Side Effects and Management of Enfortumab Vedotin–Pembrolizumab Combination Therapy

According to safety data for the EV + Pembro combination, very common side effects (≥20%, approximately one in five patients or more) include:

• Skin rashes (all grades; 68%),
• Peripheral neuropathy (67%),
• Fatigue (51%),
• Itching (41%),
• Hair loss (alopecia, 35%),
• Decreased appetite (33%),
• Diarrhea (38%), and
• Weight loss (33%),
• Nausea (26%), and
• Constipation (26%).

Laboratory abnormalities such as elevated liver enzymes (AST 75%, ALT 59%; severe elevations around 5%), increased creatinine (71%), and increased blood glucose (66%; severe hyperglycemia 14%) have been reported very frequently.

Common side effects (at a lower frequency, e.g., 5–20%) include:

• Infections (e.g., urinary tract infection ~21%)
• Taste disturbance (dysgeusia, ~21%)
• Pneumonitis (approximately 10%), and
• Immune-mediated endocrine disorders (e.g., hypothyroidism).

Rare (≤5%) but serious side effects also occur. For example,

• Severe skin reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN),
• Diabetic ketoacidosis,
• Serious immune-mediated neurological reactions (e.g., Guillain–Barré syndrome), and
• Serious infections (e.g., sepsis, pneumonia) are uncommon but can be life-threatening.

The Severity of Side Effects Also Varies

Among patients receiving EV + Pembro combination therapy, the most common severe (Grade 3–4) side effects include

• severe skin rashes (15%),
• severe peripheral neuropathy (8%), and
• severe fatigue (6%).

Treatment-related deaths were reported in 3.9% of all patients, with approximately 0.9% considered directly attributable to combination therapy (for example, due to multiple organ failure, an immune-mediated lung reaction, diarrhea, or weakness).

In approximately one in three patients (35%), EV treatment was permanently discontinued because of a side effect, while Pembro was discontinued in 27%; even more patients required temporary treatment interruptions or dose reductions.

These data show that side effects are common during combination therapy, but appropriate management allows most patients to continue treatment.

Below, the key side effects of this combination therapy are discussed individually, including their frequency, mechanisms, and appropriate management strategies. Practical recommendations are also provided for patients and healthcare professionals.

Skin Reactions (Rashes and Skin Toxicity)

Frequency and Clinical Features: Skin reactions have occurred in approximately 70% of patients receiving EV + Pembro combination therapy. These reactions generally take the form of maculopapular (flat and raised red rash), macular (flat red spots), or papular (small raised bumps) rashes.

Severe skin toxicities (Grade 3–4) occurred in 17% of patients. Rare life-threatening skin reactions have also been reported: for example, one patient died from bullous dermatitis (a severe rash with fluid-filled blisters; ~0.2%). Serious skin reactions generally appear around ~1.5-2 months into treatment (median 1.7 months), although rashes have been reported immediately after the first cycle. Most patients who develop skin reactions during treatment improve over time: rashes resolved completely in approximately 59%, while generally mild-to-moderate rashes persisted in the remainder. Long-term follow-up (approximately ~4 years in the EV-103 study) found that rashes had either resolved or substantially improved in 90% of patients who developed skin reactions.

Mechanism: Because both EV and Pembro monotherapy can cause rashes, skin toxicity occurs more often with combined use. However, the mechanisms by which the two drugs cause skin reactions differ. The target of enfortumab vedotin, the Nectin-4 protein, is also expressed in skin (for example, in keratinocytes). EV can therefore bind to skin cells as well as tumor cells and release its toxic MMAE payload. This direct cytotoxic effect causes skin rashes and damage. EV-related rashes often occur in areas where skin rubs together, skin folds, the distal extremities, and the trunk; the skin in these areas may be thin and sensitive. By contrast, immunotherapies such as pembrolizumab cause skin reactions through uncontrolled activation of the immune system ; that is, immune cells attack the skin, resulting in immune-mediated rashes . Rashes with Pembro are often maculopapular, do not severely disrupt skin integrity, and may be itchy. In summary, EV rashes arise mainly through direct toxicity (and may begin rapidly), while Pembro rashes arise through an autoimmune mechanism (and tend to develop later).

