ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non–Small Cell Lung Cancer (NSCLC)

Cho, Byoung Chul; Kim, Dong Wan; Bearz, Alessandra; Laurie, Scott A.; McKeage, Mark J.; Borra, Gloria; Park, Keunchil; Kim, Sang We; Ghosn, Marwan; Ardizzoni, Andrea; Maiello, Evaristo; Greystoke, Alastair; Yu, Ruey J.; Osborne, Karen A.; Gu, Wen; Scott, Jeffrey W.; Passos, Vanessa Q.; Lau, Yvonne; Wrona, Anna

doi:10.1016/j.jtho.2017.07.005

Cited by 157 publications

(139 citation statements)

References 16 publications

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“…Overall, gastrointestinal AE (diarrhea, nausea, and vomiting) were the most frequently reported all‐causality drug‐related AE. Recent data from a phase I study of ceritinib (ASCEND‐8; NCT02299505) show that the frequency and severity of gastrointestinal toxicities was lower with a starting dose of 450 mg/day under fed condition compared to that with the currently approved recommended dose of 750 mg/day under fasted condition, with fewer patients requiring dose reduction or interruption, resulting in the higher median relative dose intensity and comparable efficacy . Thus, ceritinib treatment with this new starting dose of 450 mg/day under fed condition is expected to improve the relative dose intensity on account of a better gastrointestinal safety profile and more favorable benefit/risk profile.…”

Section: Discussionmentioning

confidence: 99%

Phase II study of ceritinib in alectinib‐pretreated patients with anaplastic lymphoma kinase‐rearranged metastatic non‐small‐cell lung cancer in Japan: ASCEND‐9

et al. 2018

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Clinical experience of ceritinib in patients who progressed on alectinib is limited. In this prospective phase II study, we evaluated the activity of ceritinib in alectinib‐pretreated patients with anaplastic lymphoma kinase (ALK)‐rearranged metastatic (stage IIIB/IV) non‐small‐cell lung cancer (NSCLC) in Japan. All patients were required to have ≥1 measurable lesion per RECIST, 1.1, and a World Health Organization Performance Status (WHO PS) of 0‐1. Prior crizotinib and/or up to 1 chemotherapy regimen was allowed. Primary endpoint was investigator‐assessed overall response rate (ORR) per RECIST 1.1. Ceritinib was given at a dose of 750 mg/day fasted. A total of 20 patients were enrolled from August 2015 to March 2017. All patients received prior alectinib (100%), 13 (65.0%) patients received prior platinum‐based chemotherapy, and 4 (20%) patients received prior crizotinib. Median duration of exposure and the follow‐up time with ceritinib were 3.7 months (range: 0.4‐15.1) and 11.6 months (range: 4.8‐23.0), respectively. Investigator‐assessed ORR was 25% (95% CI: 8.7‐49.1). Key secondary endpoints, all investigator assessed, included disease control rate (70.0%; 95% CI: 45.7‐88.1), time to response (median, 1.8 months; range: 1.8‐2.0), and duration of response (median, 6.3 months; 95% CI: 3.5‐9.2). Median progression‐free survival was 3.7 months (95% CI: 1.9‐5.3). The most common adverse events reported were diarrhea (85.0%), nausea (80.0%), and vomiting (65.0%). Based on our findings, ceritinib could be considered as one of the treatment options for patients with ALK‐positive NSCLC who progressed on alectinib. (Trial registration no. NCT02450903)

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Section: Discussionmentioning

confidence: 99%

Phase II study of ceritinib in alectinib‐pretreated patients with anaplastic lymphoma kinase‐rearranged metastatic non‐small‐cell lung cancer in Japan: ASCEND‐9

et al. 2018

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“…Consistent with prior experiences (72–75), the most common ceritinib-associated adverse events (AEs) in the phase II study were diarrhea (78%), nausea (59%), anorexia (56%), and vomiting (53%) (76)—at higher frequencies overall than observed with crizotinib (4). Alternative ceritinib dosing with food may help ameliorate these side effects going forward (77). In the ASCEND-8 study, the 450 mg daily dosing of ceritinib with meals was much better tolerated as compared to 750 mg daily dosing fasting, yet reached similar steady-state plasma levels based on pharmacokinetic studies (77).…”

Section: Ros1-targeted Therapies In Lung Cancermentioning

confidence: 99%

“…Alternative ceritinib dosing with food may help ameliorate these side effects going forward (77). In the ASCEND-8 study, the 450 mg daily dosing of ceritinib with meals was much better tolerated as compared to 750 mg daily dosing fasting, yet reached similar steady-state plasma levels based on pharmacokinetic studies (77). Confirmation that antitumor efficacy is comparable between the two dosing regimens remains to be established.…”

Section: Ros1-targeted Therapies In Lung Cancermentioning

confidence: 99%

Recent Advances in Targeting ROS1 in Lung Cancer

Lin

Shaw

2017

Journal of Thoracic Oncology

214

208

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ROS1 is a validated therapeutic target in non-small cell lung cancer (NSCLC). In a phase I study, the multi-targeted MET/ALK/ROS1 inhibitor crizotinib demonstrated remarkable efficacy in ROS1-rearranged NSCLCs, and consequently gained approval by the United States Food and Drug Administration as well as the European Medicines Agency in 2016. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquire resistance, leading to disease relapse. Novel ROS1 inhibitors and therapeutic strategies are therefore needed. Insights into the mechanisms of resistance to ROS1-directed tyrosine kinase inhibitors (TKIs) are now beginning to emerge and are helping to guide the development of new ROS1 inhibitors. This review discusses the biology and diagnosis of ROS1-rearranged NSCLC, and current and emerging treatment options for this disease. Future challenges in the field are highlighted.

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“…Given the concern regarding poor tolerance of ceritinib, the ASCEND-8 trial sought to evaluate whether lower doses of ceritinib at 450 mg and 600 mg given with a low-fat meal could reduce the adverse gastrointestinal effects of ceritinib 750 mg taken on an empty stomach. Ceritinib 450 mg taken with a low-fat meal demonstrated similar pharmacokinetics as 750 mg fasting, with less gastrointestinal (GI) adverse effects and no grade 3 GI events [42]. However, the overall rate of suspected drug-related adverse events occurred in 41% of patients at the 450 mg dose and no efficacy data with this dose is as yet available.…”

Section: Therapeutic Optionsmentioning

confidence: 99%

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

Qin

Gadgeel

2017

Targ Oncol

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Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3–7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further.

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ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non–Small Cell Lung Cancer (NSCLC)

Abstract: Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC.

Cited by 157 publications

References 16 publications

Phase II study of ceritinib in alectinib‐pretreated patients with anaplastic lymphoma kinase‐rearranged metastatic non‐small‐cell lung cancer in Japan: ASCEND‐9

Phase II study of ceritinib in alectinib‐pretreated patients with anaplastic lymphoma kinase‐rearranged metastatic non‐small‐cell lung cancer in Japan: ASCEND‐9

Recent Advances in Targeting ROS1 in Lung Cancer

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

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