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Gerson Peltz

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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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      OA02.03 - Clinical Activity of Lorlatinib in Patients with ROS1+ Advanced Non-Small Cell Lung Cancer: Phase 2 Study Cohort EXP-6 (ID 12787)

      10:50 - 11:00  |  Author(s): Gerson Peltz

      • Abstract
      • Presentation
      • Slides


      Among patients with ROS1-positive non-small cell lung cancer (NSCLC), most achieve initial benefit from crizotinib treatment but often develop resistance, and further treatment options are limited. Lorlatinib is a potent, brain-penetrant third-generation ALK/ROS1 TKI with broad mutational coverage. It has shown compelling clinical activity in patients with ALK-positive and ROS1-positive advanced NSCLC, most of whom had CNS metastases and had received prior crizotinib.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This ongoing Phase 2 study (NCT01970865) enrolled patients with ROS1-positive advanced NSCLC ± asymptomatic CNS metastases without restriction on the type or number of prior lines of therapy (cohort EXP-6). Patients received lorlatinib 100 mg QD. Primary endpoints were overall and intracranial response by independent central review. Secondary endpoints included duration of response and progression-free survival. Safety was assessed in all treated patients (cohorts EXP-1–6); molecular profiling is ongoing.

      4c3880bb027f159e801041b1021e88e8 Result

      As of the data cut-off (02 Feb 2018), 47 patients with ROS1+ NSCLC were treated; 25 had baseline CNS metastases; 34 had received prior crizotinib and 13 were crizotinib-naïve. Treatment with lorlatinib led to rapid and durable responses in both crizotinib-naïve and crizotinib-pre-exposed patients (Table).

      ICR-assessed endpoint Crizotinib-naïve Crizotinib-pre-exposed Total EXP-6
      Overall, N 13 34 47
      ORR, % (95% CI) 61.5 (31.6, 86.1) 26.5 (12.9, 44.4) 36.2 (22.7, 51.5)
      Confirmed response, n 8 9 17

      Response lasting at least 12 months, n

      5 5 10
      Median time to tumor response, months (range) 1.4 (1.3–8.3) 2.5 (1.4–4.2) 1.4 (1.3–8.3)
      Intracranial (IC), N 6 19 25
      IC ORR, % (95% CI) 66.7 (22.3, 95.7) 52.6 (28.9, 75.6) 56.0 (34.9, 75.6)
      Confirmed IC response, n 4 10 14

      IC response lasting at least 12 months, n

      1 4 5
      Median PFS, months (95% CI)a 21.0 (4.2, 26.7) 8.5 (4.4, 18.0) 9.9 (5.5, 21.0)

      ICR, independent central review; PFS, progression-free survival.

      aPer Kaplan-Meier method.

      The most common treatment-related adverse events (TRAEs) in EXP-6, were hypercholesterolemia (83%) and hypertriglyceridemia (60%). In EXP-6, 36% and 23% of patients had TRAEs leading to dose interruptions and dose reductions, respectively. No permanent treatment discontinuations due to TRAEs or treatment-related deaths occurred.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lorlatinib showed clinically meaningful benefit in patients with ROS1-positive NSCLC, including those who had received prior crizotinib or were crizotinib-naive, as demonstrated by rapid and durable responses. These findings further suggest that the activity of lorlatinib differs depending on prior exposure to crizotinib. The safety profile of lorlatinib in ROS1 patients was comparable to that previously reported in the overall ALK/ROS1 population.


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