This distinction can be important in practice: for example, a rash that persists or worsens despite interrupting treatment suggests an immune-mediated reaction (probably due to Pembro). In contrast, rashes that improve rapidly after the drug is stopped may be more attributable to the direct effects of EV.

Management and Treatment: The first step in managing skin reactions should be to determine their grade and type . Mild or moderate rashes that are not widespread generally respond well to topical treatment. For mild-to-moderate rashes, regular application of moisturizing cream (an emollient) , along with over-the-counter antihistamines and topical corticosteroid creams when needed, is generally sufficient. To help prevent EV-related dry skin and rashes, it may be useful to start applying protective barrier creams and moisturizers (for example, Bepanthol Sensiderm) to particularly vulnerable areas (skin folds, armpits, and areas exposed to friction such as the groin) as soon as treatment begins. This preventive approach helps reduce the skin damage EV can cause from the first cycles onward. Treatment can generally continue for mild rashes, with close monitoring.

If the rash is severe (Grade ≥3) or deteriorates rapidly, a more intensive approach is required. For serious skin reactions, both drugs should be temporarily withheld. Systemic corticosteroid treatment (e.g., oral or intravenous steroids) is started to suppress the immune response and control skin inflammation. Steroids are continued until the rash has improved to at least a mild level (Grade 1). Once the rash has subsided, the decision to restart treatment depends on its cause and severity. Because EV is eliminated from the body more quickly, once the rash resolves, EV can generally be restarted at the same dose or one dose level lower , with close monitoring. Pembrolizumab has no dose-reduction option, so the status of an immune-mediated rash may require withholding Pembro beyond the scheduled 3-week interval; resuming Pembro at its full dose can be considered once the rash is controlled. If it is unclear which drug caused the rash, restarting EV first and adding Pembro after a period of close observation is a recommended approach. This may help identify the drug responsible.

In particular, sudden-onset rashes or those with widespread peeling are warning signs. If a patient develops this type of serious reaction, both drugs must be stopped immediately and high-dose systemic corticosteroid treatment started. If Stevens–Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) is suspected, an urgent dermatology consultation should be requested; if the diagnosis is confirmed, both treatments must be permanently discontinued. SJS/TEN are rare but potentially life-threatening dermatological emergencies, so patients should be informed about them. Patientsshould be told to seek immediate medical attention if, along with high fever, they develop a widespread rash, skin peeling, sores in the mouth, eyes, or genital area, or skin pain/burning , which may be signs of SJS/TEN. Recognizing such a rare condition early allows better management with intensive supportive care.

In summary, mild skin reactions may be controlled with local treatment, whereas serious reactions may require treatment interruption and immunosuppression. Regular skin examinations and, when lesions are present, using a biopsy to confirm the type of rash can be helpful, particularly for atypical or treatment-resistant rashes. Avoiding re-exposure to any drug that might worsen the patient's condition until the diagnosis is clear, and taking a multidisciplinary approach (such as obtaining a dermatologist's opinion), are also important for safe management of skin toxicity.

Recommendations for Patients and Clinicians: Patients should watch for skin changes from the start of treatment. Daily moisturizer use and sun protection may improve the skin's resilience. Patients should report even the slightest sign of a rash to their doctor, because early intervention can control it and prevent progression. In particular, rashes accompanied by fever and weakness or involving mucous membranes must be reported urgently. Healthcare professionals should examine the patient's skin at every visit, including skin folds and mucous membranes , to identify early lesions. Because both EV and Pembro carry a risk of SJS/TEN, patients should be informed about this syndrome and provided with written warnings through patient education cards/leaflets . Patients should understand that simple measures (moisturizers and itch relief) are generally sufficient for mild rashes, but severe rashes require hospitalization and specialist consultation.

