Comparative Efficacy of Ceritinib and Crizotinib as Initial  ALK –Targeted Therapies in Previously Treated Advanced NSCLC: An Adjusted Comparison with External Controls

Tan, Daniel Shao-Weng; Araújo, António; Zhang, Jie; Signorovitch, James; Zhou, Zheng–Yi; Cai, Xiaopeng; Liu, Geoffrey

doi:10.1016/j.jtho.2016.05.029

Cited by 43 publications

(35 citation statements)

References 29 publications

(37 reference statements)

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“…In the absence of a randomized head to head study comparing the efficacy between ceritinib and crizotinib in the first‐line setting, previous studies addressed this by taking advantage of an indirect comparative approach using the patient cohort propensity score‐matched from the ASCEND 4 and PROFILE 1014 trials . In this indirect comparison, ceritinib showed a significantly better treatment efficacy than crizotinib . Although this approach provided preliminary and insightful findings, it remained limited by the unadjustable bias inherent in each trial.…”

Section: Discussionmentioning

confidence: 99%

“…4,14 In this indirect comparison, ceritinib showed a significantly better treatment efficacy than crizotinib. 19,20 Although this approach provided preliminary and insightful findings, it remained limited by the unadjustable bias inherent in each trial. The present study, otherwise analyzed in a manner of direct comparison, confirmed the finding noted in the previous indirect comparison.…”

Section: Discussionmentioning

confidence: 99%

“…14,17,18 In the meantime, no dedicated clinical trial which directly compares the therapeutic outcome between ceritinib and crizotinib is available, except a few reports which indirectly compare the two drugs using the patients that propensity score-matched from individual clinical trials originally conducted for the study of crizotinib and ceritinib, respectively. 19,20 These indirect comparisons are insightful for the analysis of the primary outcomes consistently defined across the original trials, such as progression-free or overall survival, although they might not be feasible for the analysis of the outcomes, such as the pattern of disease progression, as these were not consistently defined across the trials. In this study, we retrospectively compared a group of patients who received either crizotinib or ceritinib as the front-line treatment and the treatment efficacy, pattern of disease progression and toxicity profile were analyzed.…”

Section: Introductionmentioning

confidence: 99%

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Front‐line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control

Huang

Wang

et al. 2019

Thoracic Cancer

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BackgroundApproximately 3%–5% of lung adenocarcinoma is driven by anaplastic lymphoma kinase (ALK) fusion oncogene, whose activity can be suppressed by multiple ALK inhibitors. Crizotinib and ceritinib have demonstrated superior efficacy to platinum‐based chemotherapy as front‐line treatment for patients with ALK‐positive advanced non‐small cell lung cancer (NSCLC). However, the direct comparison between them in the front‐line setting remains lacking.MethodsA total of 48 patients with ALK‐positive, previously untreated advanced NSCLC, who received crizotinib and ceritinib as front‐line treatment were retrospectively investigated. The efficacy and pattern of disease progression were analyzed.ResultsPatients receiving ceritinib treatment were significantly younger than those receiving crizotinib treatment (52.0 vs. 63.0, P = 0.016). The median progression‐free survival (PFS) was significantly longer with ceritinib than with crizotinib treatment (32.3 vs. 12.9 months; log‐rank P = 0.020); the hazard ratio for disease progression or death, 0.27 (95% CI, 0.08–0.90; P = 0.033). An objective response was noted in all patients in the ceritinib group and in 23 patients in the crizotinib group (74.2%; 95% CI, 59.0 to 88.5). The rate of systemic progression was significantly lower over time with ceritinib treatment compared to crizotinib treatment (cause‐specific hazard ratio, 0.21; 95% CI 0.06–0.73; P = 0.014). Serious adverse events were noted in one (2.9%) patient showing elevated liver function in the crizotinib group and three (23.1%) patients showing diarrhea in the ceritinib group. Dose reduction was needed in five out of 13 (38.5%) patients receiving ceritinib treatment.ConclusionCeritinib showed higher efficacy associated with a better control of systemic progression compared to crizotinib for the front‐line treatment of ALK‐positive advanced NSCLCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Front‐line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control

Huang

Wang

et al. 2019

Thoracic Cancer

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“…8.3 months, respectively, and 82.6 vs . 66.0% patient survival at 12 months, respectively) . Most recently, early data from the Phase III ASCEND‐5 study of 231 European patients showed that ALK‐positive NSCLC patients that progressed on crizotinib had a longer progression‐free survival with ceritinib than pemetrexed‐docetaxel (5.4 vs .…”

