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Kiat Hon Tony Lim
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.13 - Molecular Characterisation and Clinical Outcomes in RET Rearranged Non-Small Cell Lung Cancer (NSCLC) (ID 1463)
00:00 - 00:00 | Author(s): Kiat Hon Tony Lim
- Abstract
Introduction
RET rearrangements are emerging as a targetable oncogenic fusion driver in 1-2% of NSCLC patients. Promising efficacy of novel selective RET tyrosine kinase inhibitors (TKI) such as selpercatinib and praseltinib have been demonstrated in early phase trials. However, the natural history of disease and the activity of different classes of systemic therapy remains to be defined. Furthermore, routine molecular testing for RET is not yet standard of care and the optimal method of testing is unclear. We present a comparative analysis of molecular profiling with FISH or NGS and correlations with clinical and treatment outcomes.
Methods
Patients diagnosed/treated with RET rearranged NSCLC at the National Cancer Centre Singapore between Apr 2014 and Mar 2020 were included. Multi-region whole exome sequencing (WES) was performed on one early stage pt. Baseline demographics and treatment outcomes were collected (median follow-up 20.3 months).
Results
A total of 64 patients were included, with median age 62 years (range 25-85), 56% were female, 77% Chinese ethnicity, 95% adenocarcinoma and 69% never smokers. RET rearrangement was detected by FISH in 30/34 (88%) patients, NGS in 40/43 (93%) patients, and with discordant results in 7/13 (54%) patients tested with both methods. Median TMB (n=17) was 5.4 mutations/Mb – TMB was high (>10) in 2 patients that were RET FISH positive but NGS negative. Known fusion partners were KIF5B-RET (62.5%), CCDC6-RET (30%), CNTNAP2-RET (2.5%), KIF5B-RET+CCDC6-RET (2.5%) and KIF5B-RET+THOC2-RET (2.5%). PD-L1 TPS was 0% in 6%, 1-49% in 23%, ≥50% in 18% and unknown in 52%. Multi-region WES (sectors=4) in an early stage patient revealed low TMB (median 1.6) and high intra-tumoral heterogeneity (pITH 0.66). EGFR co-mutation was detected in 8 (13%) patients, however in NGS RET positive patients it consisted only of uncommon EGFR mutations. Of 61 stage IIIB/IV or recurrent patients, prevalence of CNS metastases was 31%, and 92% received palliative systemic therapy – including platinum-pemetrexed chemotherapy (62%), immunotherapy +/- chemotherapy (28%), and multikinase (23%) or selective (57%) RET TKI therapy. Median PFS and ORR on chemotherapy was 7.7 months and 54%, on immunotherapy was 3.7 months and 29%, and on multikinase RET TKI was 3.3 months and 15% respectively. Response to immunotherapy was seen only in combination with chemotherapy. OS was prolonged in selective RET TKI treated versus untreated patients (median 49.3 vs 15.3 months; HR 0.16, 95%CI 0.06-0.40, p<0.0001), however was no different in immunotherapy treated versus untreated patients (median 37.7 vs 49.3 months; HR 1.30, 95%CI 0.53-3.19, p=0.53). OS was also prolonged in CCDC6-RET fusion versus KIF5B-RET fusion positive patients (median 113.5 vs 37.7 months; HR 0.12, 95%CI 0.04-0.38, p=0.009).
Conclusion
In RET rearranged NSCLC, selective RET TKI therapy is associated with improved survival outcomes, especially in CCDC6-RET positive patients. Immunotherapy has poor efficacy, associated with low TMB and PD-L1 expression. NGS and FISH testing methods also result in significant discordance.
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MA13 - Tumor Biology: Focus on EGFR Mutation, DNA Repair and Tumor Microenvironment (ID 214)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA13.08 - Genomic and Transcriptomic Features of Distinct Resistance Trajectories in EGFR Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 1461)
16:45 - 17:45 | Author(s): Kiat Hon Tony Lim
- Abstract
Introduction
Despite the established role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in advanced EGFR mutant NSCLC, drug resistance inevitably ensues. More than 40% of resistant patients are EGFRT790M negative (T790M-), for which a diverse range of mechanisms have been described and there remains a paucity of treatment options. Here, we performed systematic multi-omics profiling and analysis of first- and second-generation (1G/2G) TKI resistant patients to better understand molecular features of EGFRT790M positive (T790M+) and T790M- disease.
