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Jessica Jiyeong Lin



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    MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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      MA16.08 - Clinical Utility of Detecting ROS1 Genetic Alterations in Plasma (ID 13522)

      14:25 - 14:30  |  Author(s): Jessica Jiyeong Lin

      • Abstract
      • Presentation
      • Slides

      Background

      ROS1-rearranged lung cancer harbors an oncogenic fusion protein created by the juxtaposition of the ROS1 gene to various fusion partners. Due to the lack of a conserved breakpoint and inclusion of intronic segments, ROS1 rearrangements can be challenging to identify with DNA-based sequencing approaches. The feasibility and clinical utility of detecting ROS1 fusions in circulating tumor DNA is not well established.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The Guardant360 de-identified database was queried to identify lung cancer cases with plasma ROS1 fusions and describe the molecular features of the ROS1-rearranged cohort. In addition, we performed longitudinal analysis of plasma specimens from four patients at our institution who were treated with next-generation ROS1 inhibitors after progressing on crizotinib.

      4c3880bb027f159e801041b1021e88e8 Result

      From review of 24,009 plasma specimens from lung cancer patients, we identified 56 patients with ROS1 fusions. CD74 was the most common of 7 identified fusion partners [n=35 (62%) CD74, n=7 (12.5%) SDC4, n=7 (12.5%) EZR, n=3 (5%) TPM3, n=2 (4%) TFG, and n=1 (2%) each of CCDC6 and SLC34A2]. ROS1 fusions commonly co-occurred with TP53 mutations (n=36, 64%) and genes involved in cell-cycle regulation (n=11, 20%) or the WNT/ß-catenin pathway (n=16, 29%). In 4 (80%) of 5 cases where plasma genotyping occurred at crizotinib progression, we identified a putative resistance mechanism, including a ROS1 resistance mutation in 3 patients (n=2 G2032R & n=1 L2026M) and a BRAF V600E mutation in 1 patient. We analyzed longitudinal plasma specimens from 4 patients with crizotinib-resistant lung cancer who were subsequently treated with a next-generation ROS1 inhibitor (n=3 lorlatinib, n=1 entrectinib). One patient treated with lorlatinib had a pretreatment ROS1 G2032R mutation (in plasma and tissue); plasma analysis revealed stability of the G2032R allelic fraction in the setting of primary progression of pleural disease. Of the 2 patients without pretreatment ROS1 mutations who received lorlatinib, one developed a ROS1 G2032R mutation after initial response to treatment. The second patient experienced primary progression and plasma genotyping revealed low level FGFR1 copy number gain (3.3 copies); pre-crizotinib plasma was not available for comparison. One patient had a plasma PIK3CA E545K mutation at the time of crizotinib progression, and did not respond to next-line entrectinib.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Next-generation sequencing can be used to detect ROS1 fusions and resistance mutations in plasma. Longitudinal plasma analysis may provide insight into the activity of investigational drugs against ROS1 mutations that mediate resistance to crizotinib.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
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      OA02.02 - Safety and Preliminary Clinical Activity of Ropotrectinib (TPX-0005), a ROS1/TRK/ALK Inhibitor, in Advanced ROS1 Fusion-Positive NSCLC (ID 14217)

      10:40 - 10:50  |  Presenting Author(s): Jessica Jiyeong Lin

      • Abstract
      • Presentation
      • Slides

      Background

      Ropotrectinib is a potent ROS1/TRK/ALK inhibitor with a >90-fold greater ROS1 potency than crizotinib. Preclinical studies demonstrate robust activity against all known ROS1 resistance mutations, including solvent-front mutation G2032R.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this Phase 1 study (NCT03093116), TKI-naïve and TKI-refractory (≥1 TKI) pts with advanced ALK/ROS1/TRK+ solid tumors received ropotrectinib. Asymptomatic brain metastases were allowed. Primary objectives were to determine MTD and RP2D, with safety, pharmacokinetics, and preliminary antitumor efficacy as the secondary objectives. This is a safety analysis of all pts and subgroup efficacy analysis of the ROS1+ NSCLC pts on the study.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 16-April-2018, 72 pts have been treated at 6 dose levels from 40mg QD to 200mg BID. Most AEs were grade 1-2. Common (>10%) treatment-related AEs included dizziness (49%), dysgeusia (46%), paresthesias (29%), constipation (19%), fatigue (18%), nausea (11%), and anemia (11%). 4 DLTs were observed at ≥240mg/day: 1 grade 3 (Gr3) dyspnea/hypoxia, 2 Gr3 & 1 Gr2 dizziness. 31 of 72 pts had ROS1+ NSCLC by local testing (FISH, n=20; NGS, n=11) with 1 pt determined as ROS1-negative by central NGS. Antitumor activity in ROS1+ NSCLC has been observed at ROS1 dose levels 40mg QD-160mg BID per investigator assessment, with the best ORR 70% for TKI-naïve and 11% for TKI-refractory pts (17% for 1 prior TKI crizotinib, n=12) (Table). Two crizotinib-resistant pts with G2032R achieved durable cPR and cSD, respectively. Ongoing blinded independent review identified 7 evaluable pts with target CNS lesions at baseline; the intracranial best ORR was 43% (3 cPR, 1 PR*). Updated efficacy data and ctDNA biomarker analyses will be presented.

      Dose Level

      TKI Naïve (n = 10)

      TKI Refractory (n = 20)

      n

      Best Overall Response

      n

      Best Overall Response

      40 mg QD (n = 6)

      2

      2 cPR (ORR 100%)

      4

      2 cSD, 1 SD, 1 PD

      80 mg QD (n = 5)

      2

      2 cPR (ORR 100%)

      3

      1 cSD, 2 SD

      160 mg QD (n = 10)

      4

      2 cPR, 2 cSD (ORR 50%)

      6

      2 cPR, 2 cSD, 1 SD, 1 PD (ORR 33%)

      240 mg QD (n = 2)

      1

      1 cPR (ORR 100%)

      1

      1 SD

      160 mg BID (n = 7)

      1

      1 PR*

      6

      1 PR*, 1 SD*, 1 cSD, 2 SD, 1 NE

      Total (n = 30)

      10

      7 cPR, 1 PR*, 2 cSD

      20

      2 cPR, 1 PR*, 6 cSD, 1 SD*, 7 SD, 2 PD, 1 NE

      Best ORR

      70%

      11%

      Median follow-up

      8 months with 90% still on treatment

      4 months with 50% still on treatment

      cPR: confirmed partial response; SD: stable disease for 2 cycles; cSD: SD for at least 4 cycles; PR* or SD*: waiting for subsequent time point scan; PD: progressive disease; NE: inevaluable; ORR: objective response rate

      8eea62084ca7e541d918e823422bd82e Conclusion

      Ropotrectinib is well tolerated and demonstrates promising activity in pts with advanced ROS1+ NSCLC, including TKI-naïve and TKI-refractory pts. RP2D has not yet been achieved. These Phase 1 data warrant further clinical testing of ropotrectinib in ROS1+ NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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