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D.B. Costa
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.02 - Cytology and Surgical Pathology Specimens are Comparable Testing Substrates for PD-L1 Immunohistochemistry in Lung Cancer (ID 9063)
15:50 - 15:55 | Author(s): D.B. Costa
- Abstract
- Presentation
Background:
Immunohistochemical (IHC) testing for programmed death ligand 1 (PD-L1) expression by non-small cell lung cancer (NSCLC) specimens has become standard of care to help select immune checkpoint inhibitor therapy. The companion IHC assay for pembrolizumab has been validated and approved for use on surgical pathology specimens; however, the performance of this assay when applied to cytology specimens is not well characterized.
Method:
Following IRB approval, all NSCLC cytology or surgical pathology specimens obtained from 11/2015 to 5/2017 at our institution that were tested for PD-L1 expression by a commercial vendor (Integrated Oncology/LabCorp, NY) using the FDA-approved companion diagnostic PD-L1 clone 22C3 pharmDx kit on the Dako Automated Link 48 platform (Dako, Carpenteria, CA) were identified. Patient cohorts where testing was performed on diagnostic cytology vs. surgical pathology specimens were compared. Tumor PD-L1 expression was stratified by clinically relevant groups: <1%, 1-49%, and ≥50%. Tumor genotyping results for EGFR, KRAS, ALK, and ROS1 were also collected.
Result:
Cytology formalin-fixed paraffin-embedded (FFPE) cell blocks included endobronchial ultrasound transbronchial needle aspirates (57%), pleural/pericardial fluids (28%), fine needle aspirates (13%), and bronchial washings/lavages (2%). Surgical FFPE specimens included small core/incisional biopsies (60%), bronchial biopsies (12%), and large resections (28%). PD-L1 testing was successful for over 96% (223/232) of specimens (Table). Overall, EGFR mutations were more frequent with no/low PD-L1 expression, ALK rearrangements with high PD-L1 expression, but no relationship between KRAS mutations and PD-L1 expression.PD-L1 Tumor Proportion Score Stratified by Specimen Type
Chi-squared value=2.95, p>0.39 (not significant); TPS=tumor proportion scoreCytology Cell Block Surgical Pathology <1% PD-L1 TPS 35 (37.2%) 52 (37.7%) 1-49% PD-L1 TPS 20 (21.3%) 35 (25.4%) ≥50% PD-L1 TPS 33 (35.1%) 48 (34.8%) Failed Analysis 6 (6.4%) 3 (2.2%) Total 94 (100%) 138 (100%)
Conclusion:
For NSCLC, no statistically significant differences in PD-L1 expression patterns were observed between cytology cell block and surgical pathology specimens, implying that in clinical practice any adequate cytology cell block or surgical pathology specimen could be utilized for testing. Importantly, analysis of clinical outcomes with use of first line pembrolizumab based on cytology vs surgical pathology specimen PD-L1 ≥50% expression is currently ongoing.
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.06 - Using Population Dynamics Mathematical Modeling to Optimize an Intermittent Dosing Regimen for Osimertinib in EGFR-Mutant NSCLC (ID 9110)
11:35 - 11:40 | Author(s): D.B. Costa
- Abstract
- Presentation
Background:
Acquired resistance to therapy occurs with both first- and newer-generation epidermal growth factor receptor (EGFR) inhibitors. One strategy to delay the emergence of resistance is to use the most active/least toxic inhibitor and replace the traditional daily dosing with a biologically-rational dosing approach. Osimertinib is a covalent mutation-specific EGFR tyrosine kinase inhibitor (TKI) with activity against common EGFR plus EGFR-T790M mutations and less activity against the wild-type receptor. This drug is poised to become a 1[st] line EGFR TKI for treatment-naïve EGFR mutated lung adenocarcinomas. Therefore, it is an ideal candidate to devise rationale dosing schemes to maximize its efficacy and minimize tumor adaptation.
