherapy regimen starting < 30 days before death, ≥ 1 hospital admissions or emergency room visits or hospitalizations > 14 days in 30 days of death, or an ICU admission in 30 days of death.
Result:
105 patients were enrolled, 38 out of 70 patients (54%) in SOC group and 17 out of 35 patients (48%) in EPC group died. More aggressiveness of care at the EOL (97.3% vs 64.7%, p=0.003), more in-patient death (89.5% vs 58.8%; p=0.009) and longer hospitalization before death were observed in the SOC group (12 days vs 4 days, p=0.028). The cost analysis of patients who died at the hospital showed higher hospitalized cost in the SOC group (p=0.005). The EPC group received less aggressive treatments such as using less than 3 regimens of chemotherapy (77.1% vs 94.3%; p=0.028), but the survival rate was not different (11.3 months vs 6.6 months; p=0.08).
Conclusion:
Early palliative care reduced the aggressiveness of care at the end of life, shortened hospitalization and covered less cost of treatment.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
-
+
P2.01-009 - The Efficacy of Bevacizumab Adding in Standard First Line Chemotherapy and Maintenance Treatment in Advanced NSCLC: A Network Meta-Analysis (ID 7977)
09:00 - 09:00 | Author(s): Thanyanan Reungwetwattana
- Abstract
Background:
Bevacizumab (bev) is used as a standard first-line treatment in combination with doublet platinum-based chemotherapy and as the maintenance therapy with either bev alone or bev with single agent chemotherapy for advanced non-small cell lung cancer (NSCLC). However, it was not well established which is the best chemotherapy of bev combination regimen and which is the optimal dose of bev in this setting.
Method:
Phase II-III RCTs of bev containing regimens of a first line and maintenance treatment of advanced NSCLC were identified from PubMed and Scopus databases until 20 February 2017. Data was independently reviewed and extracted by two oncologists. Network meta-analysis was performed to assess the efficacy of bev in both the induction and maintenance phase. We estimate the probability of being the best combination regimen with bev using surface under the cumulative ranking curve (SUCRA) analysis. This analysis was registered with PROSPERO (CRD42016027171).
Result:
All 4,108 studies were identified from PubMed and Scopus databases. After removal of duplications and exclude ineligible studies, 27 RCTs were included. Studies were analyzed by the period of treatment as at induction period and at maintenance period. Induction treatment with platinum+pemetrexed (pem) showed a strongest benefit to control disease [RR 1.33 (95% 1.05-1.70)]. Bev is best to combine with platinum+taxane [RR 1.26 (95%CI 1.06- 1.50)]. Low dose bev (7.5 mg/kg) and standard dose bev+doublet of platinum and taxane are comparable for controlling disease [(RR 1.00 (95%CI 0.73-1.36)]. Maintenance treatment with pem+bev could be the most effective regimen to prevent disease progression and to improve response rate, however the regimen was the first rank of increasing death from adverse event [RR 3.2 (95%CI 1.11-9.21)]. Maintenance with low dose bev could control disease and also decrease both cancer-specific death and all causes of death. Risk-of-bias assessment was done and the majority of the included RCTs are low risk of bias.
Conclusion:
Bev is best to combine with doublet of platinum and taxane for induction treatment. Adding bev to doublet platinum with pem may not enhance more efficacy of induction treatment. Maintenance with low dose bev is applicable given that it had lower toxicity profiles than a conventional dose (15 mg/kg) without significant differences of benefit. Maintenance with pem+bev could decrease death from cancer and all cause of death, however there was a very high toxicity profile. Therefore, pem+bev might be the option for only selected patients with good performance status in maintenance treatment.
-
+
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)
-
+
P3.01-042 - Efficacy & Tolerability of Afatinib in NSCLC Patients Prior Exposure to 1st Generation EGFR TKI: Thailand Multicenter Study (ID 9455)
09:30 - 09:30 | Presenting Author(s): Thanyanan Reungwetwattana
- Abstract
Background:
The Compassionate-Use-Program (CUP) was available in Thailand for requesting afatinib during 2012-2014 for patients whom had failed at least one-line of platinum-based-chemotherapy and progressed following at least 6 months on 1[st]-generation EGFR-TKIs. This is a multicenter-retrospective-study in Thailand aimed to explore the efficacy and tolerability of afatinib in this group of patients.
