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Daniel SW Tan



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    ES14 - Novel Immunotherapy Strategies in NSCLC (ID 184)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
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      ES14.05 - Combining Targeted Therapies With Immunotherapy (ID 4018)

      11:45 - 12:45  |  Presenting Author(s): Daniel SW Tan

      • Abstract

      Abstract not provided

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    FP14 - Targeted Therapy - Clinically Focused (ID 252)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP14.10 - Efficacy and Safety of Selpercatinib (LOXO-292) in East Asian Patients with RET Fusion-Positive NSCLC (ID 1896)

      00:00 - 00:00  |  Author(s): Daniel SW Tan

      • Abstract
      • Slides

      Introduction

      Selpercatinib is a highly selective and potent, CNS-active, oral RET kinase inhibitor. Here we report the efficacy and safety analyses for the East Asian subgroup with RET fusion-positive NSCLC included in the Primary Analyses Set (PAS). Per regulatory authority agreement, the PAS was defined as the first 105 consecutively enrolled patients that had been previously treated with platinum-based chemotherapy.

      Methods

      Patients with RET fusion-positive NSCLC were enrolled to the global multicenter Phase 1/2 LIBRETTO-001 trial (NCT03157128), conducted in 89 sites across 16 countries, including 23 sites in 7 countries that enrolled patients who self-identified as Asian [Japan (12 patients), South Korea (11 patients), Singapore (5 patients), Hong Kong (5 patients), United States (5 patients), Australia (1 patient), and France (1 patient)]. Following the dose escalation Phase 1 portion, patients received the recommended Phase 2 dose of selpercatinib (160 mg orally, BID, 28-day cycles). The primary endpoint was independently-assessed objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. The analyses reported herein examine the East Asian PAS patient subgroup using data from the 16-Dec-2019 cutoff date.

      Results

      A total of 40 East Asian patients included in the PAS were analyzed. Baseline demographics were: 60% female; median age 56 years (range: 35–80); 95% of patients with an ECOG performance status of 0 or 1. RET fusion partners included: KIF5B-RET (57.5%), CCDC6-RET (15.0%), NCOA4-RET (2.5%), other/unknown (25%). All patients received prior systemic therapy, including platinum-based chemotherapy (100% of patients), a multi-kinase inhibitor (52.5%), and anti-PD-1/PD-L1 therapy (57.5%). The median number of prior therapies was 3.0 (range 1–15). Independently-assessed ORR was 60.0% (95% CI=43.3–75.1, n=24/40). Median DoR was not reached at a median follow-up of 12 months. In the safety analysis of all East Asian patients with NSCLC dosed with selpercatinib (N=136), treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were increased ALT/AST, dry mouth, hypertension, diarrhea, increased creatinine, QT prolongation, thrombocytopenia, peripheral edema, and rash. Only 1.5% (2 of 136) of East Asian patients discontinued selpercatinib due to TRAEs.

      Conclusion

      In this heavily pretreated population of East Asian patients with RET fusion-positive NSCLC, treatment with selpercatinib resulted in a marked and durable tumor response with a well-tolerated safety profile that was consistent with previously reported results from LIBRETTO-001. No new safety signals were identified.

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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): Daniel SW Tan

      • Abstract
      • Slides

      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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    IS13 - Satellite CME Symposium by ACE Oncology: Hot Topics in the Management of Advanced Non-Small Cell Lung Cancer: Expert Insights on Recent Advances (ID 290)

    • Event: WCLC 2020
    • Type: Satellite CME Symposia
    • Track:
    • Presentations: 3
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      IS13.01 - Welcome, Introduction, and Interactive Quiz (ID 4298)

      13:00 - 14:00  |  Presenting Author(s): Daniel SW Tan

      • Abstract

      Abstract not provided

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      IS13.04 - Enhancing Immune Checkpoint Inhibition With Bifunctional Antibodies (ID 4306)

