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Sebastian Defranchi
Moderator of
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MA25 - Precision Medicine in Advanced NSCLC (ID 352)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 10
- Now Available
- Moderators:Sebastian Defranchi, Karen Kelly
- Coordinates: 9/10/2019, 14:30 - 16:00, Dublin (1997)
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MA25.01 - Pembrolizumab Plus Chemotherapy for Advanced NSCLC Without Tumor PD-L1 Expression: Pooled Analysis of KN021G, KN189 and KN407 (Now Available) (ID 1399)
14:30 - 16:00 | Presenting Author(s): Hossein Borghaei | Author(s): Corey Jay Langer, Luis Paz-Ares, Delvys Rodriguez Abreu, Balazs Halmos, Vassiliki A Papadimitrakopoulou, Marina Chiara Garassino, Baerin Houghton, Takayasu Kurata, Ying Cheng, Jianxin Lin, M. Catherine Pietanza, Bilal Piperdi, Shirish Gadgeel
- Abstract
- Presentation
Background
Randomized studies have demonstrated that pembrolizumab plus chemotherapy improves OS, PFS, and ORR compared with chemotherapy alone in patients with advanced NSCLC regardless of tumor PD-L1 expression level. We present a post hoc pooled analysis of pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC and no PD-L1 expression (ie, TPS <1%), representing an area of unmet need.
Method
Patients enrolled in KEYNOTE-021 cohort G (nonsquamous; NCT02039674), KEYNOTE-189 (nonsquamous; NCT02578680), and KEYNOTE-407 (squamous; NCT02775435) were included. Patients with nonsquamous NSCLC were randomized to pemetrexed-platinum with or without pembrolizumab; those with squamous NSCLC were randomized to carboplatin-paclitaxel/nab-paclitaxel with or without pembrolizumab. OS, PFS, and ORR were evaluated for the pooled intent-to-treat population. Response was assessed per RECIST v1.1 by blinded independent central review. Across studies, PD-L1 expression was assessed centrally using PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA). Analyses were descriptive.
Result
Of 1298 patients enrolled across the 3 trials, 428 (33%) had PD-L1 TPS <1% (pembrolizumab plus chemotherapy, n=243; chemotherapy alone, n=185) and were included in this analysis. 52% had nonsquamous histology, 63% had ECOG PS of 1. Median (range) follow-up at data cutoff was 10.2 (0.1‒34.9) months. OS, PFS, and ORR were improved with pembrolizumab plus chemotherapy versus chemotherapy alone (Table). Grade ≥3 AEs (all-cause) occurred in 68% of patients receiving pembrolizumab plus chemotherapy versus 72% receiving chemotherapy alone. Immune-mediated AEs and infusion reactions occurred in 26% who received pembrolizumab plus chemotherapy versus 12% who received chemotherapy alone.
ConclusionPembrolizumab + Chemotherapy
n=243
Chemotherapy
Alonen=185
Median (95% CI) OS, mo
19.0 (15.2–24.0)
11.0 (9.2–13.5)
Hazard ratio (95% CI)
0.56 (0.43–0.73)
Median (95% CI) PFS, mo
6.5 (6.2–8.5)
5.4 (4.7–6.2)
Hazard ratio (95% CI)
0.67 (0.54–0.84)
ORR, % (95% CI)
46.9% (40.5%–53.4%)
28.6% (22.3%–35.7%)
Difference (95% CI)
18.3% (9.0%–27.1%)
Our results highlight the clinically meaningful efficacy benefit and acceptable safety profile of pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC and no PD-L1 expression. Benefit was consistent with that observed in the overall study populations, suggesting pembrolizumab plus chemotherapy should be considered standard-of-care first-line therapy for all patients with NSCLC, irrespective of PD-L1 expression.