Peripheral Neuropathy (Nerve Damage)

Frequency and Clinical Features: Peripheral neuropathy is the second most common side effect of the EV + Pembro combination, with neuropathy of any grade reported in ~67% of patients. Most cases are sensory neuropathy; patients may describe numbness, tingling, burning, or loss of sensation in their hands and feet. Severe neuropathy (Grade 3) occurs in approximately ~7%. Peripheral neuropathy is among the leading reasons for EV dose reduction or discontinuation ; cumulative nerve damage may eventually make EV intolerable. Indeed, neuropathy is the most common reason for EV dose interruptions. This side effect generally develops cumulatively as treatment progresses. The median onset of significant (Grade ≥2) neuropathy has been reported at approximately month 6 (with a wide range of 0.3 to 25 months). In other words, nerve damage becomes apparent after several cycles in most patients, and the risk increases with treatment duration. Unfortunately, once peripheral neuropathy develops, complete recovery may take a long time. In clinical trials, only 13% of patients with neuropathy recovered completely by the end of treatment, while 87% still had some neuropathy at the last follow-up. Nearly half (45%) of those with ongoing neuropathy had moderate or worse symptoms (Grade ≥2). Nevertheless, partial improvement in nerve damage is common over longer follow-up. For example, at the 4-year follow-up of the EV-103 studies, symptoms improved or resolved completely over time in ~70% of patients with treatment-related neuropathy. The median time for mild neuropathy to improve was approximately ~5 months.

Mechanism: The MMAE toxin carried by EV disrupts microtubules, producing a toxic effect on nerve cells . This mechanism, also seen with chemotherapeutic agents such as vinca alkaloids and taxanes, particularly damages long nerve fibers (those supplying the hands and feet). For this reason, EV-related peripheral neuropathy is considered a predictable side effect . Pembrolizumab can cause neuropathy much more rarely and indirectly ; autoimmune neuropathy syndromes in which the immune system attacks nerves (such as Guillain–Barré syndrome, peripheral demyelinating polyneuropathy, or motor neuropathy) have rarely been reported with Pembro. In short, the vast majority of peripheral neuropathies during combination treatment result from EV's cumulative toxicity and are generally sensory. If the patient develops weakness, loss of reflexes, visual disturbances, double vision (ptosis), difficulty swallowing, speech disturbances, or severe loss of balance, these unusual neurological findings suggest a serious neurological syndrome rather than ordinary peripheral neuropathy. In this situation, an immune-mediated neurological side effect (e.g., Guillain–Barré syndrome, myasthenia gravis, or encephalitis) may have developed, requiring urgent comprehensive neurological assessment and referral to the appropriate specialists. However, these conditions are extremely rare; the typical presentation is EV-related dose-cumulative peripheral neuropathy.

Management and Treatment: The most important strategy for managing peripheral neuropathy is early recognition and intervention. Because nerve damage is often irreversible or takes a long time to improve, as soon as the first symptoms appear, preventive action is necessary. Before every cycle, the healthcare team should ask about neuropathy symptoms (numbness, tingling, pain, weakness, etc.) and monitor the patient through simple neurological examinations (e.g., reflex testing, finger-to-nose testing, and gait assessment). Patient education on this issue is also very important. Many patients may initially hide numbness in their hands or feet for fear of losing access to treatment. However, progression can limit everyday activities and eventually force them to stop treatment altogether. Patients should therefore understand that reporting neuropathy symptoms to their doctor early is important for continuing treatment . Clinicians should explain that dose modifications can bring neuropathy under control, allowing the patient to receive treatment safely for longer.

Cooling gloves and socks can be used to prevent or reduce chemotherapy-induced peripheral neuropathy. This method may reduce the amount of chemotherapy reaching peripheral nerves by constricting blood vessels in the hands and feet. Cooling gloves can be worn during chemotherapy and for a specified period afterward.

When neuropathy develops, the first step is temporarily withholding EV or reducing its dose. Treatment generally continues for mild (Grade 1) peripheral neuropathy, with close monitoring. If symptoms reach Grade 2 , guidelines recommend withholding EV or interrupting it for a time until symptoms improve. EV may be restarted at a lower dose level once symptoms have improved. There is no specific dose-reduction protocol for pembrolizumab; if neuropathy is an immune-mediated side effect attributed to Pembro (e.g., Guillain–Barré syndrome), Pembro should be stopped immediately and permanently, and immunosuppressive treatments (high-dose steroids, IVIG, etc.) should be given. However, typical peripheral neuropathy generally does not require interrupting Pembro; the main intervention concerns EV.

