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ROS1-positive lung cancer is a rare fusion-driven adenocarcinoma treated with a pill. Crizotinib was the first, and the newer drugs repotrectinib and taletrectinib control the disease for about three years, reach the brain and work against the resistance mutation that defeated the older drugs.
ROS1 fusions were identified in lung cancer in 2007 alongside ALK, and because the two kinases are closely related the ALK inhibitor crizotinib also blocked ROS1. In the ROS1 cohort of PROFILE 1001 the response rate was 72 percent and median progression-free survival 19.2 months, and crizotinib was approved for ROS1-positive lung cancer in March 2016 on that single-arm evidence. Its weaknesses were poor brain penetration and resistance through the G2032R solvent-front mutation.
Entrectinib, a ROS1, NTRK and ALK inhibitor with brain penetration, was approved in August 2019 on an integrated analysis of its phase 1 and 2 studies (STARTRK-2 among them) with a response rate of 77 percent and intracranial responses. Repotrectinib, a compact macrocycle designed to fit around solvent-front mutations, was approved in November 2023 on TRIDENT-1: a 79 percent response rate and median progression-free survival of 35.7 months in inhibitor-naive patients, and a 38 percent response rate after one prior inhibitor, including G2032R disease. Taletrectinib, tested in the TRUST-I and TRUST-II studies, was approved in June 2025 with high response rates in both inhibitor-naive and crizotinib-pretreated patients and less dizziness than repotrectinib.
Zidesamtinib (NVL-520) is designed to spare TRK and so avoid the dizziness and weight gain of the current drugs. Chemotherapy with platinum-pemetrexed remains effective once inhibitors are exhausted, and checkpoint inhibitors add little. Open questions are the best first drug now that three brain-penetrant inhibitors exist and how to treat bypass resistance through MET or KRAS.
About 1 to 2 percent of non-small-cell lung cancers carry a ROS1 fusion, typically adenocarcinoma in younger patients who have never smoked; about a third have brain metastases at some point.
Central tumours arise in the large airways, peripheral ones in the alveoli; both drain to hilar then mediastinal nodes, and the pleural lining is a separate cancer site.
Same organ: Mediastinal germ cell tumour, Pleuropulmonary blastoma (types I, Ir, II and III), Type A and type AB thymoma, Type B1 and type B2 thymoma, Type B3 thymoma, Micronodular thymoma with lymphoid stroma, Adenocarcinoma of the lung, Squamous cell carcinoma of the lung, Large cell carcinoma of the lung, Sarcomatoid carcinoma of the lung, Adenosquamous carcinoma of the lung, Invasive mucinous adenocarcinoma of the lung, Adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung, Basaloid squamous cell carcinoma of the lung, Lymphoepithelial carcinoma of the lung, Pulmonary blastoma (adult), Non-small-cell lung cancer, Lung cancer (all types), Small-cell lung cancer, Mesothelioma, Pleural mesothelioma, Thymoma and thymic carcinoma, Childhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours), Inflammatory myofibroblastic tumour (IMT), EGFR-mutated non-small-cell lung cancer, ALK-positive non-small-cell lung cancer, KRAS G12C-mutant non-small-cell lung cancer, MET exon 14 and MET-amplified non-small-cell lung cancer, RET fusion-positive non-small-cell lung cancer, BRAF V600E-mutant non-small-cell lung cancer, HER2-mutant non-small-cell lung cancer, NTRK fusion-positive non-small-cell lung cancer, PD-L1-high non-small-cell lung cancer without a driver mutation, Resectable stage I to III non-small-cell lung cancer, Unresectable stage III non-small-cell lung cancer, Limited-stage small-cell lung cancer, Extensive-stage small-cell lung cancer, Lung neuroendocrine tumours (typical and atypical carcinoid), Large cell neuroendocrine carcinoma of the lung, Thymoma (WHO types A, AB, B1, B2 and B3), Thymic carcinoma
Repotrectinib (TRIDENT-1) or taletrectinib as preferred; entrectinib or crizotinib as alternatives, entrectinib when brain metastases are present.
Repotrectinib or taletrectinib, which cover G2032R; zidesamtinib in trials; platinum-pemetrexed once inhibitors are exhausted.
Brain-penetrant inhibitors (repotrectinib, taletrectinib, entrectinib) with stereotactic radiosurgery for large or symptomatic lesions.
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Repotrectinib is a preferred first-line ROS1 inhibitor because of its durability and coverage of resistance mutations, and it is also approved for NTRK fusion-positive tumours after prior TRK inhibitors.
Entrectinib is a first-line ROS1 inhibitor with brain activity, preferred over crizotinib when brain metastases are present, though repotrectinib and taletrectinib now offer longer control.
ROS1 testing became standard in lung adenocarcinoma; crizotinib was the first approved ROS1 inhibitor and remains an option, though entrectinib, repotrectinib and taletrectinib now offer brain penetration and resistance coverage.
Query for this cancer: (TITLE:"ROS1-positive non-small-cell lung cancer" OR ABSTRACT:"ROS1-positive non-small-cell lung cancer" OR TITLE:"ROS1-rearranged lung cancer" OR ABSTRACT:"ROS1-rearranged lung cancer" OR TITLE:"ROS1 fusion NSCLC" OR ABSTRACT:"ROS1 fusion NSCLC" OR TITLE:"CD74-ROS1 lung cancer" OR ABSTRACT:"CD74-ROS1 lung cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about ROS1-positive non-small-cell lung cancer, not a curated reading list.
The targets of this cancer's medicines and the ones linked to it directly.
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Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
QT: both Entrectinib and Crizotinib prolong the QT interval (known and known risk).. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
Avoid grapefruit.
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
See all on the product pages:CarboplatinCrizotinibEntrectinibPemetrexedRepotrectinibTaletrectinibZidesamtinib·Printable cards in the navigator
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