Clinical activity of brigatinib in ROS1-rearranged non-small cell lung cancer
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RESEARCH ARTICLE
Clinical activity of brigatinib in ROS1‑rearranged non‑small cell lung cancer E. Dudnik1 · A. Agbarya2 · R. Grinberg3 · A. Cyjon4 · J. Bar5,6 · M. Moskovitz7 · N. Peled3,8 on behalf of the Israel Lung Cancer Group Received: 3 April 2020 / Accepted: 7 May 2020 © Federación de Sociedades Españolas de Oncología (FESEO) 2020
Abstract Background Brigatinib is a potent ROS1 inhibitor. The existing data on its clinical activity in ROS1-rearranged non-small cell lung cancer (NSCLC) are limited to four cases. Methods Six patients with ROS1-rearranged advanced NSCLC treated with brigatinib were identified through search of the internal databases of four participating cancer centers. Four additional patients were selected by PubMed and Google Scholar search. The objective response rate (ORR), progression-free survival (PFS) (RECIST v.1.1), duration of treatment (DOT), and safety were assessed. Results Of eight patients evaluable for response assessment (crizotinib naive-1, crizotinib resistant -7), three patients demonstrated a partial response (ORR-37%). One crizotinib-naive patient had an ongoing response at 21.6 months. Of seven crizotinib-resistant patients, two patients demonstrated a partial response (ORR-29%), and one patient (14%) had stable disease. PFS, available in four crizotinib-resistant patients, was 7.6 + , 2.9, 2.0, and 0.4 months. In crizotinib-resistant patients, DOT was 9.7 + , 7.7 + , 7.6 + , 4.0, 2.0, 1.1, 0.4 months, and was not reported in two patients. Genomic profiling in one responder revealed no ROS1 alteration, suggesting that the response was attributable to “off-target” brigatinib activity. In two patients with progressive disease, genomic profiling demonstrated a cMET exon 14 mutation + KRAS G12A mutation in one case, and a persisting ROS1-CD74 fusion + TP53 K139N, FGFR2 E250G, ATM G2695D, and NF1 R2258Q mutations in the other. No grade 3–5 toxicity was observed. Conclusion Brigatinib demonstrated modest activity in crizotinib-resistant ROS1-rearranged NSCLC. Its intracranial and systemic activity should be assessed in correlation with the underlying molecular mechanism of crizotinib resistance. Plain Language Summary • • • • •
Our series is the first to describe brigatinib activity in ROS1-altered NSCLC. In crizotinib-resistant patients, ORR with brigatinib was 29%. PFS with brigatinib was 7.6+, 2.9, 2.0, and 0.4 months. DOT with brigatinib was 9.7+, 7.7+, 7.6+, 4.0, 2.0, 1.1, 0.4 months. The correlation between response and molecular resistance needs further exploration.
4
Institute of Oncology, Asaf ha-Rofe Medical Center, 70300 Zerifin, Israel
5
Thoracic Oncology Service, Institute of Oncology, Sheba Medical Center, Tel HaShomer, 5262000 Ramat Gan, Israel
6
Oncology Department, Bney Zion Medical Center, 47 Golomb St., 31048 Haifa, Israel
Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, POB 39040, 69978 Tel Aviv, Israel
7
Legacy Heritage Oncology Center, Soroka Medical Center, 84101 Beer‑Sheva, Israel
Thoracic Cancer Service, Ramb
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