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M.I. Abdul Wahid
Moderator of
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MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 12
- Moderators:M.I. Abdul Wahid, Martin Reck
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 313 + 314
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MA 11.01 - Liquid Biopsies for Monitoring BRAF Mutation (V600E) in Advanced BRAF (V600E) Non-Small Cell Lung Cancer (NSCLC) (ID 10232)
11:00 - 11:05 | Presenting Author(s): Laura Mezquita | Author(s): C. Jovelet, M. Ngocamus, E. Auclin, J. Remon, E. Green, V. Plagnol, C. Morris, A. Gazzah, C. Caramella, J. Adam, L. Lacroix, L. Friboulet, J. Soria, Benjamin Besse, David Planchard
- Abstract
- Presentation
Background:
Circulating tumor DNA (ctDNA) has been shown beneficial in monitoring EGFR mutations in blood, especially for the detection of resistance mutations, like T790M in NSCLC patients. However, the role of BRAF (V600E) ctDNA for monitoring the patient’s response has not been studied yet. The aim of this study was to determine the clinical relevance of BRAF (V600E) ctDNA for monitoring the response to BRAF inhibitors in a prospective cohort of advanced NSCLC BRAF (V600E) patients.
Method:
We prospectively enrolled advanced NSCLC patients with BRAF (V600E) treated with BRAF +/- MEK inhibitors in our institution. A blood sample was collected at different time points, including at baseline, during treatment and at progressive disease. ctDNA BRAF analysis was performed using the Inivata InVision platform (enhanced tagged-amplicon next-generation sequencing (eTAM-Seq).
Result:
Between June 2016 and June 2017, 14 patients have been included. Eight patients (57%) were females, 9 (64%) non-smokers, with a median age of 63 years (35-70). All the patients had adenocarcinoma and BRAF (V600E) mutation in tissue analysis. Thirteen patients (93%) had stage IV at diagnosis, 7 patients (50%) with bone, 6 (43%) pleural and 4 (29%) lung metastasis. The median of lines of treatment received was 2 (1-4). Thirteen patients (93%) received BRAF + MEK inhibitor and 1 patient (14%) BRAF inhibitor, with an objective response rate of 64% (1 complete, 8 partial response) and disease control rate of 86%. BRAF mutation detection was tested under treatment in 12 patients (86%). Longitudinal analysis was performed from the serial sampling in 6 patients to date: 4 patients (67%) were ctDNA positive for BRAF (V600E) at time of progression, with a range of allelic frequency of 0.11-6.16%. BRAF mutation was not detectable in patients with objective response (2/6, 33%) at time of sample collection(s). Additional BRAF (V600E) NSCLC patient samples are being analyzed.
Conclusion:
Liquid biopsy for monitoring BRAF (V600E) using ctDNA appears to be feasible and useful in advanced NSCLC patients. Updated longitudinal results for the complete patient cohort will be presented at the meeting.
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MA 11.02 - Circulating Tumour DNA in Early Stage NSCLC: High Sensitivity Analysis in Low Burden Disease. LUCID Study Update (ID 9598)
11:05 - 11:10 | Presenting Author(s): Robert Campbell Rintoul | Author(s): A. Ruiz-Valdepenas, K. Heider, G. Doughton, W. Qian, C.E. Massie, D. Chandrananda, C.G. Smith, D. Gale, E. Moseley, C. Castedo, A. Stone, C. Thorbinson, T.G. Eisen, D.M. Rassl, S.V. Harden, N. Rosenfeld
- Abstract
- Presentation
Background:
To improve treatment selection and outcomes for patients with early stage non-small cell lung cancer (NSCLC) the development of an effective biomarker to diagnose and characterise the tumour and to detect residual disease after curative-intent treatment is crucial. Circulating tumour DNA (ctDNA) is a promising means to detect and track tumours non-invasively, as the genomic alterations in plasma are representative of the tumour’s clonal populations and their levels correlate with the burden of disease. Furthermore, ctDNA has shown promise for detecting minimal residual disease after treatment in several cancer types. This could help in the selection of patients that, after surgery or radical radiotherapy, will benefit from subsequent treatment. Nonetheless, more sensitive techniques are needed to enable the detection and study of ctDNA at very low concentrations in settings such as these.