Section: Clinical Trials Investigating Alternatives To Crizotinib In mentioning

confidence: 99%

“…Only when patients were matched, median PFS and overall survival were longer in the ceritinib group in comparison to the crizotinib Group (13.8 vs. 8.3 months, respectively, and 82.6 vs. 66.0% patient survival at 12 months, respectively). 80 Most recently, early data from the Phase III ASCEND-5 study of 231 European patients showed that ALK-positive NSCLC patients that progressed on crizotinib had a longer progression-free survival with ceritinib than pemetrexed-docetaxel (5.4 vs. 1.6 months, respectively; p < 0.001), suggesting that second-line therapy should be with ceritinib and not chemotherapy. 81 As a result, ceritinib has conditional approval in Europe.…”

Section: Ceritinibmentioning

confidence: 99%

Development of crizotinib, a rationally designed tyrosine kinase inhibitor for non‐small cell lung cancer

Kelly

2017

Intl Journal of Cancer

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Non-small cell lung cancer (NSCLC) is the number one cause of global mortality. Despite aggressive treatment, the prognosis is dismal. Patients with advanced NSCLC have a median survival of 4 months from the time of diagnosis. Fortunately, molecularly based approaches to drug discovery have yielded a tyrosine kinase inhibitor, crizotinib, which significantly prolongs median progression-free survival in a subset of patients. Although initial clinical trial results demonstrate crizotinib has a promising role to play in NSCLC treatment, development of resistance leaves much to be elucidated about how to effectively combat this deadly disease. In this review, we follow the discovery and development of crizotinib from bench to bedside and provide an example of successful bottom-up drug design. Then, we explore the clinical trial results that fast-tracked its eventual use as a frontline therapy for sensitive NSCLC patients and the development of resistance. Lastly, we discuss the potential for future uses of crizotinib both within and beyond NSCLC.

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Using Electronic Health Records to Derive Control Arms for Early Phase Single‐Arm Lung Cancer Trials: Proof‐of‐Concept in Randomized Controlled Trials

Carrigan¹,

Whipple²,

Capra³

et al. 2019

Clin Pharma and Therapeutics

116

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Oncology drug development increasingly relies on single-arm clinical trials. External controls (ECs) derived from electronic health record (EHR) databases may provide additional context. Patients from a US-based oncology EHR database were aligned with patients from randomized controlled trials (RCTs) and trial-specific eligibility criteria were applied to the EHR dataset. Overall survival (OS) in the EC-derived control arm was compared with OS in the RCT experimental arm. The primary outcome was OS, defined as time from randomization or treatment initiation (EHR) to death. Cox regression models were used to obtain effect estimates using EHR data. EC-derived hazard ratio estimates aligned closely with those from the corresponding RCT with one exception. Comparing log HRs among all RCT and EC results gave a Pearson correlation coefficient of 0.86. Properly selected control arms from contemporaneous EHR data could be used to put single-arm trials of OS in advanced non-small cell lung cancer into context.The need to bring safe and effective oncology treatment options to patients quickly is highlighted by the 21st Century Cures Act 1-3 and the Cancer Moonshot initiative. 4 Oncology research in recent years has included novel trial designs sometimes with only a single treatment arm. Precision oncology drugs increasingly receive accelerated or breakthrough regulatory approval based on these single-arm trials. An inherent feature of these designs is that a standard-of-care control arm is not included, leading to challenges in interpretation of efficacy. 3,[5][6][7][8][9]

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Comparative Efficacy of Ceritinib and Crizotinib as Initial ALK –Targeted Therapies in Previously Treated Advanced NSCLC: An Adjusted Comparison with External Controls

Abstract: In an adjusted comparison across separate clinical trials, ceritinib was associated with prolonged OS and PFS compared with crizotinib when used as initial ALK-targeted therapy for previously treated ALK-positive NSCLC.

Cited by 43 publications

References 29 publications

Front‐line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control

Front‐line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control

Development of crizotinib, a rationally designed tyrosine kinase inhibitor for non‐small cell lung cancer

Using Electronic Health Records to Derive Control Arms for Early Phase Single‐Arm Lung Cancer Trials: Proof‐of‐Concept in Randomized Controlled Trials

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