Methods
We performed deep whole exome and transcriptome profiling on tumor tissue biopsies after resistance to 1/2G EGFR TKI. Tissue was obtained from 59 advanced EGFR mutant NSCLC pts treated at the National Cancer Centre Singapore, of which 38 (63%) were T790M+. Using paired tumor/normal whole exome data, we identified somatic mutations and copy number alterations with Mutect and GISTIC, respectively. Gene expression profiles were generated from paired-end tumor RNA-seq data using STAR and RSEM. Tumor heterogeneity, mutational signatures, and immune cell-type infiltration was inferred. Transcriptome profiles of cancer and stromal cells were inferred and analyzed using a novel transcriptome deconvolution approach, TUMERIC. Multiplex immunofluorescence and correlations with clinical outcomes was performed.
Results
Median age of the cohort was 59 years (range 41-79), 56% were female, 86% never smokers and 90% Chinese ethnicity. At baseline, 35 (59%) pts had EGFR exon 19 deletion, 22 (37%) pts had L858R mutation and 1 (2%) pt each had exon 19 insertion and L861Q mutation. Therapy prior to biopsy consisted of TKI alone (36%), TKI plus chemotherapy (12%) or sequential therapy with TKI and chemotherapy (52%). Median time to progression on 1/2G TKI was 10.3 (1.3-75.8) mths. Among previously reported resistance mechanisms, only MET alterations were significantly enriched in T790M- tumors (19% vs 3%, p=0.03). In contrast, we discovered genomic features associated with T790M status, including enrichment of TP53 alterations (86% vs 50%, p=0.01), 3q chromsomomal arm amplification (57% vs 13%, p<0.001), whole genome doubling (100% vs 82%, p=0.04) and proportional contribution of non-aging mutational signatures (p=0.003) in T790M- tumors. Strikingly, transcriptomic analysis revealed ubiquitous downregulation of adenocarcinoma lineage gene expression (NAPSA, NKX2-1/TTF-1, SFTA2, SFTA3) across cancer cells in T790M- tumors with corresponding upregulation of either squamous or neuroendocrine marker gene expression. Multiplex immunofluorescence confirmed decreased NAPSA and NKX2-1 expression in T790M- vs T790M+ tumors. Classifying tumors into validated transcriptomic subtypes (TRU/PP/PI) also revealed complete absence of the TRU subtype in T790M- tumors (0% vs 52%, p=0.006). Furthermore, tumors were clustered using GEP into immunehot (n=20) or immunecold (n=24) tumors, with distinct immune cell infiltrates and clinical outcomes according to T790M status. Finally, using a Bayesian statistical approach, we explored how T790M- and T790M+ disease could be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients.
Conclusion
We illustrate the interplay between genetic alterations, cell lineage plasticity and the tumor microenvironment – with distinct resistance trajectories associated with T790M status. In particular, histological transformation with lineage plasticity is underappreciated in T790M- tumors. This provides a framework for optimizing therapeutic strategies to circumvent resistance in EGFR mutant NSCLC.
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OA01 - Established Drugs in Special Populations and New Drugs in Established Populations (ID 226)
- Event: WCLC 2020
- Type: Oral
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 09:15 - 10:15, Scientific Program Auditorium
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OA01.06 - Randomised Phase 2 Study of Nivolumab (N) Versus Nivolumab and Ipilimumab (NI) Combination in EGFR Mutant NSCLC (ID 1741)
09:15 - 10:15 | Author(s): Kiat Hon Tony Lim
- Abstract
- Presentation
Introduction
Monotherapy PD1 inhibition is associated with low clinical efficacy in EGFR mutant NSCLC, in part due to preponderance for never smokers, low TMB and paucity of tumor T cell infiltration. Given the potential role for ipilimumab to enhance effector cells and deplete Treg, we sought to ascertain the efficacy, safety and pharmacodynamics of combination immune checkpoint inhibition in advanced EGFR mutant NSCLC.
