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Greg Durm



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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): Greg Durm

      • 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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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-05 - ChemoXRT W/ Consolidation Pembrolizumab in Unresectable Stage III NSCLC:  Long-Term Survival Update and Analysis of Post-Progression Therapy (Now Available) (ID 2765)

      09:45 - 18:00  |  Presenting Author(s): Greg Durm

      • Abstract
      • Slides

      Background

      Consolidation PD-1/PD-L1 inhibition following chemoradiation is a new standard of care for patients with stage III NSCLC. 3-year survival rates in patients receiving consolidation PD-1/PD-L1 have not been previously reported. In addition, the response to subsequent chemotherapy or immunotherapy in patients who experienced disease progression following consolidation PD-1/PD-L1 has also not been previously reported.

      Method

      This is a phase II, single-arm, multi-center trial of consolidation pembrolizumab 200mg IV every 3 weeks for up to a year following concurrent chemoradiation in patients with unresectable stage III NSCLC. This analysis provides the first-ever report of 3-year overall survival (OS) estimates with consolidation PD-1. In addition, treatment details for patients who experienced progression of disease on or after consolidation pembrolizumab are described.

      Result

      Median follow is 31.1 months (range 1.2-42.4). Median OS is 35.8 months (95% CI, 24.2 -not estimable). One, two, and three-year OS estimates are 81.1%, 62%, and 49.5%. Of 37 patients reported to have progressive disease (PD), subsequent treatment data were available for 35. Twenty-four received additional systemic therapy, and 11 received no subsequent systemic treatment. Fifteen experienced PD during pembrolizumab, 18 after pembrolizumab (and 4 had missing data). The best response to any systemic therapy (n=24) was 3 partial responses (PR), 9 stable disease (SD), and 12 PD. Chemotherapy was given to 21 patients and 1 patient each received erlotinib, ponatinib, and an investigational agent. Best response to chemo was 2 PR, 6 SD, and 13 PD. 11 patients received pemetrexed with 2 SD and 9 PD; 6 patients received a single agent taxane with 1 SD and 5 PD. 5 patients received combination therapy with 1 PR, 3 SD, and 1 PD. 3 patients received gemcitabine with 1 PR and 2 PD. 6 of 24 patients received subsequent PD-1 or PD-L1 inhibitors; the best response to immunotherapy was 1 PR and 5 PD. The PR was a patient who had completed pembro consolidation 14 months prior to PD and subsequently was retreated with pembro at the time of biopsy-proven recurrence (PD-L1 TPS was 90%). He responded after 3 cycles of pembro and has maintained this response for 13+ cycles.

      Conclusion

      The 3-year OS estimate indicates that nearly half of all patients treated with consolidation pembrolizumab may be long-term survivors. For patients with disease progression after consolidation pembrolizumab, response rates with chemotherapy are similar to what is expected in the 2nd line setting with 38% experiencing disease control for a period of time. Only 1 of 6 patients re-challenged with a checkpoint inhibitor responded, but this patient has maintained a durable response lasting 13+ cycles.

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