Keytruda (pembrolizumab) can cause serious, potentially life-threatening side effects by triggering the immune system to attack healthy organs. In a pooled analysis of nearly 9,000 patients, about half experienced a severe adverse event (grade 3 or higher), 12.7% had to stop treatment because of side effects, and 0.2% died from an immune-related reaction. The drug works by releasing the brakes on immune cells so they can fight cancer, but that same unleashed immune response can turn against the body’s own tissues.
How Keytruda Causes These Side Effects
Keytruda belongs to a class of drugs called immune checkpoint inhibitors. Your immune system has built-in checkpoints that prevent it from attacking your own cells. Keytruda blocks one of these checkpoints (called PD-1), which helps immune cells recognize and destroy cancer. The problem is that removing this safety mechanism can also disrupt the immune system’s ability to tell the difference between cancer cells and healthy tissue. The result is inflammation in organs that have nothing to do with the cancer being treated.
In some patients, Keytruda essentially unmasks a pre-existing autoimmune tendency that was previously kept in check. In others, immune cells trained to attack the tumor also react to similar proteins found in healthy organs. These immune-related side effects can strike virtually any organ system, and they range from manageable to fatal.
Lung Inflammation (Pneumonitis)
Pneumonitis is the single deadliest immune-related side effect of Keytruda. Of the 22 immune-related deaths recorded across 8,937 patients in clinical trials, 15 were caused by pneumonitis. Overall, about 3.4% of patients develop some degree of lung inflammation, with roughly 1.2% experiencing a severe or life-threatening form. In a lung cancer trial, the rate was slightly higher at 3.8%, and 2% of those patients had severe cases.
The median time to onset is about 57 days after starting treatment, but it can appear as early as 4 days or as late as 393 days. Episodes last a median of 40 days. Patients with a history of asthma, chronic obstructive pulmonary disease, or prior chest radiation face a higher risk, with incidence reaching 5.3% to 6% in those groups. Symptoms include a new or worsening cough, shortness of breath, and chest pain. High-dose steroids are used to treat most cases, and about 2% of patients must permanently stop Keytruda because of pneumonitis.
Severe Colitis
Immune-mediated colitis, or inflammation of the colon, occurred in 1.7% of patients in clinical trials, with 1.1% developing a severe form. Colitis was also responsible for two of the 22 immune-related deaths in the large pooled analysis. Symptoms come on suddenly: severe abdominal pain (often on the right side), bloody diarrhea, fever, nausea, and vomiting. Unlike ordinary diarrhea from other cancer treatments, immune-mediated colitis involves actual tissue damage to the intestinal lining and requires aggressive treatment with steroids. Patients who don’t respond to steroids within a few days may need additional immune-suppressing medications.
Liver Damage (Hepatitis)
Keytruda caused immune-mediated hepatitis in 0.7% of patients, with roughly 0.4% experiencing a severe form. The liver inflammation typically shows up in blood tests as sharply elevated liver enzymes before a patient feels symptoms. When symptoms do appear, they include pain in the upper right abdomen, loss of appetite, nausea, dark urine, light-colored stools, and yellowing of the skin or eyes. In clinical studies, hepatitis tended to emerge within the first five treatment cycles. Treatment involves stopping Keytruda and starting high-dose steroids.
Permanent Endocrine Damage
The endocrine system, which includes the thyroid, pituitary gland, adrenal glands, and pancreas, is one of the most commonly affected organ systems. Thyroid problems are the most frequent: 8.5% of patients develop an underactive thyroid, and 3.4% develop an overactive thyroid. These conditions are usually manageable with medication but often become permanent, requiring lifelong thyroid hormone replacement.
Less common but more dangerous are pituitary gland inflammation (0.6% of patients) and adrenal insufficiency, where the adrenal glands stop producing enough cortisol. Both can cause extreme fatigue, dizziness, low blood pressure, and weakness. Adrenal insufficiency can appear months or even years into treatment, with one case in a retrospective study emerging after the 47th treatment cycle.
Keytruda can also trigger autoimmune diabetes by destroying the insulin-producing cells in the pancreas. This occurs in an estimated 1% to 2% of patients on this type of drug. The destruction is often abrupt and irreversible, leaving patients permanently dependent on insulin. Early signs include increased thirst, frequent urination, and unexplained weight loss.
Heart, Nerve, and Muscle Reactions
Myocarditis (inflammation of the heart muscle) is rare but carries one of the highest fatality rates among Keytruda’s side effects. It accounted for two of the 22 immune-related deaths in the pooled analysis. Symptoms include unusual fatigue, shortness of breath, chest pain, a fast or irregular heartbeat, and swelling in the ankles or feet.
Neurological side effects are also uncommon but can cause lasting damage. Guillain-Barré syndrome, where the immune system attacks the nerves, was responsible for one death in the pooled analysis. Other neurological reactions include encephalitis (brain inflammation), numbness or tingling in the hands and feet, muscle weakness, confusion, trouble speaking, loss of coordination, and seizures. Treatment typically requires stopping Keytruda permanently and starting high-dose steroids, and even with treatment, some patients are left with long-term neurological problems.
Life-Threatening Skin Reactions
Most Keytruda-related skin reactions are mild rashes. Rarely, the drug triggers Stevens-Johnson syndrome or toxic epidermal necrolysis, conditions where the skin blisters and peels off in sheets. As of March 2022, 255 cases of these reactions had been reported with pembrolizumab through the FDA’s adverse event reporting system. Warning signs include a spreading rash of dark, dusky spots, pain in the skin or mucous membranes, fever, and flu-like symptoms followed by blistering. Patients taking antibiotics during Keytruda treatment may face a higher risk, as the combination appears to heighten drug sensitivity. Severe cases require treatment in a burn unit or intensive care.
When Side Effects Appear
Most immune-related side effects cluster in the first few months of treatment. In one analysis, 69% of all immune reactions occurred within the first six treatment cycles. Skin reactions tend to appear earliest, often within the first few cycles. Lung inflammation frequently shows up by the third cycle, while liver problems and thyroid dysfunction typically emerge by the fifth. But these reactions can also strike much later. The latest recorded case of pneumonitis appeared after the 66th treatment cycle, and adrenal insufficiency has been documented years into therapy.
This unpredictable timing means monitoring doesn’t stop when treatment ends. In a study of patients who completed checkpoint inhibitor therapy, 43% still had an immune-related side effect lasting at least three months after their final dose. Thyroid damage and other endocrine problems are the most likely to become permanent, while many inflammatory reactions in the lungs, liver, and colon resolve with steroid treatment.
Symptoms That Need Immediate Attention
Certain symptoms during Keytruda treatment signal a potential emergency:
- Breathing problems: new or worsening cough, chest pain, shortness of breath
- Gut symptoms: sudden severe abdominal pain, bloody or dark stools, persistent diarrhea with fever
- Liver warning signs: yellowing skin or eyes, dark urine, right-sided abdominal pain
- Heart symptoms: chest pain, rapid or irregular heartbeat, unusual fatigue, swelling in the legs
- Neurological changes: confusion, trouble speaking, muscle weakness, numbness, seizures, vision changes
- Skin reactions: spreading rash with blisters, skin peeling, rash with fever and swollen lymph nodes
- Fever: temperature of 100.4°F (38°C) or higher with chills
The difference between a manageable side effect and a dangerous one often comes down to how quickly it’s caught. Immune-related reactions that are identified early and treated with steroids usually resolve. Those that go unrecognized can progress to permanent organ damage or, in rare cases, death.