Ceritinib demonstrates activity in ROS1–positive non–small cell lung cancer

Ceritinib appeared safe and effective in patients with ROS1–rearranged non–small cell lung cancer, according to a multicenter, open-label phase 2 study.

ALK inhibitors — especially crizotinib (Xalkori, Pfizer) — effectively treat ROS1–positive cell lines and tumors. However, patients eventually develop resistance and experience a high incidence of brain recurrence.

“Treatment options beyond crizotinib are needed, and clinical development of other ROS1 inhibitors should be accelerated to improve treatment outcome of patients with ROS1–positive NSCLC,” Byoung Chul Cho, MD, PhD, assistant professor at Yonsei Cancer Center of Yonsei University College of Medicine, and colleagues wrote.

Ceritinib (Zykadia, Novartis) — a more potent and selective oral tyrosine kinase inhibitor of ALK — has demonstrated promising clinical activity in both crizotinib-naive and previously treated patients. However, no trials have evaluated its use in ROS1–rearranged NSCLC.

Cho and colleagues evaluated the efficacy and safety of ceritinib in 32 patients (median age, 62 years; 75% women) with advanced NSCLC who tested positive for ROS1 rearrangement. Two patients had previously received crizotinib.

Patients received 750 mg ceritinib administered once daily in a continuous 28-day treatment cycle until disease progression or intolerance.

Objective response rate served as the primary endpoint. Secondary endpoints included disease control rate; duration of response; PFS; OS; toxicity; and concordance among fluorescent in situ hybridization, immunohistochemistry and next-generation sequencing.

Median follow-up was 14 months.

Twenty-eight patients had data available for independent radiologic review.

Researchers reported an ORR of 62% (95% CI, 45-77), with one complete response and 19 partial responses.

In addition, 81% (95% CI, 65-91) of patients achieved disease control, 84% (95% CI, 68-93) achieved 6-month OS and 56% (95% CI, 39-72) achieved 12-month OS.

Median PFS was 9.3 months (95% CI, 0-22) and median OS was 24 months (95% CI, 5 to 43).

Tumor burden decreased from baseline in 75% of patients.

Of the eight patients with brain metastases, two demonstrated an intracranial response for an intracranial ORR of 25% (95% CI, 7-59) and five patients experienced intracranial disease control (63%; 95% CI, 31-86).

The most common grade 1 or grade 2 adverse events included diarrhea (78%), nausea (59%) and anorexia (56%). Fatigue presented as the most common grade 3 or grade 4 adverse event (16%), which appeared reversible through dose interruptions.

One patient discontinued treatment due to adverse events, and three deaths occurred but were not related to the study.

“Ceritinib is active in patients with ROS1–rearranged NSCLC who are crizotinib naive,” Cho and colleagues wrote. “This study shows durable responses and prolonged PFS, with intracranial responses in patients with asymptomatic or neurologically stable brain metastases at study entry. Toxicities are manageable with dose adjustment or interruption and supportive care. Taken together, these data expand the role of ceritinib in patients with ROS1–rearranged NSCLC.”

However, the efficacy results from this trial and other ROS1 TKIs raised several questions regarding the clinical management of these patients, Ibiayi Dagogo-Jack, MD, instructor in medicine, and Alice T. Shaw, MD, PhD, thoracic oncologist, both from Massachusetts General Hospital, wrote in an accompanying editorial.

In particular, the study did not offer definitive data to demonstrate the superiority of ROS1 TKIs compared with chemotherapy. It also did not determine the optimal first-line ROS1 TKI and confined the clinical activity to crizotinib-naive patients.

“The study by Lim [and colleagues] adds another highly effective agent to the growing roster of TKIs for advanced ROS1–positive NSCLC,” Dagogo-Jack and Shaw wrote. “However, the study also creates a new dilemma in the field, namely which ROS1 TKI should be used for patients with newly diagnosed ROS1–positive lung cancer?”

They recommended a larger, global study be conducted to establish the drug’s activity, particularly in the central nervous system, as well as further investigation into the safety and efficacy of alternative dosing regimens to maximize ceritinib’s tolerability.

“For now, on the basis of the available data, crizotinib remains the standard therapy for advanced ROS1–positive NSCLC,” Dagogo-Jack and Shaw wrote. “Although ceritinib could one day replace crizotinib as the preferred first-line ROS1–targeted therapy, the ROS1 TKIs most likely to have the greatest impact on patient outcomes will be highly potent, highly central nervous system–penetrable agents with ROS1 G2032R activity.” – by Kristie L. Kahl

Disclosure: Cho reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Dagogo-Jack reports no relevant financial disclosures. Shaw reports honoraria from Foundation Medicine, Genentech, Novartis, Pfizer and Roche; consultant/advisory roles with ARIAD Pharmaceuticals, Blueprint Medicines, Daiichi Sankyo, EMD Serono, Genentech, Ignyta, KSQ Therapeutics, Novartis, Pfizer, Roche and Taiho Pharmaceutical; and research funding from Genentech, Novartis, Pfizer and Roche.