Cases of ROS1-rearranged lung cancer: When to use crizotinib, entrectinib, lorlatinib, and beyond?

Kartik Sehgal, Andrew J. Piper-Vallillo, Hollis Viray, Adeel M. Khan, Deepa Rangachari, Daniel B. Costa

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


ROS1-rearranged (also known as ROS1 fusion-positive) non-small-cell lung cancer is an uncommon but distinct molecular subgroup seen in approximately 1-2% of cases. Oncogene addiction due to constitutive ROS1 tyrosine kinase activation has allowed development of molecularly targeted therapies with remarkable anti-tumor activity. Both crizotinib and entrectinib, multitargeted tyrosine kinase inhibitors (TKIs) have now received approval by the FDA for treatment of patients with advanced ROS1-rearranged lung cancers; however, the clinical efficacy and safety of these drugs have been derived from expansion cohorts of single-arm phase I or basket clinical trials with relatively small populations of this clinically and molecularly distinct subgroup. Both drugs lead to high objective response rates (approximately 70-80%) and have manageable side effects, although only entrectinib has potent intracranial efficacy. Lorlatinib is an oral brain-penetrant ALK/ROS1 TKI with activity in both TKI-naïve and some crizotinib-resistant settings (albeit with limited potency against the crizotinib/entrectinib-resistant ROS1-G2032R mutation). We describe cases of advanced ROS1-rearranged lung cancer receiving crizotinib, entrectinib, and/or lorlatinib in first and later line treatment settings to dissect the current state of evidence supporting management decisions for these patients. The next generation ROS1 TKIs (repotrectinib and DS-6051b), owing to their broad activity against kinase mutations including ROS1-G2032R in preclinical studies, hold promise to transform the current treatment paradigm and permit even further gains with regards to long-term outcomes in this subset of patients.

Original languageEnglish (US)
Article number17
JournalPrecision Cancer Medicine
Issue numberJune
StatePublished - Jun 2020
Externally publishedYes


  • Acquired resistance
  • Crizotinib
  • Entrectinib
  • Lorlatinib
  • Non-small-cell lung cancer (NSCLC)
  • Rearrangement
  • ROS1 fusion

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Oncology(nursing)
  • Pharmacology (medical)
  • Surgery
  • Anesthesiology and Pain Medicine


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