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Zofia Piotrowska
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MA16 - Novel Mechanisms for Molecular Profiling (ID 917)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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MA16.01 - Frequency and Genomic Context of Emerging Markers for Molecular Testing in Lung Adenocarcinoma in Cell-Free DNA NGS Analysis (ID 13465)
13:30 - 13:35 | Author(s): Zofia Piotrowska
- Abstract
- Presentation
Background
The recently updated CAP/IASLC/AMP lung cancer molecular testing guideline (Lindeman et al 2018) recommends several genes be analyzed by next-generation sequencing (NGS) in lung adenocarcinoma (LUAD), including EGFR, ALK, BRAF, KRAS, and others. It also includes a list of 20 emerging markers (EMs) for molecular testing and suggests practitioners remain aware of these and other genes between guideline updates. We investigated the frequency of genomic alterations (GAs) in several of these EMs in a cohort of patients with advanced lung adenocarcinoma who underwent clinical cell-free DNA (cfDNA) NGS analysis and assessed co-occurrence with canonical driver GAs.
a9ded1e5ce5d75814730bb4caaf49419 Method
Genomic data was reviewed from 6530 patients with at least one GA detected on clinical Guardant360 cfDNA NGS testing (Guardant Health, Inc) with an indicated diagnosis of lung adenocarcinoma from 11/25/16-3/1/18. Synonymous alterations were excluded from further analyses.
4c3880bb027f159e801041b1021e88e8 Result
2600 patients (40%) had at least one nonsynonymous alteration in the EM genes assessed; excluding GAs classified as variants of unknown significance (VUS), 1350 patients (21%) had at least one characterized alteration. Table 1 shows number and frequency of GAs observed per patient by gene and alteration type. Of EMs assessed, GAs were observed most commonly in NF1, PIK3CA, PDGFRA, KIT, and FGFR1-2. GAs in multiple EMs, including RIT1, NRAS, FGFR2-3, NTRK1, KIT, and AKT1, were observed co-occurring with established driver alterations, often in a genomic context consistent with resistance to targeted therapy at allelic fractions suggestive of subclonality.
8eea62084ca7e541d918e823422bd82e Conclusion
Effective therapies are continually emerging for a growing number of molecular biomarkers in lung cancer. Comprehensive genomic profiling with cfDNA NGS can identify GAs in both recommended and EM genes to guide therapeutic decision-making and catalyze clinical trial enrollment. Further investigation of mutual exclusivity and co-occurrence of established drivers and EMs may reveal novel resistance mechanisms and facilitate identification of rational combination therapeutic strategies.
6f8b794f3246b0c1e1780bb4d4d5dc53Only 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.
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MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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MA26.03 - Activity of Osimertinib and the Selective RET Inhibitor BLU-667 in an EGFR-Mutant Patient with Acquired RET Rearrangement (ID 14731)
13:40 - 13:45 | Presenting Author(s): Zofia Piotrowska
- Abstract
- Presentation
Background
The spectrum of acquired resistance (AR) to osimertinib is not yet fully characterized. We present a single-center cohort of osimertinib AR biopsies and results of a patient with RET-mediated AR treated with the investigational RET-specific TKI BLU-667 and osimertinib.
a9ded1e5ce5d75814730bb4caaf49419 Method
We assayed tissue via SNaPshot or Foundation One next-generation sequencing (NGS) and plasma via Guardant360 NGS under an IRB-approved protocol. In vitro studies assessed implications of RET fusions in EGFR-mutant cancers. We treated one patient with osimertinib/BLU-667 using an IRB and FDA-approved compassionate use protocol.
4c3880bb027f159e801041b1021e88e8 Result
41 EGFR-mutant patients with AR to osimertinib were assessed histologically and queried by tissue NGS (n=22), plasma NGS (n=9) or both (n=10). Key AR findings: SCLC transformation (2/32 tissue); EGFR C797S (5/32 tissue, 5/19 plasma, all cis with T790M); MET amplification (7/32 tissue, 3/19 plasma); BRAF rearrangement (2/32 tissue) and CCDC6-RET rearrangement (1/32 tissue, 1/19 plasma [distinct case]).
