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James Chih-Hsin Yang



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    FP14 - Targeted Therapy - Clinically Focused (ID 252)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • 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): James Chih-Hsin Yang

      • Abstract

      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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    IS03 - Industry Symposium Sponsored by Daiichi-Sankyo: Antibody Drug Conjugates (ADC) as Therapeutic Options for Advanced NSCLC: Opportunities and Challenges (ID 279)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 1
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      IS03.04 - ADC Therapies as Targeted Treatment Options in Patients With Advanced NSCLC (ID 4318)

      11:45 - 12:45  |  Presenting Author(s): James Chih-Hsin Yang

      • 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: 1
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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): James Chih-Hsin Yang

      • Abstract

      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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    OA03 - Promising Antibody-Drug Conjugate and Cytotoxic Therapy in NSCLC (ID 100)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
    • Presentations: 1
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      OA03.04 - Efficacy and Safety of the Novel HER3 Directed Antibody Drug Conjugate Patritumab Deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC (ID 3562)

      10:30 - 11:30  |  Author(s): James Chih-Hsin Yang

      • Abstract

      Introduction

      There are few treatment options for patients with advanced EGFR-mutated (EGFRm) NSCLC after failure of EGFR TKIs and platinum-based chemotherapy. Here we report safety and activity in such patients treated in a phase 1 study (NCT03260491) with patritumab deruxtecan, a HER3 directed antibody drug conjugate, at the 5.6 mg/kg recommended dose for expansion. These data were previously presented at ESMO Congress 2020, Helena A. Yu et al., reused with permission.

      Methods

      The dose escalation part was presented previously. The dose expansion part enrolled patients with EGFRm NSCLC with prior EGFR TKI and platinum-based chemotherapy. Primary objective is assessment of activity by confirmed ORR (blinded independent central review, BICR); secondary objectives include evaluation of safety. Patritumab deruxtecan was administered IV Q3W.

      Results

      As of 30 April 2020, 57 patients from dose escalation and dose expansion were treated at the 5.6 mg/kg dose, and 56 patients were evaluable for response. Among 28 patients continuing treatment at data cut-off, 6 had only 1 tumor evaluation. Median prior anticancer regimens for metastatic disease was 4 (range, 1-9); 51 patients [90%] received prior platinum-based chemotherapy. Median number of prior EGFR TKIs was 2 (range, 1-4); 49 patients [86%] received prior osimertinib. 27 patients (47%) had history of central nervous system metastases. Median treatment duration was 3.5 months (range, 1-14 months); median follow up was 5.4 months (range, 0.3-15 months). The most common grade ≥3 treatment-emergent adverse events were platelet count decrease (25%) and neutrophil count decrease (16%). Efficacy for the 56 efficacy-evaluable patients is shown in the table below; 3 additional patients had partial response awaiting confirmation. HER3 was expressed in nearly all tumors. Efficacy was observed in patients with various mechanisms of EGFR TKI resistance, including EGFR C797S mutation, MET amplification, HER2 mutation, BRAF fusion, and PIK3CA mutation.

      Conclusion

      Patritumab deruxtecan at 5.6 mg/kg provides promising evidence of preliminary antitumor activity and safety in heavily pre-treated patients with locally advanced or metastatic EGFRm NSCLC.

      Activity According to BICR Evaluation (Efficacy-Evaluable Population)

      Dose escalation + dose expansion cohorts

      EGFR mutated, 5.6 mg/kg patritumab deruxtecan

      (N = 56)a

      Confirmed BOR, n/N (%)

      CR

      1/56 (2)

      PR

      13/56 (23)

      SD

      25/56 (45)

      PD

      9/56 (16)

      NE

      8/56 (14)

      Confirmed ORR, n/N (%)

      95% CI

      14/56 (25)

      (14.4-38.4)

      DCR, n/N (%)

      95% CI

      39/56 (70)

      (55.9-81.2)

      DoR (95% CI) in months, median (range)

      7 (3.0-7.0)

      a22/56 (39%) patients had best percentage decrease in sum of tumor diameters ≥ 30%.

