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Xiuning Le
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FP04 - Locoregional and Oligometastatic Disease (ID 126)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Locoregional and Oligometastatic Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP04.04 - EGFR Mutations Predict Superior Survival of NSCLC Patients with Oligometastatic Disease Treated with Local Consolidative Therapy (ID 2994)
00:00 - 00:00 | Author(s): Xiuning Le
- Abstract
Introduction
Local consolidative therapy (LCT) following systemic therapy for selected patients with oligometastatic non-small cell lung cancer (NSCLC) is an evolving treatment strategy. We sought to identify predictive genomic markers for overall survival (OS) and progression free survival (PFS) in patients presenting with synchronous oligometastatic NSCLC at diagnosis.
Methods
Patients presenting to a single institution (2000-2017) with stage IV NSCLC and ≤3 synchronous metastatic lesions were identified. Of 194 patients who met our inclusion criteria, 121 received comprehensive local consolidative therapy (LCT) to all sites of disease with either surgery or radiation. Intrathoracic nodal disease was counted as one site. Univariable and multivariable Cox regressions were performed to identify factors associated with OS. A ninety-day landmark analysis was performed to limit survivorship bias. Mutational status was obtained via an institutional database, when available.
Results
Of 194 patients who met our inclusion criteria and had genomic data available, TP53 mutations were identified in 40 of 55 (72%), KRAS in 30 of 65 (46%), EGFR in 22 of 90 (24%), ALK in 4 of 81 (5%), ROS1 in 2 of 63 (3%), and BRAF in 1 of 32 (3%) patients. The median age was 62 years. After a median follow-up of 52.3 months, median OS and PFS for this cohort was 26.5 (CI 23.0-30.0) months and 11.1 (95%, 9.1-13.0) months, respectively. Among all patients, comprehensive LCT to all sites of disease (N=121) was associated with improved OS (HR 0.67, CI 0.47-0.96, p=0.03) consistent with our previous study. Among all patients, on univariable analysis, patients with EGFR mutations had improved median OS (95.5 vs 37.2 months, p=0.03) compared to EGFR WT patients. Conversely, TP53, and KRAS mutations did not predict for OS. Among patients who received comprehensive LCT with known EGFR mutational status (N=57), EGFR mutations continued to predict for improved median OS (97.5 vs 29.8 months, p=0.02) (Figure 1).
Conclusion
Aggressive consolidative therapy to the primary lesion and all metastatic sites was associated with improved OS in a large cohort of oligometastatic patients, supporting results of recent prospective trials. EGFR mutations, but not KRAS or TP53 mutations, predicted for improved OS among oligometastatic patients who are treated with comprehensive LCT in addition to systemic therapy. These data support ongoing prospective trials evaluating the benefit of local therapy in oligometastatic EGFR mutant NSCLC.
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FP07 - Pathology (ID 109)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP07.10 - Circulating Tumor DNA Analysis in NSCLC with MET exon 14 Skipping Alterations (ID 3418)
00:00 - 00:00 | Presenting Author(s): Xiuning Le
- Abstract
Introduction
MET exon 14 skipping alteration (METex14) is an established oncogene driver in non-small cell lung cancers (NSCLC). Small molecule inhibitors (crizotinib, tepotinib, capmatinib and savolitinib) have shown efficacy in this patient population. Circulating tumor DNA (ctDNA) is an effective approach to detect METex14, as utilized in the VISION trial, which showed comparable outcome to tissue biopsy in patients treated with tepotinib. Here, we present the mutation and co-mutation landscape of the METex14 NSCLC detected by ctDNA.
Methods
Guardant360® results (Guardant Health) from patients with a diagnosis of advanced lung cancer were retrospectively reviewed and treatment-naïve and previously treated patients were included. Each subject was counted once regardless of multiple ctDNA tests performed. METex14 was considered positive when a deletion or non-synonymous mutation flanking exon 14 of MET was identified.
