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Yasir Elamin
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MA03 - Clinomics and Genomics (ID 119)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Heather A Wakelee, Wilfried Ernst Erich Eberhardt
- Coordinates: 9/08/2019, 10:30 - 12:00, Colorado Springs (1994)
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MA03.05 - BRAF Mutations Are Associated with Increased Benefit from PD1/PDL1 Blockade Compared with Other Oncogenic Drivers in Non-Small Cell Lung Cancer (Now Available) (ID 1472)
10:30 - 12:00 | Author(s): Yasir Elamin
- Abstract
- Presentation
Background
PD-1/PD-L1 immune checkpoint blockade (ICB) has revolutionized the treatment of non-small cell lung cancer (NSCLC), but only a minority of patients achieve durable clinical benefit. Although classic EGFR/ALK alterations are correlated with ICB resistance, it is unknown if patients with other molecular subtypes of NSCLC also derive poorer outcomes from ICB. We investigated if there are oncogene-driven NSCLC associated with higher response rates (RR) and progression-free survival (PFS) to ICB.
Method
Two independent retrospective cohorts of oncogene-driven NSCLC treated with ICB monotherapy were analyzed for clinical outcome: MD Anderson (MDACC) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-CGDB). PD-L1 expression (Dako 22C3 - FoundationCore) and tumor mutational burden (TMB - FoundationCore; TCGA and MSK-IMPACT – cbioportal.org) were compared across distinct molecular subtypes of NSCLC to determine differences in clinical outcome.
Result
Among five oncogene defined groups from the MDACC cohort, BRAF-mutant NSCLC had the highest response rate (RR) (RECIST 1.1) (P<0.01) and PFS (P<0.01) when treated with ICB (Table). These differences remained significant after adjusting for PD-L1 expression. Classic EGFR and HER-2 mutant NSCLC had the lowest RR and PFS (Table). Similar results were observed in the independent FH-CGDB cohort where BRAF-mutant NSCLC had longer real-world (rw) PFS and OS to ICB monotherapy (Table). PD-L1 expression (tumor score ≥1% and ≥50%) and TMB were higher in BRAF-mutant NSCLC compared to EGFR and HER-2 (P<0.01). BRAF V600E NSCLC had lower TMB compared to non-V600E (5.9 vs 13.7 mut/Mb, P<0.01), but both had high PD-L1 expression (≥1%: 72% vs 61%; ≥50%: 42% vs 32%).
ConclusionKRAS
BRAF
Classic EGFR
EGFR exon 20
HER2
MDACC cohort
Patients – N
87
10 (V600E 3 / non-V600E 7)
28
25
15
RR – %
24.3
62.5
4.5b
10b
8.3
Median PFS – mo (95% CI)
2.76
(2.23-3.30)
7.37 (not estimable)a
1.78 (1.18-2.37)
2.73 (1.71-3.75)
1.88 (1.63-2.12)
FH-CGDB
Patients – N
503
68 (V600E 32 / non-V600E 36)
52
42
25
Median rwPFS -
mo (95% CI)
3.55
(3.15-4.24)
6.0
(2.89-11.6)
2.17b
(1.77-2.63)
2.66b
(2.23-5.13)
1.87b (1.31-4.34)
Median rwOS – mo (95% CI)
10.28
(8.51-12.02)
16.07
(8.64-NA)
5.29b
(3.25-17.68)
9.89b
(3.68-20.86)
10.81
(4.17-NA)
FoundationCore cohort – N
NA
188 (V600E 74 / non-V600E 114)
386
96
57
TMB – mean (mut/Mb)
NA
10.6a
3.7
3.8
5.8
PD-L1 TPS ≥ 50% (%)
NA
36a
19
23
16
a: P<0.01 vs all groups; b: P<0.05 for pairwise comparison vs BRAF.
NSCLCs with BRAF mutations are associated with increased benefit from ICB when compared to tumors harboring other targetable oncogenic drivers. Oncogene driver mutations are associated with distinct patterns of TMB and PD-L1 expression. These findings highlight the importance of developing mutation-specific clinical trials in NSCLC.
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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)
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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): Yasir Elamin
- 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.
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MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Frank Griesinger, Lecia Sequist
- Coordinates: 9/09/2019, 14:00 - 15:30, Hilton Head (1978)
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MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)
14:00 - 15:30 | Author(s): Yasir Elamin
- Abstract
- Presentation
Background
Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.
Method
620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.
Result
Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.
Conclusion
In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.
