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Ross Soo



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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): Ross Soo

      • 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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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.03 - The International Association for the Study of Lung Cancer (IASLC) Global Survey on Molecular Testing in Lung Cancer (Now Available) (ID 1198)

      14:30 - 16:00  |  Author(s): Ross Soo

      • Abstract
      • Presentation
      • Slides

      Background

      Evidence-based standards for molecular testing of lung cancer have been established, but the global frequency and practice of testing are not well understood. The IASLC conducted an international survey to evaluate current practice and barriers to molecular testing.

      Method

      Distributed to IASLC members and other healthcare professionals, content included: 7-question introduction, 32 questions for those requesting tests/treating patients, 45 questions on performing/interpreting assays, and 24 questions on tissue acquisition. All respondents were asked to provide 3-5 barriers to implementing/offering molecular testing.

      Respondents’ countries were grouped by geography or developing/developed using IASLC and World Bank criteria. Surveys were available in 7 languages. Regional comparisons used the Chi-squared test or ANOVA; free-text was analyzed with Nvivo.

      Result

      We obtained 2,537 responses from 102 countries. Respondents were 45% Medical Oncologists, 12% Pulmonologists, 12% Thoracic Surgeons, 9% Pathologists, and 22% scientists or other. 56% of responses were from developing countries, 44% developed. Regions included: 52% Asia, 19% Europe, 11% Latin America, 11% US/Canada, 7% Other.

      1683 (66%) chose the requesting/treating track (50% government, 42% academic, 8% other). 61% reported most patients in their country do not receive molecular testing, with the lowest rates in Latin America/Other (p<0.0001). 39% were not satisfied with the conditions of molecular testing in their country. Indications for requesting testing included: adenocarcinoma (89%), never-smoker (61%), female (57%), and young (54%) (variable by region, p<0.0001). 99% ordered EGFR, 95% ALK, 84% PDL1, 79% ROS1, all other tests <50%. 56% typically received results within 10 days. Only 67% were aware of CAP/IASLC/AMP guidelines, least frequently in Asia/Other (p=0.041). 37% have trouble understanding molecular testing result reports, most of whom cited a need for more technical and scientific knowledge. 75% had multidisciplinary tumor boards, but 23% met <1/month.

      The 316 (12%) testing track respondents were from laboratories that were 49% academic, 35% government, and 16% private/other. 94% of laboratories offered EGFR, 83% ALK, 69% KRAS, 68% BRAF, 64% ROS1, 56% HER2, and others <50%; 68% tested for PDL1. 57% offered Multiplex assays, less frequently in Latin America/Asia (p=0.0294). 69% tested blood-derived DNA, less frequently in US/Canada/Other (0.0013). 23% of respondents reported >10% of cases are rejected due to inadequate samples; however, 47% stated there is no policy or strategy to improve the quality of the tissue samples in their country. 52% reported patients/physicians are not satisfied with the state of molecular testing in their country. Respondents performing/interpreting assays (334, 14%) were typically informed of biopsy results (91%), and notified when the sample was inadequate (84%).

      The most frequent barrier to molecular testing in every region was cost, followed by quality/standards, turnaround-time, access, and awareness. After cost, time was the most common barrier in developed countries, while it was quality in developing countries. The second largest barrier was quality in Asia, access in Europe/Latin America/Other, and turn-around time in US/Canada.

      Conclusion

      These preliminary analyses show molecular testing usage varies across the globe. Barriers vary by region, and one-third of respondents were unaware of evidence-based guidelines. Global and regional strategies should be developed to address barriers.

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    MS01 - Immunotherapy Resistance (ID 64)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MS01.03 - Overcoming Resistance - Clinical Results? (Now Available) (ID 3441)

      10:30 - 12:00  |  Presenting Author(s): Ross Soo

      • Abstract
      • Presentation
      • Slides

      Abstract

      Overcoming resistance- clinical results.

