Barcelona, Spain—Treatment with ceritinib (Zykadia) led to excellent responses in patients with ALK-positive non–small-cell lung cancer (NSCLC) and brain metastases, according to results of the ASCEND-7 clinical trial, which enrolled only patients with ALK-positive NSCLC with newly diagnosed or progressive brain metastases.
Ceritinib treatment resulted in intracranial responses in up to 51.5% of patients, including patients with or without previous exposure to crizotinib or to radiation therapy for brain metastases.
“This is 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 are reported with other second-generation ALK inhibitors, the eligible criteria were not homogeneous across studies,” said lead investigator Laura Q. Chow, MD, FRCPC, Associate Director of Clinical Research, LIVESTRONG Cancer Institutes, Dell Medical School, University of Texas at Austin.
Brain metastases occur in approximately 50% of patients with ALK-positive NSCLC and are associated with poor outcomes. Crizotinib is approved as front-line treatment for ALK-positive NSCLC, but resistance develops in most patients, leading to progressive disease. Ceritinib is a second-generation ALK inhibitor approved by the FDA for first- and second-line treatment for ALK-positive NSCLC. Other FDA-approved second-generation ALK inhibitors include alectinib (Alecensa) and brigatinib (Alunbrig).
The phase 2, open-label ASCEND-7 clinical trial had 4 treatment arms, including 42 patients who received previous treatment with brain radiotherapy and crizotinib (arm 1); 40 patients who received previous treatment with crizotinib only (arm 2); 12 patients with previous brain radiotherapy only (arm 3); and 44 patients unexposed to previous crizotinib or to brain radiotherapy (arm 4).
Ceritinib 750 mg daily was given in 28-day cycles until disease progression or unacceptable toxicity. Baseline characteristics were comparable in the 4 arms.
High rates of whole-body response were observed across all 4 arms. For arms 1, 2, 3, and 4, the objective response rate was 35.7%, 30%, 50%, and 59.1%, respectively, in patients naïve to brain radiotherapy and crizotinib therapy. 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 in those with measurable brain metastases at baseline. The intracranial objective response rates were 39.3%, 27.6%, 28.6%, and 51.5%, respectively. The intracranial disease control rates were 75%, 82.8%, 85.7%, and 75.8%, respectively. Most responses were observed within 2 months.
“Duration of response was clinically meaningful. In arm 4, 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 4 arms,” Dr Chow said.
The median overall survival was 24 months in arm 1 and not evaluable in the other arms.
Adverse events leading to treatment discontinuation were infrequent. 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. Most of these were grade 2.
Commenting on the ASCEND-7 study, Lizza E. Hendriks, MD, PhD, Pulmonary Disease, Maastricht University Medical Center, Netherlands, said the results showed that penetration of the blood–brain barrier is important in treating patients with NSCLC and brain metastases.
“Disease control rates were high in all treatment arms, and duration of response, including intracranial response, was substantial. Ceritinib performed as expected, and the trial was well executed,” Dr Hendriks said. “We now know from ASCEND-7 that ceritinib should be taken at 450 mg/day with food, which is better tolerated than the original regimen of 750 mg/day without food. This revised dosing regimen will reduce toxicity associated with ceritinib,” Dr Hendriks added.
Noting that it is difficult to compare next-generation ALK inhibitors without head-to-head studies, Dr Hendriks said, “in general, all appear to be effective in the brain with good duration of response.”