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Gerald S Falchook



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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): Gerald S Falchook

      • 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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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Gerald S Falchook

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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