Method:
The LUCID study (early stages of non-small cell LUng cancer - CIrculating tumour DNA) was designed to prospectively collect plasma samples from patients with early-stage NSCLC before and after treatment with surgery or radiotherapy (±chemotherapy), and during a minimum follow up of 3 years after diagnosis, in order to explore the clinical utility of ctDNA. For high sensitivity detection of ctDNA, TAilored Panel Sequencing (TAPAS) was developed: exome sequencing of tumour tissue enables the creation of patient-specific panels to analyse in parallel, large numbers of mutations with high sequencing depth. Plasma samples are being analysed using this approach to assess the levels of ctDNA at diagnosis and after radical treatment.
Result:
100 patients were recruited to the study. Longitudinal plasma sample collection and analysis are on-going. Preliminary analysis of the tumour tissue and pre-surgical plasma samples from 19 surgical patients show that most patients with early-stage NSCLC have detectable ctDNA. Analysis of additional samples will be presented.
Conclusion:
Preliminary data from LUCID suggest that the methods we have developed have high sensitivity and will allow detection of ctDNA at rates higher than previously reported. These methods will enable the study of ctDNA in early-stage cancers. We are also exploring the utility of these techniques for detection of minimal residual disease after radical treatment, as a potential tool to guide adjuvant or subsequent post-radiotherapy treatment.
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MA 11.03 - Gefitinib as First-Line Treatment of Plasma CtDNA EGFR Mutation-Positive NSCLC Detected by DdPCR: BENEFIT Study (CTONG1405) (ID 9278)
11:10 - 11:15 | Presenting Author(s): Jie Wang | Author(s): Ying Cheng, Yi-Long Wu, T. An, H. Gao, K. Wang, Qing Zhou, Y. Hu, Yong Song, C. Ding, F. Peng, L. Liang, Y. Hu, C. Huang, Caicun Zhou, Y. Shi, Li Zhang, X. Ye, Y. Sun
- Abstract
- Presentation
Background:
EGFR mutations in plasma circulating free tumor-derived DNA (ctDNA) as a predictor of EGFR TKI efficacy in patients with NSCLC requires validation in prospective studies. The large, prospective Phase II, single-arm, multicenter BENEFIT study (CTONG1405; NCT02282267) validated the efficacy of first-line gefitinib in EGFR mutation-positive NSCLC detected in plasma ctDNA using droplet digital PCR (ddPCR).
Method:
Patients with stage IV lung adenocarcinoma and plasma ctDNA EGFR-sensitizing mutations (exon 19 del or exon 21 L858R; by ddPCR) received first-line gefitinib (250 mg once-daily) until progressive disease (PD). Blood samples were collected every 8 weeks for dynamic EGFR analysis until PD. Primary endpoint was ORR. Secondary endpoints included PFS, DCR (Week 8), and analysis of baseline ctDNA samples by next-generation sequencing (NGS).
Result:
From December 2014-January 2016, 426 patients from 15 Chinese centers were screened: 391 had matched tissue and blood samples; 188 had ctDNA EGFR mutation-positive NSCLC and received gefitinib; and 183 had ≥1 post-baseline tumor assessment and plasma samples every 8 weeks until PD. At data cutoff (January 31, 2017), 152 patients had progressed. ORR was 72.1% (95% CI 65.0%,78.5%); DCR (Week 8) was 92.3% (95% CI 87.5%,95.8%); and median PFS was 9.5 months (95% CI 9.07,11.04). PFS was significantly shorter in the subgroup with baseline ctDNA de novo T790M mutations (5.0%, n=9) versus the EGFR-sensitizing mutations subgroup (5.6 vs 9.6 months, HR=2.60; 95% CI 1.32,5.12, p=0.004). In patients with Week 8 on-treatment plasma samples (n=167), the subgroup who showed EGFR mutation clearance in ctDNA by ddPCR (88%, 147/167) had longer PFS compared with those who did not (11.0 vs 2.1 months, HR=7.28; 95% CI 4.35,12.18, p<0.0001). The median time to emergence of acquired T790M mutation in plasma was 7.6 months. The T790M-positive rate increased from Week 24 (15.7%) to Week 48 (32.6%), with a corresponding increase in PD rate (24.7% at Week 24, 56.9% at Week 48). Among 180 patients with baseline NGS data, 21 (11.7%) harbored aberrations in additional oncogenic drivers (MET, ERBB2, KRAS, BRAF, RET, or ROS1) and tumor suppressors (TP53, RB1, and PTEN). This subgroup had worse PFS versus those with EGFR-sensitizing mutations alone (3.9 vs 13.0 months, HR=2.83; 95% CI 1.65,4.87, p=0.00016).
