Virtual Library
Start Your Search
Paul A Bunn, Jr
Author of
-
+
ES18 - Acquired Resistance to TKIs: The Rebiopsy Case and the Future Options (ID 21)
- Event: WCLC 2019
- Type: Educational Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Teresa Moran, Matteo Giaj Levra
- Coordinates: 9/09/2019, 11:00 - 12:30, Vienna (2016)
-
+
ES18.03 - New Strategies to Overcome Resistance in EGFR Mutated NSCLC (Now Available) (ID 3254)
11:00 - 12:30 | Presenting Author(s): Paul A Bunn, Jr
- Abstract
- Presentation
Abstract
New Strategies to Overcome Resistance in EGFR Mutated NSCLC
Activating EGFR mutations occur in 15-50% of lung adenocarcinomas with a higher frequency in never or light smokers and individuals of East Asian origin. First and second generation EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, erlotinib, afatinib and dacomitinib are associated with high response rates (50-75% and median progression free survival rates of 9-14 months. Failure in the CNS is frequent because these agents have poor CNS penetration and the most frequent cause of systemic failure is the development of T790M resistance mutations. Other reported mechanisms of resistance to first and second generation EGFR TKIs include small cell transformation, AXL overexpression, HER2 mutation and overexpression, Wnt pathway overexpression and other less common alterations. Standard platinum doublet chemotherapy is generally used for those with small cell transformation and these cases usually have Rb loss and p53 mutation. The addition of cetuximab to first or second generation EGFR TKIs did not appear to improve outcomes.
Osimertinib is a third generation EGFR TKI whose advantages include high sensitivity to both activating EGFR mutations and T790M mutations with lesser sensitivity to wild type EGFR. Osimertinib also crosses the blood brain barrier. A randomized phase III trial, AURA3, demonstrated that osimertinib was superior to chemotherapy and was associated with decreased CNS relapse in the second line setting after failure on a first generation EGFR TKI due to T790M.
These data with second line osimertinib led to a first line phase III randomized trial, FLAURA, comparing osimertinib to either gefitinib or erlotinib. Osimertinib was associated with a significantly longer PFS, a significantly longer time to CNS progression, a significantly longer duration of response and a longer overall survival that had not reached significance at most recent analysis. Patterns of resistance to first line osimertinib are only emerging now but include alterations that have specific targeted therapy such as MET amplification (15%), BRAF mutations (3%), HER2 amplification (1%), ALK fusions (1%), PI3K mutations (3%), KRAS mutations (2%), C797s or other resistance mutations (2%), SCLC transformation (5%), CDK and cell cycle alterations (2-5%). Because these have specific non-chemotherapy treatment options, NGS testing should be done on blood ctDNA and if negative on tissue at the time of progression.
For those without these actionable alterations, chemotherapy is the next standard therapy although combinations of chemotherapy with checkpoint inhibitors with or without anti-VEGF agents is under investigation due to a positive subset analysis of the IMPOWER 150 trial. The addition of checkpoint inhibitors to first line TKIs has proven to have increased toxicity with low activity.
Another way to delay or prevent resistance is to use combinations in the first line therapy. Combinations of EGFR TKIs with anti-VEGF therapies, with anti-MET therapies, with anti-EGFR antibodies, and with chemotherapy are in progress. Initial trials combining erlotinib with bevacizumab demonstrated improved PFS but not OS. Current trials are combining newer EGFR TKIs such as osimertinib with anti-VEGF antibodies such as bevacizumab or ramicirumab are in progress. Trials using anti-VEGFR TKIs are also in progress. Preclinical studies indicated that combining anti-EGFR antibodies such as cetuximab or necitumumab with EGFR TKIs could overcome some resistance led to other ongoing clinical trials combining these agents. Amplification of MET is a common mechanism of resistance to EGFR TKIs, so the combination of MET TKIs with EGFR TKIs is rational and trials are ongoing. Understanding the mechanisms by which EGFR mutant cells can persist in the presence of initial EGFR TKIs remains a priority for future investigation.
