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Herbert H Loong



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    FP14 - Targeted Therapy - Clinically Focused (ID 252)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP14.05 - LIBRETTO-431: Selpercatinib in Treatment-Naïve Patients with RET Fusion-Positive Non-Small Cell Lung Cancer (NSCLC). (ID 807)

      00:00 - 00:00  |  Author(s): Herbert H Loong

      • Abstract
      • Slides

      Introduction

      Selpercatinib (LOXO-292) is a highly selective and potent inhibitor of RET signaling. In the LIBRETTO-001 Phase I/II trial, selpercatinib treatment resulted in a 64% objective response rate (ORR) (95% confidence interval [CI]: 54-73%) in the registration dataset (n=105) of patients with RET+ NSCLC who previously received platinum-based chemotherapy and an 85% ORR (95% CI: 70-94%) in treatment-naïve patients with RET+ NSCLC (n=39). Although the duration of response (DOR) and progression free-survival (PFS) were not yet mature in treatment-naïve patients, in patients who previously received chemotherapy, the median DOR was 18 months (95% CI: 12-not estimable [NE]), median PFS was 17.5 months (95% CI: 12-NE), and CNS ORR per RECIST 1.1 was 91% (95% CI: 59-100%) (n=10/11). The most common adverse reactions included dry mouth (39%), diarrhea (37%), hypertension (35%), and fatigue (35%). The majority of adverse reactions were Grade 1 or Grade 2. The most common lab abnormality was increased alanine aminotransferase (ALT) (51%)/aspartate transaminase (AST) (45%). A total of 5% of patients discontinued due to an adverse reaction.

      The LIBRETTO-431 trial, is a global, open-label, randomized, controlled, Phase 3 trial evaluating selpercatinib vs platinum-based and pemetrexed treatment +/- pembrolizumab in treatment-naïve patients with locally advanced or metastatic RET+ non-squamous NSCLC (NCT04194944).

      Methods

      Patients will be randomized to receive selpercatinib 160 mg BID in 3-week cycles (Arm A) or pemetrexed (500 mg/m2 IV) in 3-week cycles plus investigator’s choice of carboplatin (AUC 5) or cisplatin (75 mg/m2 IV) for 4 cycles (Arm B). For patients in Arm B, at the investigator’s discretion, pembrolizumab (200 mg IV) may also be given for up to 35 cycles and patients may receive maintenance pemetrexed +/- pembrolizumab. Crossover to selpercatinib is allowed for Arm B patients who have disease progression. Treatment will be discontinued for progressive disease, unacceptable toxicity, decision to withdraw or death. Stratification factors include geography: East Asian versus non-East Asian, brain metastases: presence versus absence, and intended treatment if randomized to Arm B: +/- pembrolizumab. RET status may be determined in tumor (by PCR or NGS) or in blood (by NGS) using a qualified local test or a Lilly-enabled regional test. Key eligibility criteria include age ≥18 years; treatment-naïve; non-squamous Stage IIIB-IIIC not suitable for surgery/radiation therapy or Stage IV NSCLC; measurable disease by RECIST 1.1; ECOG performance status 0-2. Key exclusion criteria include presence of other known oncogenic drivers and symptomatic central nervous system metastases. Tumor assessments will be performed until progressive disease, the start of a new anticancer treatment, death or study completion. The co-primary endpoint, PFS by independent review in intent-to-treat (ITT) patients with pembrolizumab (if assigned to control), will act as a gatekeeper to the co-primary endpoint PFS by independent review in the ITT population. Secondary endpoints include investigator assessed PFS, ORR/DOR, intracranial ORR/DOR, overall survival, time to deterioration in pulmonary symptoms, progression after the next line of therapy, RET fusion status: local versus central, and safety/tolerability. The study was initiated in March 2020 and enrollment is ongoing.

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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  |  Presenting Author(s): Herbert H Loong

      • 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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    IS04 - Industry Symposium Sponsored by Lilly Oncology: Implementing Precision Oncology in the Clinic: Diagnostic Challenges and Best Practices (ID 281)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 1
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      IS04.03 - Developing Best Practices for the Accurate Diagnosis and Treatment of All Patients With NSCLC - Practical Tips on Optimising Diagnostic Capabilities in the Clinic (ID 4322)

      13:00 - 14:00  |  Presenting Author(s): Herbert H Loong

      • Abstract

      Abstract not provided

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    IS13 - Satellite CME Symposium by ACE Oncology: Hot Topics in the Management of Advanced Non-Small Cell Lung Cancer: Expert Insights on Recent Advances (ID 290)

    • Event: WCLC 2020
    • Type: Satellite CME Symposia
    • Track:
    • Presentations: 1
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      IS13.02 - When Is the Right Time to Use NGS-Based Liquid Biopsy in Advanced NSCLC? (ID 4304)