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MA25.02 - Arrangement and Architecture of Tumor-Infiltrating Lymphocyte on H&E Slides Predict OS in Nivolumab Treated Non-Small Cell Lung Cancer (Now Available) (ID 2911)
14:30 - 16:00 | Presenting Author(s): Kaustav Bera | Author(s): Xiangxue Wang, Cristian Barrera, Cheng Lu, Michael Feldman, Kurt A Schalper, David Rimm, Vamsidhar Velcheti, Anant Madabhushi
- Abstract
- Presentation
Background
Immune checkpoint inhibitors (ICI) are a promising and novel approach to treating chemotherapy refractory advanced NSCLC as well as first-line combination therapy in certain NSCLC. Nivolumab, a PD-L1 inhibitor is a promising ICI showing durable benefit with low toxicity in these patients. While PD-L1 positivity is an established tissue based biomarker for response to Nivolumab, studies have shown response rates ranging from 20-50%. Recent research has shown that TILs have been implicated in cancer aggressiveness as well as immune response. In this work, we go beyond simply counting TILs, and apply novel computer-extracted features characterizing the interaction and spatial co-localization of TILs and cancer nuclei (SpaTIL) in stratifying patients based on OS following nivolumab therapy.
Method
H&E tissue slides obtained from pre-treatment biopsies of 96 NSCLC patients treated with nivolumab were digitized and included for this study from 3 different institutions with the tumor region annotated by pathologists. Then 85 SpaTIL features related to TIL density, architecture and co-localization with tumor cells have been extracted to represent each patient. The most discriminative and uncorrelated features were selected by Elastic-Net regularized Cox-regression model to predict OS. The model was trained on D1 (n=25) and independently validated in D2 (n=32) and D3 (n=64). Multivariate analysis with clinico-pathologic factors was also performed.
Result
The top features consisted of the abundance of TILs around tumor cells and the distribution of the TILs. On the validation set, SpaTIL classifier yielded a HR=3.03 (95%CI=1.1 -8.35; p=0.042) on D2 and HR=4.12 (95%CI=1.87-9.09; p=0.02) on D3 by a log-rank test. On multivariate analysis with stage, smoking, histologic type, total lymphocyte count (See Table 1) SpaTIL was independently prognostic of OS (HR=7.88; 95%CI=1.66 – 37.216; p=0.009).
Table 1. Multivariate analysis for overall survival on the validation sets D2 and D3 Variables
HR(95% CI)
p value
Age (>65 vs <=65 yrs)
0.99(0.97-1.03)
0.67
Gender (Male vs Female)
1.05(0.75-2.79)
0.88
Smoking Status
(Former vs Never smoker)
3.19(0.92-11.061)
0.07
Histological Subtypes (Adeno vs Squamous)1
1.06(0.13-8.54)
0.95
EGFR status
1.32(0.49-3.52)
0.58
ALK status
0.63(0.36-1.10)
0.10
Total lymphocyte count
0.99(0.99-1.00)
0.33
SpaTIL Classifier
7.88(1.66-37.216)
0.009
CI = confidence interval; HR = Mantel-Haenszel Hazard ratio. Values in bold are statistically significant, p<=0.05.
Conclusion
Spatial interaction of TILs and cancer are independently prognostic of OS in nivolumab treated NSCLC. Further validation needs to be done to evaluate its utility.
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MA25.03 - Tumor-Infiltrating Lymphocytes (TIL) and Outcomes with Immunotherapy (ICI) or Chemotherapy in Advanced NSCLC (aNSCLC) Patients (Now Available) (ID 1374)
14:30 - 16:00 | Presenting Author(s): Julien Adam | Author(s): Laura Mezquita, Ithar Gataa, Caroline Rossoni, Edouard Auclin, Myriam Kossai, Frank Aboubakar, Sylvestre Le Moulec, Julie Massé, Morgane Masson, Nina Radosevic-Robin, Mathieu Rouanne, Maria Virginia Bluthgen, CAROLINE Caramella, Lizza Hendriks, Anas Gazzah, David Planchard, Jean-Pierre Pignon, Benjamin Besse
- Abstract
- Presentation
Background
Tumor infiltrating lymphocytes (TIL) morphologically assessed is prognostic in early stages in several tumors. We previously reported the correlation of TIL with immune checkpoint inhibitors (ICI) outcomes in 98 advanced (a) NSCLC patients treated with ICI. We aimed to assess the role of TIL in a larger cohort treated with ICI, and in patients exclusively treated with chemotherapy (CT).
Method
aNSCLC patients with treated with single-agent ICI, with H&E stained sample available, were included between 11/2012 and 02/2017 in 3 cancer centers (immuno-cohort). Patient’s characteristics, biological data were retrospectively collected. The CT-cohort was extracted from the prospective MSN study (NCT02105168), between 06/2009 and 10/2016, enrolling aNSCLC patients treated with platinum-based CT, and tissue available. TIL in the stroma was evaluated in archival samples. High-TIL was defined as ≥10% density. Multivariate Cox model was used to study its prognostic values on overall and progression-free survival (OS, PFS).