The adjuvant use of EGFR TKIs after surgical resection of early stage NSCLC patients with EGFR mutations has clearly established superiority in recurrence free survival but not in overall survival. It appears that there is insufficient cell kill to lead to an increase in the cure rate but additional survival based adjuvant trials such as ”ALCHEMIST” are ongoing.
Neoadjuvant studies could provide downstaging because the response rates are high. It is not clear whether this would be more likely to provide an increase in cure rates compared to adjuvant use of these agents. These neoadjuvant trials are providing surgical samples to explore mechanisms by which cells persist after EGFR TKI therapy. This incredibly important information could lead to rational combinations that could increase pCR rates in early stage patients and improved outcomes in advanced stage patients.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Christine Lee Hann, Makoto Nishio
- Coordinates: 9/08/2019, 13:30 - 15:00, Hilton Head (1978)
-
+
OA03.03 - Initial Efficacy and Safety Results of Irinotecan Liposome Injection (nal-IRI) in Patients with Small Cell Lung Cancer (Now Available) (ID 1985)
13:30 - 15:00 | Author(s): Paul A Bunn, Jr
- Abstract
- Presentation
Background
SCLC accounts for ~15% of lung cancers, with 5-year survival <10%. 50-90% of patients with extensive disease respond to initial treatment; many rapidly relapse due to acquired resistance to front-line platinum-based chemotherapy. Limited treatment options are available for second-line patients. nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), utilizing intraliposomal stabilization technology to enable high drug load and in-vivo stability.
Method
RESILIENT (NCT03088813) is a two-part Phase 2/3 study assessing the safety, tolerability, and efficacy of monotherapy nal-IRI in SCLC patients who progressed on/after a front-line platinum regimen: Part 1 includes dose-finding then dose-expansion. Key eligibility criteria included ECOG PS 0-1 and adequate organ function, with prior exposure to immunotherapy allowed. Eligible patients received nal-IRI 70mg/m2 or 85mg/m2 (free-base equivalent) q2w. Primary endpoints were safety and tolerability. Efficacy assessments included objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), and overall survival (OS).
Result
30 patients were treated for >12 weeks in Part 1 (male, 43%; median age, 60.4y; platinum-resistant, 40%) with tumor assessments q6w. During dose-finding, 5 patients received nal-IRI 85mg/m2 (deemed not tolerable: dose-limiting toxicity) and 12 patients received nal-IRI 70mg/m2 (deemed tolerable: selected for dose expansion). At data cut-off** (median follow-up, 4.4mo), 25 patients had received nal-IRI 70mg/m2. Diarrhea was the most common gastrointestinal adverse events (AEs) (Gr3, 20%). Hematologic AEs included neutropenia (Gr3, 8%; Gr4, 8%), anemia (Gr3, 8%), febrile neutropenia (Gr3, 4%), thrombocytopenia (Gr3, 4%; Gr4, 4%). Preliminary efficacy identified 11 patients with partial responses (ORR 44%), BOR (PR+SD) of 72%, and 12-week disease control rate (DCR12wks PR+SD) of 48%. PFS and OS are not yet mature.
Conclusion
Part 1 demonstrated encouraging anti-tumor activity for nal-IRI 70mg/m2 in patients with SCLC (ORR: 44%, BOR: 72%). nal-IRI 70mg/m2 was generally well tolerated. Future research is warranted to assess nal-IRI in second-line SCLC.
