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Martin Reck
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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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MA 03 - Chemotherapy (ID 651)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Jin-Hyoung Kang, W. Su
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 502
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MA 03.06 - Effect of 2L Ramucirumab after Rapid Time to Progression on 1L Therapy: Subgroup Analysis of REVEL in Advanced NSCLC (ID 7947)
11:35 - 11:40 | Presenting Author(s): Martin Reck
- Abstract
- Presentation
Background:
In REVEL, ramucirumab+docetaxel in the second-line (2L) treatment of patients with advanced NSCLC led to improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), independent of histology. This exploratory, post-hoc analysis focuses on patients who progressed rapidly on first-line (1L), and who traditionally have a poor prognosis in the 2L setting. In REVEL, treatment benefit was observed in patients with progressive disease as their best overall response to 1L and in patients who were on 1L for only a short time (Reck M, ASCO 2017, Abstr 9079). Here, we report outcomes from patients who participated in REVEL according to their time to tumor progression (TTP) on 1L (ClinicalTrials.gov, NCT01168973).
Method:
Patients with advanced NSCLC of squamous or nonsquamous histology with disease progression during or after 1L platinum-based chemotherapy were randomized (1:1) to receive docetaxel 75 mg/m[2] and either ramucirumab 10 mg/kg or placebo on day 1 of a 21-day cycle. OS was the primary endpoint. Secondary endpoints included PFS, ORR, safety, and patient-reported quality-of-life (QoL). Response was assessed according to RECIST v1.1. QoL was assessed with the Lung Cancer Symptom Scale. TTP on 1L, defined as the time from start of 1L until progressive disease, was assessed for the REVEL intent-to-treat population.
Result:
Of 1253 patients in REVEL, 11% had TTP ≤9 weeks, 17% had TTP ≤12 weeks, and 28% had TTP ≤18 weeks on 1L therapy. Baseline characteristics of each subgroup generally were balanced between treatment arms. Efficacy, safety, and QoL outcomes by TTP are shown in the table.Outcomes in Patients From the REVEL Study by Time to Tumor Progression on First-Line Therapy
≤9 Weeks ≤12 Weeks ≤18 Weeks INTENT-TO-TREAT POPULATION Ramucirumab+Docetaxel N = 71 Placebo+Docetaxel N = 62 Ramucirumab+Docetaxel N = 111 Placebo+Docetaxel N = 98 Ramucirumab+Docetaxel N = 182 Placebo+Docetaxel N = 172 Median OS, months (95% Confidence Interval [CI]) 8.28 (5.19, 10.84) 4.83 (3.09, 6.90) 9.10 (6.70, 10.84) 5.78 (4.30, 7.49) 8.51 (6.97, 9.95) 5.95 (4.44, 6.97) Unstratified Hazard Ratio (HR) (95% CI) 0.69 (0.47, 1.01) 0.74 (0.54, 1.00) 0.80 (0.63, 1.01) 12-month survival rate, % (95% CI) 47 (35, 58) 32 (20, 44) 34 (25, 43) 23 (15, 32) 30 (23, 37) 24 (18, 31) 18-month survival rate, % (95% CI) 20 (11, 31) 12 (5, 24) 17 (10, 26) 13 (6, 22) 17 (11, 23) 13 (8, 20) Median PFS, months (95% CI) 3.01 (2.66, 4.07) 1.48 (1.41, 1.87) 3.61 (2.76, 4.21) 1.61 (1.45, 2.60) 3.22 (2.79, 4.14) 1.61 (1.48, 2.60) Unstratified HR (95% CI) 0.69 (0.48, 0.98) 0.73 (0.55, 0.97) 0.72 (0.58, 0.89) ORR (complete response [CR]+partial response [PR]), %, (95% CI) 18.3 (10.1,29.3) 3.2 (0.4, 11.2) 18.9 (12.1, 27.5) 9.2 (4.3, 16.7) 19.2 (13.8, 25.7) 10.5 (6.3, 16.0) Disease Control Rate (CR+PR+stable disease), % (95% CI) 50.7 (38.6, 62.8) 30.6 (19.6, 43.7) 49.5 (39.9, 59.2) 37.8 (28.2, 48.1) 50.5 (43.1, 