chemotherapy.
In Study A2303, 133 patients with baseline brain metastasis (66 patients in the Zykadia arm and 67 patients in the chemotherapy arm) were assessed for intracranial response by BIRC neuro-radiologist (per modified RECIST 1.1 (i.e. up to 5 lesions in the brain). The OIRR in patients with measurable disease in the brain at baseline and at least one post-baseline assessment was higher in the ceritinib arm (35.3%, 95% CI: 14.2, 61.7) compared to the chemotherapy arm (5.0%, 95% CI: 0.1, 24.9). The median PFS by BIRC using RECIST 1.1 was longer in the ceritinib arm compared to the chemotherapy arm in both subgroups of patients with brain metastases and without brain metastases. The median PFS in patients with brain metastases was 4.4 months (95% CI: 3.4, 6.2) versus 1.5 months (95% CI: 1.3, 1.8) in the ceritinib and chemotherapy arms, respectively with HR=0.54 (95% CI: 0.36, 0.80). The median PFS in patients without brain metastases was 8.3 months (95% CI: 4.1, 14.0) versus 2.8 months (95% CI: 1.4, 4.1) in the ceritinib and chemotherapy arms, respectively with HR=0.41 (95% CI: 0.24, 0.69).
Dose optimisation Study A2112 (ASCEND-8)
The efficacy of Zykadia 450 mg with food was eva luated in a multicentre, open-label dose optimisation study A2112 (ASCEND-8). A total of 81 previously untreated patients with ALK-positive locally advanced or metastatic NSCLC were randomised to receive Zykadia 450 mg once daily with food (N=41) or Zykadia 750 mg once daily under fasted conditions (N=40). A key secondary efficacy endpoint was ORR according to RECIST 1.1 as eva luated by BIRC.
The population characteristics across the two arms were: mean age 53 years, age less than 65 (79%), female (57%), Caucasian (54%), Asian (33%), never or former smoker (95%), WHO PS 0 or 1 (93%), adenocarcinoma histology (94%), and metastases to the brain (33%).
Efficacy results from ASCEND-8 are summarised in Table 5 below.
Table 5 ASCEND-8 (Study A2112) - Efficacy results in patients with previously untreated ALK-positive locally advanced or metastatic NSCLC by BIRC
Efficacy Parameter
Ceritinib 450 mg with food (N=41)
Ceritinib 750 mg fasted (N=40)
Overall Response Rate (ORR: CR+PR), n (%) (95% CI)a
32 (78.0)
(62.4, 89.4)
28 (70.0)
(53.5, 83.4)
CI: Confidence Interval
Complete Response (CR), Partial Response (PR) confirmed by repeat assessments performed not less than 4 weeks after response criteria were first met
Overall response rate determined based on BIRC assessment per RECIST 1.1
aExact binomial 95% confidence interval
Single arm studies X2101 and A2201
The use of Zykadia in the treatment of ALK-positive NSCLC patients previously treated with an ALK inhibitor was investigated in two global, multicentre, open-label, single-arm phase 1/2 studies (Study X2101 and Study A2201).
In study X2101 a total of 246 ALK-positive NSCLC patients were treated at a Zykadia dose of 750 mg once daily fasted: 163 who had received prior treatment with an ALK inhibitor and 83 who were ALK inhibitor naïve. Of the 163 ALK-positive NSCLC patients who had received prior treatment with an ALK inhibitor, the median age was 52 years (range: 24-80 years); 86.5% were younger than 65 years and 54% were female. The majority of patients were Caucasian (66.3%) or Asian (28.8%). 93.3% had adenocarcinoma and 96.9% had either never been or were former smokers. All of the patients were treated with at least one regimen prior to enrolment into the study and 84.0% with two or more regimens.
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