      13:00 - 14:00  |  Presenting Author(s): Daniel SW Tan

      • Abstract

      Abstract not provided

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      IS13.06 - Pearls for Practice (ID 4308)

      13:00 - 14:00  |  Presenting Author(s): Daniel SW Tan

      • Abstract

      Abstract not provided

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    MA04 - Health Policy and the Real World (ID 217)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Health Services Research/Health Economics
    • Presentations: 1
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      MA04.06 - Clinical Characteristics and Outcomes in Advanced KRAS Mutant NSCLC – A Multi-Centre Collaboration in Asia (ATORG-005) (ID 3475)

      16:45 - 17:45  |  Author(s): Daniel SW Tan

      • Abstract

      Introduction

      KRAS driver mutations in advanced NSCLC have long been considered to be undruggable. However, promising efficacy data from early phase trials of novel therapies targeting KRAS have renewed focus on KRAS as an oncogenic driver. There is limited data on the prognostic and predictive significance of KRAS mutation subtypes. We present an interim analysis of a real world observational multi-centre study of advanced KRAS mutant NSCLC patients from five countries in Asia, conducted by the Asian Thoracic Oncology Research Group (ATORG).

      Methods

      Patients with advanced KRAS mutant NSCLC treated with at least one line of systemic therapy at tertiary centres in five Asian countries (China, India, Japan, Singapore, South Korea) between Jan 2014 and Dec 2018 were included. Baseline clinical characteristics, molecular profile and treatment outcomes were collected (median follow-up 35.5 months, 95%CI 28.7-50.3).

      Results

      A total of 155 patients were included in this interim analysis, with median age at advanced stage diagnosis 63 years (interquartile range [IQR] 56-70), 93% were ECOG 0-1, 70% were male and 64% were current or ex-smokers. In terms of ethnicity, 39% were Korean, 36% were Chinese, 15% were Japanese, 8% were Indian and 2% were Malay. Baseline histology was adenocarcinoma in 90%, squamous cell carcinoma in 4% and other histologies in 6%. KRAS mutation was detected by NGS in 141 (91%) patients, Sanger sequencing in 12 (8%) patients and RT-PCR in 2 (1%) patients. KRAS G12C (26%) was most common, followed by G12D (23%) and G12V (21%). The incidence of KRAS G12C mutation in patients with a smoking history was 35/99 (35%) compared with 6/56 (11%) in patients without any smoking history. Co-alterations were found with EGFR mutations (14%), ALK fusions (1%), ROS1 fusions (1%) and BRAF mutations (3%). PD-L1 TPS was 0% in 22%, 1-49% in 19%, ≥50% in 14% and unknown/not tested in 45%. Brain metastases were present at advanced stage diagnosis in 25% and lifetime prevalence was 35%. Patients received a median 2 lines of therapy. First-line systemic therapy consisted of chemotherapy alone (66%), targeted therapy (15%) or other therapies (19%). Median time to next treatment (TTNT) on first-line chemotherapy alone was 7.3 months (95%CI 5.0-9.5). Overall, the median TTNT for first-line and second-line therapy was 7.7 (95%CI 6.5–10.0) and 7.0 (95%CI 5.3–10.9) months, respectively. 63% of patients had died, and 37% of patients were still alive or lost to follow-up at the time of data cut-off. Median OS for the overall cohort was 21.6 months (95%CI 15.9-27.6). Median OS was greater in immunotherapy treated (alone or in combination at any line; 45%) versus non-immunotherapy treated (55%) patients (27.6 [95%CI 19.1-37.9] months versus 15.4 [95%CI 10.3-23.7] months, HR 1.8, 95%CI 1.2-2.7, logrank p=0.005).

      Conclusion

      In Asian KRAS mutant NSCLC, duration of first-line therapy and survival outcomes remain poor – emphasising the need for greater therapeutic options for patients with a KRAS driver mutation. Additional sites/countries are planned and recruitment to this study is ongoing.