      BOR, best overall response; ORR, objective response rate; CR, complete response; DCR, disease control rate; DoR, duration of response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

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

    • Event: WCLC 2020
    • Type: Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 2
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      OA04.03 - Mobocertinib in NSCLC With EGFR Exon 20 Insertions: Results From EXCLAIM and Pooled Platinum-Pretreated Patient Populations (ID 3186)

      11:45 - 12:45  |  Author(s): James Chih-Hsin Yang

      • Abstract

      Introduction

      Mobocertinib is a potent first-in-class tyrosine kinase inhibitor (TKI) designed to target EGFR exon 20 insertion (EGFRex20ins) mutations. We report first results from the EXCLAIM extension cohort of a phase 1/2 study (NCT02716116) and results in patients with EGFRex20ins-mutant NSCLC who received prior platinum-based therapy from the dose-escalation/expansion parts of the study and the EXCLAIM extension cohort.

      Methods

      This 3-part, open-label, multicenter study included dose-escalation/expansion cohorts and the EXCLAIM extension cohort. Data are presented for all patients treated in EXCLAIM (N=96) and for platinum-pretreated patients from the dose-escalation/expansion cohorts (n=28) and from EXCLAIM (n=86); all received mobocertinib 160 mg orally QD. Enrolled patients had locally advanced/metastatic EGFRex20ins NSCLC, ECOG performance status 0–1, and ≥1 prior line of therapy for locally advanced/metastatic disease. The primary endpoint is confirmed ORR assessed by IRC per RECIST v1.1.

      Results

      In EXCLAIM, 96 patients were enrolled and treated; median age, 59 years [range: 27–80]; female, 65%; Asian, 69%; ≥2 prior systemic anticancer lines, 49% (range: 1–4). Median time on treatment was 6.5 months (range: 0–14). Confirmed ORR was 23% (22/96; 95% CI: 15%–33%) per IRC and 32% (95% CI: 23%–43%) per investigator; median DoR (Kaplan-Meier estimates) was not mature; median PFS was 7.3 months. See Table. In the analysis of platinum-pretreated patients (n=114), median age, 60 years [range: 27–84]; female, 66%; Asian, 60%; ≥2 prior systemic anticancer lines, 59% (range: 1–7). Median time on treatment was 7 months (range: 0–31); 38 patients (33%) remained on treatment as of 29-May-2020. Confirmed ORR was 26% (30/114; 95% CI: 19%–35%) per IRC and 35% (40/114; 26%–45%) per investigator. Median PFS was 7.3 months: 12-month PFS rate was 33% (95% CI: 21%–47%). Responses were observed among all prespecified subgroups, including Asian/non-Asian patients and those with/without baseline stable brain metastases. The most common treatment-related adverse events (TRAEs; ≥30%): diarrhea (90%), rash (45%), paronychia (34%), nausea (32%), decreased appetite (32%), dry skin (30%), and vomiting (30%); grade ≥3 TRAEs (≥5%): diarrhea (22%), anemia (5%), and dyspnea (5%). Nineteen patients (17%) discontinued due to AEs, most commonly diarrhea (4%) and nausea (4%). The safety profile observed in EXCLAIM was largely consistent with that observed in the platinum-pretreated population.

      table for submission.jpg

      Conclusion

      Mobocertinib demonstrated clinically meaningful benefit in previously treated patients with NSCLC and EGFRex20ins mutations, with a manageable safety profile.

