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Hidetoshi Hayashi



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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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      FP14.16 - Phase 2 Trial of the Alternating Therapy with Osimertinib and Afatinib for Treatment-Naive Patients with EGFR-Mutated Advanced Non–Small Cell Lung Cancer (WJOG10818L/Alt Trial) (ID 3084)

      00:00 - 00:00  |  Presenting Author(s): Hidetoshi Hayashi

      • Abstract
      • Presentation
      • Slides

      Introduction

      First-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is standard of care for patients with EGFR-mutated NSCLC. Whereas osimertinib is sensitive to the acquired mutation T790M in 1st/2nd generation EGFR-TKI resistant patient, afatinib overcomes the resistance of osimertinib due to highly express HER2/HER3 or C797S mutations. Osimertinib and afatinib may deliver drug efficacy in a complement manner, therefore, we conducted the phase II clinical trial to evaluate the efficacy of alternative treatment strategy of osimertinib and afatinib.

      Methods

      Patients with treatment-naive stage IV EGFR-mutated (L858R or del19) NSCLC were enrolled. Orally osimertinib 80 mg once a day for 8 weeks, followed by afatinib 20 mg once a day for 8 weeks, which was repeated alternately. Primary endpoint was one-year PFS rate evaluated by investigators based on RECIST 1.1. A minimum of 36 evaluable patients were required for the lower limit of 60% confidence interval for 1 year PFS rate to be more than the threshold of 64% with power of 80%, where the expected was assumed to be 77%.

      Results

      From Nov 2018 to Feb 2019, 46 pts were enrolled and treated with study therapy. One-year PFS rate was 70.18% (60% CI: 63.9%-75.59%, 95% CI: 54.22%-81.48%), which didn’t meet primary endpoint. Thus, the actual 60% CI lower limit is 63.9% thus very close to the threshold. The ORR and one-year survival rate were 69.6% (95% CI: 54.2%-82.3%) and 93.48% (95% CI: 81.13%-97.85%), respectively. The most common treatment-related adverse effects (TRAEs) (% any grade, % grade 3) were diarrhea (73.9%, 4.3%), rash acneiform (63.0%, 2.2%) and paronychia (52.2%, 0%). Pneumonitis was observed in 5 patients, all of whom were being treated with osimertinib. Baseline heregulin level was not correlated with the efficacy. Plasma EGFR determined by digital PCR is under evaluation.

      Conclusion

      Although current study didn’t meet the primary endpoint of one-year PFS rate, alteration therapy with osimertinib and afatinib demonstrated promising efficacy and tolerability for first-line treatment of EGFR-mutated NSCLC. Clinical trial information: jRCTs051180009

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    MA04 - Health Policy and the Real World (ID 217)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Health Services Research/Health Economics
    • Presentations: 1
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      MA04.06 - Clinical Characteristics and Outcomes in Advanced KRAS Mutant NSCLC – A Multi-Centre Collaboration in Asia (ATORG-005) (ID 3475)

      16:45 - 17:45  |  Author(s): Hidetoshi Hayashi

      • Abstract
      • Presentation
      • Slides

      Introduction

      KRAS driver mutations in advanced NSCLC have long been considered to be undruggable. However, promising efficacy data from early phase trials of novel therapies targeting KRAS have renewed focus on KRAS as an oncogenic driver. There is limited data on the prognostic and predictive significance of KRAS mutation subtypes. We present an interim analysis of a real world observational multi-centre study of advanced KRAS mutant NSCLC patients from five countries in Asia, conducted by the Asian Thoracic Oncology Research Group (ATORG).

      Methods

      Patients with advanced KRAS mutant NSCLC treated with at least one line of systemic therapy at tertiary centres in five Asian countries (China, India, Japan, Singapore, South Korea) between Jan 2014 and Dec 2018 were included. Baseline clinical characteristics, molecular profile and treatment outcomes were collected (median follow-up 35.5 months, 95%CI 28.7-50.3).

      Results

      A total of 155 patients were included in this interim analysis, with median age at advanced stage diagnosis 63 years (interquartile range [IQR] 56-70), 93% were ECOG 0-1, 70% were male and 64% were current or ex-smokers. In terms of ethnicity, 39% were Korean, 36% were Chinese, 15% were Japanese, 8% were Indian and 2% were Malay. Baseline histology was adenocarcinoma in 90%, squamous cell carcinoma in 4% and other histologies in 6%. KRAS mutation was detected by NGS in 141 (91%) patients, Sanger sequencing in 12 (8%) patients and RT-PCR in 2 (1%) patients. KRAS G12C (26%) was most common, followed by G12D (23%) and G12V (21%). The incidence of KRAS G12C mutation in patients with a smoking history was 35/99 (35%) compared with 6/56 (11%) in patients without any smoking history. Co-alterations were found with EGFR mutations (14%), ALK fusions (1%), ROS1 fusions (1%) and BRAF mutations (3%). PD-L1 TPS was 0% in 22%, 1-49% in 19%, ≥50% in 14% and unknown/not tested in 45%. Brain metastases were present at advanced stage diagnosis in 25% and lifetime prevalence was 35%. Patients received a median 2 lines of therapy. First-line systemic therapy consisted of chemotherapy alone (66%), targeted therapy (15%) or other therapies (19%). Median time to next treatment (TTNT) on first-line chemotherapy alone was 7.3 months (95%CI 5.0-9.5). Overall, the median TTNT for first-line and second-line therapy was 7.7 (95%CI 6.5–10.0) and 7.0 (95%CI 5.3–10.9) months, respectively. 63% of patients had died, and 37% of patients were still alive or lost to follow-up at the time of data cut-off. Median OS for the overall cohort was 21.6 months (95%CI 15.9-27.6). Median OS was greater in immunotherapy treated (alone or in combination at any line; 45%) versus non-immunotherapy treated (55%) patients (27.6 [95%CI 19.1-37.9] months versus 15.4 [95%CI 10.3-23.7] months, HR 1.8, 95%CI 1.2-2.7, logrank p=0.005).