For the patient's neuropathy, symptomatic treatment should not be overlooked either. For neuropathic pain caused by nerve damage, medications such as duloxetine, pregabalin, or gabapentin may be prescribed. Because their effects may take several weeks to become apparent, patients should understand that relief may not be immediate and regular use is important. In addition, physical therapy and rehabilitation can be very helpful, particularly for patients with impaired balance or muscle weakness. For example, ankle-support devices or a walking stick can reduce falls; occupational therapy may be recommended for fine motor skills in the hands.

The basic principle of neuropathy management is adjusting treatment doses early to prevent progression and teaching the patient protective measures. Once symptoms improve, the aim is to continue EV at a dose that provides maximum benefit with the lowest possible toxicity. If neuropathy worsens again, further dose reduction or discontinuation may be necessary.

Recommendations for Patients and Clinicians: During treatment, patients should report any numbness, tingling, loss of sensation, or weakness in their hands or feet immediately. Even minor symptoms should not be ignored. A brief interruption or dose reduction early on may prevent permanent nerve damage later. In daily life, patients can avoid tight shoes that might worsen burning or numbness and avoid extremes of heat and cold. They are also advised to reduce fall risks at home, avoid walking in the dark, and remove obstacles such as rugs or cables. Healthcare professionals should ask about neurological symptoms at every visit and perform an objective neurological examination. If sensory changes are accompanied by motor findings (weakness or loss of reflexes), a neurologist should be consulted without delay. Neurological evaluation may involve EMG, MRI, or lumbar puncture. While these investigations are being carried out, EV and/or Pembro should also be withheld, and the possibility of a severe immune-mediated condition should be kept in mind until the situation is clarified. Ultimately, maintaining the patient's motivation for treatment and encouraging timely reporting of symptoms and providing reassuring guidance from the care team are key to successfully managing peripheral neuropathy.

Hyperglycemia and Development of Diabetes

Frequency and Clinical Features: The combination of enfortumab vedotin + pembrolizumab can cause elevated blood glucose (hyperglycemia) and, rarely, new-onset diabetes . Hyperglycemia has also been reported with EV or Pembro monotherapy, although the mechanisms may differ (discussed below). Clinical trials reported hyperglycemia of any grade in 13% of patients receiving EV + Pembro. Severe hyperglycemia (Grade 3–4, generally above 250 mg/dL or presenting as ketoacidosis) was recorded in ~8.9%. These rates are similar to those with EV alone (EV monotherapy ~14%) and substantially higher than with Pembro alone (severe hyperglycemia with Pembro monotherapy 0.2%). Hyperglycemia generally develops very early in treatment: the median onset with either EV alone or the combination was approximately 2 weeks (0.5 months) . Patients may therefore experience elevated glucose during the first or second cycle. The good news is that most cases of EV-related hyperglycemia can improve with appropriate treatment. In the EV-103 study, glucose levels in all patients who developed hyperglycemia had returned to baseline or been brought under control by the end of follow-up. The median time to this improvement was approximately 1.6 months (approximately 6 weeks). In contrast, immune checkpoint inhibitor–associated diabetes (new-onset type 1 diabetes) is generally permanent. Pembrolizumab and similar drugs are known rarely (in 1-2% of patients) to destroy insulin-producing pancreatic beta cells through an autoimmune mechanism, causing type 1 diabetes. Because the damaged cells do not regenerate, diabetes is generally permanent and requires insulin. EV-related hyperglycemia has a different mechanism (not autoimmune, but possibly related to altered intracellular metabolic pathways or transient elevations caused by supportive steroid treatment), so EV-related glucose elevations tend to be more temporary.

Mechanism: With immunotherapies such as pembrolizumab, hyperglycemia is generally associated with the development of autoimmune diabetes . Immune attack on pancreatic beta cells prevents the body from producing insulin, resulting in type 1 diabetes. Like spontaneously developing type 1 diabetes, this process is characterized by the appearance of autoantibodies such as GAD65 and reduced C-peptide levels. Once immune-mediated diabetes develops, the condition is irreversible and the patient may remain dependent on insulin for life. The mechanism of EV-related hyperglycemia has not yet been fully clarified. It is thought not to be autoimmune; factors such as stress hyperglycemia, effects of EV's MMAE payload on the liver or other organs, or additional supportive treatments (e.g., dexamethasone premedication) may contribute. Clinical observations suggest that EV-related hyperglycemia occurs mainly in patients with risk factors . These risk factors may include obesity (BMI ≥ 30), pre-existing glucose intolerance or a history of diabetes . For example, most patients who developed hyperglycemia in EV-103 were overweight/obese or already had diabetes or borderline elevated glucose. This may suggest that EV triggers glucose elevations in people who are already predisposed. Thus, although the mechanism remains incompletely understood, EV-related hyperglycemia appears to be a more transient metabolic imbalance associated with predisposing factors .