Conclusion:
The BENEFIT study prospectively demonstrated that ctDNA-based EGFR mutation detection can be used to select patients for treatment with first-line gefitinib. Dynamic alterations in EGFR mutations could be used to predict efficacy and disease progression, ahead of radiological results.
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MA 11.04 - Discussant - MA 11.01, MA 11.02, MA 11.03 (ID 10811)
11:15 - 11:30 | Presenting Author(s): Hye Ryun Kim
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
Highly diverse somatic splice site alteration at MET exon 14 (METex14) result in exon skipping, which is supposed to be a therapeutic target in NSCLC. Here we report detection of METex14 alterations using targeted DNA- and RNA-based Next-Generation Sequencing (NGS) in pulmonary sarcomatoid carcinoma (PSC) with a high frequency of METex14 skipping.
Method:
Tumor specimens were collected from 77 Chinese PSC patients. DNA and RNA were subject to targeted NGS, allowing the detection of somatic splice site alterations and intragenic METex14 skipping respectively. Then, somatic mutations (mutation allele frequency ≥2%) that lead to METex14 skipping were recognized, and Fisher’s exact test was used to examine the association between METex14 skipping and clinical characteristics or other mutations. Two-sided P-values <0.05 were considered statistically significant. Moreover, RT-PCR and Sanger sequencing was also performed on the METex14-positive specimens.
Result:
We have detected genetic aberrations in 77 FFPE samples. For RNA-based NGS, METex14 skipping was identified in 16 (20.78%) of 77 patient cases. And 15 (93.75%) METex14-positive patients were detected somatic mutations by DNA-based NGS, including 12 (80%) cases with splice donor site mutations, 1 (6.67%) cases with splice acceptor site alterations, 1 (6.67%) case with a novel deletion (chr7: 116411868 - 116411883) at MET intron 13 region and 1 (6.67%) case with a novel deletion (chr7: 116412027 - 116412042) at MET exon14 region. In this study, 6 somatic mutations which induce METex14 skipping were firstly discovered. So far, RT-PCR and Sanger sequencing were performed on 3 specimens, including 1 sample with conflicting RNA- and DNA-based NGS results and 2 samples with unreported somatic deletions. According to the results of RT-PCR and Sanger, the unmatched sample was false negative on the basis of DNA-based NGS result. Interestingly, METex14 skipping was mutually exclusive with other recognized genomic alterations (such as mutations in KRAS, BRAF, EGFR, NRAS and PIK3CA), while no significant difference was found between METex14 skipping and single driver gene.
Conclusion:
Mutational events of MET leading to exon 14 skipping are frequent occurred in Chinese PSC patients. DNA-based NGS could discover new somatic mutations which results in METex14 skipping. However, RNA-based NGS could provide more accurate results than DNA-based NGS. METex14 skipping was mutually exclusive with other drivers, thus strongly highlighting its potential oncogenic role.
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MA 11.06 - Retrospective Analysis of NSCLC Testing in Low Tumor Content Samples: Single-Gene Tests, NGS, & the Oncomine™ Dx Target Test (ID 7577)
11:35 - 11:40 | Presenting Author(s): Tiffany M Yu | Author(s): C.D. Morrison, E.J. Gold, A. Tradonsky, A.J. Layton
- Abstract
- Presentation
Background:
Clinical practice guidelines recommend genetic testing for advanced non-small cell lung cancer (aNSCLC) to guide 1[st]-line treatment. Small biopsies and low-tumor-content samples pose challenges to testing and reporting on an increasing number of relevant biomarkers. This study compared clinical aNSCLC biomarker testing to investigational use of the Oncomine™ Dx Target Test for different sample types.