Method:
Full medical-records of 79 patients from 7 institutions were reviewed. Clinical and tumor characteristics were analyzed using descriptive statistics. The efficacy in brain metastases was explored. Survival curves were constructed using the Kaplan-Meier method. All analysis was done in Stata version14.
Result:
Sixty-eight percent of patients were younger than 65 years old, 60% were female, and 67% received more than 2 of prior-regimen. EGFR-mutation was tested in 75% of patients; comprise of 86% common-mutations, 14% uncommon-mutations. Eleven patients had T790M acquired-resistance in combination with sensitive-mutation before receiving afatinib. One patient had De-novo-T790M. The mOS, mPFS, and mTTF were 11.5, 3.9, and 5.1 months, respectively. Eighteen patients had brain-metastases at enrollment and 6 patients had new brain-metastases during afatinib treatment. The mOS, mPFS, and mTTF were not statistically different among new brain-metastases or pre-existing brain-metastases. There was no dose-reduction in 38%, 1 dose-reduction 44%, 2 dose-reductions 12%, and 3 dose-reductions 6% of patients. The mean dose for every patient was 35 mg. Time-to-first-dose-reduction significantly affected the mPFS and mTTF as shown in Table. Furthermore, number of prior-treatment more than 2 was the significant factor causing first-dose-reduction within 1 month and age younger than 65 years-old was the significant factor causing first-dose-reduction within 2 and 3 months in multivariate and univariate model, respectively.Time to 1[st] dose reduction OS PFS TTF Hazard ratio (95%CI) P-value Hazard ratio (95%CI) P-value Hazard ratio (95%CI) P-value > 1 month <= 1 month 1 1.59 (0.74-3.41) 0.23 1 1.52 (0.82-2.82) 0.19 1 1.45 (0.77-2.74) 0.25 >2 month <= 2 months 1 1.54 (0.72-3.3) 0.27 1 2.11 (1.14-3.92) 0.02 1 1.63 (0.88-3.04) 0.12 >3 months <= 3 months 1 2.31 (0.98-5.45) 0.06 1 2.67 (1.38-5.20) 0.004 1 2.12 (1.09-4.12) 0.03
Conclusion:
The mOS, mPFS, and mTTF of our study were comparable with LUX-Lung1 study. Number of prior-treatment and age were the significant factors causing dose-reduction. Taken together with time-to-first-dose-reduction also affected the survival of patients.
-
+
P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P3.03-020 - Unique Molecular Profile of NSCLC in Thai Population (ID 9847)
09:30 - 09:30 | Author(s): Thanyanan Reungwetwattana
- Abstract
Background:
Oncogenic driven mutation is the key to develop targeted therapy in lung cancer. Different ethnicity might have the different prevalence of molecular alteration. This study aimed to explore the unique molecular profile of lung adenocarcinoma in Thai population.
Method:
We studied 120 lung adenocarcinoma patients’ molecular profile by FFPE DNA extraction and using Next Generation Sequencing (NGS) on 45 genes lung cancer panel (Ion Torrent system).
Result:
We found 64% (77/120) of EGFR mutation, 13%(16/120) of BRAF V600E,32% (38/120) of KRAS mutation, 11% (13/120) of MET exon14 splice site, 7.5% (9/120) of AKT mutation (E17K), 2.5% (3/120) of ROS1 mutation, 0.8% (1/120) of PIK3CA mutation (H1047R), and 0.8% (1/120) of PTEN mutation by NGS method using the allele fraction cutoff at 2%. We also found 46 patients (38.3%) who had more than one mutation in each person. The validations by the other technique are on-going and will be presented at the WCLC 2017.
Conclusion:
Adenocarcinoma of the lung in Thai population had the unique molecular profile with high prevalence of BRAF V600E and MET exon 14 splice site comparing to the other populations. High prevalence of KRAS and dual different gene mutations in each patient are needed to be confirmed by the other technique because it could be from the artifact of formalin fixation for G12D, G12S, G13D, and G13S of KRAS mutation.