CCDC6-RET was expressed in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells, which maintained MAPK signaling and conferred resistance to osimertinib and afatinib. Inhibition of RET by BLU-667 or cabozantinib resensitized cells expressing CCDC6-RET to EGFR inhibition.
A 60-year-old woman with EGFR del19 progressed on afatinib (T790M+), then osimertinib. Tissue biopsy at osimertinib AR showed acquired CCDC6-RET (T790-wt). She began osimertinib 80mg/BLU-667 200mg daily x2 weeks, then BLU-667 was increased to 300mg daily. Her dyspnea improved within days of initiation. Scans after 8 weeks revealed a marked response with RECIST tumor shrinkage of 78% (Figure). She experienced only grade 1 toxicities of fatigue, leukopenia, hypertension, dry mouth, and elevated transaminases.
8eea62084ca7e541d918e823422bd82e Conclusion
RET rearrangements are rare but recurrent in EGFR-mutant patients with AR to osimertinib. In vivo models suggest they mediate AR and this patient provides proof-of-concept that combination EGFR+RET inhibition with osimertinib/BLU-667 is a well-tolerated and effective regimen for RET-mediated AR. Further study is ongoing.
6f8b794f3246b0c1e1780bb4d4d5dc53Only 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.
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OA10 - Right Patient, Right Target & Right Drug - Novel Treatments and Research Partnerships (ID 910)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 106
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OA10.03 - Discussant - OA 10.01, OA 10.02 (ID 14564)
10:50 - 11:05 | Presenting Author(s): Zofia Piotrowska
- 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.
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-80 - ELIOS: A Multicenter, Open-Label, Molecular Profiling Study of Patients with EGFRm and NSCLC Treated with Osimertinib (ID 13198)
16:45 - 18:00 | Presenting Author(s): Zofia Piotrowska
- Abstract
Background
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard-of-care for locally advanced/metastatic non-small cell lung cancer (NSCLC) harbouring EGFR sensitizing mutations (EGFRm). Osimertinib, a third-generation, CNS-active EGFR-TKI potently and selectively inhibits both L858R and exon19del sensitizing EGFRm and T790M mutations, is now approved for first-line treatment of EGFRm-NSCLC. Studies of osimertinib resistance have focused on patients previously treated with first-/second-generation EGFR-TKIs; however, resistance mechanisms to first-line osimertinib are not well-described.
a9ded1e5ce5d75814730bb4caaf49419 Method
ELIOS (NCT03239340) is a phase 2, open-label, single-arm study designed to prospectively characterize the molecular profile of patients who progress on first-line osimertinib. The study will enroll patients (n=100) with locally advanced/metastatic non-squamous EGFRm-NSCLC nonamenable to curative surgery/chemoradiation, WHO performance status 0-1, and life expectancy ≥12 weeks. Patients must have EGFRm known to be associated with EGFR-TKI sensitivity, must be EGFR-TKI treatment-naïve, and be eligible to receive first-line osimertinib therapy. Patients with clinically significant toxicities, history of interstitial lung disease, and EGFR exon 20 insertion will be excluded. All patients will receive 80 mg osimertinib orally once daily and will continue treatment beyond progression if they show continued clinical benefit. Mandatory tumor biopsies will be obtained prior to treatment initiation and following investigator-assessed disease progression. An optional biopsy may be obtained following 2-3 weeks of treatment. Longitudinal plasma samples will be collected for plasma-derived circulating tumor DNA (ctDNA) analysis. Tumor- and plasma-derived specimens will be analyzed by next-generation sequencing; additional exploratory analyses are also planned. The primary endpoint is the proportion of patients with a given genetic/proteomic marker at disease progression (investigator-assessed, RECIST v1.1). Relevant genetic and proteomic markers will be selected based on the profile comparison at disease progression to baseline. Relevant markers of resistance to first-line osimertinib may include, but are not limited to, EGFR resistance mutations (including C797S) and cMET/HER2 amplification; this analysis may reveal other, potentially novel, resistance mechanisms. Secondary endpoints include progression-free survival, objective response rate, duration of response, disease control rate, assessment of osimertinib efficacy post-progression using time to treatment discontinuation, and time to first subsequent therapy. Efficacy analyses based on predefined subgroups (according to the patient molecular profiles) including presence of baseline T790M mutation, EGFR Ex19del or L858R mutations, and EGFR Ex19del or L858R detectable in ctDNA, will be assessed. Safety will also be assessed. Primary analysis will be performed when ≥50 patients have paired biopsies upon progression. Recruitment is in process (May 1, 2018).
