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John Heymach
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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): John Heymach
- 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 | Author(s): John Heymach
- 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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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): John Heymach
- 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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OA07 - Immuno-biology and Novel Immunotherapeutics from Bench to Bed (ID 228)
- Event: WCLC 2020
- Type: Oral
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 10:30 - 11:30, Scientific Program Auditorium
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OA07.08 - HUDSON: An Open-Label, Multi-Drug, Biomarker-Directed, Phase II Platform Study in Patients with NSCLC, who Progressed on Anti-PD(L)1 Therapy (ID 3535)
10:30 - 11:30 | Author(s): John Heymach
- Abstract
- Presentation
Introduction
The HUDSON Platform trial (NCT03334617) is a multi-arm clinical trial for patients with non-small cell lung cancer (NSCLC) who had tumour progression on anti-PD(L)1 immunotherapy and received prior platinum-doublet chemotherapy. The study design allows efficacy, safety, and tolerability assessment of multiple tailored durvalumab based combinations. Novel treatment options for this population can be explored based on efficacy signals. Here we present initial results in Modules 1, 2, 3 and 5 and current status in Modules 6 and 7.
Methods
Patients are enrolled into cohorts defined according to a biomarker matched profile (Part A) or non-matched (Part B). Acquired resistance (ACQ) was defined as progression after >24 weeks of prior immunotherapy and primary resistance (PRI) defined as progression ≤24 weeks from onset of prior immunotherapy. Patients received durvalumab in combination with: olaparib (PARPi; Module 1), danvatirsen (STAT3i; Module 2), ceralasertib (ATRi; Module 3), oleclumab (anti-CD73 antibody; Module 5), trastuzumab deruxtecan (HER2 ADC; Module 6), and cediranib (VEGFRi; Module 7). A composite endpoint of overall response rate (ORR), progression-free survival (PFS; 6, 9 and 12 months) and overall survival (OS; 6, 9 and 12 months) was used to decide whether or not to expand the initial module size from 20 patients to 40. Safety, a secondary endpoint, was continuously monitored.
Results
Enrolment started in December 2017. As of 25th July 2020, 261 patients have been enrolled from 31 study sites in 6 countries. Enrolment into Modules 1, 2, and 5 is complete, ongoing in Modules 3, 6, and 7, and Module 4 was discontinued with one patient enrolled, when development of vistusertib was stopped. As of Q1 2020, efficacy (ORR), PFS and OS) results were available as per Table 1. Further efficacy updates for Modules 1, 2, 3 and 5 are scheduled in Q3 2020. The safety profile of combination therapy in each module was in line with the safety profile of the individual compounds.
Table 1. Enrolment and efficacy outcomes to date per patient cohort
Cohort
Enrolment status
Number
enrolled6-month OS (%)
6-month PFS (%)
ORR
(%)Median total
treatment duration (months)
Part A – Biomarker matched
LKB1 (+olaparib)
Complete
21
55.8
10.7
4.8
1.84
HRR (+olaparib)
Complete
21
57.1
21.8
4.8
3.68
ATM (+ceralasertib)
Ongoing
18
100
61.2
13.3
4.14
CD73 (+oleclumab)
Complete
23
79.9
8.3
0
2.79
HER2 (+trastuzumab deruxtecan)
Ongoing
1
–
–
–
–
Part B – Biomarker non-matched
PARPi – ACQ
(+olaparib)Complete
23
77.4
26.1
4.3
4.70
PARPi – PRI (+olaparib)
Complete
22
59.1
15.1
0
3.35
STAT3i – ACQ
(+danvatirsen)
Complete
22
75.2
38.5
0
3.15
STAT3i – PRI (+danvatirsen)
Complete
23
50.2
5.1
0
1.91
ATRi – ACQ (+ceralasertib)
Complete
24
77.3
37.0
8.7
6.44
ATRi – PRI (+ceralasertib)
Complete
20
74.8
53.8
11.1
2.78
CD73 Ab – ACQ
(+oleclumab)Complete
25
64.4
26.1
0
2.73
CD73 Ab – PRI (+oleclumab)
Complete
9
NC
NC
0
1.53
VEGFi – ACQ
(+cediranib)Ongoing
9
–
–
–
NA
Please note: OS, PFS and ORR are currently available for patients enrolled by January 2020. Number enrolled reflects the total enrolled by 25th July 2020.