Methods
In this open-label, phase 2 trial of nivolumab (N) monotherapy versus nivolumab-ipilimumab (NI) combination, patients with advanced EGFR mutant NSCLC who failed one line of standard EGFR TKI were randomized in a 1:1 ratio to nivolumab/ ipilimumab combination therapy or nivolumab monotherapy (with crossover permitted). Patients were stratified according to PDL1 status and presence of brain metastasis. The primary end point was overall response rate (ORR). Pretreatment and on treatment biopsies were acquired for exome and RNA sequencing, as were serial blood collections for immuno-monitoring using flow cytometry.
Results
Enrolment was terminated early due to futility. A total of 31 patients were enrolled: NI:16 (3 with paired biopsies), N:15 (4 crossover to NI, all with paired biopsies). 14 (45.2%) harboured EGFR T790M; 6 (19.3%) were smokers and 16 (51.6%) had a PDL1 expression level of 1% or more. 16 (51.6%) had CNS metastases at baseline. The 6-month PFS rate was 9.0% (2.5%, 31.8%) for the overall cohort, with no significant difference in survival between the 2 arms: median PFS was 1.31 months for N (1.22, NE) vs 1.22 months for NI (1.15, NE), p=0.96. Only 1 patient achieved PR in the entire cohort and received NI combination therapy. Of the 5 patients who derived clinical benefit (defined as best response of PR, or ongoing PR/SD at 6 months), 4 were T790M negative. Incidence of pneumonitis was 3.2% (n=1, G1). Other toxicities include IDDM (n=1), polymyositis (n=1), hypothyroidism (n=2), transaminitis (n=1) and rash (n=5). There were no G3-5 toxicities.
We next interrogated the immune landscape of EGFR TKI resistant NSCLC, and examined the impact of ipilumumab-nivolumab. 4/23 (17.4%) baseline samples were GEP high (2/4 were T790M positive), with enrichment for exhausted CD8, Treg and overexpression of IDO1. Of these 4 patients, 2 derived clinical benefit to N monotherapy. In sequential biopsies before and after exposure to checkpoint inhibitors, increase in infiltrating CD8 T cells was associated with clinical benefit.
Conclusion
While there were no significant toxicity concerns with combination checkpoint inhibition in TKI-resistant EGFR mutant NSCLC, durable response was not demonstrated in our study. High GEP alone did not seem to predict for response to checkpoint inhibitors in EGFR mutant NSCLC, possibly due an immunosuppressive tumor microenvironment.
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OA06 - Updates on EGFR Targeted Perioperative Therapy and Precision Adjuvant Chemotherapy (ID 118)
- Event: WCLC 2020
- Type: Oral
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 16:45 - 17:45, Scientific Program Auditorium
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OA06.05 - Molecular and Clinical Features Associated with Relapse in Early Stage EGFR-Mutated NSCLC: A Single Institution Knowledge Bank (ID 3813)
16:45 - 17:45 | Author(s): Kiat Hon Tony Lim
- Abstract
- Presentation
Introduction
The ADAURA study showed significant reduction in risk of disease recurrence/death with adjuvant osimertinib for Stage IB–IIIA resected EGFR-mutated NSCLC. However, due to early unblinding of the study coupled with paucity of data on patterns of relapse and absence of long-term survival data, the cost:benefit ratio of adjuvant osimertinib remains uncertain. We sought to determine molecular and clinical features that impact outcomes in early stage EGFR-mutated NSCLC.
Methods
Consecutive patients with AJCC v7.0 Stage IA–IIIA resected EGFR-mutated NSCLC diagnosed between 1/1/2010-30/6/2018 who underwent curative surgery at National Cancer Centre Singapore were included. Patient demographics, treatment history were collated and long-term follow up was available for 91.6% of the cohort. We analyzed 2-year DFS by Kaplan-Meier method. In exploratory analysis, exome and/or RNA-sequencing was performed in a subset of 96 patients.