58.0) 36.0 (28.9, 43.7) Average Symptom Burden Index, time to deterioration HR (95% CI) 0.60 (0.30, 1.22) 0.49 (0.27, 0.88) 0.74 (0.49, 1.12) Total Score Lung Cancer Symptom Scale, time to deterioration HR (95% CI) 0.89 (0.45, 1.78) 0.71 (0.41, 1.23) 0.90 (0.60, 1.36) SAFETY POPULATION Ramucirumab+Docetaxel N = 70 Placebo+Docetaxel N = 61 Ramucirumab+Docetaxel N = 109 Placebo+Docetaxel N = 97 Ramucirumab+Docetaxel N = 179 Placebo+Docetaxel N = 171 Any Treatment-Emergent Adverse Event (TEAE), n (%) 67 (95.7) 58 (95.1) 105 (96.3) 92 (94.8) 173 (96.6) 159 (93.0) Grade ≥3 50 (71.4) 46 (75.4) 80 (73.4) 69 (71.1) 134 (74.9) 113 (66.1) TEAE leading to discontinuation 4 (5.7) 2 (3.3) 5 (4.6) 3 (3.1) 13 (7.3) 6 (3.5) TEAE leading to dose adjustment 24 (34.3) 19 (31.1) 39 (35.8) 28 (28.9) 70 (39.1) 47 (27.5) TEAE leading to death 5 (7.1) 4 (6.6) 7 (6.4) 6 (6.2) 9 (5.0) 8 (4.7) TESAE 25 (35.7) 30 (49.2) 46 (42.2) 46 (47.4) 80 (44.7) 71 (41.5)
Conclusion:
Efficacy, toxicity, and QoL outcomes among ramucirumab+docetaxel patients who have aggressive disease with rapid TTP on 1L therapy appear consistent with the intent-to-treat population. The benefit/risk profile for these rapid progressors suggests that such patients may derive meaningful benefit from ramucirumab+docetaxel in the 2L setting.
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MA 10 - Immunotherapy I (ID 664)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:S. Wang, Robert Pirker
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 303 + 304
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MA 10.02 - Nab-Paclitaxel + Durvalumab as Second- or Third-Line Treatment of Advanced NSCLC: Results from ABOUND.2L+ (ID 8682)
11:05 - 11:10 | Author(s): Martin Reck
- Abstract
- Presentation
Background:
Chemotherapy may enhance immunotherapeutic effects by causing tumor antigen release, which primes the immune system to kill tumor cells. Early clinical data on nab-paclitaxel + carboplatin in combination with immune checkpoint inhibitors (ICI) demonstrated promising activity without compounding toxicities in patients with non-small cell lung cancer (NSCLC). ABOUND.2L+ evaluated nab-paclitaxel–based regimens in previously treated patients with advanced NSCLC. Here we report the efficacy and safety of nab-paclitaxel + durvalumab as second/third-line treatment.
Method:
Patients with advanced NSCLC were assigned to receive second/third-line (immunotherapy allowed in prior line, including platinum doublet combination) nab-paclitaxel 100 mg/m[2] on days 1 and 8 + durvalumab 1125 mg on day 15, in 21-day cycles, administered until unacceptable toxicity/progression per immune-related RECIST v1.1. Primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety.
Result:
Seventy-nine patients were enrolled. Median age was 63 years, 68% of patients were male, 23% had Eastern Cooperative Oncology Group performance status of 0, and 70% had nonsquamous NSCLC; 11% of patients received prior ICIs. Median PFS (Table) and OS were 4.5 (3.4-5.8) months and NE (7.3-NE). ORR was 27% (1 complete response) and DCR was 71%. Grade 3/4 treatment-emergent adverse events of special interest occurring in ≥ 5% of patients included neutropenia (6%) and dyspnea (5%); grade 3/4 peripheral neuropathy and anemia each occurred in 4% of patients. Median treatment duration was 24 weeks; median number of treatment cycles was 7. For nab-paclitaxel and durvalumab, median dose intensities were 59.05 mg/m[2]/week and 326.61 mg/week, respectively; median percentages of per-protocol dose were 88.58% and 87.10%.