Conclusion
Preliminary efficacy signals were observed with ATRi, which may be more pronounced in ATM selected patients. The subgroup of LKB1 selected patients appear to have the lowest 6-month OS and PFS of subgroups in Module 1 (durvalumab + olaparib). An update is scheduled for Q3 2020.
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P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)
- Event: WCLC 2020
- Type: Posters
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P01.21 - ANSELMA: Antiangiogenic Second Line Lung Cancer Meta-Analysis on Individual Patient Data in Non-Small Cell Lung Cancer, Again Relevant in ICI Era (ID 721)
00:00 - 00:00 | Author(s): John Heymach
- Abstract
Introduction
There is renewed interest in the efficacy of 2nd line treatments (2LT) with anti-angiogenics (AA), now that immunotherapy plus chemotherapy (CT) is one of the standard options in 1st line treatment of advanced non-small cell lung cancer (NSCLC). Antibodies (mAb) against VEGF, VEGFR2, or AA tyrosine kinase inhibitors (TKI) have inconsistently shown benefit in combination with CT or erlotinib (E). We performed an individual patient data (IPD) meta-analysis to validate efficacy of these combinations as 2LT.
Methods
Randomized trials of AA plus standard 2LT (CT or TKI) compared to 2LT alone that ended accrual before 2015 were identified from publication databases, abstract proceedings and trial registers. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, primary endpoint), progression-free survival (PFS) and subgroup analyses. Peto method was used to estimate survival benefit.
Results
IPD were available for 15 out of 17 eligible trials (only via remote access for 9 trials). Out of 8,502 patients (pts) enrolled, 35% were female and 64% had adenocarcinoma. At 3 years, 10.5% were alive. Addition of AA significantly prolonged OS (HR=0.93 [95% confidence interval (CI): 0.89-0.98], p=0.005) and PFS (0.80 [0.77-0.84], p<0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.9% [95% CI: -0.3%;+4.1%] and +3.6% [+2.0%;+5.2%] respectively. According to the 3 types of combinations (mAb AA + CT, TKI AA + CT, AA + E), there was no significant interaction for OS. Interaction was significant for PFS (p=0.004): HR=0.78 [0.72-0.85], 0.86 [0.80-0.91] and 0.70 [0.63-0.77] respectively. There was a significant reduction of AA benefit on OS when age increased: 0.86 [0.75-0.99], 0.89 [0.81-0.97], 0.94 [0.87-1.02] and 1.04 [0.93-1.17] for pts <50, 50-59, 60-69 and ≥70 respectively (interaction p=0.009). Effect of AA was independent of sex (p=0.98) and performance status (0, ≥1; p=0.78) and ethnicity (Asian, non-Asian, p=0.38). Subgroup results were similar for PFS.
Conclusion
In the 2LT of advanced NSCLC, adding AA modestly but significantly prolongs OS and PFS. This appears independent of type of AA drugs, but the observed benefit may be higher in younger pts.
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P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P14.26 - Diminished Efficacy of PD-(L)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma is Impacted by KRAS Mutation Status (ID 2343)
00:00 - 00:00 | Author(s): John Heymach
- Abstract
Introduction
STK11 and KEAP1 mutations (STK11m and KEAP1m) are commonly mutated in lung adenocarcinoma (LUAD). STK11m have been associated with resistance to immune checkpoint inhibition (ICI) in KRAS-mutant (KRASm) LUAD. However, whether STK11m status also impacts clinical outcomes to ICI in KRAS wild-type (wt) LUAD is unknown. Whether KEAP1m impact outcomes to ICI in KRASm and KRASwt LUAD is also unknown.
