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Byoung Chul Cho



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    ES30 - What is the Best Treatment Strategy to Target Rare Mutations (ID 241)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
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      ES30.04 - Monoclonal Antibodies Targeting the ErbB Receptors (ID 4095)

      16:45 - 17:45  |  Presenting Author(s): Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Abstract

      Blockade of a critical oncogenic target is envisioned as a promising strategy for treating cancer. The blockade of ErbB receptors with anti-ErbB monoclonal antibody represents one such strategy that has been successful in the treatment of HER2-overexpressing multiple solid tumors including NSCLC.

      Approximately 6% of EGFR mutated NSCLC have EGFR exon 20 insertion (E20Ins) mutations. EGFR E20Ins is the third most common type of EGFR mutation

      Multiple subtypes and structural differences may limit development of novel targeted therapies. Amivantamab is a fully human EGFR-MET bispecific antibody targeting activating and resistance EGFR mutations and MET mutations and amplifications. Amivantamab demonstrated clinical activity across diverse EGFR mutant NSCLC.

      In CHRYSALIS phase 1study, amivantamab showed robust efficacy with tolerable safety profile in post-platinum EGFR E20Ins NSCLC.

      HER 2 mutation occurs in about 2% of lung adenocarcinoma. HER2 mutation is more frequently found in never-smoker, women, Asian, and adenocarcinoma. Contrast to HER2 mutation, HER2 overexpression and amplification is not a definite biomarker to HER2 directed therapy. Anti-HER2 monoclonal antibody as monotherapy or in combination has shown conflicting results in HER2 overexpressed or amplified NSCLC.

      Compared to EGFR and HER2, HER3 has been somwhat ignored as a therapeutic target most likely due to lack of intrinsc kinase activity. However, upon ligand binding and subsequent dimerization with HER2, HER3 potently activates PI3K pathway and MAPK pathway. HER3 Monoclonal antibody as a monotherapu may not sufficient to fully inhibit tumor cells and combination with other ErbB therapy, chemotherapy may enhance therapeutic effects. Recently, monoclonal antibody targeting HER3 exhibited clinical activity in NRG1 fusion+ NSCLC. In conclusion, rapid pace of targeted drug development transforms lives of NSCLC patients with these rare actionable mutations.

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    FP03 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) (ID 151)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP03.02 - Interim Analysis of Neoadjuvant Chemoradiotherapy and Durvalumab for Potentially Resectable Stage III Non-Small Cell Lung Cancer (NSCLC) (ID 804)

      00:00 - 00:00  |  Author(s): Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Introduction

      Although definitive concurrent chemoradiotherapy (CRT) is considered standard of care for most stage III NSCLC patients, neoadjuvant-CRT (N-CRT) followed by surgery is an accepted practice with a potential survival benefit. Regarding synergistic effects of combining PD-1/PD-L1 blockade to CRT, we designed a two-stage phase Ib trial (ACTS-30) which assesses the safety and feasibility of the combination of N-CRT with durvalumab (PD-L1 inhibitor) in potentially resectable stage III NSCLC (ClinicalTrials.gov identifier: NCT03694236).

      Methods

      Patients with histologically confirmed, potentially resectable stage III NSCLC were eligible. N-CRT comprised intravenous weekly paclitaxel 45 mg/m2 and carboplatin AUC 2 with radiotherapy of 45 Gy in 25 fractions and durvalumab (Day 1 and 29, 1500mg) during 5 weeks and patients who completed N-CRT subsequently underwent surgery. After surgery, one year of adjuvant durvalumab was planned (every 4 weeks, 1500 mg). The primary objective was to determine the safety and tolerability of N-CRT + durvalumab regimen. The trial was composed of two-stages and the first stage included 9 patients and the trial was planned to proceed to the second stage (n = 21) if treatment-related adverse events (TRAEs) grade≥3 occurred in less than 50% of patients. The secondary endpoints are objective response rate (ORR), R0 resection rate, event-free survival (EFS), overall survival (OS), clinical or pathological downstaging rate, pathologic complete response (pCR) rate, and major pathologic response (MPR) rate. The exploratory analyses including immune marker assessment by FACS, whole-exome sequencing, single-cell RNA sequencing, and multispectral immunohistochemical staining using the specimen of pre-treatment, after surgery, and after recurrence will be performed.

      Results

      At the data cut-off (25th-Feb-2020), a total of 14 patients were enrolled. The median age was 66; 50% were male, and 50% were adenocarcinoma histology including two EGFR mutations. Since there was only one grade 3 TRAE (i.e., neutropenia) during the first stage, the trial entered the second stage. Overall, the grade 3 or more rate of TRAE was 7% (1/14). Currently, 11 patients underwent surgery (R0 resection) while one patient experienced cardiac pacemaker infection grade 3 (not considered as TRAE) and was not able to undergo surgical resection and two others are awaiting surgery. There was no postoperative in-hospital mortality. Among eleven resected patients, the pCR rate and MPR rate were 36.4% (3/11) and 72.7% (8/11), respectively. When excluding two EGFR mutant, the MPR rate was 88.9% (8/9).

      Conclusion

      These early data suggested that the N-CRT regimen with immunotherapy in stage III NSCLC was safe and feasible and had the potential to provide clinical benefit. The trial is ongoing and the final results and the biomarker analyses will be provided in the future congress and scientific journal.

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    FP13 - Immunotherapy (Phase II/III Trials) (ID 247)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP13.04 - KEYNOTE-042 3-Year Survival Update: 1L Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1+ Locally Advanced/Metastatic NSCLC (ID 1273)

      00:00 - 00:00  |  Presenting Author(s): Byoung Chul Cho

      • Abstract
      • Presentation

      Introduction

      In the KEYNOTE-042 study (NCT02220894), pembrolizumab significantly improved OS vs platinum-based chemotherapy as first-line treatment for locally advanced/metastatic NSCLC without sensitizing EGFR/ALK alterations with PD-L1 tumor proportion score (TPS) ≥1%. We present updated data from KEYNOTE-042 with >3 years follow-up from randomization, including an exploratory analysis of time to progression on next-line therapy (PFS-2). Outcomes in patients who completed 35 cycles of pembrolizumab and in those who received second-course treatment are also reported.

      Methods

      Patients were randomized 1:1 to pembrolizumab 200 mg Q3W for 35 cycles or chemotherapy (carboplatin area under the curve 6/5 plus paclitaxel 200 mg/m2 or pemetrexed 500 mg/m2) Q3W for 4‒6 cycles with optional pemetrexed maintenance (nonsquamous only). Randomization was stratified by region (East Asia vs nonEast Asia), histology (squamous vs nonsquamous), ECOG PS (0 vs 1), and PD-L1 TPS (≥50% vs 1%49%). The primary endpoint was OS in prespecified TPS groups (≥50%, ≥20%, and ≥1%). Secondary endpoints included PFS, ORR, and safety. Patients randomized to pembrolizumab who completed 35 treatment cycles with SD or better or stopped treatment after confirmed CR could receive second-course pembrolizumab after PD if eligibility criteria were met. No alpha was assigned to these analyses.

