rociletinib

Action and Spectrum

Actions and Spectrum: 

rociletinib, or CO-1686, is a targeted therapy drug used to treat particular types of non-small cell lung cancer (NSCLC) with specific genetic mutations. It falls into the category of tyrosine kinase inhibitors (TKIs). Here is information about the action and spectrum of rociletinib: 

Action: rociletinib acts by selectively inhibiting the activity of the epidermal growth factor receptor (EGFR). This protein plays a crucial role in promoting the growth and survival of cancer cells. Specifically, rociletinib targets tumors that have acquired a specific mutation in the EGFR gene called T790M mutation, which is associated with resistance to other EGFR inhibitors like erlotinib or gefitinib. 

rociletinib irreversibly binds to both the active and inactive forms of EGFR, preventing the receptor’s phosphorylation (addition of phosphate groups) and subsequent signaling pathways that promote cancer cell growth and survival. By inhibiting the EGFR activity, rociletinib can help slow down or shrink tumors in patients with NSCLC harboring the T790M mutation. 

Spectrum: rociletinib is primarily indicated for treating advanced or metastatic NSCLC in patients with the EGFR T790M mutation. This mutation is often associated with acquired resistance to first- and second-generation EGFR inhibitors. Therefore, rociletinib provides a targeted treatment option for patients with this genetic alteration. 

It’s important to note that rociletinib’s spectrum of activity is limited to NSCLC patients with the T790M mutation and is ineffective in those without this particular mutation. Therefore, genetic testing is typically performed to identify patients eligible for rociletinib therapy. 

Drug Interaction

Adverse Reaction

Black Box Warning

Black Box Warning: 

None 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

Some potential contraindications for rociletinib may include: 

• Hypersensitivity: rociletinib may be contraindicated in individuals with known hypersensitivity or allergic reactions to the drug or its components. 
• Pregnancy and breastfeeding: rociletinib may have potential risks to the developing fetus, and its safety during pregnancy has not been established. Therefore, it is typically contraindicated in pregnant or breastfeeding women. It is key to discuss this with a healthcare professional. 
• Severe liver impairment: rociletinib is primarily metabolized by the liver, so severe liver impairment may affect its clearance and safety. If a patient has severe liver dysfunction, rociletinib may be contraindicated or require dose adjustments. 
• Severe renal impairment: rociletinib is primarily eliminated from the body through the kidneys, so severe renal impairment may affect excretion. If a patient has severe renal dysfunction, rociletinib may be contraindicated or require dose adjustments. 

Caution 

Here are some general cautions that may apply: 

• Interactions with other medications: rociletinib may interact with other drugs, including over-the-counter medications, prescription medications, and herbal supplements. To avoid potential interactions, you must inform your healthcare provider about your medications and supplements. 
• Cardiovascular effects: rociletinib may have cardiovascular side effects, such as QT interval prolongation, which can increase the risk of potentially severe heart rhythm abnormalities. Patients with a earlier history of or at risk for cardiovascular disease should be closely monitored during treatment with rociletinib. 
• Pulmonary effects: rociletinib may cause pulmonary side effects, including pneumonitis (inflammation of the lungs). Patients should be monitored for symptoms like cough, shortness of breath, or new or worsening respiratory symptoms during treatment. 
• Hepatic effects: rociletinib can affect liver function, and periodic monitoring of liver function tests may be necessary during treatment. Patients with pre-existing liver disease or impaired liver function may require dose adjustments or close monitoring. 
• Renal effects: rociletinib can affect kidney function, and periodic monitoring of renal function tests may be necessary during treatment. Patients with pre-existing kidney disease or impaired renal function may require dose adjustments or close monitoring. 
• Gastrointestinal effects: rociletinib may cause gastrointestinal side effects, like nausea, vomiting, diarrhea, or abdominal pain.  
• Skin reactions: rociletinib may cause skin reactions like rash or dermatitis. Patients should promptly report any skin changes to their healthcare provider. 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: N/A 

Lactation:   

Excreted into human milk: N/A 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

rociletinib (CO-1686) is a targeted therapy drug with specific pharmacological properties.  

rociletinib is a tyrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor, a protein involved in regulating cell growth and survival. It explicitly targets tumors that have acquired the T790M mutation in the EGFR gene, associated with resistance to other EGFR inhibitors. 

rociletinib irreversibly binds to the active and inactive forms of the EGFR receptor, inhibiting its autophosphorylation and downstream signaling pathways. By blocking EGFR activity, rociletinib helps to inhibit the growth and survival of cancer cells harboring the T790M mutation. 

Pharmacodynamics: 

Mechanism of action: rociletinib (CO-1686) ‘s action involves selective inhibition of the EGFR (epidermal growth factor receptor). This protein plays a important role in regulating cell growth and survival.  