Result
A total of 221 patients were included in the immuno-cohort: 142 (64%) male, with median (m) age of 63, 182 (84%) smokers, 161 (77%) PS≤1, 162 (63%) adenocarcinoma; 125 (57%) received ICI as second-line. High-TIL was observed in 49/221 (28%), non-assessable in 46. High-TIL had independent impact on OS and PFS (HR 0.40; 95% CI 0.25-0.63, P<0.0001). The mPFS and OS were 3.1months (mo.) (2.5-4.9) and 11mo. (7.0-13.2) respectively. The high-TIL group had mPFS of 13mo. (5.0-NR) vs. 2.2mo. (1.7-3.0) in low-TIL group (P<0.0001). High-TIL group had mOS not reached (NR) (12.2-NR) vs. 8.4 mo. (5.0-11.6) in low-TIL (P=0.007). The CT-cohort (N=189) had high-TIL in 103/189 (54%). The mPFS and mOS were 5.7mo. (4.9-6.7) and 11.7mo. (9.3-13.0) respectively, with no association with TIL.
OS, Immuno-cohort (n=221) OS, Chemo-cohort (n=188) Hazard ratio (HR)
95% confidence interval (CI)P-value HR
95% CIP-value TIL
≥10% (high)0.46 (0.28-0.81) 0.006 1.03 (0.76-1.41) 0.84 Age
≥65 y0.86 (0.50-1.46) 0.57 0.99 (0.72-1.38) 0.99 Line of treatment*
≥ second line0.69 (0.44-1.09) 0.11 0.84 (0.60-1.16) 0.29 N# metastatic sites
>21.40 (0.88-2.20) 0.16 1.50 (1.07-2.12) 0.02 Performance status
≥22.75 (1.73-4.37) <0.0001 1.94 (1.23-3.04) 0.004 Histology
Squamous1.13 (0.70-1.81) 0.62 1.09 (0.65-1.83) 0.75 *Line of treatment: lines of immunotherapy for the Immuno-cohort; lines of chemotherapy for the Chemo-cohort.
Conclusion
High-TIL (≥10%) is a simple and accessible marker associated with better ICI outcomes, but not with CT. This suggests a potential predictive value that must be validated in larger prospectively studies.
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MA25.04 - Blood-Based Tumor Mutation Burden as a Predictive Biomarker for Outcomes After Pembrolizumab Based First Line Therapy in Metastatic NSCLC (Now Available) (ID 2717)
14:30 - 16:00 | Presenting Author(s): Charu Aggarwal | Author(s): Jeffrey C Thompson, Austin Chien, Katie Quinn, Martina I. Lefterova, Rebecca Nagy, Stephanie S Yee, Michael Lariviere, Christine Ciunci, Aditi Singh, Joshua M Bauml, Roger B Cohen, Corey Jay Langer, Erica Carpenter
- Abstract
- Presentation
Background
PD-1 blockade with pembrolizumab (P) as monotherapy in patients with PD-L1 TPS > 50% or in combination with platinum based chemotherapy (PC) is the current standard front-line therapy for metastatic non-small cell lung cancer (mNSCLC). We explored the correlation of blood (b) based tumor mutational burden (TMB) using circulating tumor DNA (ctDNA) with outcomes after front line P and PC therapy.
Method
Patients with newly diagnosed metastatic NSCLC starting standard of care front line P-based therapy were enrolled. Plasma was prospectively collected at baseline prior to initiation of P or PC therapy for mNSCLC. A 2.145 megabase (Mb) next-generation sequencing panel was used to assess bTMB. A bTMB cutoff of ≥16 mut/Mb was selected based on previously published data (Gandara et al, Nature 2018). Response was assessed using RECIST 1.1. Durable clinical benefit (DCB) was defined as complete response/ partial response/ stable disease that lasted > 6 months. Correlations were made for patient demographics, tumor characteristics, DCB, progression free survival (PFS), and overall survival (OS) using logistic regression and Cox proportional hazards models. Significance was determined at the 0.05 level.