      Results

      1274 patients were randomized (pembrolizumab, n=637; chemotherapy, n=637). As of February 21, 2020, median (range) time from randomization to database cutoff was 46.9 (35.8‒62.1) months. Efficacy results are summarized in the Table. Treatment-related grade 3‒5 AEs occurred in 120 (18.9%) vs 256 patients (41.6%) in the pembrolizumab vs chemotherapy groups. 102 patients completed 35 cycles (~2 years) of pembrolizumab. 86/102 (84.3%) had CR (n=2) or PR (n=84) as best response. 80/102 (78.4%) patients were alive at time of analysis. 1-year OS after completion of 35 cycles was 91.1% in patients with PD-L1 TPS ≥1%. Among 26 patients who received second-course pembrolizumab; ORR after initiation of second-course treatment was 15.4% (all PR), and the disease-control rate (CR+PR+SD) was 76.9%. 21/26 (80.8%) patients were alive at data cutoff.

      Table. Efficacy

      PD-L1 TPS ≥50%

      PD-L1 TPS ≥20%

      PD-L1 TPS ≥1%

      Pembro

      (N=299)

      Chemo

      (N=300)

      Pembro

      (N=413)

      Chemo

      (N=405)

      Pembro

      (N=637)

      Chemo

      (N=637)

      Median OS,a,b mo

      (95% CI)

      20.0

      (15.9‒24.2)

      12.2

      (10.4‒14.6)

      18.0

      (15.5‒21.5)

      13.0

      (11.6‒15.3)

      16.4

      (14.0‒19.6)

      12.1

      (11.3‒13.3)

      HR

      (95% CI)

      0.68

      (0.57‒0.82)

      0.75

      (0.64‒0.88)

      0.80

      (0.71‒0.90)

      3-y OS rate,a %

      (95% CI)

      31.3

      (26.1‒36.6)

      18.4

      (14.2‒23.0)

      28.3

      (24.1‒32.8)

      18.8

      (15.1‒22.8)

      25.3

      (22.0‒28.7)

      16.7

      (13.8‒19.7)

      Median PFS,a,b, c mo (95% CI)

      6.5

      (5.9‒8.6)

      6.5

      (6.2‒7.6)

      6.2

      (5.1‒7.4)

      6.8

      (6.3‒8.1)

      5.5

      (4.3‒6.2)

      6.8

      (6.4‒7.7)

      HR

      (95% CI)

      0.85

      (0.72‒1.02)

      0.95

      (0.82‒1.10)

      1.05

      (0.93‒1.18)

      3-y PFS rate,a % (95% CI)

      14.5

      (10.5‒19.0)

      5.3

      (3.0‒8.7)

      13.2

      (10.0‒16.9)

      4.7

      (2.7‒7.5)

      11.0

      (8.6‒13.7)

      4.1

      (2.6‒6.2)

      Median PFS-2,a,d mo (95% CI)

      15.0

      (11.6‒19.2)

      10.1

      (8.9‒11.2)

      12.9

      (10.9‒15.5)

      10.2 (9.0‒11.3)

      11.3

      (10.1‒12.9)

      9.3

      (8.6‒10.2)

      HR

      (95% CI)

      0.62

      (0.52‒0.74)

      0.66

      (0.57‒0.77)

      0.73

      (0.65‒0.82)

      ORR,b %

      39.1
      (33.6‒44.9)

      32.3
      (27.1‒37.9)

      33.2
      (28.6‒37.9)

      29.1
      (24.8‒33.8)

      27.3
      (23.9‒31.0)

      26.7
      (23.3‒30.3)

      Median DOR,a mo

      (95% CI)

      27.3

      (2.1+ to 56.0+)

      10.8

      (1.8+ to 49.6+)

      22.3

      (2.1+ to 56.0+)

      10.8

      (1.8+ to 49.6+)

      22.3

      (2.1+ to 56.0+)

      8.4

      (1.8+ to 49.6+)

      Chemo, chemotherapy; Pembro, pembrolizumab.

      “+” indicates no progressive disease at the time of last disease assessment.

      aKaplan-Meier estimate.

      bOS and PFS were calculated from the time of randomization.

      cPer RECIST v1.1 by blinded independent central review.

      dPFS-2 was defined as time from randomization to subsequent disease progression after initiation of new anticancer therapy, or death from any cause, whichever occurred first.

      Conclusion

      With long-term follow-up, first-line pembrolizumab monotherapy continued to show improved OS, ORR and PFS-2 outcomes compared with platinum-based chemotherapy in patients with locally advanced/metastatic PD-L1–positive NSCLC without sensitizing EGFR/ALK alterations, with a manageable safety profile. Patients who completed 35 cycles of pembrolizumab had durable responses, and second-course pembrolizumab was feasible and associated with antitumor activity. These findings continue to support first-line pembrolizumab in patients with locally advanced/metastatic PD-L1–positive NSCLC without sensitizing EGFR/ALK alterations.

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    FP14 - Targeted Therapy - Clinically Focused (ID 252)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 3
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP14.03 - Osimertinib + Savolitinib in pts with EGFRm MET-Amplified/Overexpressed NSCLC: Phase Ib TATTON Parts B and D Final Analysis (ID 3312)

      00:00 - 00:00  |  Author(s): Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Introduction

      Preliminary data from TATTON (NCT02143466, a multi-arm, multi-drug combination study) suggested that savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), plus osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-TKI, that potently and selectively inhibits T790M and EGFR mutations (EGFRm), may overcome MET-based resistance to EGFR-TKIs in NSCLC. We present the final data from two TATTON expansion cohorts (TATTON Parts B and D); data cutoff 4 March 2020.

      Methods

      Adult patients with locally advanced/metastatic, MET-amplified/overexpressed, EGFRm NSCLC, and disease progression on a prior EGFR-TKI. Most patients had retrospective, central confirmation of MET status by local fluorescent in-situ hybridisation (MET gene copy ≥5 or MET/CEP7 ratio ≥2), next-generation sequencing or immunohistochemistry (+3 in ≥50% of tumour cells). In Part B, patients received osimertinib 80 mg plus savolitinib 600 mg orally once daily; after a protocol amendment, patients ≤55 kg received savolitinib 300 mg. In Part D, patients who had received no prior third-generation EGFR-TKI and were T790M-negative, received osimertinib plus savolitinib 300 mg. The primary endpoint was safety/tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and pharmacokinetics.

      Results

      In Parts B and D, 138 and 42 patients respectively, received treatment. Grade ≥3 adverse events (AEs) were reported in 62% and 50% of patients, in Parts B and D respectively; serious AEs were reported in 49% and 38% of patients, respectively. AEs led to discontinuation of savolitinib in 49 (36%) and 15 (36%) patients, and osimertinib in 24 (17%) and 8 (19%) patients, for Parts B and D, respectively. In Part B, seven patients died due to AEs; two cases were possibly treatment-related. In Part D, two patients died due to AEs; neither was considered treatment-related. PFS and ORR results are included in the Table. Pharmacokinetics of savolitinib and osimertinib were consistent with other patient populations in TATTON and previous studies.