• EGFR and EGFR Mutations: EGFR is a receptor tyrosine kinase which is expressed on the surface of many cell types, including cancer cells. Activation of EGFR leads to the activation of intracellular signaling pathways involved in cell proliferation, survival, and angiogenesis. 

In some non-small cell lung cancer cases, mutations occur in the EGFR gene. One such mutation is the T790M mutation, associated with acquired resistance to other EGFR inhibitors like erlotinib or gefitinib. 

• Selective Inhibition of EGFR T790M Mutation: rociletinib is designed to selectively target and inhibit the activity of EGFR with the T790M mutation, which is found in a significant portion of NSCLC patients who have developed resistance to other EGFR inhibitors. 
• Irreversible Binding to EGFR: rociletinib irreversibly binds to both the active and also inactive forms of the EGFR receptor. By forming a covalent bond with the receptor, rociletinib prevents the autophosphorylation of EGFR and subsequent activation of downstream signaling pathways. 
• Inhibition of Cell Growth and Survival: By inhibiting the EGFR activity, rociletinib disrupts the signaling pathways that promote cancer cell growth and survival. This can reduce tumor growth and potentially induce tumor regression in NSCLC patients with the EGFR T790M mutation. 

Pharmacokinetics: 

Absorption 

rociletinib is administered orally in the form of tablets. After oral administration, it is absorbed rapidly from the gastrointestinal tract into the bloodstream. The peak plasma concentration (Tmax) is typically around 2 hours. 

Distribution 

Once absorbed, rociletinib is distributed throughout the body. It has a moderate volume of distribution, indicating that it distributes into tissues beyond the bloodstream. The exact distribution characteristics of rociletinib in various tissues and organs are not extensively documented. 

Metabolism 

rociletinib is primarily metabolized in the liver through various enzymatic processes. The primary enzyme involved in its metabolism is cytochrome P450 3A4 (CYP3A4), along with other minor metabolic pathways. The significant metabolites formed are the O-desmethyl metabolite and glucuronide conjugates. These metabolites have significantly less activity against the EGFR receptor than the parent compound. 

Elimination and Excretion 

The elimination of rociletinib and its metabolites occurs primarily through the feces (approximately 81% of the dose) and, to a lesser extent, through the urine (approximately 12% of the dose). The exact mechanisms and pathways of excretion for rociletinib and its metabolites have yet to be extensively characterized. 

Adminstartion

Administration: 

The specific administration instructions for rociletinib may vary based on the formulation and the patient’s condition. It’s essential to follow the prescribing information the healthcare professional provides or consult with a healthcare professional for specific administration instructions. However, here are some general points to consider: 

• Dosage: rociletinib is typically available as oral tablets. The healthcare professional determines the dosage and treatment schedule based on factors such as the patient’s weight, overall health, and specific mutation status. 
• Timing: rociletinib is usually taken once or twice daily, as the healthcare professional prescribes. It’s essential to take the medication simultaneously (s) every day to maintain consistent levels in the body. 
• Food interactions: rociletinib can be taken with or without food, but specific instructions regarding food interactions may be provided in the prescribing information. It’s essential to follow these instructions to ensure optimal absorption and effectiveness. 
• Swallowing: The tablets should be swallowed whole with a glass of water. They should only be crushed, chewed, or divided if specifically instructed by the healthcare professional. 
• Compliance: It’s crucial to take rociletinib precisely as the healthcare professional prescribes. Only alter the dosage or treatment schedule after consulting a healthcare professional. 
• Missed dose: If a dose is missed, taking it as soon as possible is generally recommended. However, if the next scheduled dose is missed, it should be skipped and the following dose should be taken at the appropriate time. It is important to avoid taking a double dose of the medication to compensate for the missed dose.

Patient Information Leaflet

Patient information leaflet 

Generic Name: rociletinib 

Why do we use rociletinib? 

rociletinib (CO-1686) is a targeted therapy drug for treating non-small cell lung cancer (NSCLC) with specific genetic mutations. Here are the primary uses of rociletinib: 

• EGFR T790M-positive NSCLC: rociletinib is specifically indicated for treating advanced or metastatic NSCLC in patients with the epidermal growth factor receptor T790M mutation. This mutation is associated with acquired resistance to other EGFR inhibitors like erlotinib or gefitinib. rociletinib provides a targeted treatment option for patients with this specific genetic alteration. 

It’s important to note that rociletinib is used in patients who have developed resistance to previous EGFR inhibitors due to the T790M mutation. It is not a 1st line treatment option for EGFR-mutated NSCLC. 

The use of rociletinib may be considered after failure or intolerance to other available treatment options.