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    MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
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      MA11.09 - Efficacy and Safety of Larotrectinib in Patients with Tropomyosin Receptor Kinase (TRK) Fusion Lung Cancer (ID 1796)

      14:15 - 15:15  |  Presenting Author(s): Daniel SW Tan

      • Abstract

      Introduction

      Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers that occur in a wide range of tumor types. Larotrectinib, a highly selective Food and Drug Administration and European Medicines Agency approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% and a median duration of response (DoR) of 35 months across multiple cancers (Hong et al. Lancet Oncol 2020). Here we report updated data for patients with TRK fusion lung cancer assessed by independent review committee (IRC) and investigators (INV).

      Methods

      Patients with lung cancer harboring an NTRK gene fusion enrolled in two clinical trials (NCT02122913 and NCT02576431) were included in this analysis. Larotrectinib 100 mg twice daily was administered on a continuous 28-day schedule. Response was assessed by IRC and by INV per RECIST v1.1.

      Results

      As of July 15, 2019, 14 patients with metastatic TRK fusion lung cancer were enrolled: 13 with non-small cell lung cancer (NSCLC) and 1 patient with small cell lung cancer (SCLC). Seven (6 NSCLC, 1 SCLC) patients had baseline central nervous system (CNS) metastases. The median age was 52 years (range 25–76). Eleven patients (79%) had fusions involving NTRK1 and three patients (21%) had fusions involving NTRK3. Patients were heavily pre-treated with a median of three prior therapies (range 1–5). Among 13 IRC-evaluable patients the ORR was 77% (95% confidence interval [CI] 46–95). ORR was 71% (95% CI 42–92) per INV. ORR in patients with CNS metastases was 71% (95% CI 29–96) and 57% (95% CI 18–90) per IRC and per INV, respectively (Table). The overall DoR per IRC ranged from 3.6 to 36.8+ months. The median progression-free survival (PFS) had not been reached (range 1.8 to 30.3+ months), with an estimated PFS rate at 12 months of 69%. Larotrectinib was well tolerated, with treatment-emergent adverse events being mainly Grade 1–2.

      All patients
      (N=14)

      Patients with brain
      metastases at baseline
      (n=7)

      INV

      IRC

      INV

      IRC

      ORR, % (95% CI)

      71 (42–92)

      77 (46–95)

      57 (18–90)

      71 (29–96)

      CR, n (%)

      1 (7)

      2 (15)

      0

      0

      PR, n (%)

      9 (64)

      8 (62)

      4 (57)

      5 (71)

      SD, n (%)

      3 (21)

      3 (23)

      2 (29)

      2 (29)

      PD, n (%)

      1 (7)

      0

      1 (14)

      0

      IRC data missing for one patient. Extracranial progression detected.
      CI, confidence interval; CR, complete response; INV, investigator assessment; IRC, independent review committee assessment; PD, progressive disease; PR, partial response; SD, stable disease.

      Conclusion

      In this updated dataset, larotrectinib was shown to be highly active in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. The drug has a favorable safety profile. These results support inclusion of NTRK gene fusions in the routine molecular testing of patients with lung cancer.

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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
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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): Daniel SW Tan

      • 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
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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): Daniel SW Tan

      • Abstract

      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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    OA05 - Value and Quality in Lung Cancer (ID 216)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Health Services Research/Health Economics
    • Presentations: 1
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      OA05.03 - Real-World Global Data on Targeting Epidermal Growth Factor Receptor in Stage III Non-Small Cell Lung Cancer: The Results of the KINDLE Study (ID 2229)

      15:30 - 16:30  |  Author(s): Daniel SW Tan

      • Abstract

      Introduction

      Tyrosine kinase inhibitors (TKIs) are the standard of care for patients with metastatic non-small cell lung cancers (NSCLC) harbouring epidermal growth factor receptor mutations (EGFRm). However, the role of TKIs is not established in the management of stage III EGFRm disease. We describe the real-world practice of EGFRm testing and use of TKIs in stage III NSCLC in the KINDLE study, a multicentre, multi-country observational non-interventional study.