      Conclusion

      Osimertinib plus savolitinib was generally well tolerated and the safety profile was in-line with that previously reported. Our results support that osimertinib plus savolitinib may overcome MET-based resistance in patients with NSCLC whose disease has progressed on prior EGFR-TKI. Further exploration of the osimertinib plus savolitinib combination is underway in the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies.

      Table

      Part B: osimertinib 80 mg + savolitinib 600/300* mg

      Part D: osimertinib 80 mg + savolitinib 300 mg

      Endpoint

      Previously treated with a 3G EGFR-TKI

      No prior 3G EGFR-TKI, T790M-negative

      No prior 3G EGFR-TKI, T790M-positive

      No prior 3G EGFR-TKI, T790M-negative

      n=69

      n=51

      n=18

      n=42

      ORR, n (%)

      [95% CI]

      23 (33)

      [22.4, 45.7]

      33 (65)

      [50.1, 77.6]

      12 (67)

      [41.0, 86.7]

      26 (62)

      [45.6, 76.4]

      Median PFS, months
      [95% CI]

      5.5
      [4.1, 7.7]

      9.1
      [5.5,12.8]

      11.1
      [4.1,22.1]

      9.0
      [5.6, 12.7]

      Total PFS events, n (%)

      51 (74)

      36 (71)

      12 (67)

      29 (69)

      * Most patients were enrolled to 600 mg savolitinib, prior to weight-based dosing implementation, but following a protocol amendment, the final 21 patients enrolled in Part B were dosed with savolitinib by body weight as follows: patients who weighed ≤55 kg (n=7) received 300 mg daily and those weighing >55 kg (n=14) received 600 mg daily

      All confirmed responses were partial response.

      3G, third generation; CI, confidence interval; ORR, objective response rate; PFS, progression-free survival

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      FP14.10 - Efficacy and Safety of Selpercatinib (LOXO-292) in East Asian Patients with RET Fusion-Positive NSCLC (ID 1896)

      00:00 - 00:00  |  Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      Selpercatinib is a highly selective and potent, CNS-active, oral RET kinase inhibitor. Here we report the efficacy and safety analyses for the East Asian subgroup with RET fusion-positive NSCLC included in the Primary Analyses Set (PAS). Per regulatory authority agreement, the PAS was defined as the first 105 consecutively enrolled patients that had been previously treated with platinum-based chemotherapy.

      Methods

      Patients with RET fusion-positive NSCLC were enrolled to the global multicenter Phase 1/2 LIBRETTO-001 trial (NCT03157128), conducted in 89 sites across 16 countries, including 23 sites in 7 countries that enrolled patients who self-identified as Asian [Japan (12 patients), South Korea (11 patients), Singapore (5 patients), Hong Kong (5 patients), United States (5 patients), Australia (1 patient), and France (1 patient)]. Following the dose escalation Phase 1 portion, patients received the recommended Phase 2 dose of selpercatinib (160 mg orally, BID, 28-day cycles). The primary endpoint was independently-assessed objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. The analyses reported herein examine the East Asian PAS patient subgroup using data from the 16-Dec-2019 cutoff date.

      Results

      A total of 40 East Asian patients included in the PAS were analyzed. Baseline demographics were: 60% female; median age 56 years (range: 35–80); 95% of patients with an ECOG performance status of 0 or 1. RET fusion partners included: KIF5B-RET (57.5%), CCDC6-RET (15.0%), NCOA4-RET (2.5%), other/unknown (25%). All patients received prior systemic therapy, including platinum-based chemotherapy (100% of patients), a multi-kinase inhibitor (52.5%), and anti-PD-1/PD-L1 therapy (57.5%). The median number of prior therapies was 3.0 (range 1–15). Independently-assessed ORR was 60.0% (95% CI=43.3–75.1, n=24/40). Median DoR was not reached at a median follow-up of 12 months. In the safety analysis of all East Asian patients with NSCLC dosed with selpercatinib (N=136), treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were increased ALT/AST, dry mouth, hypertension, diarrhea, increased creatinine, QT prolongation, thrombocytopenia, peripheral edema, and rash. Only 1.5% (2 of 136) of East Asian patients discontinued selpercatinib due to TRAEs.

      Conclusion

      In this heavily pretreated population of East Asian patients with RET fusion-positive NSCLC, treatment with selpercatinib resulted in a marked and durable tumor response with a well-tolerated safety profile that was consistent with previously reported results from LIBRETTO-001. No new safety signals were identified.

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      FP14.14 - Post Hoc Analyses from an Open Label, Multi-Centre, ASTRIS Trial of Efficacy of Osimertinib for CNS Metastases with T790M-Positive Advanced NSCLC (ID 2279)

      00:00 - 00:00  |  Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      Up to 40% of patients with epithelial growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) develop central nervous system(CNS) metastases throughout their disease. CNS metastasis has a negative impact on survival and quality of life including neurological dysfunction and cognitive impairment. However, the first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) have limited efficacy because of their limited blood-brain barrier permeability. Osimertinib, third-generation EGFR-TKI with selective activity for both sensitizing and EGFR T790M mutations, have showed higher CNS penetration ability over first- and second-generation EGFR-TKIs. Herein we conducted post hoc analyses of ASTRIS, a clinical study of osimertinib to demonstrate its potential role of intracranial response in a real-world cohort.

      Methods

      This was a preplanned, exploratory analysis of CNS activity of osimertinib in Korean subgroup of ASTRIS trial, an open-label, single-arm, real-world treatment study to evaluate the efficacy and safety of osimertinib (80mg orally, once daily) in patients with EGFR T790M mutation-positive NSCLC who progressed upon prior EGFR-TKIs. We classified the patients according to the baseline brain status including leptomeningeal metastases(LM) by blinded independent central review (BICR). A CNS measurable lesion was defined as the lesion which was ≥ 10mm in longest diameter by BICR.We collected the information regarding patients’ baseline characteristics, mutation stutus, intracranial and extracranial responses with duration for ananlysis.

      Results

      The median age was 60 years and 69.7% of patients were female. Seventy-seven patients (86.5%) were Eastern Cooperative Oncology Group performance status (ECOG) less than 2. All patients had common baseline EGFR mutation (Exon 19deletion or L858R) except one patients with G719X mutation. Sixty-five patient (73.0%) had BM at baseline and 19 patients (23.5%) had additional LM. Among patients with BM, 24 (36.9%) had ≥ 1 measurable lesion and 16 had evaluated for the objective response. For the patient with BM and/or LM at baseline, eventually 28 patient had intracranial progression and for the paitent without BM or LM at baseline two had newly developed lesion during treatment. The Intracranial objective response rate (cORR) and disease control rate(cDCR) was 62.5% (95% confidence interval [CI], 38.3–82.6%) and 93.8% (95% CI, 74.3–99.3%), respectively. The median intracranial progression-free survival (cPFS) which included any cause of death as an event, was 13.0 (95% CI, 7.21–18.8) month including patients with measurable and/or non-measurable BM or LM.

