Rx Road Map: Adagrasib With Cetuximab for KRAS G12C-Mutated mCRC

For Whom Is Adagrasib Approved?

On June 21, 2024, the FDA approved adagrasib (Krazati), a KRAS G12C inhibitor, with cetuximab (Erbitux), an EGFR inhibitor, for KRAS G12C-mutated metastatic colorectal cancer (mCRC) previously treated with standard therapies.¹

Adagrasib was approved for KRAS G12C-mutated non–small cell lung cancer after systemic therapy in 2022.²

What Efficacy Data Back It Up?

The multicenter, single-arm, open-label expansion cohort phase 1/2 KRYSTAL-1 trial (NCT03785249), upon which the combination’s approval was based, evaluated adagrasib as a monotherapy, in combination with cetuximab, and in combination with other agents, in KRAS G12C-mutant mCRC and other solid tumors.³

The primary efficacy outcomes measured were the combined objective response rate (ORR) and duration of response (DOR). Data cited in the combination’s approval demonstrated an ORR of 34% (95% CI, 25%-45%) and a DOR of 5.8 months (95% CI, 4.2-7.6), with 31% achieving a DOR of 6 months or greater.^1,3

In an analysis of KRYSTAL-1 published in the New England Journal of Medicine comparing adagrasib monotherapy with adagrasib/cetuximab, adagrasib monotherapy showed an ORR of 19% (95% CI, 8%-33%) with a median DOR of 4.3 months (95% CI, 2.3-8.3), while adagrasib/cetuximab showed an ORR of 46% (95% CI, 26%-66%) and a median DOR of 7.6 months (95% CI, 5.7-not estimable).⁴ KRYSTAL-1 underscored the significance of EGFR inhibition in KRAS G12C-mutated mCRC.

How It Works

Adagrasib inhibits KRAS G12C, stopping tumor growth by blocking the RAS/mitogen-activated protein kinase pathway. However, cancer cells can bypass this pathway by reactivating EGFR, allowing cancer cells to continue growing. Cetuximab blocks EGFR to stop cell proliferation but is ineffective alone in KRAS-mutant CRC. Combined, adagrasib and cetuximab prevent EGFR reactivation and enhance tumor suppression.

How It’s Administered

Adagrasib is an oral medication.

Cetuximab is available in a 50 mL vial containing 100 mg of cetuximab at a concentration of 2 mg/mL. The solution should be clear and colorless, although a few white crystals may be present. It is administered intravenously via piggyback into the patient’s infusion line through a 0.22-µm in-line filter placed as close to the patient as possible. The tubing should be primed with cetuximab prior to infusion. The infusion rate should not exceed 5 mL per minute. Following the infusion, flush the line with 0.9% saline.

The Recommended Dose

Adagrasib: 600 mg orally twice daily.

Cetuximab: 500 mg/m² biweekly, or 400 mg/m² initially, then 250 mg/m² weekly.

Treatment with the combination should continue until disease progression or unacceptable toxicities occur.

How to Manage Associated Adverse Events

Common adverse events (AEs) of adagrasib include gastrointestinal issues such as diarrhea, nausea, and vomiting.³ Providers should discuss these potential AEs with patients to ensure early recognition and treatment.

To manage diarrhea, patients should eat small meals and avoid greasy or spicy foods, milk, caffeine, and alcohol. The BRAT diet (bananas, rice, applesauce, and toast/decaffeinated tea) can be helpful, and consuming 64 ounces of fluids per day is essential for maintaining adequate hydration. Medications such as diphenoxylate-atropine or loperamide may be considered.

Nausea and vomiting can be managed by taking adagrasib with food and eating smaller, more frequent meals during the day. Medication management includes using antiemetics, such as ondansetron (Zofran) for mild cases and adding NK1 receptor agonists or olanzapine (Zyprexa) for refractory cases. QTc prolongation is also a risk associated with adagrasib; therefore, ondansetron should be used cautiously and avoided should patients express an underlying predisposition to QTc prolongation or if it occurs. Potassium and magnesium levels should be monitored in patients with diarrhea or vomiting.⁵

The most common AEs associated with cetuximab include dermatologic toxicities affecting the skin and fingernails. Patients should practice good general skin care, including using mild soap and water for routine bathing, a cream-based moisturizer, and a broad-spectrum sunscreen with an SPF of at least 30. Topical steroids and oral antibiotics may be prescribed for grades 1 to 3 rashes. Paronychia may gradually develop within weeks of beginning treatment. Patients should be instructed to avoid repeated friction, trauma, or excessive pressure on the nails. Patients should regularly trim their nails to keep them straight; however, they should avoid cutting them too short.⁶

What to Inform Patients About to Start Treatment

Patients should be instructed to use adagrasib as prescribed and inform their health care provider of any missed doses. Due to numerous drug interactions, they should inform their health care provider of any new medications, including over-the-counter medications and herbal supplements.

Patients receiving cetuximab should contact their health care provider and report any signs or symptoms of infusion reactions, including fever, chills, or breathing difficulties. Inform patients about the risk of cardiopulmonary arrest or sudden death and advise them to report any history of coronary artery disease, congestive heart failure, or arrhythmias. They should immediately contact their health care provider if they experience a new or worsening cough, chest pain, or shortness of breath, as these may indicate pulmonary toxicity.³

Advice for Nurses Who Administer This Agent

Ensure that adagrasib is available to the patient and that they are informed about oral dosing prior to administering cetuximab.

Cetuximab can cause low levels of magnesium, calcium, or potassium. Check values before administration and throughout treatment.

Due to the risk of hypersensitivity reactions associated with cetuximab, always ensure that emergency equipment and medications are readily available before initiating treatment. Premedicate patients with 50 mg of intravenous diphenhydramine and monitor them closely during the infusion. In the event of any infusion reactions, interrupt the infusion, follow institutional guidelines for treatment, and notify the prescriber. For mild reactions, the infusion may continue at a reduced rate. Severe reactions may occur, particularly during the first infusion, and require immediate medical intervention. These severe reactions include symptoms such as airway constriction (bronchospasm, stridor, or hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Cetuximab should be permanently discontinued if severe infusion reactions occur.³

Observe patients for at least 1 hour post infusion, or longer if reactions occur.

How to Safely Handle This Drug

Wash hands with soap and water before and after handling adagrasib; gloves should be worn if someone other than the patient is dispensing the medication. The medication should be transferred from its original container to a small disposable cup and taken immediately with water.

Unopened vials of cetuximab should be stored in a refrigerator (36 °F to 46 °F). The drug is stable for up to 12 hours when refrigerated and for 8 hours at room temperature (68 °F to 77 °F) in infusion containers. Any remaining solutions or vials should be discarded after these times.³

References

1. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. FDA. June 21, 2024. Accessed October 30, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer
2. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. FDA. December 12, 2022. Accessed October 30, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc
3. Adagrasib. Prescribing information. Bristol Myers Squibb; 2024. Accessed October 30, 2025. https://packageinserts.bms.com/pi/pi_krazati.pdf
4. Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023;388(1):44-54. doi:10.1056/NEJMoa2212419
5. Zhang J, Johnson M, Barve M, et al. Practical guidance for the management of adverse events in patients with KRASG12C-mutated non-small cell lung cancer receiving adagrasib. Oncologist. 2023;28(4):287-296. doi:10.1093/oncolo/oyad051
6. Lacouture ME, Sibaud V, Gerber PA, et al; ESMO Guidelines Committee. Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines. Ann Oncol. 2021;32(2):157-170. doi:10.1016/j.annonc.2020.11.005