Table 1. Baseline Demographic, Patient Disposition, Safety & Tolerability, and Clinical Efficacy for Part 1 of the RESILIENT studyDose-Finding /
Dose-Exploration PhaseIrinotecan
Liposome
Injection
85mg/m2
(N=5)Irinotecan
Liposome
Injection
70mg/m2
(N=25)Baseline Characteristics Gender, Male, n (%) 3 (60.0) 10 (40.0) Age (Years, median) 62.0 59.0 Baseline ECOG 0 1 (20.0) 3 (12.0) 1 4 (80.0) 22 (88.0) Time Since Most Recent Progression (Weeks, median) 3.4 3.2 Disease Location, n (%) Locally Advanced 0 2 (8.0) Metastatic 5 (100.0) 23 (92.0) Disposition, n (%) Patient Completed Study 4 (80.0) 12 (48.0) Patient Currently Ongoing* – 7 (28.0) Deaths 2 (40.0) 6 (24.0) Disease Related 1 3 Adverse Event Not Related to Study Drug 1 1 Cardiac Arrest 1 - Hepatic Failure - 1 Adverse Event Related to Study Drug 0 2 Abdominal Sepsis - 2 Patient Discontinued Treatment 5 (100.0) 18 (72.0) Safety & Tolerability, n (%) Any Treatment-Emergent Adverse Event (TEAE) 5 (100.0) 25 (100.0) Grade 3 or Higher TEAE (≥ 2 patients) 5 (100.0) 15 (60.0) Neutropenia 1 (20.0) 4 (16.0) Anemia – 2 (8.0) Thrombocytopenia – 2 (8.0) Diarrhea 3 (60.0) 5 (20.0) Asthenia – 2 (8.0) General Physical Health Deterioration – 2 (8.0) Pneumonia 2 (40.0) 1 (4.0) Abdominal Sepsis – 2 (8.0) Hypokalemia 1 (20.0) 2 (8.0) Renal Failure – 2 (8.0) Best Overall Response Complete Response (CR) – – Partial Response (PR) 2 (40.0) 11 (44.0) Stable Disease 1 (20.0) 7 (28.0) Progressive Disease 1 (20.0) 5 (20.0) Non-evaluable 1 (20.0) 2 (8.0) Objective Response Rate CR + PR 2 (40.0) 11 (44.0) Non-responder 3 (60.0) 14 (56.0) ** Data Cut-off: May 8, 2019. * Per RECIST v1.1 or RANO criteria. Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)
- Event: WCLC 2019
- Type: Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Tomasz Grodzki, Kenji Suzuki
- Coordinates: 9/10/2019, 11:30 - 13:00, Toronto (1985)
-
+
OA13.07 - Neoadjuvant Atezolizumab in Resectable NSCLC Patients: Immunophenotyping Results from the Interim Analysis of the Multicenter Trial LCMC3 (Now Available) (ID 1755)
11:30 - 13:00 | Author(s): Paul A Bunn, Jr
- Abstract
- Presentation
Background
The immune mechanisms dictating response and resistance to PD-(L)1 blockade are not well understood in early stage non-small cell lung cancer (NSCLC). Understanding these mechanisms will be key to improve outcomes and identify the next generation of predictive biomarkers of response to these therapies. Here, we present updated immunophenotyping at time of interim analysis of LCMC3, a multicenter trial of neoadjuvant atezolizumab in resectable NSCLC (NCT02927301).
Method
Patients received 2 cycles of atezolizumab before resection. Tumor, LN biopsies and PB were obtained pre-atezolizumab and at surgery. Paired PB, screening and surgical LN were analyzed using IMMUNOME flow cytometry. Plasma-based cytokine arrays were performed on a subset of patients. Immunophenotypic analyses were correlated with treatment effect, major pathologic response (MPR, primary endpoint) and preoperative treatment-related adverse events (preop-TRAE).
Result
We report on 55 patients with paired PB samples (analyzed within 72h after collection) and completed surgery. We observed preop-TRAE in 32/55 patients (18 grade 1, 13 grade 2, 1 grade 3). CD1c+ and CD141+ myeloid cells (MC) were lower at baseline in patients developing preop-TRAEs, while monocytic M-MDSCs were higher in those patients. Senescent T cells decreased in patients with preop-TRAE and increased in patients with non-preop-TRAE. After treatment, the absolute cell counts of late activated CD4+and CD8+T cells decreased in patients achieving MPR. LN IMMUNOME data, cytokine data and 12-month follow-up (DFS, OS) will be reported.