Method:
A retrospective analysis was conducted using lung tissue testing data from a large, US-based commercial laboratory that offered single-gene tests (EGFR therascreen, ALK Vysis, BRAF cobas, and laboratory developed tests [LDT] for ROS1, HER2, BRAF, KRAS, MET, RET, and FGFR1) and a 173-gene next-generation sequencing (NGS) LDT panel (Illumina NextSeq 500). Clinical test orders received September 2015 – October 2016 were evaluated. This laboratory also conducted investigational testing on the Oncomine™ Dx Target Test (Ion Torrent PGM Dx) using archival tissue. Testing success rates and slide consumption were evaluated for core needle biopsies (CNBs; overall and by tumor content), fine needle aspirations (FNAs), and surgical resections.
Result:
Clinical testing orders were received on 1,029 CNBs, 144 FNAs, and 181 surgical resections. Among CNBs, 934 had tumor content data: 214 were 1-24% tumor; 720 were ≥25% tumor. Altogether, 3,571 single-gene tests and 198 NGS LDT panels were ordered. The Oncomine™ Dx Target Test was conducted on 169 archival samples: 69 CNBs (41 were 1-24% tumor; 28 were ≥25% tumor); 13 FNAs; 87 surgical resections.Sample characteristics Single-gene tests per clinical sample (N)* 173-gene NGS LDT (N) Oncomine™ Dx Target Test (N) 1 2 3 4 5 6 7 N samples 1,295 1,039 633 191 114 98 28 198 169 % samples able to successfully generate results for at least X tests, when ordered[†] CNB[‡] 89.2% (988) 85.3% (788) 76.2% (495) 77.9% (154) 70.8% (96) 61.9% (84) 58.3% (24) N/A[§] 75.4% (69) • 1-24% tumor 95.7% (209) 87.1% (170) 70.0% (110) 70.8% (24) 62.5% (16) 60.0% (15) N/A (4) 70.7% (41) • ≥25% tumor 98.2% (685) 91.8% (570) 82.9% (362) 85.8% (120) 76.3% (76) 66.2% (65) 61.1% (18) 82.1% (28) FNA 79.3% (140) 72.4% (116) 75.0% (60) 40.0% (10) N/A (4) N/A (4) N/A (1) 69.2% (13) Surgical resection 100% (167) 98.5% (135) 91.0% (78) 88.9% (27) 64.3% (14) 50.0% (10) N/A (3) 98.9% (87) Total number of slides used to initiate exactly X tests CNB[‡] 2.6 (165) 4.1 (268) 5.5 (324) 8.7 (56) 8.5 (11) 11.8 (55) 16.8 (16) 16.5 (24) 1.0[¶] • 1-24% tumor 2.7 (39) 4.8 (60) 5.9 (83) 9.5 (8) 9.0 (1) 12.3 (11) 18.3 (3) 18.7 (3) • ≥25% tumor 2.6 (118) 3.9 (208) 5.4 (241) 8.7 (47) 8.4 (10) 11.7 (44) 16.5 (13) 16.1 (21) FNA 2.4 (21) 4.3 (41) 6.1 (42) 9.8 (5) N/A (0) 11.5 (2) 18.0 (1) 14.0 (2) Surgical resection 1.8 (32) 4.5 (57) 5.4 (51) 9.5 (13) 11.0 (4) 16.3 (7) 14.0 (2) 8.2 (13) * Excludes clinical samples on which the NGS LDT panel had been initiated. † Success rates were not evaluated if N<10. ‡ While all samples had tumor content >0%, exact percentages were missing for 94 CNBs, 28 FNAs, and 1 surgical resection. § Success rates not evaluated; nearly all NGS LDT panels were ordered on samples that also initiated single-gene tests, and tissue depletion prevented initiation of most of the ordered NGS LDT panels. ¶ All tests were conducted using 1 slide according to protocol.