Results
A total of 345 lung cancer patients with METex14 were identified, including adenocarcinoma (79.1%), squamous cell carcinoma (9.8%), NSCLC NOS (7.8%), small-cell lung cancer (2%), and large-cell lung cancer (1.2%). The median age was 77 (range: 41-94) years, and 59% were female. The prevalence by functional sites were: 5’ splice donor site (45.8%), 3’ splice acceptor site (31.0%), D1010 splice mutation (18.3%), Y1003 – CBL mediated MET degradation (4.0%), others (0.9%). No significant gender differences were observed regarding the functional sites. The most frequent mutation type was base substitution (58.4%), followed by indel (41.6%). Whole-exon deletion was not found in this dataset (Table 1). The most frequent oncogene co-alterations included MET amplifications (9.0%), EGFR (7.2%) amplifications, KRAS mutation (6.9%, 15/24 subclonal), CDK4 (4.3%) amplifications and BRAF mutation (4.0%, 11/14 subclonal), while ALK-, ROS1-, RET-, and NTRK-fusions (1.4%) were uncommon. Additionally, TP53 mutations were detected in 53.8% of cases.
Table 1. Functional site by mutation types of METex14 in lung cancer (N=345) n (%) Acceptor site 107 (31.0) Indel 96 (27.8) Base substitution 11 (3.2) Donor site 158 (45.8) Indel 46 (13.3) Base substitution 112 (32.5) Y1003 14 (4.0) Insertion 1 (0.3) Base substitution 13 (3.8) D1010 63 (18.3) Base substitution 63 (18.3) Others 3 (0.9)
Conclusion
In this real-world cohort of 345 cases of METex14-mutant NSCLC, detected using Guardant360, up to 21% were non-adenocarcinomas. The distribution of alterations of METex14 identified using liquid biopsy were similar to previously reported cohorts from tissue biopsies. Other driver oncogene alterations co-occur with METex14 at a low frequency.
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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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FP14.09 - Tepotinib Safety in MET Exon 14 (METex14) Skipping NSCLC: Updated Results from the VISION Trial (ID 821)
00:00 - 00:00 | Author(s): Xiuning Le
- Abstract
Introduction
Tepotinib, a highly selective MET inhibitor, demonstrated durable clinical activity in patients with METex14 skipping NSCLC in the Phase II VISION trial (NCT02864992). Here, we report updated safety data from this ongoing study of the largest prospective population of patients with METex14 skipping NSCLC to date.
Methods
Patients with advanced EGFR/ALK wild-type NSCLC and METex14 skipping identified by liquid or tissue biopsy received oral tepotinib 500 mg once daily until disease progression, unacceptable toxicity or withdrawal for other reasons. To manage adverse events (AEs), treatment could be interrupted for up to 21 days or the tepotinib dose could be reduced. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.
Results
As of July 1, 2020, 255 patients had received tepotinib for a median of 5.1 months (range 0 to 43.4) and treatment was ongoing in 101 patients (39.6%). Median age was 72.0 years (range 41 to 94), 132 patients (51.8%) were female, 171 (67.1%) were white and 184 (72.2%) had Eastern Cooperative Oncology Group performance status 1. The most common treatment-related AEs (TRAEs) were peripheral edema, nausea, diarrhea, blood creatinine increased, and hypoalbuminemia, which were mostly mild or moderate (table). TRAEs led to dose reduction in 71 patients (27.8%), treatment interruption in 90 patients (35.3%) and discontinuation in 27 patients (10.6%). The most common TRAE leading to treatment modification was peripheral edema (dose reduction in 36 patients [14.1%], treatment interruption in 41 patients [16.1%], and discontinuation in 9 patients [3.5%]). Serious TRAEs were reported for 31 patients (12.2%), of which the most common were pleural effusion (9 patients [3.5%]) and peripheral edema (6 patients [2.4%]). Two patients (0.8%) had TRAEs that led to death: one patient with dyspnea, and one patient with dyspnea and acute respiratory failure. Information on TRAEs in patient subgroups and time to onset, resolution and management of key AEs will be presented.