      Conclusion

      In Asian KRAS mutant NSCLC, duration of first-line therapy and survival outcomes remain poor – emphasising the need for greater therapeutic options for patients with a KRAS driver mutation. Additional sites/countries are planned and recruitment to this study is ongoing.

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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): Hidetoshi Hayashi

      • Abstract
      • Presentation
      • Slides

      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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    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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      P01.04 - Dynamics of Molecular Markers in EGFR-Mutated NSCLC Patients Treated with Patritumab Deruxtecan (HER3-DXd; U3-1402) (ID 3570)

      00:00 - 00:00  |  Author(s): Hidetoshi Hayashi

      • Abstract
      • Slides

      Introduction

      Patritumab deruxtecan is an investigational human epidermal growth factor receptor 3 (HER3)-directed antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload, and it has shown preliminary antitumor activity in patients with previously treated metastatic or locally advanced epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer (NSCLC) in an ongoing phase 1 study (NCT03260491). Here we present initial observations from comprehensive genomic profiling in tumor tissue and circulating tumor DNA (ctDNA), tumor HER3 expression and its association with prior treatment and with the clinical activity of patritumab deruxtecan, and dynamic changes in a ctDNA panel during study treatment.

      Methods

      We evaluated tumor tissue and peripheral blood samples from 56 patients with EGFR-mutated NSCLC treated with 5.6 mg/kg patritumab deruxtecan (intravenously once every 3 weeks) after failure of EGFR tyrosine kinase inhibitor (TKI). Blood samples for ctDNA were collected before each dose and at the end of treatment. Pre-treatment tumor samples were evaluated by immunohistochemistry for HER3 expression. Genomic profiling of pre-treatment tumor tissue and analyses of ctDNA were performed using the Oncomine™ Comprehensive Assay v3 and the GuardantOMNI™ panel, respectively. In addition, serial ctDNA samples were analyzed using the Biodesix platform to detect changes in the presence of four types of EGFR mutated alleles: Ex19Del, L858R, T790M, and C797S.

      Results

      To be drafted when final data are available.

      Conclusion

      To be drafted when final data are available.

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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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      P84.09 - Asian Subgroup Analysis of a Phase II Study Evaluating Lorlatinib Efficacy in Previously Treated ALK-Positive Advanced NSCLC (ID 3566)

      00:00 - 00:00  |  Author(s): Hidetoshi Hayashi

      • Abstract
      • Slides

      Introduction

      Lorlatinib is a selective, potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ALK and ROS1. In a global Phase II trial, lorlatinib showed substantial overall and intracranial activity in patients with ALK- or ROS1-positive advanced non-small cell lung cancer (NSCLC). Here we report the efficacy and biomarkers of lorlatinib from the Asian subgroup analysis of this trial.

      Methods

      In this ongoing, open-label, Phase II trial (NCT01970865), eligible patients with ALK- or ROS1-positive advanced NSCLC, with or without central nervous system (CNS) metastases were enrolled into six different expansion cohorts based on their ALK and ROS1 status and previous therapy, and received lorlatinib 100 mg once daily. The primary study endpoint was objective tumor response and intracranial (IC) tumor response. Efficacy analyses were conducted for Asian patients (based on race) with ALK-positive NSCLC, who received at least one previous ALK tyrosine kinase inhibitor (this is the first presentation with new data cut-off May 14, 2019). Correlation analyses with tumor tissue and cfDNA ALK resistance mutations are ongoing.

      Results

      Baseline characteristics of the 70 Asian patients (61% female, 51 years median age, 41%/54%/4% ECOG Performance Status 0/1/2, 57% brain metastases at baseline) were similar to the overall population (59% female, 53 years median age, 45%/52%/4% ECOG Performance Status 0/1/2, 67% brain metastases at baseline). Efficacy results of the total Asian population (summarized in Table 1) were similar to the overall population; with ORR of 56% versus 47%, IC-ORR of 59% versus 63% and median PFS of 8.2 versus 7.3 months, respectively.


      table 1.jpg

      Conclusion

      Lorlatinib exhibited similar efficacy in this Asian subgroup compared with the overall population.

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