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Hongming Pan



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    EP1.03 - Biology (ID 193)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.03-09 - Epidemiological Study of TSC1 Mutations Among Non-Small Cell Lung Cancer Patients in China (ID 115)

      08:00 - 18:00  |  Author(s): Hongming Pan

      • Abstract

      Background

      The tuberous sclerosis complex 1 (TSC1) is an endogenous regulator of the mechanistic target of rapamycin (mTOR). While mTOR has been shown to play an important role in neoplasm. The aim of this study is to investigate mutations and prognosis of NSCLC harboring TSC1 mutations.

      Method

      A total of 1106 patients with non-small-cell lung cancer were recruited between July 2012 and December 2016. The status of TSC1 mutations and other genes were detected by next generation sequencing.

      Result

      TSC1 gene mutation rate was 1.90% (21/1106) in non-small cell lung cancer, including Q654E (2 patients), R429K (2 patients), A1072D (1 patient), R850S (1 patient), E625K (1 patient), R715Q (1 patient), A84T (1 patient), S1038G (1 patient), M1090I (1 patient), D903H (1 patient), I143N (1 patient), Q3H (1 patient), L134F (1 patient), T1065M (1 patient), V407M (1 patient), S673F (1 patient), D675Y (1 patient), Q149H (1 patient) and T1144P plus L916M (1 patient), and median overall survival (OS) for these patients was 14.0 months. Among them, all patients were TSC1 gene with co-occurring mutations. Briefly, patients with (n=12) or without (n=9) co-occurring TP53 mutations had a median OS of 14.0 months and 15.0 months respectively (P=0.58); patients with (n=9) or without (n=12) co-occurring KRAS mutations had a median OS of not up to now and 14.0 months respectively (P=0.56); patients with (n=2) or without (n=19) co-occurring BRAF mutations had a median OS of 18.5 months and 12.0 months respectively (P=0.71); patients with (n=4) or without (n=17) co-occurring CDKN2A mutations had a median OS of 8.0 months and 18.0 months respectively (P=0.47).

      Conclusion

      Accompanied gene has not well been connected with TSC1 gene mutations. Our finding expands the mutant spectrum of TSC1 gene and adds new understanding of the phenotype.

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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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      MA09.09 - Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with <i>EGFR</i>-Mutant NSCLC and MET Dysregulation: 18‑Month Follow-Up (Now Available) (ID 1783)

      15:15 - 16:45  |  Author(s): Hongming Pan

      • Abstract
      • Presentation
      • Slides

      Background

      In EGFR-mutant NSCLC, MET amplification may cause resistance to EGFR tyrosine kinase inhibitors (TKIs). In a Phase Ib/II study in EGFR TKI-resistant patients with EGFR-mutant MET+ NSCLC, progression-free survival (PFS) and objective response rate (ORR) after ≥6 months of follow-up were improved with tepotinib (a highly selective MET TKI) plus gefitinib, compared with chemotherapy, particularly in patients with MET amplification. Here we present data at ≥18 months of follow-up.

      Method

      Asian patients with advanced, EGFR+, T790M-, MET+ NSCLC with resistance to prior EGFR TKIs were randomized to receive oral tepotinib 500 mg/day+gefitinib 250 mg/day or ≤6 cycles of cisplatin/carboplatin+pemetrexed chemotherapy±pemetrexed maintenance until confirmed progression, unacceptable toxicity, or withdrawal. Primary endpoint was investigator-assessed PFS. Secondary endpoints included ORR, overall survival (OS) and safety. Subgroup analyses were preplanned in MET IHC3+ and MET amplification populations (NCT01982955).

      Result

      Low recruitment halted full enrolment with 55 of 156 planned patients enrolled.

      As of 12-Dec-2018, median (range) duration of treatment with tepotinib+gefitinib was 21.4 (4.6, 110.9) weeks, with 3 patients still receiving treatment; and with pemetrexed was 18.0 (3.0, 60.4) weeks. 15 patients (62.5%) received ≥4 cisplatin/carboplatin cycles.

      Better outcomes were reported with tepotinib+gefitinib vs chemotherapy (Table), particularly in patients with MET IHC3+ (PFS: HR 0.35 [90% CI 0.17–0.74], OS: 0.32 [0.14–0.75]) or MET amplification (PFS: HR 0.13 [90% CI 0.04–0.43], OS: 0.08 [0.01–0.51]).

