temsirolimus
Regulatory sources consulted
Approved indications
- Advanced renal cell carcinoma in adults.
- Relapsed or refractory mantle-cell lymphoma in adults.
Contraindications
Absolute
- Hypersensitivity to temsirolimus, sirolimus, polysorbate 80, or excipients; FDA: bilirubin >1.5×ULN. CIMA: mantle-cell lymphoma with moderate or severe hepatic impairment.
Clinical warnings
- Potentially fatal infusion reactions can occur from the first dose. Monitor during infusion; stop and treat the reaction, and restart more slowly only if the specialist team considers it safe. — OpenFDA, set_id 1c207bed-10e3-46f0-ad2c-69d5e5c97736
- Monitor ILD, infections, glucose, lipids, renal function, proteinuria, bowel perforation, and wound healing. Withhold for suspected ILD and assess anti-infective or corticosteroid treatment. — OpenFDA, set_id 1c207bed-10e3-46f0-ad2c-69d5e5c97736
Drug interactions
- HighStrong CYP3A4/5 inhibitors or inducers
Mechanism: They alter exposure to the active metabolite sirolimus.
Recommendation: Avoid when possible; if essential, apply the label-specific dose modification and return to the prior dose after the stated washout period.
OpenFDA, set_id 1c207bed-10e3-46f0-ad2c-69d5e5c97736
- HighSunitinib, ACE inhibitors, or calcium-channel blockers
Mechanism: Sunitinib caused dose-limiting toxicity; ACE inhibitors and calcium-channel blockers may increase angioedema.
Recommendation: Do not combine with sunitinib and closely monitor angioedema with ACE inhibitors or calcium-channel blockers.
CIMA/AEMPS, ficha técnica 07424001
Adverse events
Common (≥1%)
rash · asthenia · mucositis · nausea · edema · decreased appetite
Pregnancy and lactation
It may cause fetal harm. Women and men with partners who can become pregnant must use contraception during treatment and for 3 months afterward. Do not breastfeed during treatment or for 3 weeks afterward.
Recent literature (PubMed)
Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st century. There are 80 FDA-approved therapeutic agents that target about two dozen different protein kinases and seven of these drugs were approved in 2023. Of the approved drugs, thirteen target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), twenty block nonreceptor protein-tyrosine kinases, and 43 inhibit receptor protein-tyrosine kinases. The data indicate that 69 of these drugs are prescribed for the treatment of neoplasms. Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis). Of the 80 approved drugs, nearly two dozen are used in the treatment of multiple diseases. The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.
Because of the deregulation of protein kinase action in many inflammatory diseases and cancer, the protein kinase family has become one of the most significant drug targets in the 21st century. There are 85 FDA-approved protein kinase antagonists that target about two dozen different enzymes and four of these drugs were approved in 2024 and a fifth was approved in 2025. Of these drugs, five target dual specificity protein kinases (MEK1/2), fourteen inhibit protein-serine/threonine protein kinases, twenty-one block nonreceptor protein-tyrosine kinases, and 45 target receptor protein-tyrosine kinases. The data indicate that 75 of these drugs are prescribed for the treatment of neoplasms. Seven drugs (abrocitinib, baricitinib, deucravacitinib, deuruxolitinib, ritlecitinib, tofacitinib, upadacitinib) are prescribed for the management of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis). Of the 85 FDA-approved agents, about two dozen are used in the treatment of multiple diseases. The following four drugs received FDA approval in 2024 - deuruxolitinib (alopecia areata), ensartinib and lazertinib (non-small cell lung cancer), and tovorafenib (pediatric glioma) while mirdametinib was approved in 2025 for the treatment of type I neurofibromatosis (von Recklinghausen disease). Apart from netarsudil, temsirolimus, and trilaciclib, the approved protein kinase blockers are orally bioavailable. This article summarizes the physicochemical properties of all 85 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, ligand efficiency, lipophilic efficiency, polar surface area, and solubility. A total of 39 of the 85 FDA-approved drugs have a least one Lipinski rule of 5 violation.
The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy. ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy
Clinical trial enrollment should be actively encouraged in all patients diagnosed with advanced, surgically unresectable chondrosarcoma (CS) due to the lack of consensus treatment recommendations. In the absence of an appropriate clinical trial, treatments are determined based on histologic subtype of CS with consideration given to targetable mutations (i.e., IDH1). Conventional CS is inherently resistant to cytotoxic chemotherapy and patients may benefit from antiangiogenic therapy including off-label use of pazopanib. Individuals harboring an IDH1 mutation may derive clinical benefit from ivosidenib, an IDH1 inhibitor. Upon progression and with functional status permitting, alternative options include mTOR inhibitors (sirolimus, temsirolimus) or other tyrosine kinase inhibitors (dasatinib), though no clear sequencing data exists. For dedifferentiated CS, conventional chemotherapies with osteosarcoma-like regimens are upfront options although prospective data is limited with minimal overall benefit. Alternative treatment options include immunotherapy with pembrolizumab or ivosidenib in IDH1-mutant, dedifferentiated CS, but questionable efficacy was observed in small sample sizes with either approach. In mesenchymal CS, treatment with Ewing sarcoma-like chemotherapy regimens may be considered, although data supporting its use is even more limited given its rarity.
Cancer often involves the overactivation of RAS/RAF/MEK/ERK (MAPK) and PI3K-Akt-mTOR pathways due to mutations in genes like RAS, RAF, PTEN, and PIK3CA. Various strategies are employed to address the overactivation of these pathways, among which targeted therapy emerges as a promising approach. Directly targeting specific proteins, leads to encouraging results in cancer treatment. For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation. These inhibitors have shown potent efficacy against Non-Small Cell Lung Cancer. Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins. Additionally, inhibition of proteins like SOS, SH2 domain, and Ras demonstrate promising anti-tumor activity both in vivo and in vitro. Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and Hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins within the RAS upstream and downstream signaling pathways in cancer.