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A. Bearz



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    OA 05 - Next Generation TKI (ID 657)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 05.06 - Phase 2 Study of Lorlatinib in Patients with Advanced ALK<sup>+</sup>/ROS1<sup>+</sup> Non-Small-Cell Lung Cancer (ID 8573)

      16:40 - 16:50  |  Author(s): A. Bearz

      • Abstract
      • Presentation
      • Slides

      Background:
      Lorlatinib, a selective, potent, brain-penetrant ALK/ROS1 TKI, is active against most known ALK kinase domain mutations. In phase 1 of this ongoing study (NCT01970865), lorlatinib displayed robust clinical activity among patients with ALK[+]/ROS1[+] non-small-cell lung cancer (NSCLC), most of whom were heavily pretreated and had CNS metastases. Phase 2 evaluated efficacy (overall and intracranial), according to prior treatment, and safety at the recommended phase 2 dose (100 mg QD).

      Method:
      Patients with NSCLC ± asymptomatic CNS metastases enrolled in 6 cohorts (EXP1–5, ALK[+]; EXP6, ROS1[+]). The primary endpoint was objective response rate (ORR) and intracranial ORR by independent central review. Safety, patient-reported outcomes and molecular profiling were also assessed.

      Result:
      As of 15-March-2017, 227 ALK[+] patients were evaluated for ORR (Table), including 140 with CNS involvement who were evaluated for intracranial ORR.

      Confirmed ORR Confirmed IC-ORR
      N n (%) N n (%)
      ALK[+] cohorts
      EXP1 (treatment-naïve, no prior ALK-TKIs or CT) 30 27 (90) 8 6 (75)
      EXP2 (prior crizotinib only) 27 20 (74) 17 10 (59)
      EXP3 (1 prior ALK TKI ± CT) 59 30 (51) 32 20 (63)
      EXP3A (prior crizotinib + CT) 32 21 (66) 20 15 (75)
      EXP3B (any 1 other ALK TKI ± CT) 27 9 (33) 12 5 (42)
      EXP4 (2 prior ALK TKIs ± CT) 65 27 (42) 45 25 (56)
      EXP5 (3 prior ALK TKIs ± CT) 46 16 (35) 38 (15 (39)
      CT, chemotherapy; IC, intracranial.
      Of 219 ALK+ patients analyzed for ALK kinase domain mutations at baseline, 46/219 (21%) had ≥1 mutation detected in circulating free DNA; most derived treatment benefit with an ORR of (27/46) 59%. Across all cohorts (N=275), the most common treatment-related adverse events (AEs) and grade 3/4 treatment-related AEs were hypercholesterolemia (81%/16%) and hypertriglyceridemia (60%/16%); 30% and 22% of patients had treatment-related AEs associated with dose interruptions and reductions, respectively. No treatment-related deaths occurred; 7 patients (3%) had treatment-related AEs leading to treatment discontinuation. 157/275 (57%) patients remained on treatment at data cutoff. Most patients reported stable/improved global quality of life (40%/43%).

      Conclusion:
      Lorlatinib showed clinically meaningful activity, including substantial intracranial efficacy, among ALK[+]/ROS1[+] patients who were either treatment-naïve or failed ≥1 prior ALK TKI. Overall lorlatinib was well tolerated and when needed, AEs were managed by dose delay/reduction or standard medical therapy.

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