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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): James Chih-Hsin Yang

      • Abstract

      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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    P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P01.01 - HERTHENA-Lung01: A Randomized Phase 2 Study of Patritumab Deruxtecan (HER3-DXd; U3-1402) in Previously Treated Metastatic EGFR-mutated NSCLC (ID 3412)

      00:00 - 00:00  |  Author(s): James Chih-Hsin Yang

      • Abstract

      Introduction

      Few treatment options have demonstrated meaningful therapeutic benefit for patients with epidermal growth factor receptor- (EGFR-) mutated non-small cell lung cancer (NSCLC) that has progressed after treatment with EGFR tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy. HER3, a member of the human epidermal growth factor family, is detectable in the majority of EGFR-mutated NSCLC, and expression has been associated with worse clinical outcomes. Currently, there are no approved HER3 directed therapies for the treatment of NSCLC. Patritumab deruxtecan is a novel, investigational antibody drug conjugate comprising an anti-HER3 monoclonal antibody, a tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In an ongoing Phase 1 study of patritumab deruxtecan in patients with EGFR-mutated TKI-resistant NSCLC, preliminary evidence of safety and antitumor activity were observed, providing proof of concept of patritumab deruxtecan. This Phase 2 study (HERTHENA-Lung01) is further evaluating patritumab deruxtecan in patients with previously treated metastatic or locally advanced EGFR-mutated NSCLC.

      Methods

      This is a randomized, open-label, global Phase 2 study that will enroll up to 300 patients at approximately 60 study sites across North America, Europe, and Asia. Eligible patients will have metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R), progression during or after systemic treatment with ≥1 EGFR TKI and ≥1 platinum-based chemotherapy regimen, and at least 1 measurable lesion confirmed by blinded independent central review (BICR) per RECIST v1.1. Patients with an EGFR T790M mutation must have received and progressed on prior osimertinib. Patients will be excluded if they have evidence of previous small cell or combined small cell/non-small cell histology or any history of interstitial lung disease. Tumor tissue will be assessed retrospectively for HER3 expression and molecular mechanisms of TKI resistance. The HER3 expression results will not be used to select patients for enrollment. Two Q3W dose regimens will be independently evaluated: 5.6 mg/kg patritumab deruxtecan in a fixed-dose regimen (Arm 1), or an up-titration dose regimen (Arm 2: Cycle 1, 3.2 mg/kg; Cycle 2, 4.8 mg/kg; Cycle 3 and subsequent cycles, 6.4 mg/kg). Patients will be randomized 1:1 to receive 1 of the 2 regimens. After initial review of ongoing phase 1 study data in an interim analysis, a decision will be made to continue with enrollment into 1 or both study arms. The primary objective of the study is to evaluate the efficacy of patritumab deruxtecan as measured by objective response rate (ORR) according to BICR. Secondary objectives are to evaluate the efficacy and safety/tolerability of patritumab deruxtecan, as well as to assess the relationship between efficacy and HER3 expression. Secondary endpoints include duration of response, progression-free survival, ORR by investigator assessment per RECIST v1.1, disease control rate, time to response, best percentage change in the sum of diameters of measurable lesions, and overall survival. Anticipated total study duration is expected to be 26 months, consisting of approximately 12 months for enrollment and 14 months on treatment. The study is planned to begin in 2020.

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    P37 - Pathology - Biomarker Testing (ID 107)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P37.05 - Prognostic Characteristics and Immunotherapy Response of Non-Squamous NSCLC Patients with KRAS Mutation in East Asian Populations (ID 2313)

      00:00 - 00:00  |  Author(s): James Chih-Hsin Yang

      • Abstract

      Introduction

      Kras mutation is the most common driver oncogene present in non-small cell lung cancer (NSCLC) patients in Western countries. However, the incidence of Kras mutation in Asian patients is low. Recently, the precision medicine for Kras-mutated NSCLC patients has been under investigation. This study aimed to analyze the clinical characteristics and prognostic factors of patients with Kras-mutant NSCLC.

      Methods

      From 2005–2018, we collected non-squamous NSCLC tissue samples for Kras mutation analysis using direct Sanger sequencing or MassARRAY genotyping (SEQUENOM). Patients with Kras mutations were enrolled. Clinical characteristics, treatment course, time to tumor recurrence (TTR), and overall survival (OS) were analyzed using multivariate Cox models, to estimate adjusted hazard ratios (HR).