Conclusion
Preliminary immunophenotyping data from the interim analysis showed significantly lower baseline immunosuppressive cell subsets in patients with preop-TRAE and decreased late activated CD4+and CD8+T cells from PB in patients with MPR.These results, together with additional LN IMMUNOME and cytokine analyses, may improve our understanding of immunophenotypic features associated with outcome, and changes induced by neoadjuvant atezolizumab in early stage NSCLC patients.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
-
+
P1.01-87 - Acquired Resistance Mechanisms and Clinical Outcomes for Patients with Epidermal Growth Factor Receptor (EGFR) Positive Non-Small Cell Lung Cancer (NSCLC) Treated with Osimertinib (Now Available) (ID 2960)
09:45 - 18:00 | Author(s): Paul A Bunn, Jr
- Abstract
Background
Osimertinib is a 3rd generation TKI approved for stage IV EGFR+ NSCLC in the first line or post-progression with T790M. The spectrum of osimertinib resistance mutations and clinical outcomes post-osimertinib progression are not well described.
Method
Single-center retrospective review of patients with stage IV EGFR+ NSCLC treated with osimertinib was conducted. Resistance mutations were determined via tissue biopsy or circulating tumor DNA (Guardant) prior to and at time of progression on osimertinib. PFS was calculated using Kaplan-Meier method. PFS1 is start of osimertinib to radiographic progression. PFS2 is start of next therapy after osimertinib to next radiographic progression.
Result
We identified 95 patients with stage IV EGFR+ lung adenocarcinoma treated with osimertinib detected via NGS (56/95), real-time PCR (29/95), Sanger sequencing (8/95), and other techniques (2/95). Most patients were female (63/95) and never smokers (72/95). Osimertinib resistance and post-progression patterns are shown in Table 1. Potentially targetable mutations were found in 55% (26/47) samples and 14% (6/47) samples had oncogenes targetable with available TKIs. TP53 mutations prior to osimertinib did not significantly influence PFS (36 weeks vs 39 weeks; p = 0.13). MET amplification was only seen in the setting of undetectable T790M or in patients who received first line osimertinib. Median PFS1 for 1st line EGFR TKI (n=17), 2nd line EGFR TKI (n=41), 3rd or greater line EGFR TKI (n=29) was 36, 45 and 39 weeks respectively (p=0.268) with median follow up of 59, 81, and 64 weeks. 10 patients received locally ablative radiotherapy for oligoprogressive disease (defined as ≤ 3 progressive sites) and continued osimertinib post-progression with median PFS2 of 49 weeks.
Conclusion
There is utility to repeat biopsy after progression on osimertinib as targetable oncogenes can be found. Presence of TP53 prior to starting osimertinib did not influence PFS1. Continuing osimertinib and adding radiotherapy for oligoprogressive disease does increase post-progression PFS.
-
+
P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.03-06 - Detection of ctDNA and Correlation with Tumor Mutation Testing in Early Stage NSCLC (ID 2950)
10:15 - 18:15 | Author(s): Paul A Bunn, Jr
- Abstract
Background
In advanced disease, circulating tumor (ctDNA) has proven a viable alternative to tissue based molecular testing to identify patients with lung adenocarcinoma (LUAD) eligible for targeted therapies. ctDNA is under investigation for utility in early cancer detection and non-invasive companion diagnostics to allow for identification of targetable biomarkers in patients who may benefit from neoadjuvant targeted therapy. However, in the early stage cancer setting, ctDNA has been limited by reliance on interrogation of genomic alterations alone resulting in low detection rates (13% stage I, 22% stage II, 40% stage III, Abbosh et al, Nature 2017). Herein, we test the ability of the novel ctDNA-based assay to detect ctDNA in patients with early stage LUAD, and secondarily, to identify targetable oncogenes in these patients.