Conclusion:
Among lung tissue samples submitted for clinical testing, 13.4% were surgical resections, 10.6% FNAs, and 76% CNBs. The Oncomine™ Dx Target Test had higher testing success rates using fewer slides than single-gene testing for ≥5 biomarkers on CNBs, ≥4 on FNAs, and ≥2 on surgical resections. These preliminary results suggest the Oncomine™ Dx Target Test may facilitate multiple-biomarker testing for more aNSCLC patients to support therapy decisions as more gene targets are identified.
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MA 11.07 - Exosomes-Transmitted MicroRNAs Promote EGFR-TKIs Resistance in NSCLC by Activating PI3K/AKT Signaling Pathway (ID 9446)
11:40 - 11:45 | Presenting Author(s): Xiaozhen Liu | Author(s): Tao Jiang, X. Li, J. Li, L. Zhang, S. Zhao, Y. Jia, Jinpeng Shi, C. Zhao, M. Qiao, Fei Zhou, J. Zhao, Caicun Zhou
- Abstract
- Presentation
Background:
Acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) resistance is a major factor contributing to targeted therapy failure in EGFR mutant non-small cell lung cancer (NSCLC), among which T790M mutation accounts for 50-60%. Emerging evidence has shown that as mediators between cells, exosomes shed by drug resistant cancer cells have the ability to horizontally transfer drug resistant phenotype to drug sensitive cells, which has been described as an important mechanism of dissemination of drug resistance. However, whether exosomes derived from EGFR-TKIs resistant NSCLC cells harboring T790M mutation could transfer resistance to sensitive cells has not been understood and the potential mechanism also remains unknown.
Method:
Exosomes were isolated from supernatants of T790M mutant NSCLC cell line (H1975) and characterized by transmission electron microscopy, nanosight and western blot. Their potential roles in mediating gefitinib resistance in sensitive cell line (PC9) were investigated in vitro and in vivo. Cell viability and the effects of exosomes on downstream signaling pathways were analyzed by CCK-8 assays and western blot. The roles of exosomes in regulating gefitinib resistance in vivo were assessed by subcutaneous transplantation tumor model in athymic nude mice. Exosomes miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were used for exploring the underlying mechanism.
Result:
Exosomes isolated from conditioned medium of NSCLC cell lines were cup-shaped membranous vesicles with a diameter of 30-100 nm and expressed the exosomal marker CD63. Exosomes derived from H1975 could transmit gefitinib resistance to PC9 (P＜0.01) in vitro while exosomes released from PC9 cell don’t have this effect. Treatment of PC9 with H1975-derived exosomes and the inhibitor of exosomes production (GW4869) could restore gefitinib response. In vivo, the tumor volume of xenograft model of PC9 cells treated with gefitinib plus H1975-derived exosomes was significantly larger than those mice treated with gefitinib alone (P＜0.05). Furthermore, H1975 xenografts could disseminate gefitinib resistance to PC9 xenografts in the same mice. This difference disappeared by the addition of GW4869. Mechanistically, intercellular transfer of microRNAs (miR-522-3p and miR-454-3p) by exosomes disseminated gefitinib resistance through activating PI3K/AKT and MEK/ERK signaling pathways
Conclusion:
Our findings demonstrate that EGFR-TKIs resistant cells could disseminate drug resistance to sensitive cells by intercellular transfer of exosome-transmitted microRNAs and then activating PI3K/AKT and MEK/ERK signaling pathways, which reveals a novel mechanism of acquired resistance to EGFR-TKIs in NSCLC.
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MA 11.08 - Discussant - MA 11.05, MA 11.06, MA 11.07 (ID 10812)
11:45 - 12:00 | Presenting Author(s): Justin F Gainor
- Abstract
- Presentation
Abstract not provided
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MA 11.09 - Real World Data of Rebiopsy, Mutation Status, and Its Association with Plasma Genotyping after EGFR TKI Failure in NSCLC (ID 8234)
12:00 - 12:05 | Presenting Author(s): Min Hee Hong | Author(s): B.C. Ahn, Hye Ryun Kim, S.J. Heo, J.H. Kim, I.Y. Bang, R. Kim, H.W. Jung, H.J. Cho, H. Kim, H. Kim, Byoung Chul Cho
- Abstract
- Presentation
Background:
After the introduction of third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in non-small cell lung cancer (NSCLC), the second tumor biopsy and EGFR mutation test to confirm T790M status is an established standard practice. But second biopsy is invasive, cost and time-consuming and occasionally impossible. We aimed to investigate the success rate of tissue rebiopsy and incidence of T790M mutation in tissue and plasma at the time of progression with earlier-generation EGFR TKIs in real world setting. Also, we studied the association between the efficacy of osimertinib and the status of tissue and/or plasma T790M mutation.
