Virtual Library

Start Your Search

T. Li



Author of

  • +

    MINI 14 - Pre-Clinical Therapy (ID 119)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
    • +

      MINI14.01 - EGFR-Mutated PDX in NSCLC: Molecular Fidelity and Correlation of PDX and Patient Response to EGFR Inhibition (ID 2191)

      10:45 - 12:15  |  Author(s): T. Li

      • Abstract
      • Presentation
      • Slides

      Background:
      Inevitable emergence of resistance to tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated NSCLC warrants development of pro-active therapeutic strategies to delay or circumvent this evolution. To model such approaches, we are employing a clinically and genomically annotated patient derived xenotransplant (PDX) resource designed to duplicate relevant known mechanisms of resistance to TKI therapy. This analysis examines molecular fidelity and correlates response between patient and PDX in EGFR-mutant NSCLC.

      Methods:
      Six EGFR-mutated NSCLC, 1 EGFR-TKI naïve and 5 after progressive disease on erlotinib, were implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mice as previously described (DR Gandara, Clin Lung Cancer 2015). Models were considered established when PDX growth was confirmed in passage 1 (P1); tumor growth studies were conducted in P3-P5. The donor patient tumor (PT) and the resultant PDX were analyzed for driver mutations (Response Genetics Inc., and Illumina TSCAP), copy number variants (CNV) and global RNA expression (Affymetrix arrays). Informed consent was obtained from all patients. EGFR-mutant PDX treatments included: erlotinib, afatinib, cetuximab, and afatinib+cetuximab. Patient response was graded by RECIST 1.1 and measured in PDX by tumor shrinkage from pre-treatment baseline. In select models, pharmacodynamic studies (kinase arrays; immunoblotting) were also performed.

      Results:
      The EGFR mutation subtypes identified in the donor PT were preserved in all PDX models (4 EGFR E19del and 2 EGFR L858R). Corresponding putative mechanisms of resistance were identical in both PT and PDX in 3 cases: EGFR T790M (2 of 5) and MET amplification (1 of 5). Of 5 post-erlotinib progression PDX models, 3 had progressive disease (PD) and 2 had transient tumor shrinkage to erlotinib. The PDX derived from an erlotinib-naïve patient (EGFR E19del) demonstrated sustained tumor shrinkage to erlotinib. Patient-PDX treatment correlations were possible in 3 post erlotinib-progression models. Two of these patients received afatinib-cetuximab: 1 with partial response (PR) and 1 with PD. The two models corresponding to these patients, when treated with afatinib-cetuximab, underwent complete regression of tumor (CR) and PD, respectively. Pharmacodynamic assessment of the responding model at 24h showed near complete diminishment of pEGFR following afatinib-cetuximab, concomitant with decreased pHer2, pERK, pAKT and p38. Erlotinib showed transient inhibition on signaling in this model at 6h, returning to baseline by 24h. In contrast, the non-responding model showed minimal effects on target inhibition and signal transduction following treatment with any EGFR inhibitor.

      Conclusion:
      Genomic fidelity was preserved in EGFR-mutant PDX, including putative mechanisms of resistance in the post-erlotinib progression models. The majority (3/5) of the EGFR-mutant PDXs created after erlotinib resistance demonstrated PD. In the other post-erlotinib progression models transient tumor shrinkage was noted, which may reflect PDX passaging in the absence of selective pressure of EGFR-inhibition or pharmacokinetic considerations. Overall, the PDX response to treatment reflected the corresponding patient’s clinical course. Pharmacodynamic studies of select models informed PDX response to treatment.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

  • +

    ORAL 17 - EGFR Mutant Lung Cancer (ID 116)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
    • +

      ORAL17.06 - Phase I/II Study of INC280 plus Erlotinib in Patients with MET Expressing Adenocarcinoma of the Lung (ID 1064)

      10:45 - 12:15  |  Author(s): T. Li

      • Abstract
      • Presentation
      • Slides

      Background:
      MET dysregulation is one mechanism responsible for EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) resistance in patients (pts) with EGFR mutated lung cancer. INC280 is a potent oral small molecular inhibitor of the c-MET kinase. We conducted a phase I/II study of INC280 plus erlotinib to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of this combination. Tumor analysis of the EGFR and MET pathways was exploratory.

      Methods:
      Using a 3 + 3, dose escalation design, INC280 was increased over 5 dose levels (DL) from 100 - 600 mg po bid. Daily erlotinib was given at 100 mg in DL1 and 150 mg in DL 2- 6. DL 6 is a transition cohort from INC280 capsules (600 mg) to tablets (400 mg). Both agents were given for 28 days (1 cycle). Key eligibility included: lung adenocarcinoma with MET expression by a CLIA certified lab, age > 18, ECOG PS of < 2, acceptable organ function, and > 1 systemic therapy for advanced disease.