      The management of oncogene negative advancednon-small cell lunghas been transformed with the use of immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1). However, in a significant number of patients, either primary or acquired resistance has been observed. Primary resistance, usually defined as disease progression upon the first radiologic evaluation, represents an important clinical problem and has been reported in up to 20% of patients. Acquired resistance, defined as tumors with initial response following treatment but eventually develop disease progression, has been reported in approximately 20-40% of patients.

      The mechanisms of primary and acquired resistance to immunotherapy are complex and are interdependent, involving alterations in immune cells, cytokines, metabolic and oncogene signaling pathways in the tumor cell and the tumor microenvironment. The usual treatment following progression on first line immune checkpoint inhibitor with or without a platinum doublet is single agent docetaxel or a platinum doublet +/- bevacizumab.

      With an improvement in the understanding of the mechanisms of resistance to immune checkpoint inhibitors, to improve patients’ outcomes following resistance, strategies have been devised to tailor subsequent therapy according to the mechanism of resistance, including the use of therapies to increase antigenicity, enhance immune cell function, and modulate the tumor microenvironment.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.02 - IMpower131: Final OS Results of Carboplatin + Nab-Paclitaxel ± Atezolizumab in Advanced Squamous NSCLC (ID 1915)

      11:30 - 13:00  |  Author(s): Ross Soo

      • Abstract
      • Slides

      Background

      IMpower131 (NCT02367794) is a randomised Phase III trial of atezolizumab + chemotherapy vs chemotherapy alone as first-line therapy in Stage IV squamous NSCLC. Here we report the final OS results (Arm B vs Arm C).

      Method

      Enrolled patients were randomised 1:1:1 to Arm A (atezolizumab 1200 mg q3w + carboplatin AUC 6 q3w + paclitaxel 200 mg/m2 q3w), Arm B (atezolizumab + carboplatin + nab-paclitaxel 100 mg/m2 qw) or Arm C (carboplatin + nab-paclitaxel) for 4 or 6 cycles followed by atezolizumab maintenance therapy (Arms A and B) until loss of clinical benefit or progressive disease. Coprimary endpoints were investigator-assessed PFS and OS in the ITT population. Data cutoff: October 3, 2018.

      Result

      1021 patients were enrolled, with 343 in Arm B and 340 in Arm C. Median age was 65 years (range, 23-83 [Arm B] and 38-86 [Arm C]) and ≈80% of patients were male. The proportion of patients with high (14% vs 13%), positive (39% vs 37%) or negative (47% vs 50%) PD-L1 expression was similar between arms. Median OS in the ITT population was 14.2 months in Arm B vs 13.5 months in Arm C (HR, 0.88 [95% CI: 0.73, 1.05]; P = 0.158; Table), not crossing the boundary for statistical significance. In the PD-L1–high subgroup, median OS was 23.4 vs 10.2 months, respectively (HR, 0.48 [95% CI: 0.29, 0.81]; not formally tested). Treatment-related Grade 3-4 AEs and treatment-related SAEs occurred in 68.0% and 21.0% (Arm B) and 57.5% and 10.5% (Arm C) of patients; no new safety signals were identified, consistent with previous analyses.

      Conclusion

      Final OS in Arm B vs C did not cross the boundary for statistical significance. Clinically meaningful OS improvement was observed in the PD-L1–high subgroup, despite not being formally tested. No new or unexpected safety signals were reported.

      Arm B

      Atezolizumab + Carboplatin
      + Nab-Paclitaxel

      (n = 343)

      Arm C

      Carboplatin +
      Nab-Paclitaxel

      (n = 340)

      HR (95% CI)

      Median OS, mo

      ITT

      14.2

      13.5

      0.88 (0.73, 1.05); P = 0.16

      PD-L1 high (TC3 or IC3)

      23.4

      10.2

      0.48 (0.29, 0.81)

      PD-L1 positive (TC1/2/3 or IC1/2/3)

      14.8

      15.0

      0.86 (0.67, 1.11)

      PD-L1 negative (TC0 or IC0)

      14.0

      12.5

      0.87 (0.67, 1.13)

      Median PFS, mo

      6.5

      5.6

      0.75 (0.64, 0.88)

      Confirmed ORR, n/N (%)a

      170/342 (49.7)

      139/339 (41.0)

      a Patients were classified as missing or unevaluable when no post-baseline response assessments were available or all post-baseline response assessments were unevaluable.