N Any grade, n (%) Grade ≥3, n (%) TRAEs 255 220 (86.3) 64 (25.1) Peripheral edema 255 138 (54.1) 19 (7.5) Nausea 255 51 (20.0) 1 (0.4) Diarrhea 255 50 (19.6) 1 (0.4) Blood creatinine increased 255 45 (17.6) 1 (0.4) Hypoalbuminemia 255 37 (14.5) 6 (2.4) TRAE, Treatment-related adverse event.
Conclusion
In the largest prospective study of patients with NSCLC and METex14 skipping to date, tepotinib was generally well tolerated. Peripheral edema, which is a class effect of MET inhibitors, was generally mild or moderate and considered manageable with tepotinib dose reduction or treatment interruption. Proactive monitoring for edema is recommended, with potential consideration of early or prophylactic conservative management measures (e.g. support stockings, limb elevation and increased physical activity).
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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: 2
- Moderators:
- Coordinates: 1/31/2021, 14:15 - 15:15, Scientific Program Auditorium
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MA11.04 - Updated Efficacy, Safety and Dosing Management of Poziotinib in Previously Treated EGFR and HER2 Exon 20 NSCLC Patients (ID 1630)
14:15 - 15:15 | Author(s): Xiuning Le
- Abstract
Introduction
Management of non-small cell lung cancer (NSCLC) with EGFR or HER2 exon 20 mutations is an unmet medical need. Poziotinib, a potent, irreversible, tyrosine kinase inhibitor (TKI) of EGFR and HER2 exon 20 mutations, is being studied in a multi-cohort, multicenter, Phase 2 study (ZENITH20). Here, we present updated efficacy results across subgroups of NSCLC patients with EGFR and HER2 exon 20 insertion mutations. Topline results for 2nd line EGFR and HER2 cohorts (ZENITH20-1 and -2) were presented previously.
Methods
Patients enrolled in ZENITH20 had EGFR or HER2 exon 20 insertion mutations per a CLIA certified (or equivalent) NGS test. Poziotinib (16 mg) was administered orally, once daily (QD), and dose interruptions/reductions were allowed for toxicity if needed. The endpoints were objective response rate (ORR), progression-free-survival, and duration of response (DOR) as evaluated by a central, independent image review committee using RECIST 1.1.
Results
In this ongoing study, 205 patients were enrolled in first 2 cohorts (115 2nd line EGFR and 90 2nd line HER2 respectively) and the enrollment is ongoing in the remaining cohorts. Patients had a median age of 61 years, 66% were females, 67% were non-smokers, and 13% had concurrent stable brain metastases at entry. Median number of prior therapies was 2 (range, 1 – 9). 94% of patients had prior chemo/platinum-based therapy; 65% immunotherapy, including checkpoint inhibitors; 28% monoclonal antibodies; 20% TKI therapy. The most common treatment-related Grade ≥3 AEs were rash (29%), diarrhea (26%), and mucosal inflammation (10%). The onset of most related AEs occurred in Cycle 1 resulting in 87% dose interruptions and 72% dose reductions. 14% had permanent drug discontinuation for related AEs.
ORRs in the As-Treated patients were 14.8%/27.8% in EGFR/HER2 with median DORs of 7.4 and 5.1 months, respectively. In the Evaluable patient population, ORRs were 18.3%/35.1% respectively. Consistent responses were seen in patients with multiple lines of prior therapy in both cohorts with ORRs of 15%, 16% in EGFR and 30%, 39% in HER2 for 2+, 3+ lines of therapy respectively. Similar responses were observed across various prior therapy types. Additional analysis of efficacy will be provided for mutation status and CNS activity in both cohorts.
Conclusion
Clinical activity was observed in previously treated patiens in both NSCLC EGFR or HER2 exon 20 mutations regardless of specific mutations and prior therapy with consistent responses seen in more heavily pre-treated patients. The safety data shows a manageable toxicity profile that is typical of 2nd generation TKIs. Additional cohorts are enrolling with alternative dose levels and BID dosing.