      Conclusion

      Our cORR, cDCR, and cPFS were comparable to those observed in previous clinical trials. The outcome of this study is expected to be helpful demonstrating the potential role of intracranial efficacies of osimertinib 80 mg administration in T790M-positive advanced NSCLC with/without BM or LM. Further analysis of overall survival, specific response rate of patient with LM and biomarker for intracranial response or progression are ongoing.

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    IS08 - Industry Symposium Sponsored by Janssen Oncology: What the Future Holds for Advanced NSCLC Patients with Resistance to EGFR TKIs (ID 285)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 1
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      IS08.02 - A Light at the End of the Tunnel - Hope for Patients With EGFR Exon20 Insertion Mutations (ID 4342)

      13:00 - 14:00  |  Presenting Author(s): Byoung Chul Cho

      • Abstract

      Abstract not provided

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    MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 2
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      MA11.05 - Tepotinib in Patients with MET exon 14 (METex14) Skipping Advanced NSCLC: Updated Efficacy Results from VISION Cohort A (ID 1361)

      14:15 - 15:15  |  Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      In the Phase II VISION study (NCT02864992), tepotinib demonstrated durable efficacy and a tolerable safety in patients with NSCLC harboring METex14 skipping. Here, we report updated efficacy outcomes from a preplanned data cut-off (July 1, 2020) in patients with at least 9 months of follow-up, including detailed subgroup analyses of treatment-naïve and previously treated patients.

      Methods

      Patients with advanced, EGFR/ALK wild-type, METex14 skipping NSCLC received oral tepotinib 500 mg once daily. Patients enrolled in Cohort A with ≥9 months of follow-up were assessed for efficacy. All patients with METex14 skipping NSCLC who received tepotinib in Cohort A, or confirmatory Cohort C, were assessed for safety. Primary endpoint was objective response rate (ORR) by independent review committee (IRC) using RECIST 1.1. Secondary endpoints included ORR by investigator assessment, duration of response (DOR), and safety.

      Results

      As of July 1, 2020, 146 patients had ≥9 months of follow-up and were assessed for efficacy; 255 patients were evaluated for safety. In the efficacy population, patients had a median age of 73.4 years (range 41 to 94), 76 were male (52.1%), 76 had a smoking history (52.1%), and 81 had received prior treatment for advanced/metastatic disease (55.5%). 72 patients had received prior platinum-based chemotherapy for metastatic disease, either alone (n=63) or in combination with immunotherapy (n=9).

      The overall ORR by IRC was 45.2% (95% confidence interval [CI]: 37.0, 53.6), with a median DOR of 11.1 months (95% CI: 8.4, 18.5). ORR by investigator assessment was 54.1% (95% CI: 45.7, 62.4), with a median DOR of 12.7 months (95% CI: 9.7, 18.3).

      ORR by IRC was similar in patients who were treatment-naïve (44.6%; 95% CI: 32.3, 57.5) or previously treated for advanced/metastatic disease (45.7%; 95% CI: 34.6, 57.1), and in those who received prior-platinum based chemotherapy for metastatic disease (50.0%; 95% CI: 38.0, 62.0). ORR was also comparable in patients who received immunotherapy, regardless of the treatment regimen used (figure).

      Grade ≥3 treatment-related adverse events (TRAEs) were reported in 25.1% of patients; 27 (10.6%) discontinued due to TRAEs. Peripheral edema was mostly low grade and rarely led to discontinuation (3.5%). The safety profile was similar across subgroups.

      wclc_cohorta_forest plot.jpg

      Conclusion

      In VISION, the largest study in patients with NSCLC harboring METex14 skipping, treatment with tepotinib showed durable clinical activity that was consistent across clinically relevant subgroups. Tepotinib demonstrated a safety profile consisting of mostly mild-to-moderate AEs with few treatment discontinuations.

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      MA11.07 - Phase 1/2 TRIDENT-1 Study of Repotrectinib in Patients with ROS1+ or NTRK+ Advanced Solid Tumors (ID 3255)

      14:15 - 15:15  |  Presenting Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      Repotrectinib is a next-generation ROS1/TRK TKI with >90-fold greater potency than crizotinib and entrectinib against ROS1 and >100-fold greater potency than larotrectinib against TRK in engineered Ba/F3 cell proliferation assays. In the Phase 1 portion of TRIDENT-1 study, repotrectinib demonstrated encouraging overall clinical activity in patients (pts) with ROS1 fusion+ NSCLC and TRK fusion+ solid tumors, especially in those pts with ROS1+ NSCLC who are TKI naive.

      Methods

      In Phase 1 portion of the study, the Recommended Phase 2 Dose (RP2D) for repotrectinib was determined to be 160 mg QD for 14 days followed by 160 mg BID if tolerated. Currently, this global trial (Clinical trial information: NCT03093116) is actively enrolling pts whose cancers harbor a ROS1 or NTRK1/2/3 fusion in six phase 2 expansion cohorts (see table). The primary endpoint for the Phase 2 portion is confirmed overall response rate (cORR) by Blinded Independent Central Review (BICR) using RECIST v1.1. An early interim analysis on 39 pts enrolled in Phase 2 was conducted using investigator assessment.

      Results

      Phase 1: Utilizing a 22 July 2019 data cutoff, cORR was 91% by BICR in 11 ROS1 TKI-naïve pts with 5 responses ongoing. The median duration of response (DOR) for the 10 confirmed responders was 23.1 months (95% CI: 5.6–not reached [NR]) and median progression-free survival (PFS) was 24.6 months (95% CI: 7.2 – NR). As of 6 April 2020, with an additional 8.5 months of follow-up, 4 of the 5 previously responding TKI-naïve pts remained in a partial response (PR) per physician assessment data and 7 TKI-naïve pts remained on treatment, range (17.3+ - 34.2+ months).

      Phase 2: The early Phase 2 TRIDENT-1 dataset utilizing a July 10, 2020 data cutoff includes the first 39 treated pts across six cohorts who have had at least one post-baseline scan. Data are summarized in table below:

      TRIDENT-1 Study of Repotrectinib

      (Phase 2 Cohorts)

      ORR

      95% CI

      ROS1+ TKI-Naïve, up to 1 line of chemotherapy or immunotherapy

      (EXP-1)

      86%*

      (6/7)

      (42-100)

      ROS1+ TKI-Pretreated, 1 prior TKI, with prior platinum-based chemotherapy

      (EXP-2)

      40%

      (2/5)

      (5-85)

      ROS1+ TKI-Pretreated, 1 prior TKI, without prior platinum-based chemotherapy

      (EXP-4)

      67%

      (4/6)

      (22-96)

      ROS1+ TKI-Pretreated 2-prior TKIs, without prior platinum-based chemotherapy

      (EXP-Other)

      40%

      (2/5)

      (5-85)

      NTRK TKI-Pretreated

      (EXP-6)

      50%

      (3/6)

      (12-88)

      * Since the data cutoff the 7th ROS1 TKI-naïve patient achieved an unconfirmed PR.