Result
66 pts with mNSCLC were enrolled, median age 67 years (range 47-89), current or ex-smokers (n=61, 92%). Thirty-one patients (47%) received P (all PD-L1>50%); 35 received platinum-pemetrexed based PC. At the time of data cut off, median OS for P was 14.8 months, and not reached for PC. bTMB was evaluable for 52 patients (n=26 P, 26 PC), median bTMB was 16.8 mutations per Mb (mut/Mb, range 1.9-52.5). There was no correlation between bTMB and tumor PD-L1 (p=0.28). Median bTMB for patients achieving DCB was higher than for those with no clinical benefit, 21.3 mut/Mb vs. 12.4 mut/Mb, p=0.004. For patients with bTMB ≥ 16 mut/Mb, median PFS was 13.8 vs. 4.7 months for patients with bTMB <16 mut/Mb (HR 0.27 [0.13-0.55]). Median OS was not reached for bTMB ≥ 16 mut/Mb (HR 0.47 [0.20-1.1]). Loss of function mutations in STK11, KEAP1, or PTEN, or ERBB2 exon 20 insertion were enriched in patients with no clinical benefit. Combined score using bTMB ≥ 16 mut/Mb and mutations in STK11, KEAP1, or PTEN, or ERBB2 exon 20 insertions resulted in improved prediction for DCB; PFS HR of 0.18 [0.08-0.41] and OS HR of 0.27 [0.10-0.73].
Conclusion
Our early results suggest that bTMB using plasma ctDNA may predict therapeutic outcomes after first line P-based therapy in mNSCLC. Loss of function mutations in STK11/KEAP/PTEN and ERBB2 exon 20 insertion mutations appear to be negative predictors of benefit. As the sample size is limited and findings are reported on a pooled group of P and PC patients, the role of bTMB and response to P and PC based therapy separately should be validated in a larger prospective study.
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MA25.05 - Discussant - MA25.01, MA25.02, MA25.03, MA25.04 (Now Available) (ID 3815)
14:30 - 16:00 | Presenting Author(s): Karen Kelly
- Abstract
- Presentation
Abstract not provided
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MA25.07 - Genomic Profiling of Lung Adenocarcinoma by Targeted NGS Using Extracellular Vesicle-Derived DNA in Bronchoalveolar Lavage Fluid (Now Available) (ID 1532)
14:30 - 16:00 | Presenting Author(s): Seungeun Lee | Author(s): Kye Young Lee, Jae Young Hur, Heejoung Kim, Wan Seop Kim, In Ae Kim, Ha Young Park
- Abstract
- Presentation
Background
Extracellular vesicles (EV) are membrane-bound and nanometer-sized particles shed from most types of cells in our body and found in circulation, containing double-stranded genomic DNA reflecting mutational status of the parental tumor cells. Recently, we demonstrated that EVs successfully isolated from bronchoalveolar lavage fluid (BALF) in non-small cell lung cancer (NSCLC) patients. Several studies also have shown that EV-derived DNA is superior to cfDNA in plasma for detection of mutations in NSCLC and pancreatic cancer. We identified that liquid biopsy for EGFR genotyping using EV-derived DNA in BALF showed almost 100% sensitivity with tissue typing in advanced NSCLC patients. Therefore, we hypothesized that targeted next–generation sequencing (NGS) using EV-derived DNA in BALF may correlate with results using tissue in patients with EGFR-mutated lung adenocarcinoma.
Method
To address this hypothesis, we compared with the targeted NGS profile using between BALF EV-derived DNA and tissue DNA in 20 patients with EGFR-mutated lung adenocarcinoma. Four types of somatic variants (SNVs, small indels, CNVs and gene fusions) of BALF-EV or FFPE tissue samples were analyzed by CancerSCANTM, a capture-based targeted sequencing platform, which targets 375 genes covering about 2.5-megabase genomic regions including full CDSs of 374 genes, selected intronic regions of 23 genes for fusion detection, and 1kb TERT promoter region.
