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Vincent Lam



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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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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): Vincent Lam

      • Abstract
      • Presentation
      • Slides

      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
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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): Vincent Lam

      • Abstract
      • Presentation
      • Slides

      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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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.10 - Clinical Outcomes in Metastatic Squamous Lung Cancer with Targetable Driver Alterations (Now Available) (ID 527)

      15:45 - 17:15  |  Author(s): Vincent Lam

      • Abstract
      • Presentation
      • Slides

      Background

      Genomic profiling is not routinely performed for metastatic squamous (SCC) and adenosquamous (ASC) NSCLC. However molecular profiling may be ordered if demographic features suggest a higher likelihood of a targetable driver alteration (e.g. never or remote smoking history). Response and survival data are scant in pts with actionable alterations treated with targeted therapy.

      Method

      We reviewed the clinical data and molecular profiling (FISH, PCR, tissue NGS, ctDNA) of metastatic SCC and ASC pts treated at our institution from Feb 2010-Dec 2018. Pts with typical sensitizing mutations in EGFR or BRAF V600E or fusions in ALK or ROS1 treated with matched targeted therapy for ≥ 2 months were included in this analysis. Response assessment was based on RECIST v1.1.

      Result

      Among 261 metastatic SCC or ASC pts with available molecular profiling, 16 total pts (6%) were found to have actionable targets, consisting of 13 SCC and 2 ASC (median age 53, 81% female, 88% never-smoker). The distribution of driver alterations in this cohort was 56% (9/16) EGFR ex19del/L858R/G719A, 38% (6/16) ALK fusion, and 6% (1/16) BRAF. The overall objective response rate (ORR) and median progression free survival (PFS) to targeted therapy was 69% and 5.2 months respectively. By mutational subgroup, ORR was 67% (6/9) for EGFR, 67% (4/6) for ALK, and 100% (1/1) for BRAF. Median PFS was only 4.5 months (95% CI 3.0 – 6.0) for EGFR pts and 2.8 months (95% CI 0 – 6.4) for ALK pts, and the lone BRAF pt had a PFS of 8.5 months. In EGFR pts with available NGS, co-mutations in TP53 (75% [6/8]) and PIK3CA (38% [3/8]) were seen at rates higher than previously reported in EGFR+ ADC (TP53 55%, PIK3CA 12%; Blakely et al, Nat Gen 2017). In ALK pts with available NGS, co-mutations in TP53 (80% [4/5]) were also higher than recently reported in ALK+ ADC (24%; Kron et al, Ann Oncol 2018).

      Conclusion

      Despite initial responses comparable to those previously reported in ADC, matched targeted therapy in pts with SCC and ASC histology is associated with shorter PFS. A higher prevalence of adverse co-mutations such as TP53 and PIK3CA may contribute to early targeted therapy resistance in these histologies. These findings may have implications for the use of targeted therapy in squamous lung cancer.

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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
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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): Vincent Lam

      • Abstract
      • Presentation
      • Slides

      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): Vincent Lam

      • 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:

      table.jpgpfs graph.jpg

      Conclusion

      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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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-90 - Nodal Immune Flare (NIF) Following Neoadjuvant Anti-PD-1 and Anti-CTLA-4 Therapy in Non-Small Cell Lung Cancer   (Now Available) (ID 2065)

      10:15 - 18:15  |  Author(s): Vincent Lam

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have induced durable responses in selected non-small cell lung cancer (NSCLC) patients. However, ICIs have also shown to induce tumor pseudo-progression in some cases. We report the incidence and consequences of a distinct phenomenon – the apparent radiographic progression of lymph nodes without pathological evidence of tumor – that we define “nodal immune flare” (NIF), following neoadjuvant ICIs in the NEOSTAR phase 2 trial of nivolumab or nivolumab plus ipilimumab for operable NSCLCs.

      Method

      NEOSTAR randomized 44 patients with stage I-IIIA (AJCC 7th edition) to nivolumab (3 mg/kg IV, days 1, 15, 29) or nivolumab/ipilimumab (1 mg/kg IV, day 1) with planned surgery between 3-6 weeks after last dose. Computed tomography (CT) and positron emission tomography (PET-CT) were obtained prior to ICIs and prior to resection. Response Evaluation Criteria in Solid Tumors v1.1 were used to evaluate responses.

      Result

      44 patients, median age 66 years (range 43-83), 28 (64%) males, 37 (84%) white were randomized to nivolumab (n=23) or nivolumab/ipilimumab (n=21). 26 (59%) had adenocarcinoma, 17 (39%) squamous cell, 1 (2%) adenosquamous carcinoma. 23 (52%) stage I, 12 (27%) stage II, 9 (20%) stage IIIA. 39 (89%) underwent complete resection, 2 off trial, and 5 (11%) were not resected.

      NIF occurred in 5/44 (11%) patients, 3 post nivolumab (3/23, 13%) and 2 (2/21, 10%) post nivolumab/ipilimumab. All patients had no evidence of malignancy in nodes of interest prior to ICIs. 2 (2/26, 8%) occurred in adenocarcinoma and 3 (3/17, 18%) in squamous cell. 2 (5%) required additional invasive restaging, 3 (7%) change in surgical plan, 1 (2%) declined surgery, 1 (2%) was thought to have disease progression and was treated with chemotherapy plus ICI prior to resection off study, and 1 (2%) underwent planned resection. Pathologic evaluation of the flared nodes revealed no evidence of cancer in all 5 patients, rather demonstrated noncaseating granulomata.

      In a previous neoadjuvant trial utilizing platinum-based chemotherapy with nintedanib, we did not observe NIF in 21 patients in absence of pathologic evidence of tumor progression (primary or nodal metastases).

      Conclusion

      NIF occurred in 11% of patients following neoadjuvant ICIs and changed treatment plan in 9% of patients. This is the first preliminary report of NIF in operable NSCLCs treated with neoadjuvant single and combined ICIs. Considering the number of ongoing neoadjuvant immunotherapy trials, we highlight the importance of judicious and invasive restaging of sites of suspected progression after neoadjuvant ICIs prior to definitive treatment decisions.

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