      Methods

      The KINDLE study retrospectively captured all diagnostics and treatments received by patients with stage III NSCLC between Jan 01st, 2013 and December 31st, 2017, as well as their associated outcomes. In this analysis we included patients who were tested for EGFRm as well as patients who were treated with EGFR TKIs. Baseline characteristics and treatments were described and progression free survival (PFS) and overall survival (OS) from first therapy were analysed using Kaplan Meier methods.

      Results

      3148 patients were enrolled in the KINDLE study across three regions: Asia (n=1873), Middle East & North Africa (MENA) (n=1045), and Latin America (LA) (n=230). Of those, 1114 patients (35.4%) were tested for the presence of an EGFRm (46.2% in Asia, 16.7% in MENA and 32.1% in LA). An EGFRm was detected in 31.7% of tested patients (34.3% in Asia, 20.0% in MENA and 28.4% in LA). TKIs were included in 5 different regimens as first therapy; as monotherapy, or in combination with any of the following, radiotherapy (RT), chemotherapy (CT), CT and immunotherapy (IO), RT and IO. Two additional regimens were used in subsequent lines (in combination with IO, or with RT and CT).

      Patients with EGFRm stage III NSCLC treated with a TKI, without irradiation, as initial monotherapy (n=68) had a median PFS of 10.6 months (95% CI; 7.5-13.4) and a median OS of 25.4 months (95% CI; 21.6-34.9). In unresectable stage III NSCLC treated with cCRT, for EGFRm patients (n=37) the median PFS of 10.5 months (5.1-16.2) and median OS of 48.0 months (47.2-NC) were similar to those for EGFR wild-type patients (n=145); median PFS 10.8 months (8.5-12.7), median OS 40.6 months (25.6-51.2). In patients with unresectable stage III EGFRm NSCLC (n=34) treated with TKIs, as initial monotherapy, the median PFS and OS were 14.6 months (8.0-18.5) and 24.4 months (15.4-34.9), respectively.

      Conclusion

      Concomitant CRT followed by durvalumab is currently the standard of care for unresectable stage III NSCLC, regardless of EGFR mutation status. The KINDLE study showed that in a real-world setting the minority of stage III NSCLC patients are tested for EGFRm and in patients with the mutation treatment is heterogenous. Unresectable patients with EGFRm had similar outcomes from cCRT compared with EGFR wild-type patients. Unresectable patients with EGFRm NSCLC who received a TKI, without irradiation, as initial monotherapy had worse OS than the ones treated with cCRT.The ongoing LAURA study (NCT03521154) will help define the role of TKIs in EGFRm stage III NSCLC treated with cCRT.

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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
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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): Daniel SW Tan

      • Abstract

      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  |  Author(s): Daniel SW Tan

      • Abstract
      • Slides

      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): Daniel SW Tan

      • Abstract
      • Slides

      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): Daniel SW Tan

      • Abstract
      • Slides

      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): Daniel SW Tan

      • 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: 3
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P76.03 - Efficacy and Safety of Capmatinib Plus Nivolumab in Pretreated Patients with EGFR Wild-Type Non–Small Cell Lung Cancer (ID 817)

      00:00 - 00:00  |  Author(s): Daniel SW Tan

      • Abstract
      • Slides

      Introduction

      Dysregulation of the MET gene can be an oncogenic driver event in non-small cell lung cancer (NSCLC). Capmatinib is a highly potent and selective MET inhibitor. The results of the GEOMETRY mono-1 trial demonstrated efficacy of capmatinib in patients with locally advanced/metastatic METex14-mutated NSCLC (Wolf J. et al, ASCO 2019). In addition, MET was found to directly modulate immune cell function, leading to suppression of anti-cancer immune responses. Further, capmatinib was shown to enhance efficacy of cancer immunotherapy in mice models irrespective of the tumor MET status. Nivolumab is a programmed death receptor-1 inhibitor approved for metastatic NSCLC in patients who progressed after platinum-based chemotherapy. Combining a MET inhibitor with a PD-1 inhibitor may yield sustained clinical benefits in advanced NSCLC.

