New Dose Strategy for Ceritinib May Improve Outcomes in ALK-Positive NSCLC

Patients with ALK-positive non–small cell lung cancer (NSCLC) and brain metastases achieved better objective response rates (ORRs) and disease control rates (DCRs) when given ceritinib (Zykadia) 450 mg with food compared with 750 mg whilst fasting, according to results from a real-world study.

Roughly 30% to 50% of patients with ALK-positive NSCLC develop brain metastases, and with the inevitability of resistance to frontline crizotinib (Xalori), oncologists count on ceritinib to manage disease in patients being treated in the second-line setting. In China, ceritinib 450 mg was granted FDA approval for the treatment of patients with ALK-positive NSCLC who are intolerant to or progressed on crizotinib in May 2018. To access outcomes of Chinese patients receiving the newly approved treatment, a real-world study was launch in October 2018. The key goal of the study was to assess the intracranial and systemic efficacy of ceritinib with food, as well as safety.

A total of 57 patients with ALK-positive NSCLC and brain metastases who visited West China Hospital between October 2018 and May 2020 were enrolled. Data from these patients were retrospectively reviewed for the purpose of the real-world study. The study was powered to assess ORR and DCR in patients according to their characteristics. The study also evaluated the median progression-free survival (PFS), and predictions of event-free survival (EFS) rates at the 6- and 12-month marks.

Of the 57 patients included in the study, baseline characteristics showed that 45.6% were male, and 54.4% were female. The majority of patients enrolled (45.6%) had an ECOG performance status of 1, followed by 2 for 29.8%, 3 for 14%, and 4 for 10.5% of patients. Notably, 7% had a family history of cancer. All of the patients enrolled were had stage IV disease.

The disease characteristics of the patient population observed at baseline showed that 98.2% had ALK-positive NSCLC, and 1.8% had both ALK- and BRAF-positive disease. The most common site of metastasis in this study was the liver, which was seen in 22.8% of patients. Another 3.5% of patients had meningeal metastases.

Treatment history for patients enrolled in the retrospective study consisted of crizotinib (92.3%), brain radiotherapy (41/1%), chemotherapy (36.8%) alectinib (Alecensa; 1.8%), and brain surgery (8.8%). As a heavily pretreated group of patients, 63.2% had 3 to 5 prior lines of ceritinib, and 36.8% of patients had 1 to 2 prior lines of ceritinib.

The results show that the use of ceritinib led to an intracranial ORR of 73.7% (95% CI, 62.3-85.1) and a DCR of 93.0% (95% CI, 86.3-99.6). Response in the brain included complete responses (CRs) in 2% of patients, partial responses (PRs) in 72%, and stable disease (SD) in 19%. Progressive disease (PD) was also observed in 7% of patients.

In the whole body, ceritinib led to an ORR of 87.7% (95% CI, 79.2-96.2) with a DCR of 98.2% (95% CI, 94.8-100.0). The CR rate was 2%, and PRs were observed in 86% of patients. Eleven percent of patients had SD, and only 2% had PD. Based on a correlative analysis, it was determined that the subset of patients who had prior brain radiotherapy achieved significantly higher ORRs compared with patients who received other prior therapies. (P = .044). Other differences in patient characteristics were not significant in relation to ORR and DCR.

Intracranial PFS was available by the last follow-up for 15 patients and whole-body PFS was available for 12 patients.

The median was not reached for intracranial PFS, but the prediction was a 12.9-month improvement in PFS. The 6-month EFS was estimated to be 94.1% (95% CI, 87.8-100.1) and the 12-month EFS was estimated to be 68.1% (95% CI, 54.1-85.7). Patients with prior brain radiotherapy were shown to have a significantly higher probability of 12-month EFS in intracranial lesions of 93.8% compared with 47.1%, for those who did not have prior brain radiotherapy (P = .0006).

In 12 patients, the whole-body PFS observed was 7.6 months (95% CI, 6.1-NE). The median was not reached for the total study population. Investigators predicted a median PFS of 15.2 months, however. EFS was estimated to be 94.1% (95% CI, 87.9-100.1) at 6 months and 74.7% (95% CI, 61.8-90.3) at 12 months.

Safety was assessed for all 57 patients involved in the study. The safety analysis showed adverse events (AEs) in 77.2% of patients. The most common AEs observed were diarrhea (19.3%), nausea (10.5%), vomiting (10.5%), and anorexia (8.8%).

Overall, this retrospective study demonstrated better outcomes with ceritinib 450 mg with food as compared with prior studies of ceritinib 750 mg whilst fasting and revealed that having prior brain radiotherapy can improve responses and extend survival in patients with ALK-positive NSCLC and brain metastases.

_Reference:

_{Qiu Z, Xian X, Liu C, et al. Clinical Data from the real world: efficacy analysis of ceritinib(450mg/d) in ALK-positive non-small cell lung cancer patients with brain metastases inChina. Presented at: European Society of Medical Oncology Asia Virtual Congress 2020; Nov 22–29, 2020. Abstract 392P.}