Management and Treatment: Monitoring blood glucose during combination treatment is essential for managing hyperglycemia. All patients should have fasting blood glucose measured before treatment ; those with a history of diabetes should have their metabolic control assessed using measures such as HbA1c. Once treatment begins, checking blood glucose before every EV dose, even without fasting, is recommended. Steroid premedication on the day of EV, or EV itself, can raise glucose regardless of whether the patient has fasted. If measurements show blood glucose above 250 mg/dL , the EV dose should not be given and the patient should receive appropriate intervention. This critical threshold is intended to prevent severe hyperglycemia and, particularly, diabetic ketoacidosis (DKA) .

When hyperglycemia is detected, its likely cause should first be assessed. Factors such as a simple infection (e.g., a urinary tract infection) or another medication (e.g., high-dose corticosteroids) can also raise glucose. The clinician should therefore check other possible causes before attributing it solely to the treatment drugs. If elevated glucose is accompanied by signs of ketoacidosis (e.g., urinary ketones, acidosis on blood gas testing, or confusion), or glucose remains very high, an urgent endocrinology consultation should be requested. Both drugs are generally withheld while the metabolic disturbance is corrected. Standard DKA treatment includes insulin infusion, fluids, and electrolyte replacement. Pancreatic autoantibody testing can help establish whether immune-mediated diabetes has developed; positive GAD65, IA-2, or islet-cell antibodies with low C-peptide support immune-mediated type 1 diabetes and distinguish it from transient EV-related hyperglycemia. In this situation, continuing pembrolizumab is generally not recommended, because immune attack on beta cells has occurred. The patient should receive diabetes education and begin insulin treatment, while Pembro is discontinued and an alternative cancer treatment is planned.

If there are no signs of immune-mediated diabetes and the patient is metabolically stable, hyperglycemia most likely arose from EV or other accompanying factors. In this case, once glucose is controlled, EV treatment can be resumed. According to the relevant protocols, EV may be restarted at the same dose when glucose falls to ≤250 mg/dL and the patient is clinically stable. If necessary, the EV dose may be reduced by one level in later cycles, although hyperglycemia can generally be managed without dose modification because it is usually controlled with appropriate medical treatment (diet, oral glucose-lowering drugs, or insulin). Pembro may also be restarted after the interruption when hyperglycemia is attributed to EV and the patient has returned to normal. Nevertheless, if hyperglycemia becomes recurrent or difficult to manage, extending EV dosing intervals, reducing the dose, or, in severe cases, permanently stopping EV may be considered.

Recommendations for Patients and Clinicians: During this combination treatment, patients should watch for symptoms of diabetes . Excessive thirst, frequent urination, unexplained fatigue, dry mouth, or blurred vision should be reported to their doctor immediately. Patients with a history of diabetes or who are overweight should particularly be encouraged to monitor glucose at home. They should receive guidance on diet, avoiding excessive carbohydrates, and measuring glucose at home if they take steroids on treatment days. Healthcare workers should make blood glucose measurement on every treatment day routine and arrange endocrinology support for patients at risk of diabetes. For example, patients with diabetes may initially need adjustments to insulin doses or oral medication. Patients should also be informed about signs of ketoacidosis (vomiting, abdominal pain, an acetone smell on the breath, or rapid breathing) and told to attend the emergency department if these occur. To detect immune-mediated diabetes early, the care team may consider periodically checking C-peptide and diabetes autoantibodies , particularly for unexplained, persistent hyperglycemia. In summary, proactive monitoring and patient education usually allow hyperglycemia to be controlled so patients can continue treatment safely.