Results
A total of 396 patients were included. Median age at diagnosis 64 years, 63.6% were females and 80.6% were non-smokers. Stage IA comprised 42.2%, Stage IB 23.2%, Stage 2 15.6% and Stage 3A 18.7%. Exon19 deletion mutations comprised 48.7%; while L858R 37.9%. Of the 376 patients (94.9%) who underwent lobectomy, 88.9% had a complete resection. Adenocarcinomas made up 98.5% of the cohort, of which acinar subtype was predominant (61.9%). Majority of Stage II (53.2%) and III (73.0%) patients received adjuvant chemotherapy. 8.6% of patients received post-operative radiotherapy.
At a median follow up of 46 months, 168 patients (42.4%) had recurrent disease. Of the 168 patients with recurrent disease, 41.7% had received adjuvant systemic treatment and 8.9% of them had received neoadjuvant treatment. Median time to recurrence was 17 months. 2-year DFS rate was 79.6% for Stage I, 57.3% for Stage II and 47.1% for Stage III. At the time of analysis, 94 patients had died and 62.8% were attributed to NSCLC. Of the 254 patients with at least 3 years of follow up, 120 have relapsed–representing 35/167 of Stage IA (21.0%), 22/92 (23.9%) Stage IB, 24/62 (38.7%) Stage II and 39/74 (52.7%) Stage IIIA. In terms of sites of disease at relapse, 32.1% had locoregional relapse and 23.2% had intracranial relapse. Lung was the most common site of distant metastases at 47.6%, followed by pleura (20.8%) and bone (17.3%). In a subset of patients with exome and RNA-sequencing performed, we employed various feature selection methods on 69 pre-selected clinical, pathological and molecular features that may contribute to RFS. We identified RHPN2 mutation, CTNBB1 mutation, micropapillary subtype and loss of heterozygosity in human leucocyte antigen as negative prognostic features when controlling for stage and other potential confounding factors.
Conclusion
Our study confirms that despite curative resection and adjuvant chemotherapy, recurrence rates remain high in early stage EGFR-mutated NSCLC, and worrisomely even in stage IA. The 2-year RFS in our cohort is comparable to the control arm of ADAURA, with almost a quarter of patients suffering from intracranial relapse. Our exploratory analysis highlights how molecular features can complement clinical features to improve risk stratification. Further studies are needed to elucidate individualized surveillance and adjuvant treatment strategies for early stage EGFR-mutated NSCLC.
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P37 - Pathology - Biomarker Testing (ID 107)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P37.18 - Lung NSCLC Molecular Diagnostic Comparison Between NGS and Multiplex PCR Assays (ID 3825)
00:00 - 00:00 | Presenting Author(s): Kiat Hon Tony Lim
- Abstract
Introduction
Background: Lung NSCLC has led the targeted oncologic treatment landscape with several approval first line therapies and emerging targets. Single gene testing for diagnostic workup is becoming outpaced by panel and multigene testing. Next generation sequencing and multiplex PCR assays are able to provide practical solutions to the evolving clinical diagnostic requirements. In this study we compared the results and utility in clinical testing.
Methods
Methods: Sixty eight retrospective Lung NSCLC FFPE samples were used for both DNA and RNA assays by clinically validated and/or FDA approved NGS panels Thermofisher OncomineTM Focus assay / Oncomine comprehensive V3 Fusion ( 52 genes and 51 fusions drivers )and the AmoyDxR Pan Lung Cancer PCR Panel multiplex PCR assay ( 11 genes). Optimization of the PCR panel was done by the laboratory. Only gene targets present in both the NGS and PCR panel were used to show concordance. Other parameters for quality control including assay quality control and practical considerations were reviewed.
Results
Results: Preliminary analysis showed 93% (63/68)concordance for the DNA assay and 87% ( 59/68) concordance for the RNA assay. Up to 35% (21/68) of the samples showed suboptimal library quality control for the NGS assay but performed optimally on the PCR panel. There were differences in the requirements for input material, turn around time and costs.
Conclusion
Conclusion: There was high concordance rate of the results between the assays. RNA quality in FFPE may show some limitations and performed better on the PCR panel. Both assays have their own advantages. Further evaluation and consideration in the clinical treatment roles will depend on practical evaluation in the laboratory and in the broader clinical testing environment.