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MA11.05 - Tepotinib in Patients with MET exon 14 (METex14) Skipping Advanced NSCLC: Updated Efficacy Results from VISION Cohort A (ID 1361)
14:15 - 15:15 | Author(s): Xiuning Le
- Abstract
Introduction
In the Phase II VISION study (NCT02864992), tepotinib demonstrated durable efficacy and a tolerable safety in patients with NSCLC harboring METex14 skipping. Here, we report updated efficacy outcomes from a preplanned data cut-off (July 1, 2020) in patients with at least 9 months of follow-up, including detailed subgroup analyses of treatment-naïve and previously treated patients.
Methods
Patients with advanced, EGFR/ALK wild-type, METex14 skipping NSCLC received oral tepotinib 500 mg once daily. Patients enrolled in Cohort A with ≥9 months of follow-up were assessed for efficacy. All patients with METex14 skipping NSCLC who received tepotinib in Cohort A, or confirmatory Cohort C, were assessed for safety. Primary endpoint was objective response rate (ORR) by independent review committee (IRC) using RECIST 1.1. Secondary endpoints included ORR by investigator assessment, duration of response (DOR), and safety.
Results
As of July 1, 2020, 146 patients had ≥9 months of follow-up and were assessed for efficacy; 255 patients were evaluated for safety. In the efficacy population, patients had a median age of 73.4 years (range 41 to 94), 76 were male (52.1%), 76 had a smoking history (52.1%), and 81 had received prior treatment for advanced/metastatic disease (55.5%). 72 patients had received prior platinum-based chemotherapy for metastatic disease, either alone (n=63) or in combination with immunotherapy (n=9).
The overall ORR by IRC was 45.2% (95% confidence interval [CI]: 37.0, 53.6), with a median DOR of 11.1 months (95% CI: 8.4, 18.5). ORR by investigator assessment was 54.1% (95% CI: 45.7, 62.4), with a median DOR of 12.7 months (95% CI: 9.7, 18.3).
ORR by IRC was similar in patients who were treatment-naïve (44.6%; 95% CI: 32.3, 57.5) or previously treated for advanced/metastatic disease (45.7%; 95% CI: 34.6, 57.1), and in those who received prior-platinum based chemotherapy for metastatic disease (50.0%; 95% CI: 38.0, 62.0). ORR was also comparable in patients who received immunotherapy, regardless of the treatment regimen used (figure).
Grade ≥3 treatment-related adverse events (TRAEs) were reported in 25.1% of patients; 27 (10.6%) discontinued due to TRAEs. Peripheral edema was mostly low grade and rarely led to discontinuation (3.5%). The safety profile was similar across subgroups.
Conclusion
In VISION, the largest study in patients with NSCLC harboring METex14 skipping, treatment with tepotinib showed durable clinical activity that was consistent across clinically relevant subgroups. Tepotinib demonstrated a safety profile consisting of mostly mild-to-moderate AEs with few treatment discontinuations.
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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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MA13.07 - Structural Classification of Atypical EGFR Mutations Identifies 4 Major Subgroups with Distinct Patterns of Drug Sensitivity (ID 3760)
16:45 - 17:45 | Author(s): Xiuning Le
- Abstract
Introduction
While osimertinib has resulted in striking improvements in outcomes for patients with NSCLC harboring classical EGFR mutations (Ex19del, L858R, and/or T790M), patients with atypical EGFR mutations have shown heterogeneous and in some cases inferior responses to EGFR inhibitors. The frequency, structural and clinical implications of atypical EGFR mutations are less understood.
Methods
We characterized the mutational landscape (N=16,715 patients with EGFR mutations), in vitro sensitivity (N=70 Ba/F3 cell lines), and in silico structure of primary and co-occurring acquired EGFR mutations to determine functional groups. Clinical outcomes in patients with atypical EGFR mutations treated with EGFR TKIs were evaluated through a retrospective analysis from the MD Anderson GEMINI database and Moffitt Cancer Center.