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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)
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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): Yasir Elamin
- 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.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-98 - Outcomes in Advanced NSCLC Patients Treated with 1st Line EGFR-TKI Based on Mutation Detection from Tissue or cfDNA-Based Genomic Sequencing (ID 1861)
09:45 - 18:00 | Author(s): Yasir Elamin
- Abstract
Background
Tumor genomic information from tissue has been the standard of practice for identifying actionable molecular alterations. The same genomic profiling is also widely available by a non-invasive blood test (cfDNA). We hypothesized that treatment naïve patients with advanced non-small cell lung cancer (NSCLC) and actionable oncogenic driver mutations identified by tumor and cfDNA would have similar clinical outcomes after treatment with targeted therapies.
Method
Patients with any EGFR-TKI sensitive mutation and received FDA-approved EGFR-TKI as first line therapy for their advanced NSCLC were included in this retrospective analysis. Consecutive patients were identified from our GEMINI database with therapy initiated that was based solely from either the tissue or cfDNA report were divided into each cohort, respectively. Assessment of PFS was from date of therapy initiation until disease progression. Tissue genomic profiling was performed on our institution’s CLIA-certified hotspot NGS assay covering 40-50 genes. For blood based genomic profiling, blood was sent for NGS of cfDNA with a panel of up to 70 cancer-related genes at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA). Kaplan–Meier methodology was used to calculate median PFS with Log-rank (Mantel-Cox) test assessment at significance level 5%.
Result
Forty patients for each group were identified between 2014-2016. The results as summarized in table and PFS graph below:
There was no progression-free survival difference in patients treated with FDA-approved front-line EGFR-TKI directed by genomic profiling from tissue vs blood -based testing. These results indicate that similar treatment outcomes with targeted therapy based on tissue or blood-based NGS profiling are both viable options for patient with newly diagnosed, advanced NSCLC.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-08 - Activity of Poziotinib and Other 2nd-Gen Quinazoline EGFR TKIs in Atypical Exon18 and Acquired Osimertinib Resistance Mutants (ID 2694)
09:45 - 18:00 | Author(s): Yasir Elamin
- Abstract
Background
In EGFR, exon 18 encodes for the P-loop (L718-V726), and mutations in this region (G719S/A, L718Q/V, G724S) are known to reduce sensitivity to osimertinib and first-generation EGFR TKIs. Osimertinib resistance is associated with a number of acquired mutations in exons 19 and 20 (S784F, L747S, C797S and L792H). We investigated the frequency and drug sensitivity of these and other osimertinib-resistant EGFR mutations
Method
We generated ~50 different Ba/F3 cell line models expressing classical and/or atypical EGFR mutations (exons 18-21) and evaluated the transforming ability and sensitivity to 14 EGFR TKIs including non-covalent (first-generation), afatinib, dacomitinib, and poziotinib (quinazoline and covalent, second-generation), and covalent T790M-specific (third-generation) inhibitors. Impact of atypical mutations was analyzed by in silico modeling.
Result
We found 3.6% (N=32/895) of EGFR-mutant patients had atypical, exon 18, P-loop mutations in the MD Anderson GEMINI database. Modeling of classical EGFR mutations revealed osimertinib has distinct interactions between the solvent front of osimertinib and residues within the P-loop of EGFR, whereas second-generation quinazoline TKIs, such as poziotinib, extend into the pocket, near T790, lacking these interactions. Mutations in the P-loop were predicted to shift osimertinib out of alignment with V726 and F723, causing resistance to osimertinib but not quinazoline-based TKIs. Atypical exon 18 mutations (G719S/A, L718Q/V, G724S) had IC50 values of 113.6nM, 1.6nM, and 137.5nM for first-, second-, and third-generation TKIs, respectively. Second-generation TKIs inhibited G719S/A-T790M mutations at concentrations 2-fold lower than third-generation TKIs (IC50 = 23.4nM and 46nM). Osimertinib-resistance mutations (L747S, S784F, C797S, L792H) co-occurring with classical sensitizing mutations (L858R or ex19del) had IC50 values of 56.8nM, 1.4nM, and 996nM to first, second and third-generation inhibitors. Of the second-generation TKIs tested, poziotinib was the most potent for atypical exon 18 P-loop mutations; G719S/A-T790M mutations; and classical mutants with acquired osimertinib-resistance mutations (IC50= 0.4nM, 3.2nM, 0.8nM).
Conclusion
Exon 18 atypical P-loop mutations and osimertinib-resistance mutations demonstrated high sensitivity to second-generation quinazoline TKIs, compared to first- and third-generation inhibitors. Mutations in the P-loop of EGFR confer resistance to third-generation TKIs by destabilizing solvent front interactions of the molecule, and osimertinib-resistance mutations interfere with covalent binding at C797. Second-generation TKIs, especially poziotinib, are potent inhibitors of these mutations because they have increased hydrophobic interactions at the back of the drug binding cleft that are retained without covalent binding. Together, these data indicate that poziotinib and other second-generation TKIs may be useful for the treatment of NSCLC patients with atypical P-loop and selected osimertinib-resistant EGFR mutations.