      Drug-related grade ≥3 adverse events (AEs) occurred in 17 (54.8%) patients receiving tepotinib+gefitinib and 12 (52.2%) patients receiving chemotherapy. Any-cause AEs leading to discontinuation occurred in 3 (9.7%) patients receiving tepotinib+gefitinib and 1 (4.3%) receiving chemotherapy. Dose reductions due to AEs were reported in 5 (16.1%) vs 4 (17.4%) patients.

      Conclusion

      Tepotinib+gefitinib has durable antitumor activity in patients with EGFR-mutant NSCLC with MET IHC3+ or MET amplification, and was generally well tolerated. MET amplification will be further explored as a biomarker for tepotinib.

      Table: Summary of efficacy data

      Population

      Tepotinib + gefitinib

      Chemotherapy

      HR/OR
      (90% CI)

      Overall MET+*

      Patients, n

      31

      24

      mPFS, months (90% CI)

      4.9 (3.9, 6.9)

      4.4 (4.2, 6.8)

      0.67 (0.35, 1.28)

      mOS, months (90% CI)

      17.3 (12.1, 37.3)

      18.7 (15.9, 20.7)

      0.67 (0.33, 1.37)

      ORR, n (%) [90% CI]

      14 (45.2) [29.7, 61.3]

      8 (33.3) [17.8, 52.1]

      1.99 (0.56, 6.87)

      MET IHC3+

      Patients, n

      19

      15

      mPFS, months (90% CI)

      8.3 (4.1, 21.2)

      4.4 (4.1, 6.8)

      0.35 (0.17, 0.74)

      mOS, months (90% CI)

      37.3 (24.2, 37.3)

      17.9 (12.0, 20.7)

      0.32 (0.14, 0.78)

      ORR, n (%) [90% CI]

      13 (68.4) [47.0, 85.3]

      5 (33.3) [14.2, 57.7]

      4.33 (1.03, 18.33)

      MET amplification

      Patients, n

      12

      7

      mPFS, months (90% CI)

      21.2 (8.3, NE)

      4.2 (1.4, 7.0)

      0.13 (0.04, 0.43)

      mOS, months (90% CI)

      37.3 (NE, NE)

      13.1 (3.3, NE)

      0.08 (0.01, 0.51)

      ORR, n (%) [90% CI]

      8 (66.7) [39.1, 87.7]

      3 (42.9) [12.9, 77.5]

      2.67 (0.37, 19.56)

      CEP-7, centromere protein 7; CI, confidence interval; EGFR, epidermal growth factor receptor; GCN, gene copy number; HR, hazard ratio; IHC, immunohistochemistry; IRC, independent review committee; ITT, intention to treat; MET, mesenchymal-epithelial transition factor; NE, not estimable; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival

      All efficacy outcomes are investigator-assessed by RECIST v1.1.

      *IHC2+/IHC3+/gene amplification.

      MET amplification is defined as GCN ≥5 and/or MET/CEP-7 ratio ≥2. 17 of 19 patients with MET amplification have MET overexpression (IHC3+).

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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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      MA14.05 - A Randomized Phase III Trial of Fruquintinib Versus Placebo in Patients with Advanced Non-Small Cell Lung Cancer (FALUCA) (Now Available) (ID 1490)

      15:45 - 17:15  |  Author(s): Hongming Pan

      • Abstract
      • Presentation
      • Slides

      Background

      Fruquintinib, an orally active kinase inhibitor that selectively targets vascular endothelial growth factor (VEGF) receptor, demonstrated significant benefit in progression-free survival and disease control in a randomized Phase II study in patients with non-small-cell lung cancer (NSCLC) who had failed two lines of chemotherapy. This Phase III FALUCA trial is a randomized, double-blind, placebo-controlled, multicenter trial designed to confirm the efficacy in the same patient population (NCT02691299).

      Method

      From December 2015 to February 2018, 45 clinical centers across China participated in the trial. A total of 730 patients aged 18-75 with advanced NSCLC who had failed two lines of chemotherapy were screened and 527 who met the eligibility criteria were enrolled into the study. Patients were stratified based on epidermal growth factor receptor mutation status and prior use of VEGF inhibitor therapy, and were randomized in a 2:1 ratio to receive fruquintinib (n=354) or placebo (n=173) once daily in a 3 weeks on/1 week off 4-week cycle. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response. The final data cutoff was on September 21, 2018.