Results
Among EGFR mutant NSCLC patients, 67% had classical mutations, 31% had atypical EGFR mutations, and 3% had a tertiary mutation including Ex19del/L858R with T790M plus an atypical mutation. Atypical mutations included exon 20 insertions (9%), other primary atypical mutations (13%), and complex mutations including an atypical mutation (9%). EGFR mutations could be separated into four distinct functional subgroups: 1) classical-like, 2) T790M-like including a subset of tertiary mutations, 3) exon 20 insertions, and 4) ATP-Binding Pocket Volume-Reducing (PVR) mutations. The classical-like were broadly sensitive to 1st, 2nd, and 3rd-generation inhibitors with a drug binding pocket similar to classical mutations. T790M-like mutations were sensitive to 3rd-generation EGFR inhibitors, but resistant to first- and second-generation inhibitors irrespective of co-occurring mutations. Tertiary mutations were generally resistant to EGFR inhibitors, but a drug repurposing screen identified select PKC and ALK inhibitors as having activity. The exon 20 insertion mutations, which cause significant reduction in drug binding pocket volume, were highly resistant to the majority of EGFR inhibitors but sensitive to novel exon 20 specific inhibitors. Lastly, we found a fourth group of mutations, ATP-Binding Pocket Volume Reducing (PVR) mutations that were associated with resistance to 1st- and 3rd-generation inhibitors, but selectively sensitive to quinazoline-based, 2nd-generation inhibitors such as afatinib and poziotinib preclinically. These mutations were primary located in the P-loop (exon 18), the c-terminal loop of the αc-helix (exon 20), and the A-loop (exon 21) of EGFR. Retrospective analysis of patients with PVR mutations revealed that patients had a significantly longer median progression free survival (mPFS) when treated with a 2nd-generation inhibitor (mPFS = 24mo) versus a 1st-generation (mPFS = 9.5mo, p = 0.013, HR = 4.2) or 3rd-generation inhibitor (mPFS = 6.4mo, p <0.0001, HR = 3.4). Three patients with NSCLC, who acquired PVR mutations after first-line osimertinib treatment had clinical benefit after receiving 2nd-generation EGFR inhibitors.
Conclusion
EGFR mutations can be separated into four distinct subgroups based on the structural changes caused by the mutation and differential sensitivity to EGFR inhibitors. The PVR subgroup, largely comprised of exon 18 or 20 point mutations, had greater relative sensitivity to 2nd-generation drugs with a quinazoline core than 3rd-generation drugs such as osimertinib in vitro, and improved outcomes in patients treated with these agents compared with osimertinib. These findings define subgroups of EGFR mutations that may better guide future treatment approaches for atypical EGFR mutations.
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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): Xiuning Le
- Abstract
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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P76.27 - ORCHARD: A Biomarker-Directed Phase 2 Platform Study in pts with Advanced EGFRm NSCLC Progressing on First-Line Osimertinib (ID 1397)
00:00 - 00:00 | Author(s): Xiuning Le
- Abstract
Introduction
Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in EGFRm advanced NSCLC, including central nervous system metastases. Most patients’ (pts) tumors develop resistance to osimertinib through secondary EGFR mutations (including C797S, G724S and L718V/Q) and off-target genomic alterations (including MET amplification and gene fusions). Data suggest that off-target alterations such as ALK and RET fusions may be resistance mechanisms to first-line osimertinib in some pts (each <5%). The ORCHARD study (NCT03944772) aims to better characterize resistance mechanisms to first-line osimertinib, and evaluate post-progression treatments. The flexible, platform-based design allows for new cohorts and treatment arms, for broader exploration of targeting resistance mechanisms. Previously presented: WCLC 2019 (Yu H, et al. J Thorac Oncol;14[10 suppl]:S647).