Method
Eligible patients had stage IA-IIIA LUAD deemed surgically resectable. Following consent, plasma samples were collected prior to surgery or neoadjuvant therapy. Circulating free DNA (cfDNA) was analyzed for ctDNA with the LUNAR assay (Guardant Health), which utilizes an integrated genomic and epigenomic ctDNA assessment at a tumor allelic fraction down to 0.01% to report “ctDNA detected” or “ctDNA not detected”. This single blood sample cfDNA assay utilizes a variant filter to distinguish tumor from non-tumor derived cfDNA alterations in the absence of other genomic DNA (e.g. tissue sequencing or peripheral blood mononuclear cells). Molecular analysis of paired FFPE primary tumor specimens was performed using the Illumina TruSight Tumor 26 or ArcherDx VariantPlex Solid Tumor library preparation kits followed by next-generation sequencing (NGS) on the Illumina platform in a CLIA-certified laboratory. Sensitivity for tumor driver mutation detection is evaluated by comparing tumor drivers identified in ctDNA with those identified in corresponding paired primary tumor specimens.
Result
We enrolled 31 patients with early stage LUAD who ultimately underwent surgical resection, 29 of whom completed LUNAR testing (19 with stage I, 4 with stage II and 6 with stage IIIA). Analysis of tumor tissue identified a driver mutation in 83% (24/29) of cases (KRAS=11, EGFR=10, MET=3, ALK=1). A genomic cancer-associated mutation was identified in 16%, 25% and 67% in stage I, II, and III, respectively. The LUNAR assay demonstrated 100% specificity for EGFR and KRAS mutations. The incorporation of the epigenomic classifier enhanced pre-operative ctDNA detection to 26% of Stage I, 50% of stage II, and 67% of stage III patients.
Conclusion
The majority of patients with early stage LUAD had an identifiable oncogene alteration, consistent with data from advanced disease. Utilizing a plasma only, integrated genomic and epigenomic ctDNA assay demonstrated improved performance over tumor informed approaches. The ctDNA detection rate increased with disease stage, consistent with increased tumor burden. With 100% tissue concordance of EGFR and KRAS alterations identified in ctDNA, ctDNA may prove an option for not only identification of early stage LUAD, but also identifying biomarker positive LUAD eligible for clinical trials utilizing targeted therapy in the neoadjuvant setting.
-
+
P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.04-88 - Surgical Outcomes of a Multicenter Phase II Trial of Neoadjuvant Atezolizumab in Resectable Stages IB-IIIB NSCLC: Update on LCMC3 Clinical Trial (ID 1817)
10:15 - 18:15 | Author(s): Paul A Bunn, Jr
- Abstract
Background
The role of immune checkpoint inhibitors in resectable NSCLC remains undefined. We report the updated safety results of the first multicenter trial assessing neoadjuvant atezolizumab (a PD-L1 inhibitor) for resectable NSCLC.
Method
Eligible patients with clinical stage IB-IIIB resectable NSCLC received 2 cycles of neoadjuvant atezolizumab (1200 mg, days 1, 22) followed by surgical resection (day 40±10). Pre- and post-treatment PET/CT, pulmonary function tests (PFT), and bio-specimens were obtained. Adverse events (AE) were recorded according to CTCAEv.4.0. Preoperative treatment-related TRAE (preop-TRAE) and postoperative TRAE (postop-TRAE) defined as AE onset on, or after date of surgery, were analyzed.