Result
Targeted sequencing resulted in over 99% of the target regions covered at a mean depth of 190-750× except one sample. DNA yields were higher in tissue DNA than EV-derived DNA (827.02ng vs 89.10ng). Depth of coverage (753x vs 379x) and estimated tumor purity (53% vs 23%) were also higher in tissue DNA than EV-derived DNA. However, estimated library size was not significantly different between tissue DNA and EV-derived DNA (50G vs 47G) and fragment size of DNA were longer in EV-derived DNA than tissue DNA (175.5bp vs 169.5bp). These findings support that EV-derived DNA has sufficient quality and quantity for NGS. By using mutations detected in tissue DNA as a reference, we achieved 83% sensitivity for somatic and clinically significant variants in EV-derived DNA. Clinically significant mutations in EGFR, TP53, PTEN, APC, JAK3 and PIK3CA were identified with an overall concordance of 81% in matched tissue DNA and EV-derived DNA. Variants in EGFR and TP53 were most common, with concordance of 80% and 100%, respectively. Variant allele frequencies of EGFR and TP53 were most abundant in range of 10-25% in tissue DNA, while much lower (<5%) in EV-derived DNA. Tumor mutation burdens (TMB) of EV-derived DNA showed correlation with tissue DNA (R2=0.21).
Conclusion
To our knowledge, this is the first of study of comprehensive clinical NGS panel using EV-derived DNA of BALF and matched tumor tissue biopsies in patients with lung adenocarcinoma. Although EV-derived DNA demonstrated comparable results to tissue DNA, it is needed much higher sequencing coverage and optimization of NGS-pipeline to detect low-allele frequency variants of EV-derived DNA. This study demonstrates the feasibility and clinical utility of BALF EV-derived DNA for patients with lung adenocarcinoma.
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MA25.08 - Characterisation of Tumor Aetiology Using Mutational Signatures from the Non-Small Cell Lung Cancer Genome (Now Available) (ID 2667)
14:30 - 16:00 | Presenting Author(s): Colin Lindsay | Author(s): Shereen Rafee, Pantelis Nicola, Andrew Wallace, George Burghel, Helene Schlecht, Katie Baker, Eleanor Baker, Lynsey Priest, Jane Rogan, Sharzad Moghadam, Mat Carter, William Newman, Fiona Blackhall
- Abstract
- Presentation
Background
Somatic genome and exome analyses in cancer are currently dominated by a search for actionable mutations that inform new treatments for stage IV patients. Tumour mutational signatures, originally described by the Sanger centre, offer the potential to understand cancer cure and prevention strategies by using the genome/exome to define aetiological contributions to cancer from both environmental and endogenous sources.
Method
132 NSCLC samples were resected from 131 Greater Manchester patients and submitted to the UK 100,000 Genomes Project (Genomics England). A 5×5×5 mm fresh tumour sample was taken from the surgical specimen and stored at -80°C before undergoing genomic testing. To determine the neoplastic cell count, an additional tumour biopsy was taken for routine histological assessment. Germline DNA for comparable whole genome analysis was extracted from peripheral blood lymphocytes from a paired whole blood sample.Whole genome sequencing (WGS) was performed on tumor specimens and matched blood samples. Through the 100,000 Genomes Project pipeline, coverage was calculated from high-quality, non-overlapping bases present on well-mapped reads, as defined by SAMtools v1.1. Whole genome sequencing analysis was undertaken with the Illumina North Star pipeline v2.6.53.23. Data were then mined for tumour mutational burden (TMB) and mutational signature profiles. Signatures were extracted if they accounted for >5% of the mutations per sample. Clinical characteristics including tumor size, nodal status and stage were documented. Mann-Whitney and Fisher’s exact tests were used for statistical comparisons.
Result
Signature 8 (unknown aetiology) was the most prevalent mutational process overall (122/132 samples, 92.4%), while smoking signature 4 was the main mutational process in 86/131 (65.6%) of NSCLC cases. SIgnature 4 contributed as a principal or secondary mutational process to a total of 105/131 (80.2%) cancers; 104/105 (99%) of these patients were annotated as smokers or ex-smokers. Signature 5 (unknown aetiology) was the second most common driving signature (24/131, 18.3% cancers), contributing to an additional 19 cancers as a secondary mutational process (43/131, 32.8% of cancers overall). Median number of signatures contributing to signature 4 NSCLC was four, whilst non-smoking mediated NSCLC had contributions from a median of 5.5 mutational signatures (range 2-8). A median of four signatures contributed to both adenocarcinomas and squamous cancers, with 61/88 (69.3%) adenocarcinomas and 25/41 (61%) squamous cancers associated with signature 4 as their main mutational process. More results will follow on duration of signature 4 persistence following discontinuation of smoking, as well as prevalence of each signature according to common molecular subtypes of NSCLC.