Methods
In this open-label, multicenter, multidrug, biomarker-directed Phase 2 platform-based study (Figure), adult pts with locally advanced/metastatic EGFRm NSCLC whose disease progressed on first-line osimertinib are eligible. Treatment is assigned per molecular characterization of a mandatory tissue biopsy from a progressing lesion, analyzed by next-generation sequencing (Foundation Medicine Inc.). The protocol has recently been amended: Group A now includes treatment arms for pts with ALK/RET rearrangements, who will receive osimertinib plus alectinib/selpercatinib, respectively. The ‘MET alterations’ arm has been expanded from MET-amplification to also include MET exon 14 skipping, and the ‘EGFR alterations’ arm has been expanded from EGFR-amplification to also include mutations at the EGFR L718/G724 residue, or insertion in EGFR exon 20. Group B encompasses pts with no identifiable resistance mechanism; Group C is observational, for pts whose tumors harbor resistance mechanisms not currently addressed within the study. Tumor assessments (RECIST 1.1) will be performed every 6 weeks for 24 weeks, and every 9 weeks thereafter until disease progression or treatment discontinuation. Interim analyses will be performed on the first 16 pts in each cohort who have had the opportunity for two post-baseline RECIST assessments; individual cohorts may be stopped (if there is <10% probability for objective response rate [ORR] to be above target value [45%, equaling ≤4 of the 16 pts with confirmed responses]), or expanded to 30–40 pts for further evaluation. Primary endpoint: confirmed ORR (investigator assessed); secondary endpoints include: progression-free survival, duration of response, overall survival, and pharmacokinetics. Safety will also be reported. A summary of the observed genomic landscape during enrolment will be presented.
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P76.62 - RAMOSE: An Open-Label Randomized Phase II Study of Osimertinib with or without Ramucirumab in TKI-Naïve EGFR-Mutant Metastatic NSCLC (ID 3246)
00:00 - 00:00 | Author(s): Xiuning Le
- Abstract
Introduction
The third-generation EGFR tyrosine kinase inhibitor osimertinib is currently used as a standard first-line therapy for patients with metastatic EGFR-mutant NSCLC. However, a majority of patients’ cancers will develop resistance to osimertinib in less than 2 years, with a median progression-free survival of approximately 19 months.
Preclinical models demonstrate upregulated VEGF signaling as a mechanism of acquired resistance to EGFR therapies, and improved efficacy when combining VEGF and EGFR inhibition. Ramucirumab, a monoclonal antibody targeting VEGF receptor 2, was recently approved by the US FDA in combination with erlotinib in patients with metastatic untreated EGFR-mutant NSCLC, based on a significant improvement in progression-free survival (PFS) with the combination seen in the RELAY trial.
A phase I study of osimertinib with ramucirumab (NCT02789345) demonstrated safety and feasibility of this combination. With this strong preclinical and clinical evidence, we are conducting a phase 2 trial to evaluate the osimertinib ramucirumab combination’s efficacy in treatment-naïve EGFR-mutant NSCLC.
Methods
RAMOSE (HCRN LUN-18-335; NCT03909334) is a randomized, open-label phase 2 study comparing osimertinib 80mg PO daily + ramucirumab 10 mg/kg IV q3 weeks (O + R) to osimertinib 80mg PO daily monotherapy (O) for initial treatment of metastatic EGFR-mutant NSCLC. Patients are randomized 2:1 to the O+R versus O groups, with stratification based on type of EGFR mutation and presence of CNS metastasis. The trial plans to enroll total of 150 patients, allocating 100 to O+R and 50 to O monotherapy. The primary endpoint is PFS. Secondary endpoints include ORR, OS and DCR, as well as safety/toxicity. Major inclusion criteria include patients with metastatic NSCLC harboring activating EGFR mutations (L858R or Exon 19 del). Major exclusion criteria include prior anti-EGFR or anti-VEGF treatments. Patients with stable CNS metastasis are allowed. We hypothesize an improvement of PFS from 18.9 months to 29.7 months, corresponding to a hazard ratio of 0.65.
The study is currently open at 9 sites in the USA, with additional sites planned. Hoosier Cancer Research Network is facilitating execution of the trial. Analysis by a study Data Safety Monitoring Board (DSMB) is performed annually. In addition, a planned interim analysis for efficacy will be performed after the first 75 subjects are enrolled.
