Clinical activity of ceritinib in ROS1-rearranged non-small cell lung cancer: Bench to bedside report

We read with great interest the article by Davare et al. (1) on structural insight of ROS1 tyrosine kinase inhibitors. Non-small cell lung cancer (NSCLC) is no longer a single disease but a collection of genetically heterogeneous tumors with different therapeutic options [e.g., aberrations in EGFR, BRAF, HER2/Neu, RET, anaplastic lymphoma kinase (ALK), and ROS1-rearranged tumors]. Each of these options has different clinical characteristics and therapeutic options with agents that have varying degrees of systemic activity. ROS1 gene rearrangements define a distinct molecular subgroup of NSCLC. ROS1 rearrangement leads to constitutive ROS1 activation and activity of crizotinib against ROS1-rearranged NSCLC was noted and crizotinib received regulatory approval for the treatment of ROS1 rearranged NSCLC (2). However, patients develop resistance and newer agents are needed. As shown by Davare et al. (1), molecular docking simulations and preclinical studies demonstrate that ceritinib (LDK 378), a recently approved ALK inhibitor, may also be active against ROS1-rearranged NSCLC (1, 3, 4). Herein we describe, to our knowledge, the first clinical report of systemic activity of ceritinib in a patient with ROS1-rearranged NSCLC after experiencing progression on crizotinib. Treatment and consent on investigational trials, and data collection, were performed in accordance with the guidelines of the University of Texas MD Anderson Cancer Center Institutional Review Board (IRB) and Quorum Central IRB.

A 77-y-old man presented with dyspnea. Chest X-ray revealed a right lower lobe nodule. Biopsy was positive for CK7, TTF-1, indicating adenocarcinoma. Thoracotomy staging revealed a T2aN1M0, stage IIA NSCLC. Molecular testing was negative for EGFR, KRAS, and BRAF mutations, and ALK gene rearrangement. After adjuvant chemotherapy with four cycles of carboplatin and pemetrexed, a fludeoxyglucose positron emission tomography-computed tomography scan showed an increase in size of pleural nodularity. Comprehensive next-generation sequencing genomic profiling revealed a CD72-ROS1 rearrangement. The patient was started on crizotinib at 250 mg orally twice daily and exhibited resolution of metastatic disease. The patient remained disease-free for 13 mo when CT-scan showed a relapse with two nodules in the right lower lobe. He underwent stereotactic radiation therapy. Imaging showed a treatment response but new pleural nodules. MRI brain scan showed new intracranial metastases. After undergoing gamma knife radiosurgery, the patient was enrolled in an ipilimumab and radiation trial (NCT02239900). His disease progressed on ipilimumab. The patient was next enrolled on the “Signature Trial,” a modular phase II study to link targeted therapy to patients with pathway activated tumors; in this study patients whose tumors have aberrations in ALK or ROS1 are treated with ceritinib (LDK378) at 750 mg orally daily (NCT02186821) (5). Restaging scans after two cycles and confirmed after four cycles showed a partial response (56% decrease) per RECIST1.1 (Fig. 1 A and B). Moreover, MRI showed that his brain metastases decreased as well (Fig. 1 C and D).

Fig. 1.

CT scan of the chest showing nodule in the right lateral chest wall: (A) before ceritinib; (B) 8 wk after ceritinib. MRI brain scan showing cerebellar metastasis: (C) before ceritinib; (D) 8 wk after ceritinib.

To our knowledge, this is the first clinical report that suggests that ROS1 inhibition with ceritinib has antitumor activity in a patient with ROS1-rearranged NSCLC after progression on crizotinib. This finding should be viewed as anecdotal and preliminary. Observation in more patients will be required to determine the efficacy of, frequency and durability of responses to, mechanisms of potential resistance to, and side effects of ceritinib.