      Repotrectenib was well tolerated, with predominantly grades 1/2 adverse events. TEAEs in > 25 % of pts were dizziness (62%), fatigue (39%), constipation (33%), dysgeusia (33%), and dyspnea (28%). 90% of 39 treated pts in Phase 2 escalated to 160 mg twice daily (BID) after 14 days per the study defined dose titration approach. There were no Grade 4 or Grade 5 TRAEs.

      Conclusion

      Repotrectinib was well tolerated and continues to demonstrate encouraging overall clinical activity in pts with ROS1 fusion-positive NSCLC and TRK fusion-positive solid tumors.

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    OA04 - New Data from Rare EGFR Alterations (ID 223)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
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      OA04.04 - Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer (ID 3031)

      11:45 - 12:45  |  Author(s): Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Introduction

      Despite sharing similar tumor biology to other epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) tumors, no targeted therapies have been approved for NSCLC harboring EGFR Exon 20 insertion mutations (Exon20ins). The standard of care remains platinum-based chemotherapy for the front-line, with no clear subsequent options available. Amivantamab (JNJ-61186372) is a novel, fully human EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations, as well as MET mutations and amplifications, and has received FDA Breakthrough Therapy Designation for the treatment of patients with EGFR Exon20ins NSCLC after platinum-based chemotherapy. Here we present updated results on the Exon20ins cohort from the CHRYSALIS study (NCT02609776).

      Methods

      The dose escalation phase enrolled patients with advanced NSCLC to determine the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg for ≥80 kg) amivantamab. The dose expansion phase assessed the safety and efficacy of amivantamab in patients with EGFR- and MET-mutant NSCLC treated at the RP2D. Disease response was assessed by the investigator per RECIST v1.1 and is presented for those patients with Exon20ins NSCLC who had progressed on prior platinum-based chemotherapy, were treated at the RP2D, and had at least 3 post-baseline disease assessments (18 weeks) or discontinued, progressed, or died prior to the 3rd assessment (the Post-Platinum Cohort). The data cutoff date was 8 Jun 2020.

      Results

      In the Post-Platinum Cohort (n=81), median age was 62 (42 – 84), 59% were women, 49% were Asian, median prior lines of therapy was 2 (1 – 7), and 53% were never-smokers. At a median follow-up of 6.5 months (1.1 – 29.3), investigator-assessed overall response rate (ORR) was 36% (29/81; 95% CI, 25 – 47), with all responders achieving partial response (PR). The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 73% (59/81; 95% CI, 62 – 82). Responses were durable at a median of 6.8 months (95% CI, 5.0 – not reached) with ongoing responses in 18/29 (longest at 16+ months). Median progression-free survival was 8.3 months (95% CI, 5.5 – 12.7) and median overall survival was 22.8 months (95% CI, 14.0 – not reached).

      Among all phase 1 patients, across a variety of EGFR genomic alterations and lines of therapy, treated with amivantamab monotherapy at the RP2D (n=258), the most common adverse events (AEs) were rash (78%), infusion related reaction (IRR; 65%), and paronychia (40%). Additional EGFR-related AEs were stomatitis (19%), pruritus (19%), and diarrhea (11%). Grade ≥3 AEs were reported in 39% of patients; 14% were considered treatment-related, with rash (3%) and IRR (2%) being most frequent. No treatment-related deaths were reported. The incidence of treatment-related AEs leading to dose reduction and discontinuation was 10% and 3%, respectively.

      Conclusion

      Amivantamab treatment led to promising efficacy with durable responses in patients with EGFR Exon20ins NSCLC post-platinum doublet and continues to demonstrate a manageable safety profile in over 250 patients treated at the RP2D. A phase 3 study, PAPILLON, evaluating amivantamab in combination with chemotherapy in the front-line setting is in planning stages.

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    OA05 - Value and Quality in Lung Cancer (ID 216)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Health Services Research/Health Economics
    • Presentations: 1
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      OA05.03 - Real-World Global Data on Targeting Epidermal Growth Factor Receptor in Stage III Non-Small Cell Lung Cancer: The Results of the KINDLE Study (ID 2229)

      15:30 - 16:30  |  Author(s): Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Introduction

      Tyrosine kinase inhibitors (TKIs) are the standard of care for patients with metastatic non-small cell lung cancers (NSCLC) harbouring epidermal growth factor receptor mutations (EGFRm). However, the role of TKIs is not established in the management of stage III EGFRm disease. We describe the real-world practice of EGFRm testing and use of TKIs in stage III NSCLC in the KINDLE study, a multicentre, multi-country observational non-interventional study.

      Methods

      The KINDLE study retrospectively captured all diagnostics and treatments received by patients with stage III NSCLC between Jan 01st, 2013 and December 31st, 2017, as well as their associated outcomes. In this analysis we included patients who were tested for EGFRm as well as patients who were treated with EGFR TKIs. Baseline characteristics and treatments were described and progression free survival (PFS) and overall survival (OS) from first therapy were analysed using Kaplan Meier methods.

      Results

      3148 patients were enrolled in the KINDLE study across three regions: Asia (n=1873), Middle East & North Africa (MENA) (n=1045), and Latin America (LA) (n=230). Of those, 1114 patients (35.4%) were tested for the presence of an EGFRm (46.2% in Asia, 16.7% in MENA and 32.1% in LA). An EGFRm was detected in 31.7% of tested patients (34.3% in Asia, 20.0% in MENA and 28.4% in LA). TKIs were included in 5 different regimens as first therapy; as monotherapy, or in combination with any of the following, radiotherapy (RT), chemotherapy (CT), CT and immunotherapy (IO), RT and IO. Two additional regimens were used in subsequent lines (in combination with IO, or with RT and CT).

      Patients with EGFRm stage III NSCLC treated with a TKI, without irradiation, as initial monotherapy (n=68) had a median PFS of 10.6 months (95% CI; 7.5-13.4) and a median OS of 25.4 months (95% CI; 21.6-34.9). In unresectable stage III NSCLC treated with cCRT, for EGFRm patients (n=37) the median PFS of 10.5 months (5.1-16.2) and median OS of 48.0 months (47.2-NC) were similar to those for EGFR wild-type patients (n=145); median PFS 10.8 months (8.5-12.7), median OS 40.6 months (25.6-51.2). In patients with unresectable stage III EGFRm NSCLC (n=34) treated with TKIs, as initial monotherapy, the median PFS and OS were 14.6 months (8.0-18.5) and 24.4 months (15.4-34.9), respectively.

      Conclusion

      Concomitant CRT followed by durvalumab is currently the standard of care for unresectable stage III NSCLC, regardless of EGFR mutation status. The KINDLE study showed that in a real-world setting the minority of stage III NSCLC patients are tested for EGFRm and in patients with the mutation treatment is heterogenous. Unresectable patients with EGFRm had similar outcomes from cCRT compared with EGFR wild-type patients. Unresectable patients with EGFRm NSCLC who received a TKI, without irradiation, as initial monotherapy had worse OS than the ones treated with cCRT.The ongoing LAURA study (NCT03521154) will help define the role of TKIs in EGFRm stage III NSCLC treated with cCRT.