      CI, confidence interval; HR, hazard ratio; IC, tumour-infiltrating immune cell; ITT, intention-to-treat; OS, overall survival; ORR, objective response rate; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TC, tumour cell.
      TC3 or IC3: PD-L1 expression on ≥50% of TC or ≥10% of IC; TC1/2/3 or IC1/2/3: PD-L1 expression on ≥1% of TC or IC; TC0 and IC0: PD-L1 expression on <1% of TC and IC.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-118 - Overall Survival in Pts with EGFRm+ NSCLC Receiving Sequential Afatinib and Osimertinib: Updated Analysis of the GioTag Study (ID 2211)

      09:45 - 18:00  |  Author(s): Ross Soo

      • Abstract
      • Slides

      Background

      With three generations of EGFR tyrosine kinase inhibitors (TKIs) now available for the treatment of EGFR mutation-positive (EGFRm+) NSCLC, it will be important to identify the optimal sequence of EGFR TKIs to maximise survival. The observational GioTag study (NCT03370770) investigated outcomes in patients with EGFRm+ NSCLC who were treated with sequential afatinib and osimertinib in a ‘real-world’ clinical setting, including patients with poor prognosis (ECOG PS ≥2: 15%; stable brain metastases: 10%).1 Time to treatment failure (TTF) was encouraging (overall: 27.6 months; Del19-positive patients: 30.3 months; Asians: 46.7 months). In this updated analysis, we report OS and updated TTF.

      Method

      Data were retrospectively collected between Dec 2017 and June 2018 for 203 pts with EGFRm+ (Del19, L858R) NSCLC who had T790M-positive disease after first-line afatinib and subsequently received osimertinib. TTF was the primary outcome; OS analysis was exploratory. Data were collected from electronic health records (EHRs; n=126) or medical charts (n=77). For logistical reasons, this interim analysis includes updated data (as at April 2019) from patients with available EHRs (all from USA; n=94); final analysis incorporating updated data from manual chart reviews is anticipated in early 2020.

      Result

      After a median follow-up of 30.3 months, median OS was 41.3 months (90% CI: 36.8–46.3) in the overall dataset (n=203) and 45.7 months (90% CI: 45.3–51.5) in Del19-positive patients (n=149); 80% of patients were alive after 2 years. OS in Asians was immature. Updated median TTF was 28.1 months (90% CI: 26.8–30.3) in the overall dataset, and 30.6 months (90% CI: 27.6–32.0) in Del19-positive patients. Outcomes were not affected by afatinib starting dose. Median TTF with osimertinib was 15.6 months (90% CI: 13.817.1) in the overall dataset, and 16.4 months (90% CI: 14.917.9) in Del19-positive patients.

      Conclusion

      Sequential afatinib and osimertinib is associated with encouraging OS and TTF in pts with EGFR T790M-positive NSCLC, especially in Del19-positive patients, indicating that the sequential regimen is a feasible option in this setting. Of note, prior treatment with afatinib did not preclude prolonged TTF with second-line osimertinib (15.6 months overall; 16.4 months in Del19-positive patients). The final analysis will provide further insights into the long-term OS of patients treated with sequential afatinib–osimertinib, including Asians.