Methods
We analyzed clinical outcomes of patients (pts) with LUAD treated with ICI according to KRAS and STK11 and KEAP1 mutation status in two independent cohorts (Cohort 1 [DFCI/MGH] and Cohort 2 [MSKCC/MDACC]). TCGA and xCell data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 co-mutation status.
Results
Of 1261 pts with advanced LUAD treated with ICI, 42.5% had a KRASm, 20.6% and 19.2% had pathogenic STK11 and KEAP1 mutations, respectively. Co-occurring mutations in KRAS/STK11, KRAS/KEAP1, and STK11/KEAP1 were found in 10.9%, 8.4%, and 9.4% of cases, respectively. In both Cohort 1 and Cohort 2, STK11 and KEAP1 mutations were associated with significantly worse clinical outcomes to ICI among KRASm cases, but not among KRASwt cases (Table 1). The presence of an STK11 and KEAP1 mutation in KRASm NSCLCs was confirmed to be independent predictors of shorter PFS (STK11: HR 1.51, P=0.006; KEAP1: HR 2.01, P<0.01) and shorter OS (STK11: HR 1.81, P <0.001; KEAP1: HR 2.41, P<0.0001) in multivariable analysis in the combined cohort (Cohort 1 + Cohort 2). Gene ontology analysis from TCGA revealed that among KRASm but not KRASwt LUAD, STK11m was associated with the downregulation of MHC class II-related genes, including CD74 (P<0.01), HLA-DOA (P<0.01), HLA-DRB5 (P=0.03), HLA-DRB1 (P=0.03), and HLA-DMB (P<0.01). KEAP1m was associated with a significant downregulation of positive regulators of type I interferon and inflammatory cytokine production, such as STING (P<0.001), DDX58 (P<0.01), TLR4 (P<0.01), and TLR7 (P<0.01) among KRASm but not KRASwt LUAD. Cell subset transcriptome analysis showed that STK11m was associated with a significantly lower proportions of M1 macrophages among KRASm but not KRASwt LUAD (P<0.01). KEAP1m was associated with a significantly lower proportions of CD8+ T cells (P<0.001) and B cells (P<0.01) among KRASm but not KRASwt LUADs.
Conclusion
The deleterious impact of STK11 and/or KEAP1 mutations on ICI efficacy in patients with advanced LUAD differs according to KRAS mutation status. KRAS/STK11 and KRAS/KEAP1 co-mutations identify subsets of lung cancers with distinct therapeutic outcomes and immune profiles.
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P16 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Translational) (ID 155)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P16.07 - Immuno-Modulatory Effects of Ceralasertib in Combination with Durvalumab in NSCLC with Progression on Anti-PD(L)1 Treatment (HUDSON) (ID 3491)
00:00 - 00:00 | Author(s): John Heymach
- Abstract
Introduction
The HUDSON platform trial (NCT03334617) is a multi-arm clinical trial for patients with non-small cell lung cancer (NSCLC) who had tumour progression on anti-PD(L)1 immunotherapy and received prior platinum-doublet chemotherapy. We report preliminary translational data, where available, from patients treated with ceralasertib (an ataxia telangiectasia and Rad3-related protein inhibitor, ATRi) and the PDL1 inhibitor durvalumab.
Methods
The study protocol included analyses of archival and fresh tumour biopsies, and longitudinal liquid biopsies. Patients were enrolled into biomarker matched (ATM-selected) or unmatched arms after the development of primary or acquired resistance to PD-(L)1 immunotherapy. Primary and acquired resistance were defined as progression before or after 6 months on anti-PD(L)1 therapy respectively. Biomarker status was determined using next generation sequencing (Foundation Medicine) for ATM mutation status or immunohistochemistry (IHC, Ventana) for ATM protein expression. Gene expression from whole blood samples (PAXgene®) was analysed using the PanCancer IO gene panel from Nanostring Technologies.