Conclusion:
The combination of durvalumab with nab-paclitaxel demonstrated antitumor activity with manageable toxicity in the second/third-line setting. Further details will be presented. NCT02250326Nab-P Durva Median PFS (range), months Overall (n = 79) 4.5 (3.4-5.8) ICI pretreated (n = 9)[a] ICI naive (n = 69)[a] 6.9 (1.4-NE) 4.4 (3.0-5.7) Squamous (n = 23)[a] Nonsquamous (n = 55)[a] 5.9 (3.0-7.8) 4.2 (2.9-5.7) ICI, immune checkpoint inhibitor; NE, not estimable; PFS, progression-free survival. [a] Data pending for 1 patient.
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.03 - Nintedanib + Pemetrexed/Cisplatin in Malignant Pleural Mesothelioma (MPM): Phase II Biomarker Data from the LUME‑Meso Study (ID 8111)
11:10 - 11:15 | Author(s): Martin Reck
- Abstract
- Presentation
Background:
Nintedanib is a triple angiokinase inhibitor. LUME-Meso (NCT01907100) is a randomised, Phase II/III study of ≤6 cycles of nintedanib+pemetrexed/cisplatin versus placebo+pemetrexed/cisplatin, followed by nintedanib or placebo maintenance, in chemo-naïve patients with MPM. In Phase II results, nintedanib+pemetrexed/cisplatin improved progression-free survival (PFS) versus control (hazard ratio [HR]=0.54; p=0.010), with a trend for prolonged overall survival (OS; HR=0.77; p=0.319). Benefit was most pronounced in patients with epithelioid tumours. Since no pharmacodynamic/predictive biomarkers are validated for anti-angiogenic therapies, exploratory analyses were conducted to investigate potential associations of plasma-derived angiogenic factors and genomic markers with treatment outcome in the LUME-Meso Phase II epithelioid population.
Method:
Blood samples were collected at baseline and, for patients receiving maintenance, at monotherapy Cycle 3 (C3mono) and end of monotherapy (EoTmono). Analyses focused on 58 angiogenic factors (Human AngiogenesisMAP[®] panel, Myriad RBM) and single-nucleotide polymorphisms (SNPs) in genes implicated in mesothelioma and/or associated with response to anti-angiogenic therapies in other tumour types (VEGFR1, VEGFR3 and mesothelin). Associations of biomarkers with treatment effect were evaluated by Cox regression and tested for interaction with false discovery rate (FDR) adjustment. Adjusted mean changes in angiogenic factor levels were compared between arms by ANCOVA. Analyses were exploratory, limited by small sample size, and considered hypothesis generating.
Result:
Of 77 patients with epithelioid tumours, angiogenic factor and genomic data were available for 71 and 67 patients, respectively. PFS/OS benefit of nintedanib appeared potentially more pronounced in patients with baseline plasma endoglin level below the median. There were possible weak associations between major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A), and OS benefit and between VEGFR1 SNP rs9582036 A/A genotype and PFS benefit. Biomarker treatment associations were limited by small subgroup size, especially for low-frequency SNPs, and interaction tests were not significant after FDR adjustment. Regarding pharmacodynamic effects, adjusted mean change in interleukin-8 levels with nintedanib was greater from baseline to C3mono and lower from C3mono until EoTmono, compared with placebo. Nintedanib showed lower adjusted mean changes versus placebo for VEGFR2 from baseline to C3mono, and for VEGFR2 and VEGFR3 from baseline to EoTmono.
Conclusion:
These analyses represent the first biomarker results for nintedanib-treated MPM. While there seemed to be signals for greater PFS and OS improvement in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, no biomarkers showed clear significant association with treatment benefit. These findings warrant further evaluation in the Phase III study.
