LETTER Clinical activity of ceritinib in ROS1-rearranged non-small cell lung cancer: Bench to bedside report LETTER Vivek Subbiaha,1, David S. Honga, and Funda Meric-Bernstama We read with great interest the article by Davare et al. (1) profiling revealed a CD72-ROS1 rearrangement. The on structural insight of ROS1 tyrosine kinase inhibitors. patient was started on crizotinib at 250 mg orally twice Non-small cell lung cancer (NSCLC) is no longer a single daily and exhibited resolution of metastatic disease. disease but a collection of genetically heterogeneous The patient remained disease-free for 13 mo when tumors with different therapeutic options [e.g., aberra- CT-scan showed a relapse with two nodules in the tions in EGFR, BRAF, HER2/Neu, RET, anaplastic lym- right lower lobe. He underwent stereotactic radiation phoma kinase (ALK), and ROS1-rearranged tumors]. therapy. Imaging showed a treatment response but Each of these options has different clinical characteristics new pleural nodules. MRI brain scan showed new in- and therapeutic options with agents that have varying tracranial metastases. After undergoing gamma knife degrees of systemic activity. ROS1 gene rearrange- radiosurgery, the patient was enrolled in an ipilimumab ments define a distinct molecular subgroup of NSCLC. and radiation trial (NCT02239900). His disease pro- ROS1 rearrangement leads to constitutive ROS1 activa- gressed on ipilimumab. The patient was next enrolled tion and activity of crizotinib against ROS1-rearranged on the “Signature Trial,” a modular phase II study to link NSCLC was noted and crizotinib received regulatory targeted therapy to patients with pathway activated tu- approval for the treatment of ROS1 rearranged NSCLC mors; in this study patients whose tumors have aberra- (2). However, patients develop resistance and newer tions in ALK or ROS1 are treated with ceritinib (LDK378) agents are needed. As shown by Davare et al. (1), mo- at 750 mg orally daily (NCT02186821) (5). Restaging lecular docking simulations and preclinical studies dem- scans after two cycles and confirmed after four cycles onstrate that ceritinib (LDK 378), a recently approved showed a partial response (56% decrease) per RECIST1.1 ALK inhibitor, may also be active against ROS1-rear- (Fig. 1 A and B). Moreover, MRI showed that his brain ranged NSCLC (1, 3, 4). Herein we describe, to our metastases decreased as well (Fig. 1 C and D). knowledge, the first clinical report of systemic activity To our knowledge, this is the first clinical report of ceritinib in a patient with ROS1-rearranged NSCLC that suggests that ROS1 inhibition with ceritinib has after experiencing progression on crizotinib. Treat- antitumor activity in a patient with ROS1-rearranged ment and consent on investigational trials, and data NSCLC after progression on crizotinib. This finding collection, were performed in accordance with the should be viewed as anecdotal and preliminary. Ob- guidelines of the University of Texas MD Anderson servationinmorepatientswillberequiredtodetermine Cancer Center Institutional Review Board (IRB) and the efficacy of, frequency and durability of responses to, Quorum Central IRB. mechanisms of potential resistance to, and side effects A 77-y-old man presented with dyspnea. Chest of ceritinib. X-ray revealed a right lower lobe nodule. Biopsy was positive for CK7, TTF-1, indicating adenocarcinoma. Acknowledgments Thoracotomy staging revealed a T2aN1M0, stage IIA The authors acknowledge The University of Texas MD NSCLC. Molecular testing was negative for EGFR, Anderson Cancer Center, National Institutes of Health KRAS, and BRAF mutations, and ALK gene rearrange- Cancer Center Support Grant CA016672, and Novartis ment. After adjuvant chemotherapy with four cycles of for providing the drugs for the clinical trial. This work was carboplatin and pemetrexed, a fludeoxyglucose pos- supported in part by Cancer Prevention Research Institute itron emission tomography-computed tomography of Texas Grant RP110584 and National Center for scan showed an increase in size of pleural nodularity. Advancing Translational Sciences Grant UL1 TR000371 Comprehensive next-generation sequencing genomic (Center for Clinical and Translational Sciences). aDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 Author contributions: V.S., D.S.H., and F.M.-B. designed research; V.S., D.S.H., and F.M.-B. performed research; V.S., D.S.H., and F.M.-B. analyzed data; V.S. and F.M.-B. wrote the paper; and V.S. treated the patient. The authors declare no conflict of interest. 1To whom correspondence should be addressed. Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1522052113 PNAS | March 15, 2016 | vol. 113 | no. 11 | E1419–E1420 Downloaded by guest on October 1, 2021 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. 1 Davare MA, et al. (2015) Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors. Proc Natl Acad Sci USA 112(39):E5381–E5390. 2 Shaw AT, et al. (2014) Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371(21):1963–1971. 3 Shen L, Ji HF (2014) Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370(26):2537. 4 Shaw AT, et al. (2014) Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370(13):1189–1197. 5 Kang BP, et al. (2015) The signature program: Bringing the protocol to the patient. Clin Pharmacol Ther 98(2):124–126. E1420 | www.pnas.org/cgi/doi/10.1073/pnas.1522052113 Subbiah et al. Downloaded by guest on October 1, 2021.