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Bob T Li



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    JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)

    • Event: WCLC 2019
    • Type: Joint IASLC-CSCO-CAALC Session
    • Track:
    • Presentations: 1
    • Now Available
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      JCSE01.12 - Discussant Oral Abstracts (Now Available) (ID 3426)

      07:00 - 11:15  |  Presenting Author(s): Bob T Li

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
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      OA02.02 - Phase 1 Study of Safety, Tolerability, P­­K and Efficacy of AMG 510, a Novel KRAS G12C Inhibitor, Evaluated in NSCLC (ID 1020)

      10:30 - 12:00  |  Author(s): Bob T Li

      • Abstract
      • Slides

      Background

      The KRASG12C mutation is found in approximately 14% of lung adenocarcinoma and 11% of NSCLC pts. Currently, no approved therapy targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRASG12C by locking it in an inactive GDP-bound state.

      Method

      A phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult pts with locally-advanced or metastatic KRASG12C mutant solid tumors, including NSCLC pts. Safety is the primary endpoint; ORR (assessed every 6 wks), DOR, PFS, and PK are key secondary endpoints. Important inclusion criteria: KRASG12C mutation identified through DNA sequencing; measurable or evaluable disease; progression on standard therapy; ECOG PS ≤2; life expectancy >3 mo. Important exclusion criteria: active brain metastases; myocardial infarction within 6 mo. The maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) will be identified during the dose exploration. Once identified, additional pts with advanced solid tumors carrying the KRASG12C mutation will be enrolled during dose expansion. AMG 510 is given PO until disease progression, intolerance, or consent withdrawal.

      Result

      As of 4 April 2019, thirteen [5 men and 8 women; median age 63 yrs (range: 53–77)] of 35 pts enrolled in 4 dose exploration cohorts have NSCLC. These pts had a median of 3 (range: 1–5) prior lines of treatment (tx). On-study tx duration had a median of 59 days (range:9–192 d). No DLTs have been reported. Six NSCLC pts reported 10 treatment-related AEs (6 grade 1; 2 grade 2; 2 grade 3). The grade 3 related AEs were anemia in a pt with baseline grade 2 anemia and diarrhea lasting 2 d in a second pt. The most frequently reported AEs were decreased appetite (n=4 subjects) and diarrhea (n=3 subjects). Best tumor response has been evaluated in 10 NSCLC pts; 3 pts have not reached their first assessment. Of these 10 evaluable pts, 5 pts had a PR (2 of which are confirmed PRs), 4 had SD and 1 had PD. Of 13 NSCLC pts, 11 pts remain on-study and continue their AMG 510 and 2 pts have discontinued treatment due to PD during study wks 6 and 26.

      Conclusion

      AMG 510 has been well tolerated at all 4 dose levels explored and has shown antitumor activity when administered as monotherapy to pts with advanced KRASG12C mutant NSCLC. Enrollment is on-going.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-122 - A Clinical Utility Study of Plasma DNA Next Generation Sequencing Guided Treatment of Uncommon Drivers in Advanced Non-Small-Cell Lung Cancers (ID 2997)

      09:45 - 18:00  |  Author(s): Bob T Li

      • Abstract
      • Slides

      Background

      Although EGFR and ALK testing in non-small-cell lung cancers (NSCLC) is now considered standard practice, next generation sequencing (NGS) for extended molecular testing of uncommon drivers is often difficult to perform in the community due to factors surrounding tissue adequacy, availability and turnaround time. We set out to prospectively determine the clinical utility of plasma ctDNA NGS in detecting uncommon actionable drivers and their plasma guided treatment response.

      Method

      Patients with advanced NSCLC who were driver unknown after routine EGFR and ALK testing were eligible. Patients were enrolled prospectively at Memorial Sloan Kettering Cancer Center (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood (10-20mL) was collected and sent to Resolution Bioscience (Kirkland, WA) for targeted ctDNA NGS using a bias-corrected hybrid-capture 21 gene assay in a CLIA laboratory achieving a mean unique read of at least 3000x and sensitivity above 0.1%. Clinical endpoints included detection of uncommon oncogenic drivers defined as actionable alterations in ROS1, RET, BRAF, MET, HER2, turnaround time, concordance with tissue NGS when available, and plasma guided treatment outcome.