Conclusion
Tumor mutational signatures have the potential to inform cancer prevention by offering a new level of genetic detail that reflects environmental and endogenous carcinogenesis. As expected, signature 4 offers the main contribution to NSCLC although a number of other aetiological factors are involved in its carcinogenesis. In particular, signatures 5 and 8, both currently of unknown aetiology, significantly contribute to the NSCLC genome. Along with that reported by the Sanger centre, this work lays the foundations for characterisation and identification of new carcinogens.
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MA25.09 - Navigating Anlotinib Precision Therapy Through the Genetic Profiling of Circulating DNA in Non-Small Cell Lung Cancer Patients (Now Available) (ID 1055)
14:30 - 16:00 | Presenting Author(s): Jun Lu | Author(s): Hua Zhong, Jun Wu, Tianqing Chu, Lele Zhang, Hua Li, Qiming Wang, Rong Li, Yizhuo Zhao, Aiqin Gu, Chunlei Shi, Liwen Xiong, Xueyan Zhang, Wei Zhang, Yuqing Lou, Bo Yan, Yu Dong, Yanwei Zhang, Baolan Li, Li Zhang, Xiaodong Zhao, Kai Li, Baohui Han
- Abstract
- Presentation
Background
Anlotinib is an oral multi-targeted anti-angiogenic drug, and its clinical predictor for non-small cell lung cancer (NSCLC) patients is still elusive. The aim of this study is to screen predictor for anlotinib via non-invasive genetic profiling of plasma cell free DNA and circulating tumor DNA (cfDNA & ctDNA).
Method
Tumor-specific target capture to profile the circulating DNA of ALTER0303 (Evaluating NSCLC clinical anti-tumor efficacy through anlotinib therapy) study participants. Acquired mutations were screened out via comparing genetic profiling between baseline (BL) and progression disease (PD), and were used for anlotinib stratification. Based on the sequencing data at BL, tumor mutation index (TMI) was established from three independent predictors germline and somatic mutation burden (G+S MB), nonsynonymous and synonymous mutation burden (N+S MB) and unfavorable mutation score (UMS), and was used for predicting anlotinib responders. In addition, TMI combined with IDH1Exon4 mutation status also be examined for serving as predictor for anlotinib stratification.
Result
Our data firstly indicated no benefit (NB, PFS ≤ 45 days) patients can be mainly excluded via analysis of ARID1A and BRCA2 genetic profiling. Secondly, for the no durable benefit (NDB, 45 days < PFS ≤ 130 days) and durable clinical benefit (DCB, PFS > 130 days) patients, harboring lower mutation burden (G+S MB, N+S MB, and UMS) received more benefit from anlotinib therapy. Subsequently, we found the predictor-TMI can predict anlotinib responders upon discovery cohort (Median PFS: 210 days vs 126 days; p = 0.0238; AUC = 0.77), and validation cohort (Median PFS: 210 days vs 127 days; p = 0.0352) and all patients (Median PFS: 210 days vs 127 days; p = 0.0044) more effectively. Furthermore, the IDH1Exon4 mutation was identified as an unfavorable factor to anlotinib therapy under TMI-based stratification. Lastly, the TMI plus IDH1Exon4 mutation status predict response to anlotinib significantly (Median PFS: 210 days vs 127 days, p < 0.0001, AUC = 0.90; Median OS: 423 days vs 162 days, p < 0.0001, AUC = 0.80).
Conclusion
This study provides circulating DNA sequencing-based stratification for underlying anlotinib responders via non-invasive approach, and thus potentially improve clinical outcome for NSCLC patients at 3rd line.
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MA25.10 - First-In-Human Phase 1 Study of DS-1062a (TROP2 Antibody-Drug Conjugate) in Patients with Advanced Non-Small Cell Lung Cancer (Now Available) (ID 3854)
14:30 - 16:00 | Presenting Author(s): Rebecca S Heist | Author(s): Jacob Sands, Toshio Shimizu, Edward Garon, Antoine Yver, Jonathan Greenberg, Penny Phillips, Yukata Noguchi, Alexander Spira, Noboru Yamamoto, Melissa Johnson, Funda Meric-Bernstam, Kiyotaka Yoh, Aaron Lisberg
- Abstract
- Presentation
Background
DS-1062a is a trophoblast cell-surface antigen 2 (TROP2)-targeting antibody-drug conjugate with Daiichi-Sankyo exatecan derivative (DXd) technology. TROP2 is highly expressed in epithelial cancers, including non-small cell lung cancer (NSCLC), and is associated with poor survival. In preclinical studies DS-1062a showed promising antitumor activity in xenograft mouse models. Updated results from the dose escalation part of a phase 1 study of DS-1062a in patients with advanced NSCLC are reported.
