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Shuanglian Li



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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): Shuanglian Li

      • Abstract
      • Slides

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 947)

    • 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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      P1.15-05 - The Frequency and Spectrum of EGFR Exon 20 Insertions in NSCLC: A Global Literature Review (ID 11975)

      16:45 - 18:00  |  Author(s): Shuanglian Li

      • Abstract
      • Slides

      Background

      There are limited epidemiological data on non-small cell lung cancer (NSCLC) patients with non-classical (uncommon) epidermal growth factor receptor (EGFR) mutations. In light of ongoing development of TAK-788, we describe the global frequency and spectrum of EGFR exon 20 insertions in NSCLC based on a comprehensive literature review as well as highlight possible regional variations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A literature search was conducted to identify publications reporting the frequency of EGFR exon 20 insertions in unselected NSCLC patients. PubMed and ASCO, ESMO, and IASLC meeting abstracts were searched up to April 2018 using the following keywords: non-small cell lung cancer, epidermal growth factor receptor, exon 20, insertions and uncommon mutations. Only publications in English were included. The pooled frequency of EGFR exon 20 insertions for each country were determined, and insertion variants (where available) were described at the global level.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 26 studies from 25 countries were included, reporting on 569 patients with EGFR exon 20 insertions among 41,321 NSCLC patients. The highest mutation frequency was seen in China (2.9%) and the lowest in Indonesia (0.1%). When pooled by country, exon 20 insertions were found in 0.1−2.1% of all NSCLC.

      frequency of egfr exon 20 insertions in patients with nsclc.jpg

      Over 50 insertion variants were reported, covering amino acids 761−774. The most commonly detected mutations included D770_N771insSVD, V769_D770InsASV, H773_V774InsH, H773_V774insNPH, and A763_Y763insFQEA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The frequency of EGFR exon 20 insertions was 0.1−2.1% of NSCLC patients, with a high variability in both length and position of insertions within exon 20. Currently, available data are sparse and come primarily from studies based on single-center experiences, with data gaps across several large geographic regions and populations. Results also indicate a need to further explore underlying geographic variations in epidemiology. Larger, multi-center global studies will further help to refine the frequency of exon 20 insertions and other uncommon mutations in NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-32 - TAK-788 is a Novel and Potent Tyrosine Kinase Inhibitor with Selective Activity Against EGFR/HER2 (ID 12643)

      16:45 - 18:00  |  Author(s): Shuanglian Li

      • Abstract
      • Slides

      Background

      Dysregulation of the EGFR family member HER2 (human epidermal growth factor receptor 2) plays an important role in many cancers. HER2 exon 20 in-frame insertion mutations occur in 2−4% of non-small cell lung carcinomas (NSCLC). Despite current HER2-directed treatments, no approved therapies exist for patients with cancers harboring HER2 mutations. Unlike other activating mutations, exon 20 insertions induce a conformational change leading to significant homology to the ATP-binding pocket of WT proteins. As such, clinical development of tyrosine kinase inhibitors (TKIs) against these insertions has been challenging, as inhibition of WT-EGFR is associated with clinical dose-limiting toxicities, such as diarrhea and skin rash. TAK-788 was designed to potently inhibit oncogenic variants with desirable selectivity over WT-EGFR. TAK-788 inhibits mutant EGFR and HER2 via covalent modification of EGFR-Cys797 and HER2-Cys805. Here, we characterized the non-clinical activity of TAK-788 in HER2 exon 20 insertion and substitution mutants and contrasted it with other TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In vitro activity was assessed by measuring viability in engineered Ba/F3 lines expressing different HER2 mutation variants (substitutions and insertions). Inhibition of WT-EGFR was assessed by measuring EGFR phosphorylation in A431 cells that overexpress WT-EGFR. In vivo activity was assessed by monitoring tumor volume.

      4c3880bb027f159e801041b1021e88e8 Result

      TAK-788 inhibited all HER2 mutations tested, including exon 20 insertions and point mutations, more potently than it inhibits WT-EGFR (Figure), suggesting an acceptable therapeutic window compared with other TKIs. TAK-788 in vitro potency in these mutations has also been confirmed in vivo with tumor xenograft models and in a phase 1 clinical trial.

      figure.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The favorable selectivity and potency observed in these in vitro experiments for HER2 exon 20 insertions/point mutations supports the ongoing exploration of TAK-788 in NSCLC patients with HER2 mutations (NCT02716116) as well as in other HER2 mutant−driven cancer patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 981)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.15-03 - Capturing the Patient Experience for the Treatment of EGFR Exon 20 Mutations in Non-Small Cell Lung Cancer (ID 12301)

      12:00 - 13:30  |  Author(s): Shuanglian Li

      • Abstract
      • Slides

      Background

      Non-small cell lung cancer (NSCLC) accounts for 80−85% of new lung cancer cases, which presents as metastatic disease 40−50% of the time. The prevalence of NSCLC patients with a mutation in the epidermal growth factor receptor (EGFR) varies by ethnicity, ranging from 15−50%, and EGFR exon 20 insertion mutations specifically account for 7−12% of all EGFR mutations.

      Health-related quality of life (HRQOL) was widely used, as generic measures may lack the sensitivity required to demonstrate clinical change related to new therapies. Assessments of disease-specific patient-reported outcomes (PROs) play an important role in clinical trials to evaluate the benefits of new treatments on HRQOL and in making treatment decisions for patients. This study aimed to better understand the overall symptom experience and HRQOL impact from the perspective of NSCLC EGFR exon 20 patients to evaluate the effectiveness of new treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A targeted literature review was conducted in Embase and Medline (2007−2017) to identify PROs used in previous NSCLC studies for evidence of content coverage. Interviews with expert clinicians were conducted to explore the clinical perspective on treatment and observed patient experience. Following approval from an independent review board, semi-structured qualitative interviews were conducted with NSCLC patients identified through the International Cancer Advocacy Network.

      4c3880bb027f159e801041b1021e88e8 Result

      Five oncologists were interviewed, reporting a wide range of NSCLC symptoms, notably shortness of breath, chest pain, bone/other pain, and substantial emotional impacts. Ten patient interviews were conducted (median age 55 [42−83] years; 60% female, 90% EGFR exon 20 insertions, median disease duration 1.8 [<1−6] years, 60% self-reported brain metastases). The most frequently reported disease related symptoms included fatigue (90%), pain (70%), shortness of breath (70%), cough (60%), weakness (30%), phlegm/congestion (30%), and hemoptysis (20%). Symptoms indicative of brain metastases included issues with vision and headaches (both 30%), speaking (20%), and balance (10%). All patients mentioned experiencing a psychological or emotional impact, with 60% describing worry/anxiety around treatment, the future, or finances. Patients also described experiencing negative impacts on daily activities, including household chores and self-care (60%), work (50%), social activities (50%), and family life (40%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Incorporation of the patient voice provided valuable in-depth insight on the NSCLC patient experience. Symptom and HRQOL impact concepts identified will inform the iterative development of a conceptual disease model. Results show the significant social, emotional, and physical impact on patients’ lives, which fill an important gap and help to inform treatment decision making.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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