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.02 - Updated Efficacy Results From the BIRCH Study: First-Line Atezolizumab Therapy in PD-L1–Selected Patients With Advanced NSCLC (ID 8006)
14:40 - 14:50 | Author(s): Martin Reck
- Abstract
- Presentation
Background:
The anti–PD-L1 mAb atezolizumab blocks the interactions between PD-L1 and its receptors, PD-1 and B7.1, thus restoring anti-tumor immunity. A Phase II study of atezolizumab monotherapy was conducted across multiple lines of therapy in PD-L1–selected patients with advanced NSCLC (BIRCH; NCT02031458). The primary analyses showed meaningful and durable clinical benefit with atezolizumab monotherapy in 1L and 2L+ NSCLC. Here we present updated survival data (median follow-up, 29.7 months) in patients receiving 1L atezolizumab.
Method:
Eligible patients had chemotherapy-naive, locally advanced or metastatic NSCLC without CNS metastases. Prior TKI therapy was required in patients with EGFR mutation or ALK rearrangement. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was centrally evaluated (VENTANA SP142 IHC assay). Patients who were TC2/3 or IC2/3 (PD-L1 expression on ≥ 5% of TC or IC) were enrolled. Atezolizumab 1200 mg was administered IV q3w until disease progression or unacceptable toxicity. The primary endpoint was independent review facility (IRF)–assessed ORR. Secondary endpoints included investigator (INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.
Result:
With a median follow-up of 29.7 months, median OS was 26.9 months (TC3 or IC3 subgroup) and 24.0 months (all treated patients); INV-assessed ORR was 35% (TC3 or IC3 subgroup) and 26% (all treated patients; Table). Among evaluable patients, the ORR was 31% for mutant EGFR (4/13) vs 23% for wild-type EGFR patients (24/103), and 31% for mutant KRAS (10/32) vs 24% for wild-type KRAS patients (16/66). No new safety signals were observed.
Conclusion:
With more than 2 years of follow-up, atezolizumab continued to demonstrate durable clinical activity in 1L NSCLC, regardless of EGFR and KRAS mutational status. These data suggest that atezolizumab monotherapy has promising activity as a frontline therapy. Ongoing Phase III trials are evaluating atezolizumab-based regimens vs chemotherapy in 1L NSCLC.Endpoint (95% CI) TC3 or IC3[a ](n = 65) TC2 or IC2[b] (n = 73) All Treated Patients (N = 138) INV-assessed ORR, % 35% (23.9, 48.2) 18% (9.8, 28.5) 26% (19.0, 34.2) EGFR mutant/wild-type, % 25%/33% 33%/15% 31%/23% KRAS mutant/wild-type, % 38%/33% 25%/15% 31%/24% mDOR, mo 16.5 (8.5, NE) 12.5 (8.3, 17.9) 13.1 (9.9, NE) mOS, mo 26.9 (12.0. NE) 23.5 (18.1, NE) 24.0 (18.1, 31.9) 12-mo OS rate, % 61% (49.0, 74.0) 71% (59.8, 81.5) 66% (58.1, 74.6) 24-mo OS rate, % 52% (39.3, 65.2) 49% (37.0, 61.1) 50% (41.5, 59.2) 30-mo OS rate, % 48% (35.3, 61.5) 39% (27.2, 51.2) 43% (34.3, 52.1) mPFS, mo 7.3 (4.9, 12.0) 7.6 (4.0, 9.7) 7.6 (5.7, 9.7) 12-mo PFS rate, % 38% (25.1, 49.9) 30% (19.2, 41.2) 34% (25.3, 41.9) 24-mo PFS rate, % 28% (16.5, 40.0) 13% (4.5, 21.5) 20% (12.9, 27.5) 30-mo PFS rate, % 19% (5.4, 33.5) 9% (1.4, 16.4) 14% (6.5, 21.9) NE, not estimable. [a ]TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells.[b ]TC2/3 or IC2/3 excluding TC3 or IC3.
