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Clinical Activity of Alectinib in Advanced RET-Rearranged Non-Small Cell Lung Cancer
Jessica J Lin1, Elizabeth Kennedy1, Lecia V Sequist1
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Introduction:
Chromosomal rearrangements involving rearranged during transfection gene (RET) occur in 1% to 2% of NSCLCs and may confer sensitivity to rearranged during transfection (RET) inhibitors. Alectinib is an anaplastic lymphoma kinase tyrosine kinase inhibitor (TKI) that also has anti-RET activity in vitro. The clinical activity of alectinib in patients with RET-rearranged NSCLC has not yet been reported.
Methods:
We have described four patients with advanced RET-rearranged NSCLC who were treated with alectinib (600 mg twice daily [n = 3] or 900 mg twice daily [n = 1]) as part of single-patient compassionate use protocols or off-label use of the commercially available drug.
Results:
Four patients with metastatic RET-rearranged NSCLC were identified. Three of the four had received prior RET TKIs, including cabozantinib and experimental RET inhibitors. In total, we observed two (50%) objective radiographic responses after treatment with alectinib (one confirmed and one unconfirmed), with durations of therapy of 6 months and more than 5 months (treatment ongoing), respectively. Notably, one of these two patients had his dose of alectinib escalated to 900 mg twice daily and had clinical improvement in central nervous system metastases. In addition, one patient (25%) experienced a best response of stable disease lasting approximately 6 weeks (the drug discontinued for toxicity). A fourth patient who was RET TKI-naive had primary progression while receiving alectinib.
Conclusions:
Alectinib demonstrated preliminary antitumor activity in patients with advanced RET-rearranged NSCLC, most of whom had received prior RET inhibitors. Larger prospective studies with longer follow-up are needed to assess the efficacy of alectinib in RET-rearranged NSCLC and other RET-driven malignancies. In parallel, development of more selective, potent RET TKIs is warranted.
Insights
Alectinib showed early signs of effectiveness in patients with advanced rearranged during transfection (RET) gene-rearranged non-small cell lung cancer (NSCLC), even those previously treated with other RET inhibitors. Further research is needed to confirm these findings.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Rearranged during transfection (RET) gene rearrangements occur in 1-2% of non-small cell lung cancers (NSCLC).
- RET alterations can predict sensitivity to RET tyrosine kinase inhibitors (TKIs).
- Alectinib, an anaplastic lymphoma kinase (ALK) TKI, exhibits anti-RET activity in vitro.
Observation:
- Four patients with advanced RET-rearranged NSCLC received alectinib.
- Three patients had prior treatment with other RET TKIs.
- Dosing varied between 600 mg and 900 mg twice daily.
Findings:
- Two patients (50%) experienced objective radiographic responses, with one ongoing.
- One patient showed improvement in central nervous system metastases after dose escalation.
- One patient had stable disease, and one had primary progression.
Implications:
- Alectinib demonstrates preliminary antitumor activity in RET-rearranged NSCLC.
- Further prospective studies are necessary to validate alectinib's efficacy.
- Development of more selective RET TKIs is warranted.
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