      Result

      Median OS was 8.94 months for fruquintinib and 10.38 months for placebo (hazard ratio, 1.02; 95% CI, 0.816 to 1.283; p=0.841). Median PFS was 3.68 months for fruquintinib comparing to 0.99 months for placebo, respectively (hazard ratio, 0.34; 95%CI, 0.279 to 0.425; p<0.001). The ORR and DCR were 13.8% and 66.7% for fruquintinib, compared with 0.6% and 24.9% for placebo (both p<0.001), respectively. The most frequent treatment-emergent adverse events with fruquintinib (≥grade 3) were hypertension (20.7%), hand-foot syndrome (11.0%), and proteinuria (1.4%). A sensitivity analysis revealed that median OS was significantly prolonged with fruquintinib compared with placebo in patients who received no subsequent systemic anti-tumor therapies (7.00 months versus 5.06 months ; hazard ratio, 0.64; 95%CI, 0.453 to 0.903; p=0.010).

      Conclusion

      The FALUCA trial failed to meet the primary end point of OS while confirming significant benefit in secondary end points including PFS, ORR and DCR. The safety profile of fruquintinib in this patient population was acceptable and consistent with that identified in the Phase II study. A post-hoc sensitivity analysis revealed that the anti-tumor therapies that patients received post disease progression probably contributed to the failure of this study on the primary end point.

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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      OA02.03 - The Third Generation EGFR Inhibitor (EGFR-TKI) HS-10296 in Advanced NSCLC Patients with Resistance to First Generation EGFR-TKI (Now Available) (ID 766)

      10:30 - 12:00  |  Author(s): Hongming Pan

      • Abstract
      • Presentation
      • Slides

      Background

      HS-10296 is an oral, potent, high selective third generation EGFR tyrosine-kinase inhibitor (EGFR-TKI) for sensitizing mutations, and the EGFR Thr790Met (T790M) resistance mutation which has been demonstrated by phase I study. This phase II, open-label, multicenter single-arm study was designed to confirm the efficacy and safety of HS-10296 in a large population of non-small-cell lung cancer (NSCLC) patients with EGFR T790M mutation, who had progressed after first generation EGFR-TKI treatment.

      Method

      Patients aged at least 18 years with centrally confirmed EGFR T790M-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC after first generation EGFR-TKI treatment received HS-10296 110 mg orally once daily until disease progression, or intolerable toxicity, or patient withdrawal. Patients with asymptomatic, stable brain metastases not requiring steroids were allowed to enroll. The primary endpoint was the objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1 every 6 weeks. Response endpoints (ORR and disease control rate [DCR]) were assessed in response analysis set. Secondary end points including progression-free survival (PFS), duration of response (DoR), depth of response (DepOR), overall survival (OS) and safety were evaluated in full analysis set. The final data cutoff was on Jan 5, 2019. The study is still ongoing.

      Result

      Totally, 244 patients (median age 60.8) entered study in 36 sites in mainland China (189 patients) and Taiwan (55 patients) between May 16, 2018 to Oct 23, 2018. 2 patients were excluded from the evaluable for response analysis set (n=242) due to absence of measurable disease at baseline by independent central review. At data cutoff, 182 (74.6%) patients remained on treatment. The median duration of follow-up was 4.7 months. 160 of 242 patients achieved confirmed partial responses by independent central review. The ORR was 66.1% (95% CI: 59.8-72.1). The DCR was 93.4% (95% CI: 89.5-96.2). The most common adverse reactions (≥ 10%) were blood creatine phosphokinase increased (43 [17.6%]), aspartate aminotransferase increased (29 [11.9%]), pruritus (28 [11.5%]), rash (28 [11.5%]) and alanine aminotransferase increased (26 [10.7%]). The most common all-causality grade 3 and 4 adverse events were blood creatine phosphokinase increased (14 [5.7%]) and hyponatraemia (4 [1.6%]). Serious adverse events were reported in 30 (12.3%) patients, of which 19 (7.8%) were investigator assessed as possibly treatment-related to HS-10296. Three deaths were due to adverse events; one was related to cardiopulmonary failure, other two events occurred after disease progression. There was no interstitial lung disease during study treatment.

      Conclusion

      HS-10296 has demonstrated good clinical benefit with minimal toxicity in patients with EGFR T790M-positive NSCLC patients who have progressed after first generation EGFR-TKI treatment. The Phase III study has already launched comparing HS-10296 with gefinitib in advanced NSCLC patients with EGFR sensitizing mutations. (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

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