Method:
We explored pulse dosing of osimertinib, to delay the emergence of acquired resistance. We applied population dynamics mathematical modeling to this question, using key parameters (“birth rate” and “death rate”), established through cellular assays. These parameters are presumed to be dose-dependent. First, we experimentally determined the “birth-rates” of PC9 lung cancer cells, PC9 cells bearing the T790M resistance mutation, and PC9 cells that were resistant to osimertinib, with increasing concentrations of osimertinib (0 - 10μM, total of eight doses at half log intervals) using cell viability assays (MTS assay). Next, we determined cellular “death-rates” using annexin V/propidium iodide (PI) fluorescence-activated cell sorting (FACS). We then applied those parameters to our population dynamics model and simulated various treatment conditions with different dosing strategies, to identify the most effective regimens at delaying or preventing the emergence of resistance to osimertinib.
Result:
Using our mathematical model, we predicted that high-dose weekly treatment of osimertinib with a low maintenance dose led to minimal cell proliferation in comparison to daily dosing. Following this in silico prediction of the superiority of pulse dose treatment, we experimentally compared the frequency of emergence of resistance with different treatment dosing regimens, using a long-term cell culture system. Indeed, weekly administration of 5uM osimertinib to PC9 cells, followed by a maintenance dose of 0.25uM, suppressed the emergence of resistance for up to 5-7 weeks in culture.
Conclusion:
We have established a population dynamics mathematical model to predict optimal dosing regimens for osimertinib in treatment-naïve EGFR mutated lung cancers. The model was experimentally validated using a long-term culture system. Future validation in additional preclinical models (cell lines, xenografts and genetically engineered mice) can lead to rationale development of pulse-maintenance clinical trials of osimertinib and eventually establish a novel paradigm for clinical use of EGFR TKIs.
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.02 - Final Results of a Phase 2 Study of the hsp90 Inhibitor Luminespib (AUY922) in NSCLC Patients Harboring EGFR Exon 20 Insertions (ID 10182)
11:10 - 11:20 | Author(s): D.B. Costa
- Abstract
- Presentation
Background:
EGFR exon 20 insertions (ins20) comprise 4-10% of EGFR mutations in NSCLC and are refractory to 1[st]/2[nd] generation EGFR TKIs. No effective targeted therapies exist for patients with EGFR ins20. EGFR is a client protein of the molecular chaperone Heat Shock Protein 90 (hsp90). Here, we present the final results of a phase II investigator-initiated trial to assess the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20 (NCT01854034).
Method:
Between 8/2013 and 10/2016, the study enrolled 29 patients with stage IV NSCLC, EGFR ins20 identified on local testing, ECOG PS 0-2, at least one prior line of therapy and no untreated brain metastases. The study was closed on 2/28/17 when the available drug supply was exhausted. Luminespib was given at 70mg/m2 IV weekly. Response was assessed by RECIST 1.1 every 6 weeks; treatment beyond progression was allowed. Dose interruptions and dose reductions were allowed as needed for toxicity management. Primary endpoint was ORR with a target disease control rate (DCR; PR/CR plus SD lasting > 3 mos) of > 20%. Secondary endpoints were PFS, OS, safety and response by EGFR ins20 subtype.
Result:
29 patients (18 female/11 male, median age 60 (range, 31-79)) were enrolled. Median number of prior therapies = 1 (range, 1-5.) 4/29 achieved PR and 1 CR (ORR 5/29; 17%). 15 patients had SD and 9 had PD as their best response. mPFS was 2.9 mos (95% CI, 1.4-5.6,) mOS was 13 mos (95% CI, 4.9-19.5.) DCR was 11/29 (38%). Among 19 patients with baseline PS 0-1 and < 2 prior therapies, ORR = 21% and mPFS = 5.1 mos (95% CI, 2.1-11.8.) The most common luminespib-related toxicities were visual changes (22/29; 76%) diarrhea (21/29; 72%) and fatigue (13/29; 45%). Treatment-related grade 3 toxicities included ocular toxicity (1/29; 3%), hypertension (3/29; 10%) and hypophosphatemia (1/29; 3%). All study treatment was stopped on 2/28/17 due to lack of drug availability; 3 patients were on treatment without progression at study termination.
Conclusion:
The study met its primary endpoint and suggests that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other Hsp90 inhibitors in this population is warranted, as are novel systems to continue drug supply for benefitting patients when availability of experimental compounds is limited.
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