Results
Translational data are currently only available from a subset of patients. Clinical response data will be presented separately. Tumour and liquid biopsy samples were collected from patients treated with ceralasertib and durvalumab. Gene expression data were available from 8 ATM biomarker-positive and 17 biomarker-negative patients. Peripheral gene expression analyses in responding patients showed greater than two-fold higher granzyme levels at baseline, when compared with non-responders. The 19 patients with controlled disease on ceralasertib (partial response or stable disease by RECIST v1.1) and available gene expression data also showed a two-fold reduction in peripheral IL-8 gene expression in paired blood samples when compared with the six patients showing progressive disease with available gene expression data. Samples collected during a ceralasertib-only period prior to durvalumab treatment showed modified biomarkers of peripheral immunity including significant increases in antigen presentation gene signature and significant decreases in both exhausted T cell and NK cell signatures from bulk whole-blood RNA samples. Ceralasertib also decreased 4 macrophage gene expression signatures in on-treatment samples. Similar gene expression profiles were not observed from comparable samples on other HUDSON arms. No correlation between ATM biomarker status and RECIST response was observed. No significant correlations with ceralasertib response were observed between tumour mutation burden or PDL1 status by IHC.
Conclusion
Taken together, these data support a role of immune activation by ceralasertib as a feature of response to combination therapy with ceralasertib plus durvalumab in NSCLC following progression on anti-PD(L)1.
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P71 - Tumor Biology and Systems Biology - Basic and Translational Science - RTK/VEGF (ID 212)
- 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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P71.02 - Estrogen Promotes Resistance to Bevacizumab Treatment in Non-Small Cell Lung Cancer (NSCLC) Xenograft Models (ID 3682)
00:00 - 00:00 | Author(s): John Heymach
- Abstract
Introduction
Lung cancer is the leading cause of cancer-related deaths with over 130,000 deaths estimated in 2020 alone, and while the rate of lung cancer mortality in the United States has declined among men, it has remained stable in females. In clinical studies, anti-angiogenic therapy (bevacizumab) combined with chemotherapy preferentially benefited male NSCLC (non-small cell lung cancer) patients compared to females, suggesting that estrogen may contribute to lung cancer progression and resistance to anti-angiogenic therapy.
Methods
Using NSCLC xenograft models, we investigated the impact of estrogen on tumor growth, angiogenesis, and response to bevacizumab. We generated A549 and HCC827 xenograft NSCLC mouse models by subcutaneous injection of these cells into female ovariectomized nude mice with or without estrogen (estradiol 17-β) treatment delivered via continuous release (approximately 80 pg/ml). Animals were randomized to receive vehicle or bevacizumab (10 mg/kg). Tumors were collected after treatment and immunostained to determine pericyte coverage (CD31 and desmin) and myeloid infiltration (CD11b+). Serum levels of angiogenic factors were measured by multiplex bead assay.
Results
As expected, non-estrogen treated mice showed a reduction of tumor growth with bevacizumab (A549, p = 0.0005, HCC827, p = 0.02) and the efficacy of bevacizumab was diminished when both models were treated with estrogen. We show that estrogen increased pericyte coverage in the tumor vascular network and elevated serum levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGFBB), critical regulators of tumor angiogenesis. In addition to an enhanced maturation of tumor-associated blood vessels, we observed that estrogen induced the recruitment of tumor-infiltrating myeloid cells mediated by increased secretion of granulocyte colony-stimulating factor (G-CSF) and chemokine ligand 1 (CXCL1). Blockade of estrogen receptor signaling using fulvestrant re-sensitized tumors to VEGF targeting as evidenced by reduced tumor vasculature and an increase in overall survival in NSCLC xenograft models.
Conclusion
Taken together, our preclinical data indicate that estrogen receptor signaling indeed promotes resistance to anti-angiogenic agents and that inhibition of this pathway can enhance the efficacy of VEGF blockade. These data have important clinical implications for female NSCLC patients and support the future clinical testing of estrogen receptor blockade in combination with anti-angiogenic regimens.
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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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P76.62 - 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): John Heymach
- 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.