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    P04 - Early Stage/Localized Disease - Perioperative Therapy (Neoadjuvant Therapy, Surgery, Adjuvant Therapy) (ID 113)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P04.03 - Patient Characteristics and Clinical Outcomes of Stage III NSCLC in a Real-World Setting: KINDLE Korean Subset Data. (ID 3233)

      00:00 - 00:00  |  Presenting Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      Stage III NSCLC is a heterogeneous disease requiring a multimodality approach. We investigated real-world patient journey as a KINDLE study. Here we report Korean subset data.

      Methods

      KINDLE study is an international real-world study capturing data on patient and disease characteristics, treatments and outcomes. The study included patients with stage III NSCLC diagnosed between January 1st, 2013 and December 31st, 2017 and with at least 9 months of documented follow-up. Descriptive statistics were used to describe patient demographics, disease characteristics and treatment modalities. Inferential statistics was used to correlate various clinical and treatment variables with progression free survival (PFS) and overall survival (OS).

      Results

      461 patients were enrolled at 8 centers in Korea. Median age was 66 years (range 24-87); 75.7% were male; 74.0% with a smoking history; 69.2% were staged as IIIA; 48.8% had adenocarcinoma. 18.9% of patients presented disease through cancer screening program. As biomarker tests, EGFR test was performed in 65.3% (279 of 427) and 25.4% (71 of 279) were known to have an EGFR mutation. PD-L1 was evaluated in 31.7% (146 of 461) and 37.7% (55 of 146) were PD-L1 negative. The median follow-up duration was 772 days (range 4-2280) and 314 patients were alive or censored. A total of 108 patient cases (23.4%) were discussed in multidisciplinary team meeting. As first line therapy, the most common being concurrent chemo-radiotherapy (cCRT) in 34.5%, curative surgical resection in 26.8%. Median PFS for resectable (N=193) and unresectable (N=244) was 26.3 months (95% CI; 20.17 – 39.95) and 11.1 months (95% CI; 9.43 – 13.14), respectively. Median OS for resectable and unresectable was 66.7 months (95% CI; 65.38 – not calculated [NC]) and NC (95% CI; 37.52 – NC), respectively.

      Conclusion

      This study reveals the diversity of treatment patterns that exist in stage III NSCLC and provides insights on the outcomes in a real-world setting. The unmet medical need remains high and approaches are required to optimize patient outcomes including multidisciplinary team approach and improved access to innovative medicines.

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    P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P76.18 - Tissue- and Plasma-Based Landscape of Resistance to Osimertinib (ID 1236)

      00:00 - 00:00  |  Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      Osimertinib is a third generation EGFR tyrosine kinase inhibitor (TKI) that is approved for in EGFR-mutant non-small cell lung cancer (NSCLC) patients who failed initial EGFR TKI treatment or in the first-line settings. However, resistance develops invariably within approximately 1 to 2 years. C797S acquired mutation has been reported as the most described resistance mechanism to Osimertinib which is detected in approximately 20% of patients, but the other prevalent resistant mechanisms are still need to be identified. In this study, we investigated the acquired resistance mechanisms to Osimertinib in NSCLC patients using plasma and tumor samples collected at baseline, and at the time of progression.

      Methods

      Formalin-fixed paraffin-embedded tumor samples and plasma samples from 55 NSCLC patients who were treated with both osimertinb in 2nd line or beyond were prospectively collected at baseline and at progressive disease (PD). Next-generation sequencing was performed in tumor and plasma samples using a 600-gene hybrid capture panel designed by AstraZeneca. Clinicopathological parameters were obtained from chart review and statistical analysis was performed using R -4.0.2. Osimertinib-resistant cell lines and patient-derived xenografts and cells were generated and whole exome sequencing and RNA sequencing were performed. In vitro experiments were performed to functionally study the acquired mutations identified.

      Results

      A total of 55 patients and a total of 149 samples (57 tumor samples and 92 plasma samples) were analyzed, and among them 33 patients had matched pre- and post-treatment samples. We identified both EGFR-dependent and EGFR-independent mechanisms of resistance to osimertinib. As expected, EGFR C797S (14%) mutation was the most frequent EGFR-dependent mechanism, followed by EGFR G824D (6%), V726M (3%), V843I (3%). Among EGFR-independent mechanisms, alterations in TP53 (58%), NF1 (28%), PIK3CA (14%), APC (11%), ERBB2 (3%), BRAF (3%), NF2 (3%) were for resistance to osimertinib. Matched pre- and post-treatment sample analysis nominated mechanisms of acquired resistance. EGFR C797S was still most frequent (11%), and we noted that EGFR G824D (6%), V726M (3%), V843I (3%) were acquired, all of which the functional effects were unknown. Structure wise, EGFR V726M may produce steric hindrance to Osimertinib binding. Of EGFR-independent mechanisms, PIK3CA ALK, BRAF, EP300, KRAS, RAF1 mutations were notable. MET copy number gain was found to be most frequent (9%) copy number gain, followed by HER2 (6%). Serial plasma sample analysis was performed in six patients who received osimertinib beyond progression. PIK3CA R38H mutation was associated with liver metastasis, whereas EGFR C797S mutation was associated with primary lung cancer progression. Among Osimertinib-resistant cell lines and patient-derived organoids, we noted acquired mutations which were potentially targetable such as NRAS p.Q61K, in which resistance could be overcome with combination of osimertinib and trametinib.

      Conclusion

      In this study, we explored the genetic profiles of osimertinib resistance NSCLC patient samples using targeted sequencing. Genetic alteration profiles showed that osimertinib resistance was associated with both EGFR dependent and –independent genomic alterations. Further in vitro and in vivo validation studies are ongoing, and are to be presented at the meeting.

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      P76.27 - ORCHARD: A Biomarker-Directed Phase 2 Platform Study in pts with Advanced EGFRm NSCLC Progressing on First-Line Osimertinib (ID 1397)

      00:00 - 00:00  |  Presenting Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in EGFRm advanced NSCLC, including central nervous system metastases. Most patients’ (pts) tumors develop resistance to osimertinib through secondary EGFR mutations (including C797S, G724S and L718V/Q) and off-target genomic alterations (including MET amplification and gene fusions). Data suggest that off-target alterations such as ALK and RET fusions may be resistance mechanisms to first-line osimertinib in some pts (each <5%). The ORCHARD study (NCT03944772) aims to better characterize resistance mechanisms to first-line osimertinib, and evaluate post-progression treatments. The flexible, platform-based design allows for new cohorts and treatment arms, for broader exploration of targeting resistance mechanisms. Previously presented: WCLC 2019 (Yu H, et al. J Thorac Oncol;14[10 suppl]:S647).