      Methods

      This phase 2 trial (NCT02323126) evaluated the efficacy and safety of capmatinib plus nivolumab in patients with advanced/metastatic EGFR wild-type NSCLC who had progressed on platinum-doublet therapy and were anti-PD-1/PD-L1 therapy-naïve. Patients received capmatinib 400 mg orally twice daily plus nivolumab 3 mg/kg intravenous every 2 weeks. Patients were grouped into high MET (immunohistochemistry [IHC]=3+ in ≥50% tumor cells [TCs] or IHC=2+ in ≥50% TCs and gene copy number (GCN)≥5 or METex14+) and low MET (all others) cohorts. The primary endpoint was progression-free survival (PFS) rate at 6 months using RECISTv1.1. Secondary endpoints included overall response rate, disease control rate, other PFS endpoints, 1-year overall survival (OS)-rate and safety.

      Results

      As of Sep 10, 2019, 46 patients (high MET [n=16] and low MET [n=30]) were enrolled from February 2015–April 2019; median age: 65 years; male: 50%; Stage IV: 93.5%; ECOG PS 0 or 1: 97.8%. At this preliminary data analysis (June 11, 2019), the 6 month-PFS rate (95% CI) was 60.7% (29.1%–81.7%) in the high MET and 41.7% (22.7%–59.6%) in the low MET cohorts, whereas 1-year-OS data was immature. The ORR (95% CI) was 25.0% (7.3%–52.4%) in the high MET cohort compared to 16.7% (5.6%–34.7%) in the low MET cohort. The DCR (95% CI) was 81.3% (54.4%–96.0%) and 43.3% (25.5%–62.6%) in the high MET and low MET cohorts, respectively. Twenty-nine PFS events were reported; high MET: 9 (56.3%) and low MET: 20 (66.7%). The median PFS (95% CI) was 13.8 (3.5–19.2) months in the high MET cohort versus 4.2 (1.8–7.6) months in the low MET cohort. Most frequent AEs (≥30%; any grade) were nausea (54.3%), vomiting (39.1%), increased amylase, asthenia, increased blood creatinine, and peripheral edema (32.6% each). Most frequent Grade 3/4 AEs (≥10%) were dyspnea and increased amylase (15.2% each) and increased lipase (10.9%). Dyspnea (10.9%), pyrexia (8.7%) and vomiting (6.5%) were most commonly reported serious AEs. Serious treatment-related AEs were reported in 23.9% patients, of which the most common were pyrexia and vomiting (6.5% each).

      Conclusion

      Capmatinib plus nivolumab showed clinical activity in pretreated patients with advanced/metastatic EGFR wild-type NSCLC with a manageable safety profile. While anti-tumor activity was evident in both high MET and low MET cohorts, 6 month-PFS-rate, ORR and DCR were numerically higher in patients with high MET tumors.

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      P76.46 - First-Line Osimertinib in Asian Patients with Advanced EGFR-Mutant Lung Cancer   (ID 2154)

      00:00 - 00:00  |  Author(s): Daniel SW Tan

      • Abstract
      • Slides

      Introduction

      Osimertinib is an oral, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used in treatment of advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). We describe the clinicopathological characteristics and clinical outcomes of advanced EGFRm+ NSCLC patients treated with first-line osimertinib.

      Methods

      We reviewed 66 consecutive Asian patients with advanced EGFRm+ NSCLC from the Lung Cancer Consortium Singapore database on first-line osimertinib. Clinical data including patient characteristics, concomitant mutations, presence of baseline brain metastases (BM), time-to-treatment failure and survival outcomes were retrospectively analyzed. All patients with adenocarcinoma histology were routinely tested for ALK, ROS 1, RET and cMET alterations/rearrangements by fluorescence-in-situ-hybridisation (FISH).