Pneumonitis (Immune-Mediated Lung Reaction)

Frequency and Clinical Features: Pneumonitismeans inflammation of lung tissue and is a side effect seen most often in cancer patients receiving immunotherapy. Low rates of pneumonitis are reported with both EV and Pembro monotherapy (around ~3%). However, the risk increases when EV + Pembro are given together. Clinical studies recorded pneumonitis of any grade in 10% of patients receiving the combination. Approximately 4% of these cases were serious (Grade 3 or higher) and required intensive treatment, while pneumonitis caused death in 0.4% (2 of 564 patients). During combination treatment, pneumonitis generally may develop over months; the median onset was reported at ~4 months (with a wide range of 0.3 to 26 months). Thus, it can occur within the first few months in some patients and even after a year in others. Its symptoms can easily be confused with other lung conditions: Dry cough, shortness of breath, weakness, and sometimes a mild fever may suggest pneumonitis. Chest X-rays or CT scans may show new infiltrates (white patches). However, distinguishing it from infectious pneumonia can be difficult; not every episode of shortness of breath is pneumonitis, so careful assessment is required.

Mechanism: With pembrolizumab, pneumonitis is a classic immune-mediated side effect. Immune cells perceive lung tissue as "foreign" and attack it, causing inflammation between the alveoli. It is therefore also called "immune-related pneumonitis." EV's association with pneumonitis has been tentatively explained by mechanisms such as lung injury caused by its MMAE payload or inflammation triggered by EV-related material released from tumor cells. Cases of interstitial lung disease/pneumonitis in EV monotherapy trials indicate that EV also carries some risk of lung toxicity. During combination treatment, these risks may be cumulative or synergistic ; both immune mechanisms and EV's potential toxicity may contribute. The literature particularly notes a higher risk of immune pneumonitis in patients with previous lung radiotherapy. Patients receiving the combination who have more vulnerable lungs (e.g., COPD, a smoking history, or previous radiation) should therefore be monitored especially closely for pneumonitis.

Management and Treatment: When pneumonitis is suspected, early, intensive intervention can be lifesaving. If a patient develops unexplained respiratory distress or a new cough, pneumonitis should be among the first conditions considered. In this situation, both treatments should be temporarily withheld immediately. Regardless of its underlying cause, pneumonitis can progress and rapidly increase the patient's oxygen requirement. After interrupting treatment, the first step should be to start corticosteroid treatment . High-dose corticosteroids (such as prednisone 1-2 mg/kg/day) reduce immune attack on the lungs and suppress inflammation. At this point, to establish whether the pneumonitis is truly drug-related, infection must be ruled out. Sputum cultures and, if necessary, samples obtained through bronchoscopy can undergo microbiological testing; chest CT may reveal a typical immune-pneumonitis pattern. However, an important warning is that diagnostic procedures (bronchoscopy, biopsy, etc.) should not delay steroid treatment . If the clinical picture strongly suggests pneumonitis, steroids are started even before infection has been excluded, because delayed treatment of immune pneumonitis can lead to respiratory failure. If an infection is identified, appropriate antibiotics are added or the steroid dose is reconsidered.

The treatment approach depends on pneumonitis grade: Mild pneumonitis (Grade 1) is usually detected incidentally on imaging without prominent symptoms; close observation and low-dose steroids when needed may be sufficient. Moderate pneumonitis (Grade 2) causes cough and exertional breathlessness but no oxygen requirement. In this situation, pembrolizumab must be withheld (temporarily stopped) and the patient should receive oral corticosteroid treatment. EV is also interrupted, although the decision to withhold it may be more flexible than for Pembro: if EV is thought to cause pneumonitis through a non-immune mechanism, continuing low-dose EV may sometimes be possible. In practice, both drugs are generally withheld. As symptoms improve on moderate-dose steroids (e.g., over several weeks), the steroid dose is gradually tapered. Once pneumonitis has resolved completely or substantially (to Grade 0–1), a decision is made about restarting treatment. Based on expert experience, if the responsible drug cannot be identified with certainty, EV is restarted first with close observation for a period. If respiratory distress does not recur after EV is reintroduced, after some time (perhaps several weeks), pembrolizumab may be given again; however, trying the drugs sequentially rather than restarting both simultaneously is safer. This can help identify the responsible drug if pneumonitis recurs.