Method
This is an ongoing US and Japan dose-escalation/dose-expansion phase 1 study of DS-1062a in patients with unselected NSCLC (NCT03401385). Adult (age ≥20 years [Japan] or ≥18 years [US]) patients with measurable disease per RECIST v1.1 and available tumor for TROP2 measurement were eligible. The primary objectives are to identify the maximum tolerated dose (MTD) and recommended dose for expansion, assess safety and tolerability. Endpoints include safety, efficacy, pharmacokinetics, and molecular and genomic analyses.
Result
At most recent data cutoff (April 12, 2019) 39 patients with advanced NSCLC were treated with DS-1062a at doses of 0.27 (n=4), 0.5 (n=5), 1.0 (n=7), 2.0 (n=6), 4.0 (n=6), 6.0 (n=8) and 8.0 (n=3) mg/kg. Overall, patients were exposed to a median (range) of 3.0 (1–10) treatment cycles over a duration of 8.86 (3.0–31.1) weeks. Patient disposition included dose interruption (n=2), reduction (n=1) and discontinuation (n=23; primary reason was progressive disease (PD) per RECIST in 13/23 patients). The majority (87.2%; 34/39) of patients reported ≥1 treatment-emergent adverse event (TEAE), regardless of severity or causality; the most common (in ≥30% of patients) were fatigue (33.3%) and nausea (30.8%). Grade ≥3 TEAEs were reported in 41.0% (16/39) of patients, of which 12.5% (2/16) were considered drug related. Drug-related TEAEs occurred in 59.0% (23/39 [21/23 grade 1 or 2], and serious TEAEs in 25.6% (10/39 [n=8 grade 3 (n=1 grade 5/sepsis/6.0-mg/kg dose; n=1 grade 3/drug-related/maculopapular rash/6.0-mg/kg dose; n=1 grade 2/drug-related/pyrexia/4.0-mg/kg dose) of patients. One DLT (maculopapular rash, grade 3; resolved) occurred with the 6.0-mg/kg dose; the MTD has not been reached. Of tumor-evaluable patients, as of May 23, 2019, 10 partial responses (PR) were observed (7 PRs were observed at the April 12, 2019 datacut), with a clear dose response and good durability: n=1 in the 2mg/kg, n=2 in the 4-mg/kg, n=3 in the 6 mg/kg, and n=4/5 evaluable in the 8.0-mg/kg groups (4 of the PRs remain to be confirmed). Across all dose groups (April 12, 2019 datacut), 16 stable disease (SD), and 11 PD were observed. Systemic DS-1062a exposure increased in an approximate dose-proportional manner; plasma DS-1062a levels and total anti-TROP2 antibody were similar, suggesting DS-1062a stability in circulation. Updated tumor response profile and durability, biomarker analyses and correlation with clinical outcome will be presented, including immunohistochemistry and circulating tumor DNA analysis of baseline and sequential on-treatment samples, and other related markers.
Conclusion
DS-1062a was well tolerated and 10 PRs were observed during dose selection in unselected NSCLC patients having progressed on standard of care, including immune checkpoint inhibition in 8 of 10 patients. Updated data will be presented.
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MA25.11 - Discussant - MA25.07, MA25.08, MA25.09, MA25.10 (Now Available) (ID 3816)
14:30 - 16:00 | Presenting Author(s): Sebastian Defranchi
- Abstract
- Presentation
Abstract not provided
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MA25 - Precision Medicine in Advanced NSCLC (ID 352)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Sebastian Defranchi, Karen Kelly
- Coordinates: 9/10/2019, 14:30 - 16:00, Dublin (1997)
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MA25.11 - Discussant - MA25.07, MA25.08, MA25.09, MA25.10 (Now Available) (ID 3816)
14:30 - 16:00 | Presenting Author(s): Sebastian Defranchi
- Abstract
- Presentation
Abstract not provided
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