      Results

      Between June 2016 and October 2019, we identified 66 patients with advanced EGFRm+ NSCLC who were treated with first-line osimertinib. Median age of patients was 64 years (IQR 56-73), 65.2% were females, 75.8% never-smokers, and 90.9% with ECOG 0-1 at start of osimertinib. All had adenocarcinoma histology. Thirty-six (54.5%) patients harboured sensitizing EGFR exon 19 deletion (exon 19+) and 24 (36.4%) had exon 21 mutation (exon 21+). The remaining 6 had exon 20 mutation (exon 20+) co-existing with either exon 19+ (3.0%) or exon 21+ (6.1%). Among those with exon 20+, 5 were p.T790M and 1 p.S768I mutation. Baseline BM were present in 36 (54.5%) patients, of which 9 (25%) received radiotherapy (RT) to BM before starting osimertinib. Eight (12.1%) patients tested positive for cMET-polysomy (defined as ratio of MET to CEP 7 <2.0 with ≥5 copies of MET gene per nucleus), 48 (72.7%) negative for cMET polysomy/amplification and 10 (15.2%) unknown cMET. One patient had RET-rearrangement. PD-L1 status was known in 48 patients (72.8%) with 37 low PD-L1 tumor proportion score (TPS) <50% and 11 high PD-L1 (TPS ≥50%). Investigator-assessed response rate (RR) was 83% (95% CI 72.1-91.4%) – same regardless of presence/absence of baseline BM and exon 19+ or exon 21+. After median follow-up of 22 (95% CI 17.3-25.0) months, median progression-free survival (PFS) for all patients was 16.7 (95% CI 13.17-20.93) months and TTF 18.8 (95% CI 16.76-25.49) months. PFS for exon 19+ patients was 17.1 (95% CI 14.49-22.31) months and 11.0 (95% CI 8.02-22.70) months for exon 21+ (p=0.1). Median overall survival (OS) was 30.7 mths (95% CI 21.68-not estimable) but not yet mature. CNS disease progression (PD) occurred in 13 (20%) patients, of which 12/13 had baseline BM and 2/12 had RT to baseline BM before starting osimertinib. By univariable analysis, ECOG ≥2 was significantly associated with shorter PFS (HR 2.61, p=0.03) and MET-polysomy with shorter TTF (HR 3.33, p=0.01). PD-L1 status was not significantly associated with PFS. Patients with baseline BM and exon 21+ had significantly higher risk of CNS PD compared with those without baseline BM (33.3% vs 3.3%, p=0.002) and with exon 19+ (37.5% vs 11.1%, p=0.03), respectively.

      Conclusion

      Osimertinib is an effective first-line treatment in Asian patients with advanced EGFRm+ NSCLC with durable OS, PFS and TTF. Despite good responses in patients with baseline BM and exon 21 mutation, additional treatment strategies are needed to improve their CNS outcomes.

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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): Daniel SW Tan

      • Abstract
      • Slides

      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.

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    PL01 - Opening Plenary Session (Japanese, Mandarin, Spanish Translation Available) (ID 140)

    • Event: WCLC 2020
    • Type: Plenary
    • Track: N.A.
    • Presentations: 1
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      PL01.02 - Chair (ID 3895)

      18:00 - 20:00  |  Presenting Author(s): Daniel SW Tan

      • Abstract

      Abstract not provided

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    PL05 - Affordable and Accessible Lung Cancer Care (Japanese, Mandarin, Spanish Translation Available) (ID 146)

    • Event: WCLC 2020
    • Type: Plenary
    • Track: N.A.
    • Presentations: 1
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      PL05.03 - Chair (ID 3928)

      18:00 - 20:00  |  Presenting Author(s): Daniel SW Tan

      • Abstract

      Abstract not provided