      Methods

      In this open-label, multicenter, multidrug, biomarker-directed Phase 2 platform-based study (Figure), adult pts with locally advanced/metastatic EGFRm NSCLC whose disease progressed on first-line osimertinib are eligible. Treatment is assigned per molecular characterization of a mandatory tissue biopsy from a progressing lesion, analyzed by next-generation sequencing (Foundation Medicine Inc.). The protocol has recently been amended: Group A now includes treatment arms for pts with ALK/RET rearrangements, who will receive osimertinib plus alectinib/selpercatinib, respectively. The ‘MET alterations’ arm has been expanded from MET-amplification to also include MET exon 14 skipping, and the ‘EGFR alterations’ arm has been expanded from EGFR-amplification to also include mutations at the EGFR L718/G724 residue, or insertion in EGFR exon 20. Group B encompasses pts with no identifiable resistance mechanism; Group C is observational, for pts whose tumors harbor resistance mechanisms not currently addressed within the study. Tumor assessments (RECIST 1.1) will be performed every 6 weeks for 24 weeks, and every 9 weeks thereafter until disease progression or treatment discontinuation. Interim analyses will be performed on the first 16 pts in each cohort who have had the opportunity for two post-baseline RECIST assessments; individual cohorts may be stopped (if there is <10% probability for objective response rate [ORR] to be above target value [45%, equaling ≤4 of the 16 pts with confirmed responses]), or expanded to 30–40 pts for further evaluation. Primary endpoint: confirmed ORR (investigator assessed); secondary endpoints include: progression-free survival, duration of response, overall survival, and pharmacokinetics. Safety will also be reported. A summary of the observed genomic landscape during enrolment will be presented.

      figure.jpg

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    P77 - Immunotherapy (Phase II/III Trials) - Combining Different Immunotherapeutic Approaches (ID 254)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P77.02 - Efficacy of Tiragolumab + Atezolizumab in PD-L1 IHC and TIGIT Subgroups in the Phase II CITYSCAPE Study in First-Line NSCLC (ID 3501)

      00:00 - 00:00  |  Presenting Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      The immunomodulatory receptor TIGIT (T-cell Immunoreceptor with Ig and ITIM domains) is a novel inhibitory immune checkpoint on activated T cells and natural killer cells in multiple cancers. Tiragolumab (tira) is a humanized IgG1/kappa monoclonal antibody that binds TIGIT to prevent its interaction with its ligand PVR (CD155). Because PD-L1 expression is considered a hallmark of pre-existing immunity and is positively correlated with TIGIT expression, we investigated the combination of tira + atezolizumab (atezo) in patients with newly diagnosed PD-L1-positive metastatic NSCLC in the phase II CITYSCAPE trial. We recently reported an improvement in progression-free survival (PFS) with the tira + atezo combination over atezo monotherapy in patients whose tumors showed high PD-L1 expression (≥50% TPS or tumor proportion score) by the pharmDx immunohistochemistry (IHC) 22C3 assay (PFS hazard ratio [HR] 0.30, 95% confidence interval [CI]: 0.15-0.61) [Rodriguez-Abreu. ASCO 2020]. To determine whether these results were consistent across different PD-L1 IHC assays, we assessed the efficacy of tira + atezo in PD-L1 subgroups defined by the SP263 IHC assay. We also evaluated whether TIGIT expression was associated with tira + atezo efficacy.

      Methods

      PD-L1 expression was assessed prospectively using 22C3 IHC and retrospectively with SP263 IHC, both of which yield a tumor cell (TC) membrane staining score. TIGIT expression on tumor-infiltrating immune cells (IC) was assessed with an exploratory IHC assay.

      Results

      Among the 135 enrolled patients with PD-L1-positive NSCLC (intent-to-treat [ITT] population), 113 had results from the SP263 assay and 105 had results from the TIGIT assay. The biomarker-evaluable populations (BEP) for both of these assays were similar to the ITT population. Comparable PFS improvement with tira + atezo relative to atezo monotherapy was seen in PD-L1–high (≥50% TC) subgroups defined by SP263 (PFS HR 0.23, 95% CI: 0.10–0.53) when compared with PD-L1-high subgroups defined by 22C3. However, for patients whose tumors were defined as TIGIT-high (≥5% IC), no strong association with PFS improvement was observed.

      Biomarker subgroup

      Subgroup, n (BEP, N)

      PFS HR (CI) relative to atezo monotherapy arm

      ITT (PD-L1 IHC 22C3 >1% TPS)

      135 (135)

      0.58 (0.39–0.88)

      PD-L1 IHC 22C3 (≥50% TPS)

      58 (135)

      0.30* (0.15–0.61)

      PD-L1 IHC SP263 (≥50% TC)

      45 (113)

      0.23* (0.10–0.53)

      TIGIT IHC (≥5% IC)

      49 (105)

      0.62* (0.30–1.32)

      *Unstratified HR

      Conclusion

      Prevalence of PD-L1 subgroups in the BEP was comparable with previous reports for both IHC assays. The PFS benefit observed with tira + atezo in patients with tumors defined as PD-L1-high by 22C3 was also observed using the SP263 IHC assay, but not in tumors classified as TIGIT-high using an exploratory TIGIT IHC assay. Our results suggest that PD-L1 expression, assessed by 22C3 or SP263, may be a biomarker for tira + atezo combination therapy in metastatic PD-L1-positive untreated NSCLC.

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    P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P84.05 - Efficacy and Safety of Ceritinib 450-mg Fed vs 750-mg Fasted in Patients with ALK+ NSCLC: Final Report of the ASCEND-8 Trial (ID 3041)

      00:00 - 00:00  |  Presenting Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      The primary analysis of the open-label, phase I ASCEND-8 study (NCT02299505) showed that the patients with ALK-rearranged (ALK+) non–small cell lung cancer (NSCLC) treated with ceritinib 450 mg/day with a low fat meal (450-mg fed) had similar exposure with consistent efficacy and lesser gastrointestinal (GI) toxicity compared to 750-mg fasted dose. Here, we report the final analysis of the ASCEND-8 study comparing safety and efficacy of ceritinib 450-mg fed versus 750-mg fasted in patients with ALK+ NSCLC.

      Methods

      The primary endpoint of this phase I study comparing the steady-state pharmacokinetics of ceritinib at 450 mg/day and 600 mg/day with low fat meal and 750 mg/day under fasted state was published previously. Key secondary efficacy endpoints were blinded independent review committee (BIRC)-assessed overall response rate (ORR) and duration of response (DOR) evaluated per Response Evaluation Criteria in Solid Tumors version 1.1. Safety was assessed as the incidence and severity of adverse events (AEs) as per Common Terminology Criteria for Adverse Events version 4.03.