      1. Hochmair MJ, et al. Future Oncol. 2018;14:2861–74.

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      P1.01-84 - Interaction of Lorlatinib with CYP2B6, CYP2C9, UGT, and P-gp Probe Drugs in Patients with Advanced Non-Small Cell Lung Cancer (ID 293)

      09:45 - 18:00  |  Author(s): Ross Soo

      • Abstract
      • Slides

      Background

      Lorlatinib is a small-molecule anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). Because lorlatinib is an inducer and inhibitor of various cytochrome P450 (CYP) enzymes and transporters, an evaluation of its effect on these substrates at steady state is warranted. A drug-drug interaction (DDI) sub-study was conducted in patients with advanced NSCLC to evaluate the net effect of these interactions.

      Method

      Probe drugs utilized included bupropion for CYP2B6, tolbutamide for CYP2C9, acetaminophen for uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT), and fexofenadine for P-glycoprotein-1 (P-gp). Thirty-two patients (to have at least 6 evaluable patients per probe drug) were administered a single dose of a probe drug alone on Day −2 to determine plasma exposure of the probe drug alone. Starting on Cycle 1 Day 1, patients began lorlatinib tablets 100 mg daily. On Cycle 1 Day 15, another single dose of the same probe drug was administered concurrently with lorlatinib.

      Result

      Co-administration of lorlatinib 100 mg with bupropion, a sensitive CYP2B6 probe drug, decreased bupropion geometric mean plasma AUCinf and Cmax by 25% and 27%, respectively. For tolbutamide, a sensitive CYP2C9 probe drug, lorlatinib decreased tolbutamide AUCinf and Cmax by 43% and 15%, respectively. Likewise, for acetaminophen, a sensitive UGT substrate, lorlatinib decreased acetaminophen AUCinf and Cmax by 45% and 28%, respectively. Finally, for fexofenadine, a sensitive P-gp substrate, lorlatinib decreased fexofenadine AUCinf and Cmax by 67% and 63%, respectively.

      Conclusion

      Critical steady-state–based DDI evaluations can be conducted in patients with cancer in carefully designed studies. Per FDA guidance, strong, moderate, and weak inducers are drugs that decrease the AUC of sensitive index substrates by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively. Based on these criteria, lorlatinib behaved as a net weak inducer of CYP2B6, CYP2C9, and UGT; and a net moderate inducer of P-gp. The results of this sub-study can help guide recommendations for dose modifications when lorlatinib is given concomitantly with drugs that are metabolized by these enzymes or transporters. Based on the current results, only drugs that are P-gp substrates of narrow therapeutic index may require dose adjustments when used concomitantly with lorlatinib.

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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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      P2.04-36 - Immune Checkpoint Inhibition for Non-Small Cell Lung Cancer (NSCLC) in Patients with Pulmonary Tuberculosis or Hepatitis B (Now Available) (ID 869)

      10:15 - 18:15  |  Author(s): Ross Soo

      • Abstract
      • Slides

      Background

      Pulmonary tuberculosis (pTB) and Hepatitis B (HepB) are endemic in Asia. Multiple trials have shown a survival benefit of immune-checkpoint inhibitors (ICI), either as monotherapy or in combination with chemotherapy over chemotherapy in the treatment of NSCLC in first or second-line setting. However, patients with chronic infections are routinely excluded from such studies, and the safety and efficacy of ICI in this population is scarce.

      Method

      A retrospective review of clinical records of patients with advanced NSCLC with pTB and/or HepB, treated with ICI from January 2014 to March 2019 at a single Asian centre was conducted. The diagnosis of pTB was based on isolation of m. tuberculosis from sputum culture or nuclei acid amplification.

