Adagrasib for Non-Small Cell Lung Cancer

What Is Adagrasib?

Adagrasib belongs to a group of medicines known as antineoplastics, or anticancer drugs. It helps slow down or stop cancer cells from growing. Adagrasib works by targeting the KRAS G12C mutation (Kirsten rat sarcoma viral oncogene homolog glycine-to-cysteine), which disrupts signals that control cell growth and division.

How Does Adagrasib Work?

Adagrasib targets the KRAS G12C mutation, found in about 14 percent of people with non-small cell lung cancer (NSCLC). This mutation keeps the KRAS protein turned on, allowing cancer cells to grow without stopping.

Adagrasib is a small-molecule inhibitor that attaches to the KRAS G12C protein and blocks the signals that help cancer cells grow. By blocking this pathway, the medicine can slow down or stop the growth of some lung tumors.

Dosing and Dosage Form

Adagrasib comes as a tablet to be swallowed. Most people take it by mouth, but the dose might be different for each person.

Most people with NSCLC and the KRAS G12C mutation take 600 mg of Adagrasib twice a day. Your doctor may adjust the dose if needed.

Always take Adagrasib exactly as your doctor tells you. Tell your doctor about any other medicines or health problems, so you stay safe.

Directions

The following broad rules may be useful to patients:

• Swallow the Adagrasib tablet whole. Do not crush, chew, or break it. You can take it with or without food.

• Most people take 600 mg of Adagrasib twice per day. Your dose may differ based on your health or how you respond to the medicine.

• Try to take Adagrasib at the same time every day. This helps the medicine work best.

• Do not crush, chew, or break the tablets. This could make the medicine less effective.

For Patients

What Is Non-small-Cell Lung Cancer?

Most lung cancers, about 80 to 85 out of 100, are called non-small cell lung cancer (NSCLC). That just means these cancers are not made up of the small cells usually found in the lungs. Instead, NSCLC usually starts in the cells that line the main airways of your lungs.

There are a few main types of NSCLC:

1. Adenocarcinoma is the most common kind of non-small cell lung cancer.

2. Squamous cell carcinoma (SCC) is a type of lung cancer that begins in the flat cells lining the airways. Often connected to smoking.

3. Large cell carcinoma is a rare and fast-growing lung cancer. It can form in any part of the lung and appears different from other lung cancers under a microscope.

Adenocarcinoma is the kind you will hear about most often.

Learn More About Adagrasib

Before Starting Adagrasib

Tell your doctor if you are allergic to Adagrasib or any of its ingredients. Share a list of all medicines, vitamins, herbs, or supplements you take. Also, let your doctor know if you have heart, liver, kidney, or lung problems, or a history of long QT syndrome. Inform your doctor if you are pregnant, planning pregnancy, or breastfeeding. This medicine may affect fertility, so discuss any concerns before starting. If you are having surgery or dental treatment, tell the doctor or dentist that you are taking Adagrasib.

When and Why to Take Adagrasib?

Adagrasib is a medicine for people with a certain type of NSCLC. It is for those with cancer who have a KRAS G12C mutation. Doctors use it if surgery is not possible or if other treatments have not worked.

Usually, you will take Adagrasib twice a day. Your doctor will decide whether Adagrasib is right for you after reviewing your history and testing to confirm you have the right mutation. Always follow your doctor’s instructions for taking it.

What Are the Side Effects of Adagrasib?

Some common side effects of Adagrasib are:

1. Nausea (feeling sick to your stomach).

2. Diarrhea (loose or watery stools).

3. Fatigue (feeling very tired).

4. Reduced appetite (not feeling hungry).

5. Rash (skin changes or irritation).

6. Cough.

7. Breathing difficulty (feeling short of breath).

8. Joint or muscle ache (body pains).

Though less common, the following adverse effects are more dangerous:

• Interstitial lung disease (ILD):

This can cause coughing, trouble breathing, and lung damage.

• Heart Rhythm Problems:

This includes heart attacks or an uneven heartbeat. Tell your doctor right away if you feel chest pain, faint, or notice a racing heartbeat.

• Liver Issues:

Watch for yellow skin or eyes, dark urine, or pain near your liver (upper right belly).

• Severe Skin Reactions:

Rarely, you can get serious rashes or peeling skin (like Stevens-Johnson syndrome). If you see a new rash or your skin blisters, get medical help fast.

What Should Be Done if a Dose Is Missed?

If you miss a dose, just take it when you remember. But if it is almost time for your next dose, skip the missed one; do not double up. Taking too much can cause more side effects.

What Should Be Done to Treat an Adagrasib Overdose?

There is no special antidote if you take too much Adagrasib. Doctors will treat your symptoms, like giving you fluids, checking your blood pressure, and helping with nausea or vomiting. If you think you took too much, contact your doctor or get medical help right away.

How to Store Adagrasib?

Store Adagrasib in its original container with the lid closed tightly at room temperature, between 20°C and 25°C (68°F to 77°F). Keep it away from heat, sunlight, and moisture. Do not store it in the bathroom, refrigerator, or freezer. Make sure children and pets cannot reach it. If you have any unused or expired medicine, ask your pharmacist how to dispose of it safely.

Avoid Self-Medication

Only use Adagrasib if your doctor has prescribed it. Do not use someone else’s pills, or give yours away. Medicines can affect people differently, so stick to your doctor's instructions.

For Doctors

Indications

1. Adagrasib is a medicine used to treat non-small cell lung cancer (NSCLC) when the cancer has a certain genetic change called KRAS G12C. Doctors usually prescribe it for people whose cancer has spread or come back after trying other treatments.