Result
Follow-up data to post-surgery visit were analyzed for 101 patients out of planned 180: mean age: 64.6 years; male: 47/101(46.5%); current smokers: 23/101(22.8%); non-squamous histology: 66/101(65.3%); and clinical stages IB(10.9%), IIA(15.8%), IIB(27.7%), IIIA(38.6%), and IIIB(6.9%). Two cycles of atezolizumab were not completed in 5/101(5.0%) patients due to grade 1 or 2 AEs. Surgery was not performed in 11/101(10.9%) patients: 5 demonstrated disease progression, and 6 for ‘other’ reasons. 6/101(5.9%) patients were deemed unresectable. Surgery was delayed (outside of 10-day window) in 10/90(11.1%) patients by an average of 11(1-39) days. Two of these delays were due to TRAEs (hypothyroidism and pneumonitis), 3 were patient-elected delays, 2 were surgeon-related, and 3 for ‘other’ reasons. Intraoperative vascular complications occurred in 2/90(2.2%) and extensive hilar fibrosis was noted in 20/90(22.2%) patients. Overall, there was insignificant mean change in the PFTs pre- vs. post-atezolizumab therapy. Only 3/101(3.0%) patients had treatment-related dyspnea, dyspnea on exertion, or pneumonitis.
Table 1
ConclusionTreatment Related Adverse Events
(TRAE)
Preoperative TRAE
(N = 101)
Postoperative TRAE
(N = 90)
All AEs
Any grade
55 (54.5%)
20 (22.2%)
Grade 1
29 (28.7%)
7 (7.8%)
Grade 2
24 (23.8%)
9 (10.0%)
Grade 3
2 (2.0%)
4 (4.4%)
Grade 4
0
0
Grade 5
0
0
Specific AEs
Dyspnea
1 (1.0%; grade 2)
3 (3.3%; grade 1)
Dyspnea on exertion
1 (1.0%; grade 1)
0
Myalgia
4 (4.0%; grade 1 or 2)
0
Hyperthyroidism
3 (3.0%; grade 1 or 2)
1 (1.1%; grade 1)
Hypothyroidism
0
1 (1.1%; grade 2)
Pneumonitis
1 (1.0%; grade 3)
3 (3.3%; grade 2 or 3)
Transaminitis (AST or ALT)
8 (7.9%; grade 1 or 2)
3 (3.3%; grade 1 or 2)
Post-atezolizumab Change in Pulmonary Function Tests
PFT factor
Mean change (95% Confidence Interval)
FEV1 (N = 72)
-0.6% (-2.6% to 1.3%)
FVC (N = 72)
0.0% (-1.8% to 1.8%)
DCLO (N = 64)
-1.2% (-4.1% to 1.7%)
Treatment with neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with minimal delay to surgery, and few treatment associated AEs. This trial continues to accrue and assess MPR, survival, and other long-term endpoints.
-
+
PR01 - Press Conference (ID 92)
- Event: WCLC 2019
- Type: Press Conference
- Track:
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/07/2019, 16:00 - 17:30, CC7.1 A&B
-
+
PR01.03 - 20th WCLC Highlights (Now Available) (ID 3601)
16:00 - 17:30 | Presenting Author(s): Paul A Bunn, Jr
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
S02 - Symposium Honoring Dr. Gazdar's Legacy (Sign Up Required) (ID 97)
- Event: WCLC 2019
- Type: Symposium
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:Fred R. Hirsch, Tetsuya Mitsudomi, Ignacio Wistuba
- Coordinates: 9/07/2019, 17:30 - 19:00, Tokyo (1982)
-
+
S02.03 - The Impact of Cell Line Development in Lung Cancer Research (Now Available) (ID 3653)
17:30 - 19:00 | Presenting Author(s): Paul A Bunn, Jr
- Abstract
- Presentation
Abstract
Advances in Lung Cancer Research using patient derived cell lines and xenografts
In the 1970s there were few lung cancer preclinical models and therapy selection was generally empiric. When the NCI established a branch to specifically study lung cancer (the NCI-VA Medical Oncology Branch) a systematic effort to establish permanent lung cancer cell lines with orthotopic implantation into athymic mice was implemented. The branch was led by Dr. John Minna and the cell line efforts were led by Dr. Adi Gazdar. The cell lines were given sequential numbers starting from NCI-H1 indicating the NCI origin and that they were human cell lines. Figure 1 shows how often these lines have been use in publications on lung cancer.