Severe pneumonitis (Grade 3–4) requires a stricter approach: if the patient is short of breath even at rest or requires oxygen, the pneumonitis is high-grade . In this situation, both EV and Pembro must be permanently discontinued. The patient is hospitalized and treated with high-dose corticosteroids (and, if necessary, additional immunosuppressants such as mycophenolate or IVIG). Non-invasive ventilation or intubation in intensive care may be required. Recovery from such severe cases generally takes weeks. Even after clinical improvement, imaging (CT) abnormalities may take months to resolve completely. Imaging should therefore not be the sole criterion for recovery; ease of breathing should be the primary indicator.

When pneumonitis is suspected or treated, support from a pulmonologist or relevant specialist is strongly recommended. Pulmonologists can use bronchoscopy to exclude other causes such as infection, cancer spread (e.g., lymphangitic carcinomatosis), or radiation injury. In most cases, however, immune-mediated pneumonitis is diagnosed by excluding other causes and finding a compatible clinical/imaging picture in a patient with a history of immunotherapy. Response to treatment also supports the diagnosis: a lung condition that improves rapidly with steroids is generally immune pneumonitis.

Recommendations for Patients and Clinicians: Particularly after the first few cycles, patients should not dismiss new shortness of breath as aging or fatigue, but should report it to their doctor immediately. Respiratory symptoms such as cough, chest pain, and weakness are also important. If fever is present, investigation is essential because pneumonia (infection) is also possible. Healthcare professionals should auscultate the lungs regularly and ask about respiratory symptoms at every visit. A pretreatment chest X-ray may be useful when needed to establish a baseline. Early lung imaging in patients with a persistent cough during treatment can identify developing pneumonitis. Suspected pneumonitis should be assessed jointly by oncology and pulmonology specialists. The protocol for early initiation of high-dose steroids should be familiar to the entire team. Steps for managing these serious immune checkpoint inhibitor side effects (treatment interruptions, supportive care, and additional immunosuppressive drugs when needed) should be planned in advance. The patient should also understand that a treatment interruption in this situation is temporary and that, once the lungs recover, decisions will be based on the risk–benefit balance. This reduces anxiety and encourages patients to report symptoms rather than hide them.

Eye Side Effects

The most common eye side effect during EV + Pembro combination therapy is dry eye syndrome (keratoconjunctivitis sicca) , with dry eye of any grade reported in 24% of patients. This rate is higher in patients treated with EV monotherapy (around 40%). Eye side effects are rarer with pembrolizumab monotherapy and mainly present as immune-mediated ocular inflammation (e.g., uveitis, scleritis, and episcleritis).

Mechanism of Eye Side Effects: With EV, dry eye and keratitishave been associated with the Nectin-4 protein also being present in the ocular epithelium and tear glands . EV can bind to these sites, causing direct cytotoxicity and reduced tear secretion. Disruption of the tear film increases corneal sensitivity and may cause burning, stinging, blurred vision, and light sensitivity .

Pembrolizumab-related eye side effects arise from immune-mediated inflammatory reactions caused by excessive immune activation . In particular, inflammatory eye diseases such as uveitis, scleritis, and optic neuritisare among the serious complications that may occur during immunotherapy.

Management of Eye Side Effects: Management should be tailored to severity. Mild symptoms can generally be controlled with local treatment, whereas serious inflammatory side effects may require immunosuppression.

Practical Recommendations and Preventive Approaches:

• To prevent dry eye and mild discomfort,
  • artificial tear drops should be used regularly.
  • Ambient humidity should be increased, with particular care in air-conditioned or dry environments.
  • Prolonged screen viewing should be avoided, and frequent blinking encouraged.
• Dry Eye and Contact Lenses:
  • EV-related dry eye syndromecan make contact lenses difficult to use.
  • Reduced tear production can make contact lenses stick to the eyes, impair comfort, and cause microscopic damage to the eye surface.
  • This may increase the risk of corneal injury, infection, and keratitis (corneal inflammation).
  • Patients planning to use contact lenses should consult an ophthalmologist first.
  • Patients with dry eye should prefer daily disposable lenses.
  • If dry eye is pronounced, wearing prescription glasses instead of lenses may be safer.
• To reduce corneal injury during EV treatment:
  • Patients who notice a foreign-body sensation in the eye or light sensitivity should report it immediately.
  • Eye examinations should be performed regularly, particularly for patients receiving long-term EV treatment.
• For immune-mediated ocular side effects (such as uveitis or scleritis):
  • If sudden vision loss or severe eye redness is noticed, immediate referral to an ophthalmologist is required.
  • In mild cases, topical corticosteroid dropsmay be used, while severe cases may require systemic corticosteroids and immunosuppressive agents .
  • Pembrolizumab may be temporarily withheld or permanently discontinued, depending on severity.

