Yervoy (Ipilimumab): What It Is and What to Expect

T cells carry a receptor called CTLA-4. Its job is to hold the immune response back. Ipilimumab is a fully human monoclonal antibody that blocks it.

The result is a stronger immune attack. The label states the consequence in the same breath. Removing that brake brings the potential for immune-mediated adverse reactions. The benefit and the main risk share one mechanism.

Yervoy is the brand name. Ipilimumab is the generic name.

The FDA label lists more indications than most summaries mention.

Melanoma comes first. For disease that cannot be removed, or has spread, it is used alone or with nivolumab. That covers adults and children aged 12 and over. It is also used alone after full removal of skin melanoma with lymph node involvement greater than 1 mm.

Then come six more, all with nivolumab. Advanced renal cell carcinoma at intermediate or poor risk, first line. Colorectal cancer that is MSI-high or mismatch repair deficient, confirmed by an FDA-authorized test. That one also covers children 12 and over. Hepatocellular carcinoma, first line or after sorafenib. Metastatic non-small cell lung cancer, where PD-L1, EGFR and ALK results pick one of two schedules. Unresectable malignant pleural mesothelioma. And esophageal squamous cell carcinoma with PD-L1 of 1% or more.

There is no single ipilimumab dose, which is a common source of confusion.

For melanoma that cannot be removed, or has spread, it is the higher weight-based amount every 3 weeks. The maximum is 4 doses. After surgery for melanoma the schedule stretches: the same amount every 3 weeks for 4 doses, then every 12 weeks for up to 4 more.

For advanced renal cell carcinoma it drops to the lower amount. It follows nivolumab on the same day, every 3 weeks for 4 doses. Liver cancer goes back up to the higher amount every 3 weeks for up to 4 doses. That one runs over 30 minutes.

For metastatic lung cancer and mesothelioma, the gap widens. It is the lower amount every 6 weeks, with nivolumab every 3 weeks. Esophageal squamous cell carcinoma uses the same spacing.

In the melanoma, kidney, colorectal and liver combinations, nivolumab continues on its own once the four combined doses are finished. The lung, mesothelioma and esophageal schedules are not built around four doses, so both drugs carry on.

This is where the label spends most of its length, and the numbers are worth seeing.

Immune-mediated colitis is the most frequent. It hit 12% of 511 patients on the higher-dose single agent. Grade 3 to 5 accounted for 7%. With the lower dose plus nivolumab it rose to 25% of 456 patients with melanoma or liver cancer. Grade 3 accounted for 14%.

Immune-mediated hepatitis occurred in 4.1% on the single agent, and in 15% on the higher-dose combination with nivolumab.

The label also names immune-mediated skin reactions. Those include blistering and peeling rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS. Hormone gland reactions, pneumonitis, and nephritis with kidney dysfunction finish the list. Any organ system can be affected.

Two facts matter more than any single percentage. These reactions can begin at any time during treatment. They can also appear after the drug has been stopped.

A lab test often catches these before a symptom does. So the label sets a fixed panel. Liver enzymes, creatinine, adrenocorticotropic hormone, and thyroid function are checked at baseline. They are checked again before each dose.

The response is specified too. The drug is withheld for severe grade 3 reactions. It is stopped for good for life-threatening grade 4 ones. Steroids follow, at a weight-based daily dose of prednisone or its equivalent. They run until things improve to grade 1 or less. The taper then takes at least a month. Reactions that do not respond may need a second immunosuppressant. In the trials, about 23% of people with colitis on the higher combination dose needed infliximab added.

Three other warnings sit alongside. Infusion reactions call for slowing or stopping the drip. Fatal and serious complications can follow a donor stem cell transplant in people treated with this drug. And it can harm a fetus, so effective contraception is advised.

The pattern to watch for is new inflammation where it does not belong. None of it looks like an emergency at first, and all of it is easier to treat early.

• Call 911 or go to an emergency department if a rash blisters or peels off in sheets, your mouth or eyes ulcerate, you cannot breathe properly, or belly pain is severe with many bloody stools.
• Call your care team the same day if loose stools keep coming or carry blood, your skin or eyes look yellow, a headache changes your vision, or you feel wiped out and light-headed, which can point to a hormone gland.
• Call your care team within a day or two if a dry cough or mild breathlessness is new, urine output drops, or a rash is spreading without blistering.

These reactions can start at any point, including after the drug has been stopped, so mention ipilimumab to any clinician you see.

The label also lists the ordinary side effects, sorted by how often they turned up.

On ipilimumab alone, the reactions seen in 20% or more of people were fatigue, diarrhea, itching, rash, nausea, and headache.

Combined with nivolumab, the 20%-or-more list grows. It adds musculoskeletal pain, fever, cough, appetite loss, vomiting, abdominal pain, breathlessness, upper respiratory infection, joint pain, hypothyroidism, constipation, weight loss, and dizziness.

Add platinum chemotherapy on top, and the same threshold list narrows to fatigue, musculoskeletal pain, nausea, diarrhea, rash, appetite loss, constipation, and itching.

Two of those entries deserve a second look. Diarrhea appears on every list, and it is also the first sign of colitis. Hypothyroidism appears as a routine side effect, and it is also a hormone gland reaction. Frequency does not tell you which is which. The blood tests do.

For how this class works, see immunotherapy and its usual partner, nivolumab. The complete label sits on DailyMed, including the full Warnings and Precautions section.

• DailyMed — YERVOY (ipilimumab) injection prescribing information
• NCI — Ipilimumab