Results
The trial opened to accrual in July 2019. As of July 02, 2020 (the data cutoff for planned DSMB analysis), 29 patients had been accrued. 25 of these patients were randomized (17 to O+R arm and 8 to O arm). Among the patients currently evaluable for toxicity (N=19), grade 3 or higher adverse events (AEs) were reported in 5/14 patients on O+R arm, versus 1/5 patients on O arm. In the O+R arm, grade 3 AEs included hypertension (n=1), pleural catheter infection (n=1), musculoskeletal pain (n=1), neutrophil count decreased (n=1), and dyspnea (n=1).
Conclusion
Early analysis from the RAMOSE trial shows no unexpected signals of toxicity with the combination of O+R. Enrollment for the trial is ongoing.
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P85 - Targeted Therapy - Clinically Focused - MET (ID 262)
- 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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P85.01 - Activity of Tepotinib in Brain Metastases (BM): Preclinical and Clinical Data in MET Exon 14 (METex14) Skipping NSCLC (ID 1785)
00:00 - 00:00 | Author(s): Xiuning Le
- Abstract
Introduction
Approximately 20% of METex14 skipping NSCLC cases involve brain lesions at diagnosis. Tepotinib is an oral, once-daily, highly selective MET inhibitor that has shown clinical activity in MET-driven tumors. We investigated the activity of tepotinib in preclinical models and patients with baseline BM in the Phase II VISION study.
Methods
Brain penetration was assessed in Wistar rats (n=3) at tepotinib dose 3.66 mg/kg/h intravenously by determining unbound brain (fu br) and plasma (fu pl) concentrations using liquid chromatography with tandem mass spectrometry.
Preclinical efficacy was assessed in two patient-derived xenografts (PDX) obtained from BM harboring high MET amplification (MET copy number gain: 11 for LU5349 and 24 for LU5406). NOD-SCID mice with PDX orthotopically implanted into the brain (n=10/group) were treated with tepotinib 125 mg/kg or vehicle control orally once daily. Intracranial tumor growth was monitored by gadolinium-based MRI.
Patients enrolled in VISION Cohort A with METex14 skipping NSCLC and asymptomatic BM (prior brain-specific therapy allowed) received tepotinib 500 mg once daily. Endpoints included systemic response per RECIST v1.1, duration of response (DOR), and progression-free survival (PFS) by independent review committee (IRC).
Results
The fraction of unbound tepotinib in rat brain tissue (fu br = 0.4%) was low compared with plasma (fu pl = 4%), indicating high binding in the brain. Upon treatment with tepotinib, both PDX tumors from MET-driven NSCLC BM regressed significantly in orthotopic brain models (mean tumor volume reduction of 63% for LU5406 and 84% for LU5349).
VISION Cohort A enrolled 22 patients with baseline BM (identified by IRC or investigator assessment), whose demographic characteristics were similar to the overall population (N=152).
As of July 1, 2020, 21 patients with baseline BM had ≥9 months’ follow-up and were included in efficacy analyses. Confirmed systemic best overall response was partial response in 11 patients for an ORR (95% confidence interval [CI]) of 52.4% (29.8, 74.3), which was comparable to that in overall population (table). Median DOR (95% CI) was 9.5 months (5.5, not estimable), and median PFS (95% CI) was 9.5 months (5.7, 11.2). Case studies illustrating response of brain lesions in VISION patients will also be presented.
Patients with baseline brain metastases (n=21) Overall (N=146)
Systemic objective response rate, % (95% CI)
52.4 (29.8, 74.3)
45.2 (37.0, 53.6)
Disease control rate, % (95% CI)
76.2 (52.8, 91.8)
69.9 (61.7, 77.2)
Best overall response, n (%) Complete response 0 0 Partial response 11 (52.4) 66 (45.2) Stable disease 5 (23.8) 36 (24.7)
Conclusion
Tepotinib administration resulted in regression of orthotopic BM in preclinical models. Patients in the VISION study with baseline BM had a comparable systemic response to that in the overall population. Tepotinib activity against BM will be further assessed by follow-up brain scans in the confirmatory VISION Cohort C.