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OA 17.06 - Updated Analysis of KEYNOTE-024: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced NSCLC With PD-L1 TPS ≥50% (ID 9582)
15:25 - 15:35 | Author(s): Martin Reck
- Abstract
- Presentation
Background:
KEYNOTE-024 (ClinicalTrials.gov, NCT02142738) is a multicenter, international, phase 3, randomized, open-label, controlled trial of treatment with the anti‒PD-1 antibody pembrolizumab vs platinum-based chemotherapy as first-line therapy for patients with advanced NSCLC of any histology with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR mutations or ALK translocations. Results from the primary analysis of KEYNOTE-024 demonstrated that after a median follow-up of 11.2 months, pembrolizumab significantly improved PFS (HR=0.50; P<0.001) and OS (HR=0.60; P=0.005) and was associated with a lower rate of treatment-related AEs compared with chemotherapy.
Method:
Patients were randomly assigned to receive either 35 cycles of pembrolizumab 200 mg every 3 weeks or 4–6 cycles of investigator's choice of carboplatin/cisplatin + gemcitabine, carboplatin + paclitaxel, or carboplatin/cisplatin + pemetrexed with optional pemetrexed maintenance (for those with non-squamous histology). Randomization was stratified by ECOG performance status (0 vs 1), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Treatment continued until disease progression per RECIST version 1.1, intolerable toxicity, or withdrawal of consent. Patients in the chemotherapy arm who experienced disease progression could cross over to receive pembrolizumab monotherapy. Response was assessed every 9 weeks by blinded independent central review per RECIST version 1.1. The primary endpoint was PFS; secondary endpoints were OS, ORR, and safety.
Result:
305 patients were enrolled (pembrolizumab, n=154; chemotherapy, n=151). At the time of data cutoff (July 10, 2017) after a median follow-up of 25.2 months, 73 patients (47.4%) in the pembrolizumab arm and 96 patients (63.6%) in the chemotherapy arm had died. The hazard ratio for OS was 0.63 (95% CI, 0.47–0.86; nominal P=0.002). Median (95% CI) OS was 30.0 (18.3–not reached) months in the pembrolizumab arm and 14.2 (9.8–19.0) months in the chemotherapy arm. The Kaplan-Meier estimate of OS at 12 months was 70.3% (95% CI, 62.3%–76.9%) for the pembrolizumab group and 54.8% (95% CI, 46.4%–62.4%) for the chemotherapy group. 82 patients allocated to the chemotherapy arm crossed over to receive pembrolizumab upon meeting eligibility criteria. Treatment-related adverse events were less frequent in the pembrolizumab arm than in the chemotherapy arm (76.6% versus 90.0%, respectively) as were treatment-related grade 3-5 adverse events (31.2% versus 53.3%).
Conclusion:
With more than half of patients having OS events and prolonged follow‒up, first-line pembrolizumab monotherapy remains superior to platinum-based chemotherapy despite the crossover from the control arm to an anti-PD1 inhibitor as subsequent therapy.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-012 - First-Line Ensartinib (X396) versus Crizotinib in Advanced ALK-Rearranged NSCLC (eXalt3): A Randomized, Open-Label, Phase 3 Study (ID 8841)
09:30 - 09:30 | Author(s): Martin Reck
- Abstract
Background:
Ensartinib (X-396) is a novel, potent ALK TKI with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Its phase 1/2 study (NCT01625234) demonstrated that ensartinib is well-tolerated and induces favorable responses in both crizotinib-naïve (ORR 80%) and crizotinib-resistant ALK+ NSCLC patients (ORR 71%), as well as those with CNS metastases.
Method:
In this global, phase 3, open-label, randomized study (eXalt3), approximately 270 patients with ALK+ NSCLC who have received no prior ALK TKI and up to one prior chemotherapy regimen will be randomized with stratification by prior chemotherapy (0/1), performance status (0-1/2), brain metastases at screening (absence/presence), and geographic region (Asia Pacific/other), to receive oral ensartinib (225 mg, once daily) or crizotinib (250mg, twice daily) until disease progression or intolerable toxicity. Eligibility also includes patients ≥ 18 years of age, stage IIIB or IV ALK+ NSCLC. Patients are required to have measurable disease per RECIST 1.1, adequate organ function, and an ECOG PS of ≤2. Adequate tumor tissue (archival or fresh biopsy) must be available for central testing. The primary endpoint was progression-free survival assessed by independent radiology review based on RECIST v. 1.1 criteria. Secondary efficacy endpoints include overall survival, response rates (overall and central nervous system [CNS]), PFS by investigator assessment, time to response, duration of response, and time to CNS progression. The study has > 80% power to detect a superior effect of ensartinib over crizotinib in PFS at a 2-sided alpha level of 0.05.