Method:
We analyzed patients who were screened and enrolled into ASTRIS trial in Yonsei Cancer Center (NCT02474355). Key inclusions were advanced/metastatic NSCLC with tissue and/or plasma T790M mutation and prior EGFR-TKI therapy. Tissue and plasma EGFR mutation tests were performed using PNAClamp[TM] and PANAMutyper[TM], respectively.
Result:
We screened 193 patients with NSCLC harboring EGFR-activating mutation who experienced disease progression upon earlier-generation EGFR TKIs during study period. The second biopsy including tissue and/or cytology was performed only in 60.1% of the patients (116/193) and the success rate was 86.2% (100/116). The reasons for not trying a biopsy were as follow: inaccessibility (n=25), poor PS (n=8), previously reported plasma T790M+ (n=8), and patients’ refusal (n=4). The parenchymal lung tissue (n=61) was most commonly targeted lesion and bronchoscopy was the most frequently used method (n=35). Six patients underwent video-assisted thoracoscopic surgery. Tumor T790M mutation was reported in only 25.9% of patients (50/193). Of 193 patients, 88 patients were enrolled into ASTRIS trial and 43 patients were registered based on the plasma test only. With a median follow-up of 25.1 weeks, the objective response rate (ORR), median progression-free survival (PFS), and duration of the response (DoR) were 44.3%, 32.7 weeks, and 27.0 weeks, respectively. Median overall survival (OS) was not reached. The ORR, median PFS and DoR of tumor T790M+ (n=45) vs. plasma T790M+ (n=54) were 57.8% vs. 35.2%, 45.0 vs. 20.4 weeks, and 26.3 vs. 25.9 weeks, respectively.
Conclusion:
With the increasing importance of tissue rebiopsy after EGFR-TKI failure, there is a growing interest to overcome the challenge of subsequent biopsy. Even though relatively lower ORR and shorter PFS in patients with plasma T790M+ compared with tissue T790M+, the plasma EGFR genotyping may be good alternative to the tissue biopsy in consideration of long DoR when treated with osimertinib and low yield rate of tissue T790M testing.
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MA 11.10 - EGFR TKI Treatment Induces Active Deamination of 5-Methylcytosine and Leads to Acquired T790M Resistant Mutation (ID 9056)
12:05 - 12:10 | Presenting Author(s): Khaled A Hassan | Author(s): N. El Kadi, L. Wang, A. Davis, N. Brown, G. Kalemkerian
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) activation mutations occur in 10-50% of lung adenocarcinoma patients of Caucasian ethnicity and in 50% of Asian descent. Currently, EGFR tyrosine kinase inhibitors (TKIs) are first line therapy for stage IV non-small cell lung cancer (NSCLC) patients with EGFR mutations. Despite initial significant response to TKIs, most tumors develop resistance. The main mechanism of resistance detected in 50-60% of cases is a cytosine to thymine (C>T) single nucleotide transition mutation at position 2369. This leads to a threonine to methionine amino acid change at position 790 (i.e. T790M). Interestingly, a similar mechanism of C>T mutation is seen in imatinib treated CML and GIST tumors. Our data suggests that the C>T mutation is an acquired event secondary to 5-methylcytosine deamination with Activation Induced Cytosine Deamination enzyme (AICDA).
Method:
PC9 is a lung adenocarcinoma cell line known to have an EGFR del19 activation mutation and can acquire T790M mutation from T790M-negative clone. We utilized droplet digital PCR (ddPCR) to detect T790M mutations. In addition, qPCR was used to assess the expression of AICDA and NFκB pathway before and after TKI exposure.