      Result

      13 patients were analysed. 12 (92.3%) were male, with a median age of 67 years (range 41 – 86) and 10 (76.9%) patients had an Eastern Cooperative Oncology Group performance status of 0-1. Nine (69.2%) patients received anti-PD-1/PD-L1 monotherapy, and four received ICI in combination with chemotherapy. Seven (53.8%) patients were treatment-naïve and six received ICI in the second-line and beyond. Seven patients had a history of pTB and ten patients had HepB. Four patients had a history of both HepB and pTB. The median progression-free survival (PFS) of the entire cohort was 6.7 months (95% CI: 3.3 – 10.2 months). The median overall survival (OS) was 13.3 months (95% CI: 0.0 – 31.2 months). Five patients had an objective response, and nine patients had disease control (complete/partial response or disease control). Immune-related adverse events (irAE) occurred in four patients – one patient each with endocrinopathy (G2), pneumonitis (G3), arthritis (G3) and hepatitis (G3). There were no treatment-related deaths. Four patients had pTB prior to initiation of ICI, and three patients developed pTB after. Two patients received anti-TB therapy on ICI and developed G3 transaminases which resolved after omission of anti-TB therapy. For all the patients who had completed treatment for pTB, none experienced re-activation. Of the 10 patients with HepB, four were chronic carriers (HepB surface-antigen (HBsAg) positive and detectable viral load), and six were previously exposed (HBsAg negative, anti-hepB core-antibody positive). Only one of the patients who had previous exposure to HepB received anti-viral prophylaxis and there were no incidences of re-activation.

      Conclusion

      Based on our findings, the risks of ICI therapy do not appear to be increased in patients with pTB or HepB. Further studies identifying those who are at risk of reactivation are essential.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-20 - ATORG-003: Dacomitinib With or Without Dose Titration as First-Line Therapy for Metastatic EGFR Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 67)

      10:15 - 18:15  |  Author(s): Ross Soo

      • Abstract
      • Slides

      Background

      Dacomitinib is a second generation EGFR tyrosine kinase inhibitor (TKI) with irreversible pan-HER inhibitory activity. In the phase III ARCHER 1050 trial, median PFS was improved from 9.2 months to 14.7 months in the gefitinib and dacomitinib groups respectively. Significantly, median overall survival (OS) was also improved from 26.8 months to 34.1 months. However, dacomitinib commenced at 45 mg orally daily was associated with increased toxicity, higher rates of dose reductions and treatment discontinuation. Despite this, post-hoc analysis revealed the efficacy of dacomitinib (PFS and OS) was similar in dose-reduced patients and the overall study population. This investigator-initiated trial aims to evaluate an alternative dose titration strategy to improve the safety and tolerability of dacomitinib while maintaining treatment efficacy. The trial is being conducted by the Asian Thoracic Oncology Research Group (ATORG) – a co-operative lung cancer trials group in Asia.

      Method

      ATORG-003 is a multi-national, multi-centre, single-arm, open-label, phase 2 clinical trial of dacomitinib in newly diagnosed stage IIIB/IV or recurrent EGFR mutant (exon 19 deletion or L858R mutation) NSCLC patients. Importantly, subjects with asymptomatic central nervous system (CNS) metastases will be eligible. Patients will be administered dacomitinib 30 mg orally daily for one cycle (4 weeks), after which subjects with <G1 toxicity attributable to dacomitinib may escalate to 45 mg with shared investigator and patient decision. Dose reductions to 30 or 15 mg daily will be permitted. The primary objective is to evaluate PFS rate at 12 months. Key secondary objectives include OS, objective response rate (ORR), time to treatment failure (TTF) and intracranial objective response rate (iORR). Exploratory objectives include evaluation of dacomitinib resistance mechanism(s) using next-generation sequencing (NGS) on tissue and plasma circulating tumour DNA (ctDNA). Across 15 sites in six Asian countries (Hong Kong, Korea, Malaysia, Singapore, Taiwan, Thailand), a planned 118 subjects will be enrolled. Primary analysis will be conducted on subjects without CNS metastases only, with 94 subjects required to achieve a one-sided significance level of 5% and 90% power to detect a 15% improvement in 12 month PFS rate for dacomitinib versus historical control for gefitinib (i.e. 55% versus 40%) using the intent-to-treat (ITT) analysis population. Enrollment is due to begin in July 2019.

      Result

      Section not applicable.

      Conclusion

      Section not applicable.

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