      Results:
      18 pts were treated on 6 dose levels. Pt characteristics: median age 59 (range 52-78), M/F (7/11), ECOG 0-1/2 (16/2), MET expression by IHC/FISH/RT-PCR/NGS (6/2/9/1), EGFR mutated tumors (9) and previously treated with erlotinib (12). 17 patients completed at least 1 cycle. One DLT (grade 3 neutropenia) occurred in DL 5 (Table 1). Common drug-related adverse events (AE) of any grade were rash (50%) and diarrhea (45%), fatigue (39%), anorexia and nausea (28% each) and increased alkaline phosphatase, hypoalbuminemia and paronychia (22% each). Drug-related grade 3/4 AE were anorexia, increased amylase or lipase and neutropenia (all 6%). PK analysis revealed that INC280 exhibited a linear PK and no interaction with erlotinib. Of the 17 evaluable patients, 3 (18%) patients had partial responses, 10 (59%) had stable disease, 3 of whom had a minor response (10-29% decrease in target lesion) (Table 1). Eight pts have received treatment for >3 months. Figure 1



      Conclusion:
      In patients with MET-expressing lung adenocarcinoma, INC280 plus erlotinib is feasible, tolerable and demonstrates anti-tumor activity. The recommended phase 2 doses are INC280 400 mg (tablets) bid plus erlotinib 150 mg daily. Three expansion cohorts have been initiated: 1 - EGFR mutated tumors refractory to an EGFR-TKI, 2 - EGFR-TKI naïve in the first line setting and 3 - WT EGFR that are EGFR-TKI naïve as second or third line therapy. Updated trial results from the expansion cohorts will be presented. NCT01911507

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

  • +

    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
    • +

      P2.04-040 - Impact of Ethnicity on Incidence of Brain Metastasis in Patients with EGFR-Mutant Lung Cancer (ID 2981)

      09:30 - 17:00  |  Author(s): T. Li

      • Abstract
      • Slides

      Background:
      Better systemic control and longer survival have been cited as the reason for the higher incidence of brain metastasis observed in patients with EGFR-mutant lung cancer compared to patients with EGFR wild-type lung cancer. The prevalence of EGFR mutation is particularly dependent on patient’s ethnicity: 30-40% and 10-16% in East Asian and Caucasian patients, respectively. However, the incidence of brain metastasis in EGFR mutant lung cancer at initial diagnosis in these ethnic groups is less well defined. The objective of this study was to investigate the incidence of brain metastasis at diagnosis in East Asian and Caucasian patients with EGFR-mutant lung cancer.

      Methods:
      This retrospective study included 163 consecutive patients with EGFR-mutant metastatic NSCLC from a Chinese (N=72) and a US academic (N=91) institution. The EGFR mutation status was determined by the institutional laboratory in China and CLIA-certified laboratory in the US. East Asians in Northern California and Chinese patients in China had a similar incidence of brain metastasis at diagnosis (10/23=43.5% and 30/72=41.7%, respectively), and were combined as East Asians in the analysis. Descriptive statistics were generated for demographics, smoking habits, histology, and EGFR mutation subtypes, stratified by status of brain metastasis at diagnosis. Chi-squared tests and t-tests were used for testing associations of categorical variables and continuous variables with brain metastasis at diagnosis, respectively. Logistic regression models were used to study the association between race and brain metastasis at diagnosis, with and without adjusting for age at initial diagnosis, gender, EGFR mutation type, smoking status, and histology. Odds ratio (OR) and corresponding 95% confidence intervals (CI) were obtained. All analyses were two sided and a p value <0.05 were considered significant.

      Results:
      Three patients who were neither East Asian nor Caucasian were ineligible for analysis. Among the remaining 160 patients, 44.2% were Caucasians and 55.8% East Asians. Higher incidence of brain metastasis at diagnosis was detected in East Asian patients than Caucasian patients (42.1% vs 13.8%, p= 0.0001). There is no significant difference in the mean age (62 and 59 years old), smoking history (34.2% vs 26.5%), histology (93.8% adenocarcinoma in both groups), type of EGFR mutation (Exon 19 Deletion: 47.8% vs 48.0%; L858R: 35.4% vs 38.0%) between patients without brain metastasis and with brain metastasis at diagnosis. Comparing to Caucasians, East Asians had significantly higher incidence of brain metastasis at diagnosis (OR = 4.53, 95% CI: 2.01–10.20, p= 0.0003). The result remained significant after adjusting for other factors (aOR = 4.24, 95% CI: 1.76–10.18, p= 0.001).

      Conclusion:
      Regardless of place of residence (Northern California or China), East Asians were more likely to have brain metastasis at initial diagnosis than Caucasian patients, suggesting ethnicity-related genomic and pharmacogenomic differences and less impact of environmental factors on tumorigenesis and clinical course of EGFR-mutant lung cancer. Further study is indicated to understand the impact of ethnicity and population-related genomics and pharmacogenomics on tumor biology of EGFR-mutant lung cancer.

      Only Active 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 or select "Add to Cart" and proceed to checkout.