Ceritinib should be considered a first-line therapeutic option in patients with ALK-rearranged advanced NSCLC.

— Gilberto de Castro, Jr, MD, PhD

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Compared to chemotherapy, the use of first-line ceritinib (Zykadia) resulted in a statistically significant and clinically meaningful improvement in median progression-free survival, with an estimated 45% reduction in disease progression risk, as well as significant improvements in quality of life, in patients with advanced anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC), according to the results of the ­ASCEND-4 study. The study findings were presented by Gilberto de Castro, Jr, MD, PhD, at the 2016 World Conference on Lung Cancer in Vienna.¹

“The improvement in progression-free survival was robust and consistent across all prespecified subgroups, including patients with and without brain metastases,” said Dr. de Castro, Chief at the Unit of Head and Neck and Thoracic Tumors of the Clinical Oncology Service at the Instituto do Cancer do Estado de São Paulo, Brazil. “Ceritinib should be considered a first-line therapeutic option in patients with ALK-rearranged advanced NSCLC.”

Ceritinib is a potent second-generation ALK inhibitor approved in 2014 by the U.S. Food and Drug Administration for the treatment of ALK-positive metastatic NSCLC following treatment with crizotinib (Xalkori). In the ­ASCEND-1 and ASCEND-3 trials, ceritinib demonstrated robust antitumor activity in ALK-positive NSCLC patients who were ALK inhibitor–naive but had disease progression on chemotherapy.

Study Details

ASCEND-4 is a randomized, global, open-label phase III study that compared the efficacy and safety of first-line ceritinib vs standard platinum/pemetrexed (Alimta) therapy followed by pemetrexed maintenance in untreated patients with stage IIIB/IV ALK-­rearranged NSCLC.

Between August 2013 and May 2015, a total of 376 patients at 134 sites in 27 countries were enrolled in the ASCEND-4 study. Patients were randomized 1:1 to ceritinib at 750 mg/d (n = 189) or chemotherapy (n = 187; pemetrexed at 500 mg/m² plus cisplatin at 75 mg/m² or carboplatin at AUC 5–6 for four cycles followed by maintenance pemetrexed), until progressive disease, at which point patients could cross over to extension treatment with ceritinib (80 crossed over). The primary endpoint of the study was progression-free survival, with a key secondary endpoint of overall survival.

Baseline characteristics were well balanced between the two arms: median age was 54, a high percentage of patients were Asian (42%) or white (~54%), and 61% were never smokers. Almost all patients (95%) presented with stage IV adenocarcinoma at study entry. Brain metastases were present in 30% of ­patients.

“Importantly, 40% of patients with brain metastases had already received radiation to the brain,” Dr. de Castro added. A higher intracranial response rate was also observed with ceritinib compared to chemotherapy (72.7% vs 27.3 %), with a duration of intracranial response of 16.6 months for ceritinib.

The median duration of treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy, and the median duration of follow-up was 19.7 months. Of the 189 patients randomized to ceritinib, 94 discontinued treatment, mainly due to progressive disease. Of the 187 patients randomized to chemotherapy, 175 were treated, 72% received pemetrexed as maintenance therapy, and 157 discontinued treatment, mainly due to progressive disease. Among those who discontinued therapy, 105 patients (72%) received an ALK inhibitor as subsequent treatment after chemotherapy, he reported.

Key Findings

ASCEND-4 met its primary objective, with ceritinib demonstrating a statistically significant improvement in progression-free survival: 16.6 months, compared to 8.1 months with chemotherapy (hazard ratio [HR] = 0.55, P < .001).

Ceritinib also demonstrated a progression-free survival benefit over chemotherapy across the majority of predefined subgroups. “Overall survival data are immature at this analysis, but a positive trend for ceritinib was observed, and the curves separated early,” he said.

A higher overall objective tumor response rate was seen with ceritinib compared to chemotherapy (72.5% vs 26.7%), and the median time to first response was shorter with ceritinib compared to chemotherapy (6 vs 13 weeks). A longer duration of response was seen with ceritinib: 24 months, vs 11 months with chemotherapy. Among patients treated with ceritinib, 92% had tumor shrinkage.

A progression-free survival benefit was observed in patients with and without brain metastases. In patients without brain metastases at screening, ceritinib resulted in a 26.3-month progression-free survival, compared to 8.3 months with chemotherapy; in patients with brain metastases, progression-free survival was 10.7 months with ceritinib vs 6.7 months for chemotherapy.

The safety profile of ceritinib was consistent with previous studies. Fewer patients in the ceritinib arm discontinued treatment due to adverse events, compared to chemotherapy-treated patients (5.3% vs 11.4%). Gastrointestinal symptoms including diarrhea, nausea, vomiting, and elevation of liver enzymes were more frequently observed in patients treated with ceritinib, and dose adjustments or treatment interruptions occurred in 27% of patients with gastrointestinal toxicities, but adverse events were, in general, manageable and acceptable. Constipation, anemia, dyspnea, and neutropenia were more frequent in the chemotherapy arm. ■

Disclosure: Dr. de Castro reported no potentical conflicts of interest.

Reference

1. de Castro Jr G, Tan D, Crino L, et al: First-line ceritinib versus chemotherapy in patients with ALK-rearranged (ALK+) NSCLC: A randomized phase 3 study (ASCEND-4). 2016 World Conference on Lung Cancer. Abstract PL03.07. Presented December 6, 2016.