These lines were initially used to study various chemotherapy agents and combinations such as the etoposide/cisplatin in small cell lung cancer (SCLC) xenografts. The expression of multiple proteins such as CD56 and many neuropeptides distinguished these SCLC cell lines from NSCLC cell lines. Originally it was recognized that most SCLC cell lines grew as floating aggregates but that s minority grew attached to the plastic. These later cell lines were termed “variant” lines were as the floaters were called “classic”. Essentially all of the lines had p53 mutations and loss of Rb. More recent studies indicated that the classic lines highly expressed neuroendocrine features. The variant lines more often had amplified myc. a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1); neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). These high NE SCLC cell lines and tumors also expressed NKX2-1, the entire range of NE markers, and lacked expression of the neuronal and NE repressor REST. The low NE subtype had undergone epithelial mesenchymal transition (EMT) and had activated the Notch, Hippo and TGFβ pathways and MYC oncogene. Recent studies found that 16% of human SCLC tumors and 10% of SCLC cell lines were of the low NE subtype, as well as cell lines from the GEM model. Synaptophysin was a more commonly expressed marker for variant SCLC cell lines, which rarely showed Dopa decarboxylase activity.
These cell lines and patient samples were also used to describe the expression of N-Myc and L-Myc in small cell lung cancers. Reports demonstrated that 6 of 31 independently derived human small-cell lung cancer (SCLC) cell lines had 5- to 170-fold amplified N-myc gene sequences. A third myc-related gene (L-myc) cloned from SCLC DNA with homology to a small region of both the c-myc and N-myc genes. SCLC cell lines may prove useful in defining patients most likely to benefit from immunotherapy. For example, human SCLC cells, in contrast to other lung cancer types, are characterized by greatly reduced transcription of HLA-A,B,C and beta 2m genes, which suggests the existence of a mechanism for evading the host immune response to the tumor and of an E1a-like product in this type of tumor cell. Cell lines with myc amplification were shown to be especially sensitive to aurora kinase inhibitors.
The human lung cancer cell lines were also used to define many of the genetic, proteomic and transcription features of lung adenocarcinomas, squamous carcinomas and large cell carcinomas. Early studies demonstrated a significant correlation between EGFR gene copy number, EGFR gene mutations, and gefitinib sensitivity. EGFR protein was necessary but not sufficient for predicting sensitivity. Gefitinib-sensitive lines showed a G(1) cell cycle arrest and inactivation of downstream signaling proteins; resistant cell lines had no changes. The in vivo effects mirrored the in vitro effects.
Cell lines have also been used to study EGFR exon 20 mutations and HER2 mutations. HER2(YVMA) mutations were shown to activate cellular substrates more potently than HER2(WT); and that lung cancer cells expressing this mutation remain sensitive to HER2-targeted therapies but insensitive to EGFR TKIs. HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR exon 20 insertions.HER2 exon 20 insertions were shown to be sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib.
EGFR-mediated bypass signaling has been reported after ALK and ROS1 blockade as well as RET and NTRK1 blockade. EGFR signaling provided a critical adaptive survival mechanism that allows cancer cells to evade oncogene-specific inhibitors, providing a rationale to co-target
The RAS-MAPK dependence was shown to be a hallmark of EML4-ALK lung adenocarcinoma and provided a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.
Dr. Gazdar and colleagues also developed a method to reproducibly generate continuously replicating human bronchial epithelial cell (HBEC) lines that provide a novel resource to study the molecular pathogenesis of lung cancer and the differentiation of bronchial epithelial cells.
In summary, human lung cancer cell lines have contributed greatly to the development of novel biomarkers and therapies for lung cancer and much of the work stemmed from early development by Dr. Gazdar and his team at the NCI.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