      13:00 - 14:00  |  Presenting Author(s): Herbert H Loong

      • Abstract

      Abstract not provided

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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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      OA05.05 - Economic Impact of Next-Generation Sequencing (NGS) vs. Single-gene Testing Strategies to Detect Genomic Alterations (GAs) in mNSCLC in Asia (ID 3426)

      15:30 - 16:30  |  Presenting Author(s): Herbert H Loong

      • Abstract

      Introduction

      The economic impact of using NGS vs. single-gene testing strategies in patients (pts) with mNSCLC have substantial implications on healthcare resource allocation. Pennell et al. (JCO PO 2019) have shown the use of upfront NGS testing in pts with mNSCLC was associated with substantial cost savings and shorter time-to-test results in the United States. Such conclusions may not necessarily apply in other jurisdictions where the prevalence of pts with actionable mutations, cost of healthcare and reimbursement models differ. Taking Hong Kong (HK) as an example, we assess the economic impact of NGS vs. single-gene testing in Asia. Initial results were presented at ESMO Asia 2020. We present updated results in this forum in consideration of an additional 2 GAs (MET and RET) with new US FDA approved therapies since our last presentation.

      Methods

      A decision analytical model was built to compare sequential (SE), panel (PA), exclusionary (EX), and upfront NGS testing in pts with newly diagnosed mNSCLC. In SE and PA, pts were tested for GAs with approved treatment (EGFR, ALK, ROS1, BRAF, MET, RET) followed by SE or NGS for other GAs. In EX, EGFR and ALK were tested first, followed by NGS. 2.4 % of pts were assumed to receive re-biopsy and 25% to continue testing for nonactionable GAs. For each modality, mutation identified, time to receive testing results, and costs (2019 USD) were estimated. Sensitivity analyses (SAs) was used to test model robustness.

      Results

      For Hong Kong (~7.3M population), EX required the shortest time to receive results (1.6 weeks) and was most cost-saving compared to other modalities. If all pts use EX, $4.8M cost saving will be achieved compared with current practice, with 90.7% of actionable and 46.5% of non-actionable GA being detected. If all pts use NGS, it will cost an additional $2.7M to payer with a 100% GA detection rate. The results were sensitive to NGS price and the % of pts continued testing for non-actionable GAs.

      Conclusion

      In contrast to findings by Pennell et al., EX rather than upfront NGS is the best option in terms of cost and time to results in HK. This is also applicable for other Asia countries as this is driven by higher prevalence of mNSCLC pts with EGFR mutations in the Asian population. Moreover, with addition of MET and RET as GAs with FDA approved therapies, the cost saving of using EX increased from $3.0M to $4.8M compared with current practice. EX, however, does not capture all possible GAs. The additional cost to payer reduced from $4.5M to $2.7M if all pts use upfront NGS testing after MET and RET became actionable GAs. As more GAs become actionable and NGS testing costs reduce, NGS may potentially be a cost saving option.

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    P19 - Locoregional and Oligometastatic Disease - Oligometastatic Disease (ID 129)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Locoregional and Oligometastatic Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P19.01 - Local Ablative Radiotherapy on Oligo-Progression while Continued on EGFR-TKI in Advanced NSCLC Patients: A Longer Cohort (ID 1505)

      00:00 - 00:00  |  Author(s): Herbert H Loong

      • Abstract
      • Slides

      Introduction

      Continuation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI) in advanced Non-small cell Lung cancer (NSCLC) patients harboring sensitive mutation (Exon 19 deletion /Exon 21 L858R mutation) upon first progression according to RECIST criteria can prolong the use of EGFR-TKI for more than 3 months till change of therapy. Local ablative radiotherapy (LAR) on oligo-progression is widely used but actual benefit is yet to be quantified.

      Methods

      Health records of patients given LAR from 2012-2019 in a single centre were reviewed. Patients with stage IV NSCLC harboring epidermal growth factor receptor (EGFR) activating mutations having <5 sites of oligo-progression while on EGFR TKI and given LAR with 1-8 fractions were included. Demographics, site of oligo-progression, radiotherapy sites and dose/fractionation schedules were captured. Duration from start of TKI to oligo-progression was defined as PFS1. The primary endpoint was progression free survival from LAR to further progression that led to stop of EGFR TKI (PFS2). The secondary endpoint was overall survival from LAR. Potential factors affecting PFS2 and OS were analyzed with Cox regression model.

