Abstract 1727
Background
Previous PK analysis results from ASCEND-8 study (NCT02299505) showed that ceritinib 450 mg with food had comparable exposure and more favorable GI safety profile than ceritinib 750 mg fasted in patients (pts) with ALK+ NSCLC.
Methods
In this open-label, phase 1, 3-arm study, pts with treatment-naïve or pre-treated ALK+ advanced/metastatic NSCLC were randomized 1:1:1 to ceritinib 450 or 600 mg with food and 750 mg fasted, stratified by prior treatment and presence/absence of brain metastasis at screening. Key secondary endpoints were overall response rate (ORR) and duration of response, per BIRC using RECIST 1.1. Efficacy analysis was based on all treatment-naïve pts with ALK+ defined by IHC. Safety analysis was based on all pts who received ≥1 dose of study drug. Primary efficacy analysis and updated safety results are presented here (data cut off: 27 March 2018).
Results
A total of 306 pts were randomized to ceritinib 450 mg fed (n=108) or 600 mg fed (n=87) or 750 mg fasted (n=111). Of those, 198 were treatment-naïve with ALK+ by IHC and were assessed for efficacy (450 mg fed [n=73], 600 mg fed [n=51], and 750 mg fasted [n=74]). Median duration of study follow up was 19.6 months (mo) (range, 4.2-35.3) in all randomized pts and 14.3 mo (range, 4.2-30.2) in treatment-naïve pts who were ALK+ by IHC. ORR by BIRC was 78.1% (95% CI, 66.9-86.9), 72.5% (95% CI, 58·3-84·1), and 75.7% (95% CI, 64.3-84.9) in the 450 mg fed, 600 mg fed and 750 mg fasted arms, respectively. Other efficacy results are shown in the table. The 450 mg fed arm, when compared to 600 mg fed and 750 mg fasted arms, showed highest median relative dose intensity (100% vs 78.5% vs 83.7%), lowest proportion of pts with dose reductions (24.1% vs 65.1% vs 60.9%), all grade GI toxicities (75.9% vs 82.6% vs 91.8%) and grade 3/4 GI toxicities (2.8% vs 8.1% vs 13.6%).
| BIRC assessment | |||
|---|---|---|---|
| Ceritinib 450 mg fed (N = 73) | Ceritinib 600 mg fed (N = 51*) | Ceritinib 750 mg fasted (N = 74) | |
| Overall response rate, n (%) (95% CI) | 57 (78.1) (66.9-86.9) | 37 (72.5) (58.3-84.1) | 56 (75.7) (64.3-84.9) |
| Disease control rate, n (%) (95% CI) | 66 (90.4) (81.2-96.1) | 48 (94.1) (83.8-98.8) | 67 (90.5) (81.5-96.1) |
|
Median duration of response (in Estimated 18-month event-free probability, % (95% CI) | M† = 57 NE (11.2-NE) 52.9 (30.9-70.8) | M† = 37 20.7 (15.8-NE) 61.1 (36.7-78.5) | |
|
M† = 56 15.4 (8.3-NE) 36.7 (14.5-59.4)
| |||
| Median time to response, weeks (95% CI) | 6.3 (6.1-6.9) | 6.3 (6.1-9.3) | 6.3 (6.1-7.1) |
| Median progression-free survival, months (95% CI) Estimated 18-month event-free probability, % (95% CI) | NE (11.8-NE) 50.8 (33.7-65.7) | 17.0 (10.1-NE) 48.6 (30.7-64.3) | 12.2 (8.2-NE) 40.9 (23.3-57.8) |
| *The 600 mg fed arm has a lower number of patients because, based on the primary pharmacokinetic analysis results, the 450 mg fed arm was considered the most favorable fed dose and enrollment to the ceritinib 600 mg dose with food was closed. †M is the number of patients included in the duration of response analysis by BIRC analysis BIRC, blinded independent review committee; NE, not estimable | |||
Conclusions
Ceritinib 450 mg fed dose compared to 750 mg fasted showed consistent anti-tumor efficacy and improved GI tolerability in pts with ALK+ advanced NSCLC.
Clinical trial identification
NCT02299505
Editorial Acknowledgement
We thank Shiva Krishna Rachamadugu, Novartis Healthcare Pvt. Ltd., for providing medical editorial assistance with this abstract
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