Author of

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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

  • 25703

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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  |  Author(s): J. Jean Cui
    • 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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