Result:
Sub clones of PC9 cell line with no evidence of T790M mutation by ddPCR at baseline, were treated with EGFR TKI. After serially increasing the treatment dose, T790M mutation was detected by ddPCR associated with a significant increase in AICDA expression. Furthermore, using a UDG assay, we show that AICDA recognizes a CAC motif and can deaminate cytosine at position 2369. By mass spectrometry we established that 2369 cytosine is methylated. Deamination of 5-methylcytosine leads to thymine directly rather than uracil, explaining the C>T mutation. In addition, using ChIP assay and pharmacological inhibition we confirmed that NFκB binds AICDA promoter and induces its expression. Similarly, using a mouse xenograft model, EGFR TKI increases the expression of NFκB and AICDA; this is abrogated by concurrent use of an IKKα inhibitor. Knocking down AICDA by shRNA, decreases the rate of T790M development in PC9 cell lines after TKI exposure. Assessing AICDA expression in patients at baseline (n=4) and upon T790M mutation progression (n=4), there was a significant 20-fold increase in its expression.
Conclusion:
Our data suggest that upon exposure to EGFR TKI, AICDA is overexpressed through an NFκB dependent pathway, causing the deamination of 5-methylcytosine to thymine, manifesting as T790M mutation and leading to TKI resistance. This indicates that T790M is acquired and its development could be targeted.
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MA 11.11 - Italian Nivolumab Expanded Access Program in Non-Squamous NSCLC Patients: Results in Never Smokers and EGFR Positive Patients (ID 8404)
12:10 - 12:15 | Presenting Author(s): Marina Chiara Garassino | Author(s): Enrico Cortesi, Francesco Grossi, R. Chiari, H.J. Soto Parra, S. Cascinu, F. Cognetti, D. Turci, L. Blasi, C. Bengala, E. Mini, E.E. Baldini, T. Gamucci, G.L. Ceresoli, P. Antonelli, E. Vasile, C. Pinto, Domenico Galetta, M. Macerelli, F. De Marinis
- Abstract
- Presentation
Background:
Nivolumab is the first checkpoint inhibitor approved for the treatment of non-Squamous non small cell lung cancer (non-Sq-NSCLC). Although smoking habits are considered a relevant risk factor related to the onset of lung cancer, previous studies showed that current and former smokers patients (pts) treated with nivolumab may have a greater advantage in terms of clinical benefit than never smokers and EGFR mutated. Nevertheless, to date, no definitive conclusion may be drawn and no data are available from a real world setting. Here we report the data from Italian expanded access program (EAP) in the never smoker pts and EGFR mutated pts.
Method:
Nivolumab was provided upon physicians’ request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV non-Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Pts included in the analysis received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events.
Result:
Overall, of 1588 patients with non-Sq-NSCLC, smoking history was available for 1430 pts and 305 (21%) were never smokers and, among 1455 pts evaluable for EGFR mutation, 102 (7%) were positive. In the never smoker group, EGFR status was available for 287 pts, with 51 (18%) who harbored an activating EGFR mutation. Among never smokers, with a median follow-up (FU) of 7.0 months (0.1-20.3) and a median of 7 doses (1-38), the best objective response rate (BORR), the disease control rate (DCR) and the median overall survival (OS) were 9%, 42% and 10.0 months (8.1-11.9), respectively. Among all EGFR positive pts, with a median FU of 5.5 months (0.1-21.2) and a median of 6 doses (1-40), the BORR, DCR and median OS were 9%, 30% and 8.3 months (2.2-14.4), respectively. In the never smoker group, EGFR positive pts had 2% ORR, 26% DCR and 5.6 months (3.4-7.8) of median OS. However, it should be considered that these pts had poorer prognostic factors (ECOG performance status, brain metastasis) at baseline.
Conclusion:
These preliminary results represent the first real-life data regarding the efficacy of nivolumab in special subpopulations, including never smokers and EGFR positive pts. These results warrants further studies to evaluate the possible therapeutic options in these pts, also taking into account available alternatives and safety profile.
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MA 11.12 - Discussant - MA 11.09, MA 11.10, MA 11.11 (ID 10813)
12:15 - 12:30 | Presenting Author(s): Nicolas Girard
- Abstract
- Presentation
Abstract not provided
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