Repotrectinib Overcomes F2004V Resistance Mutation in ROS1-Rearranged NSCLC: A Case Report
Elio Gregory Pizzutilo1,2, Alberto Giuseppe Agostara1,2, Laura Roazzi1,2
1Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Abstract:
ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.
Insights
Next-generation tyrosine kinase inhibitors (TKIs) show promise for ROS1-positive non-small cell lung cancer (NSCLC) patients. Repotrectinib demonstrates activity against the F2004V resistance mutation, offering new hope for treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- ROS1-positive non-small cell lung cancer (NSCLC) patients benefit from tyrosine kinase inhibitors (TKIs).
- Acquired resistance to TKIs, including entrectinib and crizotinib, limits long-term patient responses.
- The F2004 substitution in ROS1 has been identified as a resistance mechanism.
Observation:
- A patient with advanced ROS1-positive NSCLC developed acquired resistance to entrectinib and crizotinib.
- Progression was associated with the detection of the ROS1 F2004V mutation at the site of disease.
- This mutation was identified on circulating tumor DNA.
Findings:
- The patient was subsequently treated with the next-generation TKI repotrectinib.
- Repotrectinib treatment resulted in a significant disease response.
- This represents the first clinical evidence of repotrectinib's efficacy against the ROS1 F2004V resistance mutation.
Implications:
- Repotrectinib offers a potential therapeutic option for ROS1-positive NSCLC patients who have developed resistance to earlier TKIs.
- Targeting specific resistance mutations like F2004V with next-generation TKIs is crucial for overcoming treatment failure.
- Further clinical investigation of repotrectinib in this patient population is warranted.
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