      Results

      Among 5278 non-squamous NSCLC patients, 249 (4.7%) had Kras mutations. After excluding 18 patients with double cancers, 231 were enrolled for the analysis. There were 159 (68.8%) males and 145 (61.9%) smokers. The major Kras mutation subtypes were G12C (31.8%), G12D (24%), and G12V (18.5%). Patients with Kras-G12C had a higher proportion of smokers (81.1%; p = 0.001). For the 87 early-stage (I–IIIa) patients, the difference in TTR among patients with G12C (22.8 months(mo)), G12D (41.3 mo), G12V (unmatured), and G12A/S/R/Other (114.8 mo) Kras mutation patterns was statistically significant (p = 0.040). For the 144 advanced-stage (IIIb/IV) patients, there was a borderline significant difference in OS among patients with G12C (7.7 mo), G12D (11.7 mo), G12V (5.2 mo), and G12A/S/R/Other (5.7 mo) Kras-mutation subtypes (p = 0.052). Multivariate analysis revealed association of shorter OS with stage IV disease status (HR: 2.08; p = 0.002), NSCLC-not otherwise specified histology (HR: 3.17; p = 0.040), and Kras-G12V (HR: 2.08; p = 0.022). About the treatment response of immune checkpoint inhibitors (ICIs), patients with Kras-G12C had a higher response rate (50% vs. 14.3%; p = 0.069) and longer progression-free survival (4.8 mo vs. 2.1 mo; p = 0.046) than those with Kras-non-G12C.

      Among the patients with Kras mutations, 8 (3.4%) patients had tumors with concomitant Kras- and EGFR mutations, including 4 deletion-19, 2 L858R, one G709V, and one G719S+E709A. Of them, 6 patients received EGFR TKI treatment (4 gefitinib and 2 erlotinib). The treatment responses were 3 partial response, 1 stable disease, and 2 progressive disease. In addition, co-mutation of ALK fusions (3[2.5%] of 122 patients studied), HER2 mutations (2[1.0%] of 210 patients) and BRAF mutation (1[0.5%] of 204 patients) were also detected.

      Conclusion

      Kras-G12C mutation was associated with shorter TTR in early-stage NSCLC patients, while Kras-G12V mutation was associated with shorter OS in advanced-stage patients. Kras-G12C was also associated with favorable ICIs treatment effectiveness.

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

    • 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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      P86.01 - Phase 1 Study of the AXL Inhibitor DS-1205 in Combination With Osimertinib in Subjects With Metastatic or Unresectable EGFR-Mutant NSCLC (ID 1572)

      00:00 - 00:00  |  Presenting Author(s): James Chih-Hsin Yang

      • Abstract

      Introduction

      Up-regulation of AXL tyrosine kinase expression is observed various tumor types including EGFR-mutant (EGFRm) NSCLC with progressive disease on EGFR tyrosine kinase inhibitors (TKIs), especially in a T790M negative population. Xenograft studies have demonstrated that combined inhibition of AXL and EGFR can overcome and delay the onset of resistance. Phase 1 studies of DS-1205c, which is a novel, orally administered, highly selective small molecule inhibitor of AXL, in combination with EGFR TKIs are being conducted in patients with EGFRm NSCLC.

      Methods

      An ongoing multicenter, open-label, Phase 1 study of DS-1205c in combination with osimertinib in metastatic or unresectable EGFRm NSCLC is being conducted in Taiwan. Eligible subjects must either have evidence of radiological disease progression during treatment with erlotinib, gefitinib, or afatinib without the T790M resistance mutation, or must experience disease progression during osimertinib treatment and no risk factors for QTc prolongation. Subjects initially receive DS-1205c only twice daily during a run-in period of one week, followed by continuous combination treatment with DS-1205c twice daily and osimertinib 80 mg daily (21days/cycle) until disease progression or meet other discontinuation criteria. Escalation of DS-1205c dosing is guided by the modified Continuous Reassessment Method using a Bayesian logistic regression model following the escalation with overdose control principle. Primary and secondary endpoints include safety, pharmacokinetics, and preliminary efficacy. Exploratory biomarker analyses include assessment of tumor AXL expression through immunohistochemistry and hematological biomarkers.