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P38 - Pathology - Pathology/Staging (ID 108)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P38.03 - Immunohistochemical, Histologic and Genomic Characterisation of Early Stage Pulmonary Invasive Mucinous Adenocarcinoma (ID 1458)
00:00 - 00:00 | Author(s): Kiat Hon Tony Lim
- Abstract
Introduction
Invasive mucinous adenocarcinoma (IMA) is an uncommon adenocarcinoma variant defined by goblet or columnar cells containing intracytoplasmic mucin and extensive extracellular mucin. Historically, IMAs have been associated with a poorer prognosis. However emerging evidence indicates a majority harbour potentially actionable driver oncogenes and IMA may be associated with downregulation of lung lineage-specifying transcription factor NKX2-1/TTF-1 resulting in a mid/hindgut phenotype. Morphologic features of IMA have also not been well characterised.
Methods
Patients (pts) with early stage resected pulmonary IMA (n=38) at our institution between 2009-19 were included. Morphologic features, including cell and stroma type, cytologic atypia, mitotic rate and spread through air spaces (STAS) were described. Immunohistochemistry for CDX2, CK7, CK20, Napsin-A and TTF-1 was conducted. Whole genome sequencing (WGS) was performed in a subset of pts. Histologic and genomic profiles were correlated.
Results
Median age was 66 years (range 42-82), 59% were male, 89% were of Chinese ethnicity and 55% were current/ex-smokers. Stage distribution after resection (AJCC 8th edition) was IA (50%), IB (16%), IIA (3%), IIB (18%), IIIA (8%), IIIB (3%) and IV (3%). Adjuvant therapy was given in 5 (13%) pts. Driver oncogenes were detected with mutations in EGFR (5%), and fusions in ALK (11%) and RET (3%). Histologically, most (61%) showed typical histomorphology, consisting of columnar tumour cells with basally located nuclei and apical mucin vacuole with mild degree of stratification/complexity, while the remainder (39%) showed a combination of typical mucinous subtype with other more cuboidal or polygonal cells and densely eosinophilic cytoplasm. The stroma was markedly fibrotic and desmoplastic in 68%, with a focal small fibrotic scar in 32%. The mitotic rate was low at 0-5 mitoses/10HPFs (92%), with rarely a higher mitotic rate corresponding to focal areas or more cytologic atypia (8%). Similarly, the cytologic atypia tended to be mild to moderate in 90%. Lymphovascular invasion (LVI) was rarely present (13%), and involvement of the pleura (26%) and parenchymal resection margin (5%) was uncommon. STAS was present in 68%. Pure mucinous tumours were associated with mainly columnar type tumour cells (r2=0.83, p<0.001), only mild-moderate cytologic atypia (r2=0.42, p=0.008) and absence of LVI (r2=0.48, p=0.002). Immunohistochemistry showed tumours positive for CK7 (100%), CK20 (84%), TTF-1 (71%), Napsin-A (63%) and CDX2 (45%). CDX2 positivity was associated with the presence of extensive fibrotic stroma (r2=0.38, p=0.02). After median 2.9 yrs follow-up, 6 (16%) pts had recurred – all stage II/III at baseline – with 2-year DFS of 84% and 5-year DFS of 76%. WGS in 9 (24%) pts revealed lung cancer oncogenic drivers in KRAS (33%), EGFR (11%), ERBB2 (11%), ERBB3 (11%) or no driver mutation/fusion detected (33%). Median TMB was 1.3 mutations/Mbp (range 0.03-2.1). Overall, the presence of known oncogenic drivers was associated with negative staining for CK20 (r2=0.45, p=0.005) and CDX2 (r2=0.31, p=0.06).
Conclusion
IMA is characterised by circumscribed nodules with extensive fibrotic stroma, mild to moderate cytological atypia and low mitotic rate, with good survival outcomes. CDX2 positivity is associated with fibrotic and desmoplastic stroma and absence of an oncogenic driver.