Result:
Progress report Phase 3 recruitment began in June, 2016 and currently has 66 active sites in 21 countries. The duration of recruitment will be approximately 24 months. This study is registered with ClinicalTrials.Gov as NCT02767804.
Conclusion:
Section not applicable
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-071 - Randomized Phase 1b/3 Study of Erlotinib + Ramucirumab in Untreated EGFR Mutation-Positive Stage IV NSCLC: Phase 1b Outcomes (ID 8468)
09:30 - 09:30 | Author(s): Martin Reck
- Abstract
Background:
Despite the likelihood of an initial response to an EGFR TKI, NSCLC patients with an activating EGFR mutation eventually develop disease progression. Anti-angiogenic agents in combination with an EGFR TKI may provide additional benefit in EGFR-mutant NSCLC, but additional studies are needed to confirm the benefit.
Method:
This ongoing phase 1b/3 study (NCT02411448; RELAY) enrolled patients with previously untreated stage IV NSCLC, ECOG PS 0-1, and an activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). In part A (phase 1b), patients received ramucirumab (anti-VEGFR2 antibody) 10 mg/kg intravenously on day 1 of a 14-day cycle and oral erlotinib at 150 mg/day. Treatment continued until disease progression or unacceptable toxicity. The primary objective of part A was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs) during the first two cycles of therapy, and to determine the recommended dose for Part B (phase 3). Data cutoff was 31-May-2017.
Result:
Fourteen patients were enrolled and treated in part A. Two patients discontinued prior to completion of cycle 2, due to non-DLT adverse events of grade 2 interstitial pneumonia and grade 1 hemoptysis and were therefore not eligible for DLT assessment. Of the 12 DLT-evaluable patients (Japan, n=6; US/Europe, n=6), median age was 72 years (range 51-83), 83% were female, and 75% had ECOG PS of 1. Median duration of therapy was 64.3 weeks (interquartile range [IQR] 19.5-89.0) with ramucirumab and 68 weeks (IQR 44-95) with erlotinib. Treatment-emergent adverse events (TEAEs) occurred in all patients, most commonly rash (100%), diarrhea (92%), paronychia (67%), hypertension (58%), and dry skin (58%). Ten (83%) patients experienced grade 3 TEAEs (hypertension [n=4], rash [n=3], diarrhea [n=2], neutropenia, conjunctivitis, elevation of alanine aminotransferase [DLT; resolved within 4 days], and elevation of aspartate aminotransferase). No serious or grade 4-5 adverse events occurred. Median PFS was 17.1 months (95% CI 8.8-NR; 50% censored) and the PFS survival rate at 21-months was 46.9%. Five patients remain on study treatment.
Conclusion:
Ramucirumab plus erlotinib demonstrated encouraging clinical activity with no unexpected toxicities in Part A. Randomization into Part B began in January-2016, maintaining the dose of ramucirumab at 10 mg/kg Q2W with oral erlotinib at 150 mg/day.
