Virtual Library
Start Your Search
Jonathan Kurie
Author of
-
+
MA09 - EGFR & MET (ID 128)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Jordi Remon, Juergen Wolf
- Coordinates: 9/08/2019, 15:15 - 16:45, Melbourne (1991)
-
+
MA09.03 - Identification of Mechanisms of Acquired Resistance to Poziotinib in EGFR Exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2904)
15:15 - 16:45 | Author(s): Jonathan Kurie
- Abstract
- Presentation
Background
Insertions/mutations in exon 20 of EGFR occur in ~2% Insertions/mutations in exon 20 of EGFR occur in ~2% of all lung adenocarcinomas. These alterations are characterized by primary resistance to approved tyrosine kinase inhibitors (TKIs) with response rates of <12%. We have shown that exon 20 insertions restrict the size of the drug-binding pocket, limiting binding of large inhibitors. However, poziotinib can circumvent these steric changes and is a potent inhibitor of EGFR exon 20 mutants. In our investigator-initiated phase 2 trial of EGFR exon 20 mutant NSCLC, poziotinib was associated with a best objective response rate of 55% (Heymach et al, 19th WCLC). Herein, we use preclinical models and clinical samples from our phase 2 study to identify mechanisms of acquired poziotinib resistance (NCT03066206).
Method
EGFR exon 20 insertion (D770insNPG) genetically engineered mice (GEM) were treated with poziotinib until progression. Upon progression, tumor DNA and protein were analyzed using whole exome sequencing (WES) and reverse phase protein assay (RPPA). Mandatory and optional biopsies were obtained at baseline and progression, respectively, from patients treated in our phase 2 trial of poziotinib in EGFR exon 20 mutant NSCLC. Serial cfDNA was collected at baseline, 8 weeks of therapy, and on progression. Patient samples were analyzed using targeted next generation sequencing or WES.
Result
Poziotinib acquired-resistance GEM tumors acquired mutations in ErbB4, KRAS, and other genes which represent potential targetable bypass pathways. Resistant GEM tumors displayed increased activation of MAPK, AKT, ERK and MEK compared to sensitive tumors, suggesting that poziotinib acquired resistance is associated with reactivation of the MAPK/PI3K pathways. We enrolled 50 EGFR exon 20 mutant patients in our phase 2 trial. Analysis of matched pre-poziotinib and on-progression samples from 20 responding patients revealed acquired EGFR tyrosine kinase domain point mutations in 4 patients (T790M (2), V774A (1), D770A, (1)). Ba/F3 cells co-expressing EGFR exon 20 insertion (S768supSVD) and T790M were resistant to poziotinib, suggesting that T790M is a poziotinib resistance driver. Potential acquired EGFR-independent resistance mechanisms identified in patients to date include PIK3CA E545K (1), MAP2K2 S94L (1), MET amplification (1), EGFR amplification (2), and CDK6 amplification (2).
Conclusion
Parallel to acquired resistance mechanisms seen in classical EGFR mutation, acquired resistance to poziotinib can be mediated through EGFR-dependent mechanisms, notably T790M and other EGFR tyrosine kinase domain point mutations. EGFR-independent resistance mechanisms include activation of bypass pathways. Preclinical validation of resistance mechanisms and additional analysis of patient samples will be presented at the meeting.
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)
-
+
OA13.06 - Surgical Outcomes Following Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Non-Small Cell Lung Cancer - NEOSTAR Study (Now Available) (ID 2041)
11:30 - 13:00 | Author(s): Jonathan Kurie
- Abstract
- Presentation
Background
Surgical outcomes following neoadjuvant immune checkpoint inhibitors (ICIs) are limited. We report 90-day perioperative results of the NEOSTAR phase II trial of neoadjuvant nivolumab or nivolumab/ipilimumab in resectable non-small cell lung cancers (NSCLCs).
Method
44 pts with stage I-IIIA NSCLC (AJCC 7th) were randomized to nivolumab (3 mg/kg IV, days 1, 15, 29, n=23) or nivolumab/ipilimumab (1 mg/kg IV, day 1, n=21) with resection planned between 3-6 weeks after last dose. Surgical approach and extent of resection were at surgeons’ discretion.
Result
39 (89%) patients underwent R0 resection, of those 2 (5%) were resected off trial after additional induction chemotherapy (1 nivolumab, 1 nivolumab/ipilimumab). Among 37 patients, 21 underwent surgery following nivolumab and 16 following nivolumab/ipilimumab. Median age 66 (43-83) years, 24 (65%) male, 33 (89%) white, 22 (59%) adenocarcinoma, 22 (59%) stage I, 9 (24%) stage II, 6 (16%) stage IIIA.
5 (11%) were not resected, 1 (1/23, 4%) after nivolumab (stage II), 4 (4/21, 19%) after nivolumab/ipilimumab (1 stage I, 1 stage II, 2 stage IIIA). Reasons for unresectability were change in surgeon’s judgement (n=2), toxicity (n=1), progression (n=1), and declining pneumonectomy (n=1). Median time to surgery was 31 days (range 21-87). 8 (22%) operations were delayed beyond 42 days, 5 after nivolumab/ipilimumab (5/16, 31%) and 3 after nivolumab (3/21, 14%).
33 (89%) underwent lobectomy, 2 (5%) pneumonectomy, 1 (3%) segmentectomy and 1 (3%) wedge resection. 27 (73%) had thoracotomy, 7 (19%) thoracoscopy, 3 (8%) robotic approach. 2 (5%) were electively converted from thoracoscopy to thoracotomy. Median operative time was 147 minutes (71-315), median blood loss was 100cc (50-1000), and median length of stay was 4 days (1-18).
Perioperatively, pulmonary complications occurred in 8 (22%) patients: 8 (22%) prolonged air leak, 2 (5%) pneumonitis/pneumonias, 1 (3%) empyema, and 1 (3%) bronchopleural fistula (BPF). 1 (3%) died from complications of BPF and steroid therapy for pneumonitis. 4 (11%) developed atrial fibrillation, 1 (3%) diarrhea, 1 (3%) ileus, and 1 (3%) transient ischemic attack.
Surgeons subjectively judged 15/37 (40%) of operations to be more complex than usual with 7/37 (19%) lasting > 4 hours.
Conclusion
Following three cycles of neoadjuvant ICIs 89% of patients underwent complete R0 resection, including two patients who received additional induction chemotherapy off trial. Five marginally operable patients who didn’t proceed to resection, and one perioperative mortality highlight the importance of cautious patient selection for neoadjuvant ICIs in the management of operable NSCLC.
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.
