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Retevmo
Published
Product name
Retevmo
Active ingredient
Selpercatinib
Submission type
New Chemical Entity
Decision
Approved for provisional registration
Registration date
What this medicine was approved for
Retevmo (selpercatinib) was approved for the following therapeutic use:
The provisionally approved new indication(s) for the medicine(s) are:
Retevmo has provisional approval for the treatment of adult patients with locally advanced or metastatic RET fusion positive non-small cell lung cancer (NSCLC).
The decision to approve this indication has been made on the basis of objective response rate (ORR) and duration of response (DOR) from a single arm study. Continued approval of this indication depends on verification and description of benefit in a confirmatory trial.
How this medicine works
Selpercatinib is an orally available, small molecule inhibitor of the rearranged during transfection (RET) receptor tyrosine kinase. Chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers, promoting cell proliferation and survival in tumor cell lines. Point mutations in RET can also result in constitutively activated RET proteins that can promote cell growth and survival in tumor cell lines.
In RET enzyme assays, selpercatinib inhibits the kinase activity of RET, RET-V804L, RET-V804M, RET-A883F, RET-S904F, RET-A764T, RET-S891A and RET-M918T with half maximal inhibitory concentration (IC50) values of 0.20 nM to 2.21 nM. In kinase screening assays, selpercatinib at a concentration of 100 nM inhibits only six of 329 non-RET kinases by more than 50% of the control. Among these, selpercatinib inhibits two kinases with IC50 values within 35-fold of RET: Fms-related tyrosine kinase 4 (FLT4) (0.7-fold in an enzyme-based assay and 8- fold in a cell-based assay); and FLT1 (1.6-fold). Selpercatinib inhibits platelet derived growth factor receptor beta (PDGFRB) with an IC50 value of 2100 nM, and janus kinase inhibitor (JAK1, JAK2, JAK3), TRKA, and TRKC with IC50 values greater than 5000 nM in enzyme assays.
Selpercatinib demonstrates in vitro inhibition of human cancer cell lines derived from multiple tumour types harbouring RET fusion genes and RET mutations with EC50 values equal to 10 nM or less. In in vivo mouse studies, selpercatinib demonstrates inhibition of tumor growth in RET fusion and RET mutant cancer cell lines, patient-derived RET fusion xenograft models, and a patient-derived RET fusion xenograft model harbouring a RET V804M mutation. Selpercatinib also exhibits intracranial anti-tumour activity of patient-derived RET fusion xenograft tumours implanted directly into the brain of mice.
In additional radioligand binding assays, selpercatinib inhibits two out of 54 non-kinase targets at a concentration of 1 μM: 5-HT transporter (70.2%) and α2c receptor (51.7%).
Why the TGA approved or did not approve this medicine
The decision was based on quality (chemistry and manufacturing), nonclinical (pharmacology and toxicology), clinical (pharmacology, safety and efficacy) and risk management plan information submitted by the sponsor. The benefit-risk profile of Retevmo was considered favourable for the therapeutic use approved.
Sponsor