      Results

      Dose Escalation in Cohort 1 (200 mg BID; n=6), and in Cohort 2 (400 mg BID; n=3) has been completed as of Dec 11, 2019. Two dose limiting toxicities (DLT) were observed in one subject in Cohort 1 (Grade 3 pneumonia and Grade 3 increased serum alanine aminotransferase [NCI-CTCAE v.5.0], which led study drug interruption to meet the criteria of DLT for low compliance rate). There were no serious adverse events directly related to DS-1205c. Preliminary analysis of efficacy data reveals that three patients had stable disease beyond 100 days (RECIST v.1.1).

      Conclusion

      Dose escalation is ongoing and updated clinical and biomarker data will be presented.

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      P86.08 - Phase 2 Study of Zenocutuzumab (MCLA-128), a Bispecific HER2/HER3 Antibody in NRG1 Fusion-Positive Advanced Solid Tumors (ID 3619)

      00:00 - 00:00  |  Author(s): James Chih-Hsin Yang

      • Abstract

      Introduction

      Neuregulin 1 (NRG1) gene fusions are oncogenic drivers in multiple cancer types. NRG1 fusion proteins bind to HER3 and signal through HER2/HER3 heterodimers, leading to increased downstream signaling and tumor growth. Clinical responses to agents that target this pathway have been reported. Zenocutuzumab (Zeno, MCLA-128) is a HER2/HER3 bispecific antibody that binds to or ‘docks’ onto the more abundant cell surface HER2 protein, potently blocking NRG1 fusion protein binding and preventing HER2/HER3 dimerization. As an initial proof-of-concept, three patients with chemotherapy-resistant NRG1­-positive KRAS-wild-type pancreatic adenocarcinoma or non-small cell lung cancer (NSCLC) who received Zeno through FDA-approved single-patient protocols showed significant tumor shrinkage. These data supported the further evaluation of Zeno in NRG1 fusion-positive cancers. A version of this Clinical Trials in Progress abstract was presented previously at ESMO Congress 2019 (685TiP, Schram et al. Reused with permission) and ASCO Virtual Congress 2020 (#302671; © 2020 American Society of Clinical Oncology, Inc. Reused with permission. All rights reserved).

      Methods

      The eNRGy trial is a global, open-label, multicenter phase 2 trial of Zeno in patients with solid tumors harboring NRG1 gene fusions. Main eligibility criteria include previously treated, locally advanced unresectable or metastatic NRG1 fusion-positive cancer. Genomic screening of tumor tissue is performed by local (with post-hoc central confirmation) or central (RNA sequencing) laboratories. Three cohorts of patients with NRG1 fusion-positive cancers are being enrolled: NSCLC, pancreatic cancer, and other solid tumors. The primary endpoint in all cohorts is investigator-assessed objective response rate (RECIST v1.1), and the key secondary endpoint is duration of response. Other secondary endpoints include progression-free and overall survival. Eligible patients receive a dosing regimen of 750 mg of Zeno (2-hour infusion), every 2 weeks, in 4-week cycles. The study is actively accruing patients in more than 30 sites across North America, Europe, and Asia.

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    PL02 - Innovation to Bridge Lung Cancer Care Tomorrow (Japanese, Mandarin, Spanish Translation Available) (ID 141)

    • Event: WCLC 2020
    • Type: Plenary
    • Track: N.A.
    • Presentations: 1
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      PL02.02 - Chair (ID 3902)

      07:00 - 09:00  |  Presenting Author(s): James Chih-Hsin Yang

      • Abstract

      Abstract not provided