      Results

      There were total 55 eligible patients. The mean age at delivery of LAR was 62.7 (36-88) years. Majority (89%) had sensitive mutations (Exon 19 deletion and exon 21 L858R mutation). The median PFS1 was 17.2 months (95% CI 11.4 to 23.0). Total number of lesions treated were 75, including lung (n=45), bone (n=15), cervical lymph node (n=1), adrenal (n=1) and brain (n=13). The mean radiation doses with biological equivalent dose with α/β= 10 (BED10) were: lung: 112.2Gy (100.0-151.2Gy); bone: 47.8 Gy (41.6- 100Gy); brain: 61.7Gy (37.5-70.4Gy). The patient with metastatic lymph node was given 60Gy in 8 fractions (BED10= 105Gy) and with adrenal metastasis was given 40Gy in 5 fractions (BED 10= 72Gy). The mean time from diagnosis of oligo-progression to LAR was 2.2 months (0.6 to 4.6 months). No significant toxicities were reported. The median follow-up time was 13.3 months (1.5-51.6 months).

      The median PFS1 was 17.2 months (95% CI 11.4 to 23.0). Median PFS2 was 6.9 months (95% CI 3.1- 10.7 months). The 1-year and 2-year local control rate were 86% and 78%. The 1-year and 2-year distant control rates were 29% and 16%. The median OS from LAR was 25.1 months (95% CI 10.0-40.10 months). On multivariable analysis, it was found that patients with EGFR mutation type (exon 19 deletion or L858R mutation) had superior PFS2 (HR 0.11 95% CI 0.03-0.41, p =0.001) and OS (HR 0.099 95 CI 0.010-0.961, p=0046) compared with other less common mutations, while longer time to treatment (>70 days) and more lines of TKI before LAR negatively affected PFS2 (p=0.046; 0.004). Age, sex, smoking status, CNS involvement, number of radiation sites, PFS1 and treatment dose did not affect PFS2 and OS with statistical significance.

      Conclusion

      LAR is a safe and convenient modality in treatment of oligo-progressive disease for patients with EGFR mutations positive NSCLC. Patients with EGFR exon 19 deletion or Exon 21 L858R mutation, shorter time from diagnosis to treatment, and less prior lines of EGFR-TKI may benefit more from LAR.

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    P35 - Pathology - Genomics (ID 105)

    • 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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      P35.15 - Molecular Epidemiology of KRAS G12C Mutations in Chinese Lung Cancer Patients (ID 2498)

      00:00 - 00:00  |  Presenting Author(s): Herbert H Loong

      • Abstract
      • Slides

      Introduction

      The incidence of KRAS mutations are different between the Asian and non-Asian populations. Recent development of KRAS G12C targeting drugs has shown great promise. We report on the real-world genomic landscape of KRAS G12C in Chinese cancer patients (pts).

      Methods

      Sequencing data of samples from 186 comprehensive cancer centres in China performed at a single CAP-accredited laboratory were reviewed for KRAS mutation status. Additionally, smoking status and its correlation with KRAS were analysed within the lung cancer cohort. Concomitant genomic aberrations were identified in tumors with KRAS G12C mutations through a comprehensive cancer panel encompassing 450 cancer-related genes.

      Results

      11,951 tumour samples from individual pts were collected from 11/2016 to 7/2019. Lung cancer formed the largest cohort of pts, accounting for 42% (n=5063) of samples, followed by colorectal (CRC) (9.3%), liver (8.9%), biliary tract (BTC) (8.4%), and others. KRAS mutations were observed in 16.6% of all samples. Specifically, KRAS G12C was the most common KRAS mutation identified in 4.3% (n=218) of lung cancer pts. In addition, KRAS G12C was also identified in 2.5% and 2.3% of CRC and BTC pts’ samples. In lung adenocarcinoma (LUAD) pts, KRAS mutations were more commonly identified in current and former smokers vs. non-smokers (20.7%, 20.3% 8.9% respectively, p<0.001). This correlation was not seen in pts with squamous cell carcinoma of lung. 81 (54.7%) of KRAS G12C LUAD cases had at least one potentially actionable alteration in addition to KRAS G12C (level 1 to 4), with actionable EGFR and ALK mutations were identified in 8 cases (5.4%).

      Distribution of KRAS aberration subtypes in lung cancer (N=5063)
      KRAS Aberration N (Total 607 KRAS aberrations in 591 samples) Proportions of KRAS aberrations Frequencies in lung cancer (N=5063)
      G12C 218 35.9% 4.3%
      G12V 108 17.8% 2.1%
      G12D 99 16.3% 2.0%
      Amplification 57 9.4$ 1.1%
      G12A 37 6.1% 0.7%
      Q61H 18 3.0% 0.4%
      G13C 15 2.5% 0.3%
      G13D 13 2.1% 0.3%
      G12S 7 1.2% 0.1%
      Others 35 5.8% 0.7%

      Conclusion

      We report on the largest KRAS mutation landscape in Chinese cancer patients to date. KRAS G12C mutation remains uncommon. However, more than half of LUAD pts with KRAS G12C had co-alterations which are potentially actionable. This may form the basis for future combinational drug development strategies. Other histologies with KRAS G12C have also been identified.

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