      Results

      At the study completion (06-March-2020), 306 pretreated and treatment-naïve patients were randomized to ceritinib 450-mg fed (N=108), 600-mg fed (N=87), and 750-mg fasted (N=111) arms. The safety set included patients who received ≥1 dose of ceritinib (N=304). The efficacy analysis comprised 198 treatment-naive patients: 450-mg fed (N=73), 600-mg fed (N=51), and 750-mg fasted (N=74). The median follow-up in treatment-naïve patients was 37.65 months. The enrollment in the 600-mg fed arm was closed early due to less favorable safety profile. The baseline characteristics and demographics were largely comparable across study arms. The ORR (95% confidence interval [CI]) per BIRC was 78.1% (66.9%, 86.9%) in the 450-mg fed arm and 75.7% (64.3%, 84.9%) in the 750-mg fasted arm. The DCR (95% CI) per BIRC was high in both arms; 90.4% (81.2%, 96.1%) in the 450-mg fed arm versus 90.5% (81.5%, 96.1%) in the 750-mg fasted arm. In patients with confirmed complete response or partial response, the median DOR (95% CI) per BIRC was not estimable (NE) (14.5, NE) in the 450-mg fed arm and 17.9 (12.5, NE) months in the 750-mg fasted arm. The investigator-assessed data were similar to BIRC results. The median relative dose intensity was high in the 450-mg fed (98.44%) arm versus 750-mg fasted (82.13%) arm. The incidence of AEs leading to drug discontinuation was 8.3% in the 450-mg fed arm compared to 9.1% in the 750-mg fasted arm. AEs leading to dose adjustment/interruption were less frequent in the 450-mg fed arm (56.5%) versus 750-mg fasted (77.3%) arm. The overall safety of ceritinib was comparable across study arms. However, any-grade GI toxicity (group event for nausea, diarrhea, and vomiting) was numerically lesser in the 450-mg fed (76.9%) versus 750-mg fasted (92.7%) patients. Grade 3/4 GI toxicity occurred in 1.9% patients in the 450-mg fed arm versus 17.3% in the 750-mg fasted arms.

      Conclusion

      Patients with ALK+ advanced/metastatic NSCLC treated with ceritinib at a dose of 450 mg/day with low fat meal showed favorable benefit/risk profile compared to the initially approved dose of 750 mg/day under fasted state.

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    P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P86.12 - Cardiac Safety Assessment of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer (ID 1247)

      00:00 - 00:00  |  Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      Lazertinib (YH25448, JNJ-73841937) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. The recommended phase 2 dose was determined to be 240 mg once daily (QD) in Korean patients based on the results of a first-in-human study in patients with advanced, EGFR-mutated non-small cell lung cancer at doses of 20-320 mg QD. The objective of this evaluation was to assess lazertinib cardiac safety in these patients.

      Methods

      The electrocardiogram (ECG) assessments (absolute and change from baseline QTcF) were performed in an ongoing phase 1/2 lazertinib pharmacokinetics, safety and efficacy study. A total of 224 patients [1st (n=43) and 2nd (n=181) line therapy, 20-320 mg QD dose] with baseline and postdose ECG assessments (in triplicates) along with time-matched plasma concentration data were included in exposure-QTcF analysis using linear regression. The left ventricular ejection fraction (LVEF) was assessed using an echocardiogram or multiple gated acquisition (MUGA) scan at baseline and every 12 weeks.

      Results

      Of 224 evaluable patients, no post-treatment QTcF values >500 ms were reported during the study; 26 (11.6%) patients had a post-baseline QTcF >450 ms including 3 (1.3%) patients with QTcF >480 ms. Of the 221 patients with baseline QTcF confirmed by central assessment, 22 (10.0%) patients had >30 to 60 ms increase and 1 (0.5%) had >60 ms increase in QTcF from baseline. Of the 121 patients at 240 mg, 10 (8.3%) patients had a post-baseline QTcF >450 ms including 1 (0.8%) patient with QTcF >480 ms. There were no clinical symptoms of QTc prolongation observed in any of the patients. At clinically relevant (240 mg QD dosing) plasma steady state Cmax (maximum plasma concentration) of 517.15 (43% coefficient of variation) ng/mL, the upper bound of the two-sided 90% confidence interval for change from baseline QTcF was estimated to 3.9 ms (low concern category). The exposure-QTcF assessment-based prediction suggests that a 2.5-fold and 4.8-fold higher than 517.15 ng/ml plasma concentration would be required to cause the upper bound of two-sided 90% confidence interval for the change from baseline in QTcF of ~10 ms (increasing concern category) and QTcF of ~20 ms (definite concern category), respectively. These results are in line with in vitro (hERG assay), ex-vivo (isolated perfused rabbit heart) and in vivo (instrumented male beagle dogs) preclinical findings. Of 224 patients, no treatment emergent adverse event related with heart failure or clinically meaningful decrease of LVEF was reported.

      Conclusion

      Taken together, preclinical and clinical cardiac safety assessment findings suggest that lazertinib has no clinically relevant effect on QT interval and LVEF. Time-matched plasma concentration and QTcF read-outs as well as LVEF assessments will continue to be collected in all ongoing as well as future lazertinib clinical studies to further confirm that lazertinib has no/minimal cardiac safety risk.

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    P89 - Targeted Therapy - Clinically Focused - Translational (ID 266)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P89.08 - Real-World Impact of Plasma Cell-Free DNA Next-Generation Sequencing to Detect Actionable Genomic Alterations in Advanced NSCLC (ID 1970)

      00:00 - 00:00  |  Author(s): Byoung Chul Cho

      • Abstract
      • Slides

      Introduction

      Next-generation sequencing (NGS) of plasma cell-free circulating tumor DNA (cfDNA) enables noninvasive comprehensive genomic analysis. The ability of cfDNA NGS to detect actionable genomic biomarkers in advanced non-small cell lung cancer (NSCLC) has been reported, but there are limited data on real-world usage. Here we prospectively collected the real-world cfDNA NGS data of treatment naive patients and also patients after progression to chemotherapy and/or immunotherapy and tyrosine kinase inhibitors(TKI) with negative tissue results for conventional tesing which we easily encounter in clinical practice.

      Methods

      We analyzed data from advanced NSCLC patients who underwent cfDNA NGS (Guardant360; Guardant Health, Inc.) between December 2018 and January 2020 in the clinical practice. Information regarding patient and disease characteristics, treatment decisions, and clinical outcomes were collected. Genomic alterations were considered actionable if they were included in the Onco-KB precision oncology knowledge database and classified in one of four levels of actionability based on the preclinical or clinical evidence.

      Results

      Among 405 patients, 35.1% were female; 81.2% had adenocarcinoma (LuAd). At the time of plasma collection for NGS, 143 patients (35.3 %) were treatment-naïve, 177 patients (43.7%) had progressed after chemotherapy and/or immunotherapy, and 61 patients (15.1%) had progressed after tyrosine kinase inhibitor (TKI). Tumor DNA was detectable in 356 plasma samples (87.9 %). Regarding LuAd potentially actionable level 1-4 genomic alterations were detected in 177 cases (53.6%), of which 82 patients (24.9%) had level 1-2 alterations. Twelve patients who had started treatment based on tissue data had their treatment changed due to cfDNA NGS results. At the time of data cut-off, one of these patients had a partial response, 6 had stable disease, and 5 were not yet evaluated.

      Conclusion

      Real-world cfDNA testing identified actionable genomic alterations in NSCLC not only when tissues were unavailable but also when conventional testing failed to detect actionable biomarkers. This study demonstrated that gene profiling of NSCLC using comprehensive cfDNA NGS can be a more efficient and faster strategy for deciding the therapeutic options at initial diagnosis and after progression.

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