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-008 - A Phase 1b/2 Study of Atezolizumab With or Without Daratumumab in Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) (ID 10214)
09:30 - 09:30 | Author(s): Martin Reck
- Abstract
Background:
Daratumumab (DARA), a human CD38 monoclonal antibody, is approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). DARA produces deep clinical responses in RRMM and induces T-cell expansion through the reduction of immune suppressive cell populations, such as CD38[+] myeloid-derived suppressor cells and regulatory T and B cells. Atezolizumab (atezo) is a humanized programmed death-ligand 1 (PD-L1) monoclonal antibody that blocks the interaction between PD-L1 and the programmed death-1 and B7.1 receptors, reinvigorating anticancer immune responses. Atezo was recently approved for patients with metastatic NSCLC that progressed on or during platinum therapy based on data showing improved overall survival (OS) in the atezo vs docetaxel treatment arm in two clinical trials. The combination of DARA and atezo may improve clinical responses in NSCLC by enhancing anti-tumor T-cell responses facilitated by checkpoint inhibition. This study will assess the anti-tumor activity and safety profile of DARA plus atezo vs atezo alone in patients (pts) with previously treated advanced or metastatic NSCLC.
Method:
This is an ongoing phase 1b/2 randomized, open-label, multicenter study of DARA (16 mg/kg intravenous [IV] weekly for 3 cycles [Days 1, 8, and 15] and then Day 1 of each 21-day cycle thereafter) in combination with atezo (1200 mg IV; Day 2 of Cycle 1 and Day 1 of each 21-day cycle thereafter) versus atezo alone (1200 mg IV; Day 1 of Cycle 1 of each 21-day cycle). Eligible pts (≥18 years) must have advanced or metastatic NSCLC and have received 2 or more cycles of standard platinum-based therapy with disease progression or intolerance to therapy. Eastern Cooperative Oncology Group performance status of ≤1 and known PD-L1 tumor status are required. Pts previously treated with anti-CD38 therapy, including DARA, CD137 agonists, or immune checkpoint inhibitors are excluded. The primary endpoint is overall response rate. Secondary outcomes include safety, duration of response, clinical benefit rate (≥16 weeks duration), progression-free survival, OS, and pharmacokinetics and immunogenicity of DARA and atezo when given in combination. Approximately 96 pts will be enrolled; 6 pts will receive combination therapy in a safety run-in cohort for evaluation of dose-limiting toxicity followed by 90 pts randomly (1:1) assigned to the 2 treatment arms. ClinicalTrials.gov number, NCT03023423.
Result:
Section not applicable
Conclusion:
Section not applicable
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PL 03 - Immunology in Lung Cancer Update 2017 (ID 584)
- Event: WCLC 2017
- Type: Plenary Session
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:David P Carbone, Keunchil Park
- Coordinates: 10/18/2017, 08:15 - 09:45, Plenary Hall (Exhibit Hall D)
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PL 03.04 - Current Status and Future of Immunotherapy in Lung Cancer (ID 7837)
09:25 - 09:45 | Presenting Author(s): Martin Reck
- Abstract
- Presentation
Abstract:
The therapeutic approach to overcome Tumor-induced suppression of specific T-cell activation by using specific antibodies, which are interacting with regulating pathways, the immune check-points has substantially changed treatment of patients with advanced NSCLC. In particular the development of antibodies inhibiting cytotoxic T-lymphocyte-associated antigen 4 (anti CTL4), programmed death receptor 1 (anti PD-1) or programmed death receptor ligand 1 (anti PDL-1) have shown efficacy in NSCLC. In five randomized trials anti PD-1/anti PD-L1 antibodies have shown significant improvement in overall survival (OS) compared to chemotherapy and an improved safety profile. Efficacy was correlated to PD-L1 expression on tumor cells. However confirmed activity has also been documented in patients with PD-L1 negative tumors. Besides harmonization of different existing tests for assessment of PD-L1 expression identification of novel markers like tumor mutational burden (TMB) might help to identify best benefitting patients. In selected patients with high PD-L1 expression on tumor cells (TPS =/> 50%) monotherapy with the anti PD1 antibody pembrolizumab has demonstrated superiority in response, progression free survival and OS compared to platinum based chemotherapy in first-line treatment. Current randomized trials evaluate the activity of combinations of chemotherapy with checkpoint inhibitors or of immunotherapy combinations compared to chemotherapy and will provide important information about the next steps in the development of immunotherapy in lung cancer. For the future the development of novel immunotherapeutic agents either as monotherapy or in combination with checkpoint inhibitors as well as the understanding of resistance mechanisms and strategies to overcome resistance will be of paramount importance.
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