FDA Approval: Adagrasib (Krazati) for Lung Cancer

A switch that stays on

KRAS is a protein inside the cell. It works like a switch that tells the cell when to grow. Normally it flips on, sends the signal, then flips off.

When the gene is altered at the spot called G12C, the switch can jam in the on position. The cell keeps getting a grow signal that nobody sent.

For decades KRAS was considered undruggable. Its surface offered nowhere for a drug to grip. G12C changed that, because the alteration swaps in an amino acid with a reactive chemical handle. A drug can bind to that handle and hold the switch off.

Adagrasib, sold as Krazati, is one such drug. It is a tablet. It does nothing at all for a lung cancer that does not carry KRAS G12C.

Exactly who the approval covers

FDA granted accelerated approval on December 12, 2022, under new drug application 216340.

The wording is narrow. The drug is approved for adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer, as determined by an FDA-approved test, who have received at least one prior systemic therapy.

That sets three separate conditions. The tumor must be tested and found to carry the mutation. The cancer must be locally advanced or metastatic. And a prior systemic treatment, such as chemotherapy or immunotherapy, must already have been given.

It was not approved as a first treatment. It was not approved for small cell lung cancer. Our page on biomarker testing explains why the test comes first.

What the trial showed, and what it left open

The approval rested on KRYSTAL-1. It was a single-arm study. Everyone in it got adagrasib, and there was no comparison group.

Among 112 patients assessed, 43 percent had tumors that shrank, with a 95 percent confidence interval of 34 to 53 percent. Responses lasted a median of 8.5 months, with a confidence interval of 6.2 to 13.8 months.

Tumor shrinkage is not the same as living longer. And with no comparison group, the trial cannot say whether these patients did better than they would have on something else.

That is precisely why the approval was accelerated. FDA cleared the drug on an early measure and required a proper comparison afterward.

Where that requirement stands

This is the part worth checking before treating a 2022 approval as settled.

FDA keeps three registers of accelerated approvals in cancer: ongoing, verified, and withdrawn. The Krazati lung cancer indication sits on the ongoing list. It has not been withdrawn. It has also not yet been converted to full approval.

The register names the outstanding obligation. Postmarketing requirement 4378-1 calls for a randomized comparative trial of adagrasib in this population, reporting overall survival, progression-free survival, response rate, and duration of response. FDA notes the data may come from a randomized phase 3 study of adagrasib against docetaxel in previously treated KRAS G12C lung cancer.

Adagrasib also holds a separate accelerated approval, with cetuximab, for KRAS G12C colorectal cancer. That one is on the same ongoing list, granted June 21, 2024.

Dose, monitoring, and side effects

The recommended dose is 600 mg by mouth twice a day. Tablets are swallowed whole, with or without food. Treatment continues as long as it works and is tolerated. The label calls for liver blood tests every month for the first three months. Check the amount on your own bottle rather than this page, and keep the liver test appointments.

That figure comes from the label. Follow your own prescription, since the amount is often cut when nausea or liver tests get in the way.

Across 366 people in the pooled safety group, the most common reactions were nausea in 70 percent, diarrhea in 69 percent, and vomiting in 57 percent. Fatigue affected 55 percent. Musculoskeletal pain affected 38 percent. Liver injury showed up in 37 percent, reduced kidney function in 33 percent, swelling in 30 percent, loss of appetite in 29 percent, and breathlessness in 26 percent.

The label's serious warnings cover gastrointestinal reactions and liver injury. They also cover QTc prolongation, a change in heart rhythm, with advice to avoid other drugs that do the same. And they cover interstitial lung disease, or pneumonitis, which means inflammation of the lung tissue itself. If that is confirmed, the drug is stopped for good.

What to raise with the team

• Has my tumor had molecular testing, and does the report name KRAS G12C?
• Given the treatments I have already had, do I fall inside this approval?
• Which blood tests will be checked, and how often?
• What breathing symptoms should make me call rather than wait?
• Is a randomized trial of this drug open to me instead?

Our guides to lung cancer and targeted therapy cover the wider picture.

What this does not mean

• An approval describes a group. Whether this drug fits one person depends on testing, prior treatment, organ function, and that person's own priorities.
• Approval is not a promise of benefit. It means the evidence met the regulator's bar for this use.
• Accelerated approval is provisional by design. This indication is still on FDA's ongoing list, with the confirmatory trial outstanding.
• A 43 percent response rate means most tumors in the study did not meet the shrinkage threshold.
• Nothing here applies to lung cancers without KRAS G12C, which is most of them.

Sources

• FDA approval letter, NDA 216340 (KRAZATI/adagrasib), December 12, 2022
• FDA prescribing information: KRAZATI (adagrasib) tablets
• FDA: Ongoing — Cancer Accelerated Approvals
• FDA: Withdrawn — Cancer Accelerated Approvals
• NCI drug information: Adagrasib

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

Cancer Explained is published by the National Cancer Information Foundation. It is not medical advice and does not suggest a test or treatment.

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