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P59 - Tumor Biology and Systems Biology - Basic and Translational Science - Genomics (ID 197)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P59.08 - THOR: Multi-Ethnic, Open Access Thoracic Cancer Genomics Resource (ID 2162)
00:00 - 00:00 | Author(s): Kiat Hon Tony Lim
- Abstract
Introduction
While the multi-factorial process that give rise to lung cancer is driven by exogenous carcinogens and inherited genetic changes, there is growing evidence that racial and ethnic differences also influence incidence, mortality and treatment response. Existing cancer genomics resources do not provide ethnic variability in the genomics of lung cancer, owing to data availability and the prohibitive computational costs in preparing available genomics data for analysis. For example, one state-of-the-art platform, cBioportal, maintains a large repository of pan-cancer data along with tools to carry out omics analysis, but lacks uniformly processed Asian lung cancer samples to enable cross-cohort comparisons. Here, we introduce a flexible and user-friendly thoracic cancer genomics platform, THOR, that allows for user-friendly cross-cohort lung cancer multi-omics analyses, hosting thousands of uniformly processed Asian and Caucasian lung cancer samples from published cohorts.
Methods
Published and available Asian Lung Cancer multi-omics samples (N=567 samples) along with multi-omics samples from TCGA (N=1144), were downloaded and uniformly processed with bcbio-nextgen, using best-practices analysis for high-throughput DNA sequencing. All relevant and available clinical annotations were also downloaded. This comprised consensus variant calls from 5 algorithms, copy number variation analysis, alongside batch-corrected transcript quantification and estimation of immune-cell type composition. Genetic admixture and ethnicity was uniformly inferred across all patients. The resultant data was then uploaded and hosted on the Singapore Collaborative Oncology Data Portal (OncoSG, https://src.gisapps.org/OncoSG/).
Results
The uniform and best-practices processing of all data enables accurate and fair comparisons of multi-omics data across different cohorts and ethnicities. The OncoSG platform facilitates accessible and flexible web-based analytics, visualisation and collaborative sharing of the genomic, transcriptomic, and clinical data. Using THOR, the research community is now able embark on studying ethnic differences in lung cancer molecular profiles and patient outcomes.
Conclusion
THOR comprises standardised large-scale multi-omics data of multiple Asian and Caucasian lung cancer cohorts combined with advanced data analysis and visualisation tools, providing a powerful and accessible tool for studies of ethnic differences in lung cancer.
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P69 - Tumor Biology and Systems Biology - Basic and Translational Science - RTK/EGFR (ID 208)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P69.05 - Molecular and Cellular Heterogeneity Underpin Treatment Response Across a Spectrum of EGFR-Mutant Non-Small Cell Lung Cancer (ID 1681)
00:00 - 00:00 | Author(s): Kiat Hon Tony Lim
- Abstract
Introduction
Non-small cell lung cancer (NSCLC) present a large proportion of intratumoral heterogeneity. The genetic heterogeneity affects key cancer pathways, driving phenotypic variation, and heterogeneous present in environmental parameters that influence cell metabolism, which poses a significant challenge to efficacy of targeted therapies and gaining clinical resistance.
Methods
Many monoclonal cell lines were derived from each of four EGFR-mutant non-small cell lung cancer (NSCLC) tumors, including treatment-naive/experienced, as well as primary/metastatic tumors. These cell lines were subjected to high-throughput genotyping (whole genome/exome sequencing) and phenotyping (RNA-seq, drug screens), with validation in PDX mouse models.
Results
We were able to recapitulate patient resistance to the different generations of tyrosine-kinase inhibitors (TKIs) in corresponding patient-derived cell lines. Cell lines derived from single primary tumors were more heterogeneous in their accumulated mutations and their response to a 317-compound anti-cancer drug library, compared to cell lines derived from single metastatic tumors. Overall, we find that clonal genetic and phenotypic heterogeneity tracked with response to the drug library. We were able to identify drug resistant clones by their gene expression profiles, and suggest alternative drugs to specifically target such populations in a tumor.
