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Ceritinib Active in Treating Brain Metastases in Non–Small Cell Lung Cancer


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The ALK inhibitor ceritinib demonstrated efficacy in patients with ALK-positive non–small cell lung cancer (NSCLC) and active brain metastases, according to the results of the ASCEND-7 trial reported at the European Society for Medical Oncology (ESMO) Congress 2019.1 Substantial intracranial responses of up to 51.5% were observed in patients enrolled in the trial, including those with and without prior exposure to crizotinib, those who had or had not received prior radiation therapy for brain metastases, and those exposed to neither previous crizotinib nor radiation therapy. Response rates were higher in patients who had not received prior ALK tyrosine kinase inhbitor therapy and lower in those who had received such treatment previously.

Laura Q. Chow, MD

Laura Q. Chow, MD

ASCEND-7 is distinct from other trials of ceritinib in that it enrolled only patients with ALK-positive NSCLC with newly diagnosed or progressive brain metastases, emphasized presenting author Laura Q. Chow, MD, of the University of Texas at Austin, Dell Medical School and LiveSTRONG Cancer Institutes. “The design of ASCEND-7 was based upon the intracranial responses previously reported in this group of patients in the prior ASCEND-4 to -5 studies,” she told listeners.

“These are exciting data from one of the first studies to be presented that evaluates ceritinib in patients with active brain metastases. Ceritinib had intracranial activity in this trial consistent with its known extracranial activity. Intracranial responses were rapid, high, and durable across all study arms. Although intracranial responses have been reported with other second-generation ALK inhibitors, the eligible criteria were not homogeneous across studies,” Dr. Chow noted.

Brain metastases occur in approximately 50% of patients with ALK-positive NSCLC and are associated with poor outcomes, she continued. Crizotinib, a first-generation ALK inhibitor, is approved as first-line treatment for ALK-positive NSCLC, but most patients develop resistance and progressive disease. Ceritinib is a second-generation ALK inhibitor approved by the U.S. Food and Drug Administration as a first- and second-line treatment for ALK-positive NSCLC and has demonstrated promising intracranial antitumor activity. Other approved second-generation ALK inhibitors include alectinib and brigatinib.

Study Details

Dr. Chow reported data from the phase II, open-label -ASCEND-7 for four treatment arms: arm 1 included 42 patients previously treated with brain radiotherapy and crizotinib; arm 2 included 40 patients who had received prior crizotinib alone; arm 3 included 12 patients who had prior brain radiotherapy alone; and arm 4 included 44 patients not previously exposed to crizotinib or brain radiotherapy.

Ceritinib was given at 750 mg/d every day in 28-day cycles, and treatment was continued until disease progression or unacceptable toxicity. Baseline characteristics were similar for the four study arms. As of February 2019, all 138 patients had discontinued treatment.

Key Findings

High rates of whole-body response were observed across all four arms. For arms 1, 2, 3, and 4, respectively, the objective response rate was 35.7%, 30%, 50%, and the highest response rate of 59.1% in patients naive to brain radiotherapy and crizotinib. Disease control rates were 66.7%, 82.5%, 66.7%, and 70.5%, respectively.

Intracranial response was evaluated in 28, 29, 7, and 33 patients in the respective arms having measurable brain metastases at baseline. Intracranial objective response rates were 39.3%, 27.6%, 28.6%, and 51.5%, respectively. Intracranial disease control rates were 75%, 82.8%, 85.7%, and 75.8%, respectively.

“The duration of response was clinically meaningful. In arm 4, the median duration of response was 9.2 months. The range of median whole-body progression-free survival was 5.6 months to 7.9 months in all four arms,” Dr. Chow said. The median overall survival was 24 months in arm 1 and not evaluable in the other arms.


The hope is that DNA methylation could turn out to be a predictive biomarker for patients at higher risk of developing brain metastases and pave the way for targeted therapies.
— Yun Fan, MD

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“When you add in nonmeasurable brain metastases, the intracranial response rates were slightly lower, but in general, responses were rapid and mirrored extracranial responses. Most responses were observed within 2 months,” she added.

The researchers attempted to secure 20 paired samples of plasma and cerebrospinal fluid to study pharmacokinetics, but they were able to obtain paired samples in just 3 patients. In this small sample size, there was variability and heterogeneity with central nervous system drug penetration and evidence of drug levels in the brain.

Toxicity and Dosing

Adverse events leading to treatment discontinuation were rare. The most common adverse events of all grades occurring in more than 50% of patients across all arms were diarrhea, nausea, transaminitis, vomiting, and decreased appetite. There were no new safety signals, and the adverse-event data were consistent with prior other trials of ceritinib at 750 mg/d fasting. The revised dosing of ceritinib at 450 mg/d taken with food (fed) achieves similar pharmacokinetics and drug levels as the 750 mg/d fed, with improved tolerability.

DNA Methylation: A Potential Biomarker?

A related ESMO presentation suggested that DNA methylation patterns may help to identify patients with NSCLC who will develop brain or leptomeningeal metastases.2 Researchers collected samples for targeted sequencing of somatic mutations from 29 patients with NSCLC who had paired lung primary and brain or leptomeningeal metastases, and 31 patients without

ALK Inhibitor in Lung Cancer Metastatic to the Brain

  • ASCEND-7 provides reassurance of ceritinib’s robust intracranial activity in ALK-positive NSCLC, and the study focused exclusively on patients with active brain metastases.
  • Ceritinib was effective in patients with prior exposure to crizotinib and to brain radiotherapy as well as in patients unexposed to either treatment modality.

CNS metastases until death using a panel of 520 cancer-related genes. They performed methylation analysis on tissue of the primary tumor and found that 16 methylation blocks were shared by patients with CNS metastases, but not by patients without CNS metastases.

“The hope is that this could turn out to be a predictive biomarker for patients at higher risk of developing brain metastases and pave the way for targeted therapies,” explained Yun Fan, MD, of Zhejiang Tumor Hospital, Hangzhou, China. 

DISCLOSURE: The ASCEND-7 trial was funded by Novartis. Dr. Chow reported financial relationships with Amgen, Novartis, Merck, Lilly/ImClone, Bristol-Myers Squibb, AstraZeneca/MedImmune, Pfizer, Incyte, VentiRx, Seattle Genetics, Dynavax, Genentech, and Synthorx. Dr. Fan reported no conflicts of interest.

REFERENCES

1. Chow Q, et al: Results of ASCEND-7 phase II study evaluating ALK inhibitor ceritinib in patients with ALK+ non-small cell lung cancer metastatic to the brain. ESMO Congress 2019. Abstract 1478O. Presented September 27, 2019.

2. Fan Y, et al: Integrated genomic and DNA methylation analyses of non-small cell lung cancer patients with brain metastases. ESMO Congress 2019. Abstract 1479O. Presented September 27, 2019.


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