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
6f8b794f3246b0c1e1780bb4d4d5dc53
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-44 - Safety, PK, and Preliminary Antitumor Activity of the Oral EGFR/HER2 Exon 20 Inhibitor TAK-788 in NSCLC (ID 12373)
16:45 - 18:00 | Author(s): Zofia Piotrowska
- Abstract
Background
TAK-788 (AP32788) is an investigational tyrosine kinase inhibitor (TKI) with potent, selective preclinical activity against activating EGFR and HER2 mutations, including exon 20 insertions. We report early results of a phase 1/2 first-in-human, open-label, multicenter study of TAK-788 (NCT02716116).
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with advanced non-small cell lung cancer (NSCLC) refractory to standard therapy received daily oral doses (5–120 mg) of TAK-788 in the ongoing dose-escalation phase (3+3 design). Preliminary antitumor activity (by RECIST v1.1), safety, and PK are reported for patients who received ≥1 dose.
4c3880bb027f159e801041b1021e88e8 Result
As of 8-Sep-2017, 34 patients (median age, 60 y; female, 65%; ≥2 prior anticancer therapies, 88%; Table) were treated with TAK-788; 10 remain on treatment at data cutoff. AUC0‑24,ss increased in a dose-proportional manner over the dose range evaluated; the effective t1/2 was ~16 (range 6–28) h. The most common treatment-emergent AEs (TEAEs; ≥20%) were diarrhea (47%), nausea (26%), and fatigue (21%). Grade ≥3 TEAEs in ≥2 patients (excluding disease progression) were dyspnea (n=3, 9%) and anemia, asthenia, dehydration, lung infection, pleural effusion, pneumonia, and pneumonitis (n=2 each, 6%). Two DLTs, both pneumonitis, were reported (80 mg, grade 3; 120 mg, grade 5). Of 14 evaluable patients, 3 had PR (80 mg, n=2, both confirmed; 120 mg, single PR awaiting confirmation), 6 had SD (40 mg, n=3; 80 mg, n=2; 120 mg, n=1), and 5 had PD as best response (40 mg, n=3; 80 mg, n=1; 120 mg, n=1). All patients with PR had EGFR exon 20 insertions.
8eea62084ca7e541d918e823422bd82e Conclusion
TAK-788 exhibits antitumor activity in patients with EGFR exon 20 insertions with an AE profile consistent with other EGFR TKIs. Phase 2 will begin after determination of the RP2D, with 4 molecularly defined cohorts in NSCLC. Updated data will be presented, including the recommended phase 2 dose (RP2D).
Baseline Characteristics 5 mg
(n=4)10 mg
(n=5)20 mg
(n=5)40 mg
(n=6)80 mg
(n=7)120 mg
(n=7)Total
(n=34)Mutation type,a %
Common EGFR mutations (exon 19 deletion / L8585R) 25 20 0 0 0 0 6 EGFR-T790M+ 0 0 0 0 14 0 3 EGFR exon 20 insertion 50 40 60 83 71 57 62 HER2 0 20 40 17 14 29 21 a One patient (20 mg) had both EGFR and HER2 mutations; 1 patient (80 mg) had EGFR exon 20 insertion + T790M.
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