2. Only take Adagrasib if your doctor, who knows about NSCLC, prescribes it for you. It is not meant for other types of cancer or different genetic changes.

Dosing

Adagrasib should be administered 600 mg orally twice daily for the treatment of KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) until disease progression or unacceptable toxicity occurs.

Dose Considerations

Depending on a person's unique circumstances, such as kidney or liver function, age, and other medical issues, dosage modifications may be required. Adagrasib is sold as a tablet and needs to be consumed whole with water. Avoid crushing, chewing, or breaking the tablet since doing so may reduce the medication's effectiveness and raise the possibility of adverse effects.

Pharmacology

Pharmacodynamics

Adagrasib's exposure response relationship and pharmacodynamic response time course have not been fully characterized. Adagrasib can prolong the QTc interval in a concentration-dependent manner. In patients receiving Adagrasib 600 mg twice daily, the mean increase in QTcF from baseline was approximately 18 milliseconds at steady-state maximum concentration.

Mechanism of Action

KRAS is a protein in your cells that acts like an on/off switch for cell growth. When it is “on,” your cells grow. When it is “off,” they stop growing. Normally, your body controls when KRAS turns on or off.

Sometimes, a small change (mutation) happens in the KRAS gene. In the KRAS G12C mutation, the “off” switch gets broken. This means KRAS stays “on,” so your cells keep growing, even when they should not. That is how cancer can start.

Adagrasib works by finding the faulty KRAS G12C protein and locking it in the “off” position. This helps stop cancer cells from growing out of control.

Pharmacokinetics:

Absorption

Adagrasib shows dose-proportional increases in AUC and Cmax between 400 mg and 600 mg. Steady state is reached in about eight days with approximately six-fold accumulation. The median Tmax is around six hours. A high-fat, high-calorie meal does not significantly affect its pharmacokinetics. Adagrasib can cross the central nervous system.

Dimensions of Dispersion

The apparent volume of distribution for Adagrasib is 248.85 United States liquid gallons (USLgal).

Protein Binding

Adagrasib binds 98 percent of human plasma proteins in vitro (experimentally outside the body).

Metabolism

Following a single dose, CYP3A4 is primarily responsible for Adagrasib's metabolism. Adagrasib suppresses CYP3A4 after many doses; thus, other enzymes such as CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6 participate in its steady-state metabolism.

Route of Elimination

Adagrasib is expelled from the body through urine and feces. In individuals who received a single dosage of radiolabeled Adagrasib, 4.5 percent of the dose was recovered in urine, and two percent remained unaltered. In comparison, 75 percent of the dose was recovered in feces.

Half-Life

The terminal elimination half-life of Adagrasib is 23 hours.

Toxicity

Like many medicines, Adagrasib can cause side effects. Some affect your body right away, while others might show up in lab tests or after longer use.

Clinical Toxicity:

• Trouble Breathing:

You might get short of breath, have a cough, or develop a lung infection.

• Stomach and Digestion:

This could include constipation, stomach pain, diarrhea, or other tummy troubles.

• Heart:

This medicine may affect your heart’s pumping strength, blood pressure, or heart rhythm.

• Blood:

You could develop low red cells (anemia), low platelets, or low white cells.

• Skin:

You might notice itching, a rash, or dry skin.

• Muscles and Joints:

Some people get back pain, muscle aches, or sore joints.

Non-clinical Toxicity:

• Liver:

Lab tests might show high liver enzymes, or you could have liver problems.

• Kidneys:

This might mean higher creatinine in your blood, or rarely, kidney or eye problems.

• Eyes:

Some people get eye inflammation, sores, or vision changes.

• Reproductive System:

Adagrasib can make it harder to have children and may harm an unborn baby.

Contraindications

There are some situations where taking Adagrasib is not safe. Here are a few times when you should not use this medicine:

1. If you are allergic to Adagrasib or any of its ingredients, do not take this medicine.

2. Do not use Adagrasib if you are pregnant. Also, do not breastfeed while taking this medicine, as it is safest for your baby.

3. If you have serious liver problems, your doctor will likely choose a different treatment.

Drug Interactions

Adagrasib may interact with other medicines, which can increase the risk of side effects or reduce the effectiveness of treatment. Patients should inform their doctor about all prescription medicines, over-the-counter drugs, and supplements they are taking.

1. CYP3A Inhibitors:

Adagrasib is primarily metabolized by the CYP3A enzyme. Strong CYP3A inhibitors such as Clarithromycin, Ketoconazole, Itraconazole, and Ritonavir may increase Adagrasib plasma concentrations and raise the risk of toxicity. Co-administration with strong CYP3A inhibitors should generally be avoided when possible.

2. CYP3A Inducers:

Strong CYP3A inducers such as carbamazepine, phenytoin, and rifampin may significantly reduce Adagrasib plasma concentrations and decrease its effectiveness. Concomitant use with these medicines should generally be avoided.

3. Transporter Interactions (P-glycoprotein):

Adagrasib can inhibit transport proteins such as P-glycoprotein (P-gp). This may increase the concentrations of medicines that are P-gp substrates, potentially increasing the risk of adverse effects.

4. QT-prolonging Medicines:

Adagrasib can prolong the QT interval. Taking other medicines that also prolong the QT interval, such as Quinidine, Amiodarone, or Haloperidol, may increase the risk of serious heart rhythm problems.

Other Specifications

• Adagrasib is usually not recommended during pregnancy because it may harm the baby. If you can become pregnant, use effective birth control during treatment and for at least one week after the last dose.

• Breastfeeding is not advised while taking Adagrasib and for one week after stopping it.

• In older adults, doctors may monitor health and kidney function more closely, as the risk of side effects can be higher.