NP28673 and NP28761 were Phase II, single-arm, open-label, multicenter studies, for which full methodology has been published previously.6,7 Response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Restaging scans, including brain scans, were obtained every 8 (NP28673) or 6 (NP28761) weeks. TTR and TTCR were defined, respectively, as time from date of first dose of alectinib to date of first occurrence of response in the response-evaluable (RE) population with confirmed systemic response, or in the safety population with confirmed CNS response. The studies were approved by the Institutional Review Board and the Ethics Committee of each study centre (full list available Supplementary Table 1), and were undertaken in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all patients.
The results are presented as two separate datasets rather than a pooled analysis because TTR is driven by scanning intervals. For NP28673, we present the number of patients who responded by weeks 8 and 16, and for NP28761 the number of patients who responded by weeks 6 and 12. The data cutoffs were February 1, 2016 (NP28673) and January 22, 2016 (NP28761).
The dataset comprised 138 patients from NP28673 and 87 patients from NP28761; the RE populations by independent review committee (IRC) comprised 122 and 67 patients, respectively. In the RE populations, baseline CNS metastases were present in 60.7% (NP28673) and 58.2% (NP28761) of patients. In both studies, baseline characteristics were similar in confirmed responders and in the RE population (Supplementary Table 2).
Median follow-up was 21.3 months (range 0.6–29.7) in NP28673 and 17.0 months (range 1.1–28.6) in NP28761. Time to first response, progression, and death for the patients with confirmed responses are shown in Supplementary Figure 1A and B.
In patients with a response, median TTR by IRC was 8 weeks (95% CI: 8.00–8.14) in NP28673 (n=62; Figure 1A) and 6 weeks (95% CI: 5.86–6.14) in NP28761 (n=35; Figure 1B). Most patients achieved a response by the first assessment; 72.6% (n=45/62) in NP28673 (Week 8), and 82.9% (n=29/35) in NP28761 (Week 6). Median TTR by investigator assessment was consistent with the IRC assessment in each study (Figure 1C and D). By the second assessment (Week 16 for NP28673 and Week 12 for NP28671), 90.3% (n=56/62) of responders had achieved their response in NP28673 (Figure 1A) and 91.4% (n=32/35) in NP28671 (Figure 1B).
In responders with measurable CNS disease at baseline, median TTCR by IRC was 8 weeks (95% CI: 7.86–10.29) in NP28673 (n=20; Figure 2A) and 6 weeks (5.71–not estimable [NE]) in NP28761 (n=12; Figure 2B). Overall, 75% of patients with measurable CNS disease at baseline in both NP28673 (n=15/20 patients) and NP28761 (n=9/12 patients) achieved a CNS response by the first assessment (Week 8 and Week 6, respectively). Similar results were observed in patients with measurable and/or non-measurable CNS disease at baseline (Figure 2C and D).
In responders with measurable CNS disease at baseline and no prior radiotherapy treatment, median TTCR by IRC was 7.86 weeks (95% CI: 7.86–NE) in NP28673 (n=6; Supplementary Figure 2A) and 5.71 weeks (95% CI: 5.71–NE) in NP28761 (n=5; Supplementary Figure 2B). Most CNS responses were achieved by the first assessment (83.3% [n=5/6 patients] by Week 8 in NP28763 and 80.0% [n=4/5 patients] by Week 6 in NP28761). Similar results were observed in patients with measurable and/or non-measurable CNS disease at baseline who had not received prior radiotherapy (Supplementary Figure 2C and D).
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