      Result

      614 patients were prospectively accrued. Plasma NGS detected an uncommon oncogenic driver in 7% (45/614) of patients including ROS1, RET fusions, BRAF, MET exon 14 and HER2 exon 20 mutations, of whom 3% (20/614) were matched to targeted therapy producing 12 partial responses. Mean turnaround time for plasma NGS was significantly shorter than tissue NGS (10 vs 25 days, P <0.0001). 399 patients had concurrent tissue NGS results available for concordance analysis; Overall concordance, defined as the proportion of patients for whom an uncommon driver was uniformly detected or absent in both plasma and tissue NGS, was 94.7% (378/399, 95% confidence interval [CI] 92.1 – 96.7%). Among patients who tested plasma NGS positive for uncommon drivers, 87.5% (28/32, 95% CI 71.0-96.5%) were concordant on tissue NGS, and among patients tested tissue NGS positive for uncommon driver, 62.2% (28/45, 95% CI 46.5-76.2%) were concordant on plasma NGS.

      Conclusion

      Plasma NGS uncovered uncommon oncogenic drivers with faster turnaround time than tissue NGS, directly matched patients to targeted therapy and produced clinical responses independent of tissue results. A positive finding of an oncogenic driver in plasma is highly specific and can immediately guide treatment, but a negative finding may still require tissue biopsy. Our findings provide prospective evidence to support a “blood first” approach in molecular diagnostics for the care of patients with NSCLC.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-39 - Molecular Characteristics, Immunophenotype, and Immune Checkpoint Inhibitor Response in BRAF Non-V600 Mutant Lung Cancers (ID 1529)

      09:45 - 18:00  |  Author(s): Bob T Li

      • Abstract
      • Slides

      Background

      Targeted therapy for Class I BRAF mutant lung cancers (V600) is well described and there is growing literature on their response to immune checkpoint inhibitors (ICI). In contrast, the molecular characteristics, immunophenotype, and response rates of class II and III BRAF mutations are not well defined.

      Method

      Patients with BRAF Class I, II, III mutant and variants of unknown significance (VUS) lung cancers detected on NGS (MSK-IMPACT) from 1/2014-1/2018 were identified. PD-L1 by immunohistochemistry (E1L3N) was evaluated. Tumor mutation burden (TMB; mut/Mb) was determined by MSK-IMPACT. Best objective response to ICI was assessed by RECIST v1.1. Time to treatment discontinuation (TTD) and overall survival (OS) were assessed. Statistical analysis was performed with Fisher’s exact and Kaplan-Meier. BRAF V600 lung cancers were used as a comparator and analyzed separately from BRAF non-V600.

      Result

      6.0% (177/2962) of lung cancers harbored a BRAF-mutation. Median TMB of BRAF non-V600 mutant lung cancers was 10.8 mut/Mb (n=136) overall compared to 4.9 mut/Mb in V600 (n=41; p<0.0001) and 5.9 mut/Mb in BRAF wild-type patients (n=2785; p<0.0001). 69% (127/177) of BRAF-mutant cases were metastatic (29 Class I, 36 Class II, 23 Class III, and 39 VUS). 57% of patients were female, 82% were smokers, and 90% were adenocarcinoma. More smokers were seen in the BRAF V600 group than in the non-V600 group (n = 16 vs 88 respectively, p<0.0001). PD-L1 expression in 49 non-V600 cases with available tissue was 0%, 1-49%, and >50% in 59% (n=29), 31% (n=15), and 10% (n=5) respectively. 7 BRAF V600 cases with PDL1 testing had expression of 0%, 1-49%, and >50% in 2, 3, and 2 cases, respectively. No BRAF V600 cases had concurrent RAS/NF1-alterations compared to 11 non-V600 (p=0.07).

      36 patients with BRAF non-V600 mutations received ICI (nivolumab (n=25), pembrolizumab (n=5), atezolizumab (n=2), ipilimumab/nivolumab (n=4); median line of therapy=2) with an ORR of 22% (8/36). 10 BRAF V600 mutant lung cancer patients received ICI (nivolumab (n=5), pembrolizumab (n=2), atezolizumab (n=1), ipilimumab/nivolumab (n=2); median line of therapy=2) with an ORR of 10% (1/10). There was no difference in ORR between non-V600 and V600 patients that received ICI (p=0.66). TTD in BRAF non-V600 was 3.2 months compared to 1.4 months for BRAF V600 mutant lung cancer patients (HR 0.59, p=0.26). Median TMB in patients with BRAF non-V600 mutations that responded vs those who did not was 13.2 and 10.8 mut/Mb respectively (p=0.92). One response to ICI was seen in a BRAF V600 with TMB of 19.3. OS of BRAF non-V600 patients was 1.7 years compared to 2.5 years in V600 (HR 1.25, p=0.38). OS was higher in BRAF non-V600 lung cancer patients who received ICI (2.4 years) compared to those that did not (1.2 years; HR 0.60, p=0.04).

      Conclusion

      The molecular characteristics and immunophenotype of BRAF non-V600 mutant lung cancers is typified by high TMB and low PD-L1 expression, with reasonably higher response rates and improved OS to later line ICI compared to BRAF V600. Further studies of immunotherapy in this oncogene subset is warranted.

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