Conclusion
We establish a framework for the genotypic and phenotypic dissection of clonal populations within a tumor and find that clonal genetic and phenotypic diversity are propagated as heterogeneity in response to drugs. This approach will be applicable for identifying persistent drug resistant subpopulations within a tumor through their expression profiles, and to suggest alternative approaches for therapeutically targeting such cells.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.88 - Real-World Data of Osimertinib in Patients with Metastatic EGFRm+ NSCLC who Progressed on First-Line EGFR TKIs (ID 3646)
00:00 - 00:00 | Author(s): Kiat Hon Tony Lim
- Abstract
Introduction
Osimertinib is a third-generation epidermal-growth-factor-receptor tyrosine kinase inhibitor (EGFR-TKI) approved for use in EGFR-mutant lung cancer. We examined its performance in the 2nd/subsequent line setting after resistance to 1st/2nd generation EGFR-TKI.
Methods
We reviewed n=202 patients who received Osimertinib from July 2015 to July 2018 in the 2nd/subsequent line after progression on prior EGFR-TKI. Clinical data including patient characteristics, primary EGFR mutation, T790M mutation status, presence of baseline brain metastases (BM), first-line EGFR-TKI use and survival outcomes were retrospectively analyzed.
Results
Complete data from 193 patients was analyzed. Median age at diagnosis was 63 years (IQR
55-70), 59.6% patients were females, 79.8% never-smokers, 79.3% ECOG 0-1 at start of osimertinib. Majority had EGFR exon 19 (60.6%) and exon 21 (32.1%) mutations at diagnosis. At resistance, T790M mutation was positive in 151 (78.2%) patients: 96/193 (49.2%) tumour samples and 63/193 (32.6%) plasma samples, negative in 20 (10.4%) and unknown in 22 (11.4)%. 100 (51.8%) patients received osimertinib as 2nd line, and the rest in 3rd/subsequent line. 144 (75%) received first-line gefitinib or erlotinib (1G-TKI), 47 (24%) afatinib and 2 (1%) others. Baseline BM was present in 55/192 (28.5%) patients, 37/55 (67.3%) had whole brain radiotherapy (WBRT). Baseline BM were significantly more common in the afatinib group compared to 1G-TKI group (46.8% vs 22.9%, p=0.002).
After median follow up of 37 (95% CI 31.8-41.6) months, median progression-free survival (PFS) was 10.3 (95% CI 8.64-11.50) months and median overall survival (OS) 20 (95% CI 15.61-23.13) months. PFS was 6.3 months for those treated with prior afatinib vs 10.5 months in those who received 1G-TKI (HR 1.57, p=0.01). OS in T790M+ patients was 22.6 months vs 7.9 months in T790M-negative patients (HR 0.43, p=0.001), and PFS was 11.2 months vs 3.1 months respectively (HR 0.52, p=0.01). PFS for second-line use of osimertinib was 10.0 (95% CI 6.34-12.29) months and 10.3 (95% CI 8.05-14.03) months for third-line/beyond (p=0.3); OS was 20.5 (95% CI 15.18-23.89) and 18.7 (95% CI 14.13-23.75) months, respectively (p=0.7). Tumour T790M-positivity was associated with longer PFS (p=0.007) and OS (p=0.01) than tumour T790M-negative patients, but significance was not seen with plasma T790M-positivity.
Physician-assessed overall response rate to osimertinib was 43% (95% CI 35.9-50.3): 48.3% in T790M+ vs 20% in T790M-negative patients. Duration of response was 11.1 (95% CI 8.28-13.67) months in T790M-positive patients.
By multivariable analysis (MVA), ECOG ≥2 (HR 2.53, p<0.001) was associated with shorter OS, and presence of T790M+ with longer OS (HR 0.50, p=0.008). Presence of T790M+ was significantly associated with longer PFS compared to T790M-negative (HR 0.57, p=0.03). ECOG ≥2 (HR 2.10, p<0.001) and first-line afatinib use (HR 1.58, p=0.009) compared to 1G-TKI, were significantly associated with shorter PFS by MVA.
Conclusion
In our cohort, we confirmed that osimertinib is effective even beyond second-line for advanced EGFRm+ NSCLC for T790M+ patients. The shorter PFS in patients who received first-line Afatinib compared to 1G-TKI may be explained by significantly higher proportion of baseline BM in this group. EGFR T790M-negative disease at resistance remain an unmet treatment need.