In conclusion, ophthalmic side effects of the EV + Pembro combination are generally mild and can be controlled with appropriate supportive care. Serious inflammatory side effects can nevertheless occur rarely and may cause vision loss, making early diagnosis and intervention critical. Patients should be educated about eye health and advised to contact their doctor for even the slightest visual change, light sensitivity, or eye pain.

Other Immune-Related and Systemic Side Effects

In addition to the skin, neurological, metabolic, and lung side effects detailed above, the EV + Pembro combination can cause other side effects associated with immune checkpoint inhibitors . Endocrine disorders commonly seen with pembrolizumab monotherapy may also occur with the combination. For example, hypothyroidism (an underactive thyroid)occurs in 10-20% of patients receiving immunotherapy and may cause weakness, weight gain, and cold intolerance. It is generally permanent and is readily managed with levothyroxine replacement. Hyperthyroidism may also occur, followed by hypothyroidism as thyroid function becomes depleted. Adrenal insufficiency (primary adrenalitis) or hypophysitis (inflammation of the pituitary gland, particularly more common with combined immunotherapies) are rarer but serious immune-related hormonal disorders. Therefore, regular thyroid function tests and, when appropriate, cortisol measurement are recommended. Unexplained fatigue, low blood pressure, or electrolyte disturbances should prompt an endocrinology assessment.

Gastrointestinal immune-related side effects should not be overlooked. Although EV itself can cause diarrhea, immune-related colitis may present as a different condition. In cases of colitis with severe, bloody diarrhea, abdominal pain, and fever, Pembro should be stopped and high-dose corticosteroids used to suppress the immune response. In addition, elevated liver enzymes have been common during combination treatment (increased AST/ALT in ~60-75% of patients, usually mild). This is generally asymptomatic and detected through blood tests. Rarely, however, immune hepatitis can develop, posing a risk of jaundice and liver failure. Liver tests should therefore be monitored periodically; ALT or AST exceeding 3-5 times the upper limit of normal requires careful evaluation. Similarly, hematological and kidney side effects of immunotherapy (such as hemolytic anemia and nephritis) may occur during combination treatment, although infrequently.

For all these potential immune side effects, close monitoring and a multidisciplinary approach are important. Patient care may require collaboration between the oncologist and specialists such as endocrinologists, gastroenterologists, and nephrologists. Before treatment, patients should understand that immunotherapy can cause side effects affecting almost any organ, but many can be reversed through early detection and appropriate treatment. This awareness helps both patients and the healthcare team prepare.

Key Points for Preventing Side Effects with EV + Pembro

The following measures should be taken to minimize and manage side effects:

1. Preventing Skin Reactions

   • Regularly use moisturizers and barrier creams .
   • Use sunscreen to protect the skin from irritation.
   • At the first signs of a rash, use topical steroid creams and antihistamines.

2. Reducing Peripheral Neuropathy

   • During treatment, use hand and foot cooling techniques .
   • If numbness or loss of sensation progresses, EV dose reduction or treatment interruption should be considered.

3. Managing Hyperglycemia and Diabetes Risk

   • Blood glucose monitoring before treatment and regular glucose measurements are required.
   • A low-carbohydrate diet and exercise should be recommended.
   • If blood glucose is above 250 mg/dL, the EV dose should be delayed and insulin or oral glucose-lowering treatment given.

4. Reducing the Risk of Pneumonitis (Lung Infection)

   • Symptoms such as cough, shortness of breath, or fever should be reported to the doctor immediately.
   • Early lung imaging should be used to assess the risk.
   • In moderate-to-severe cases, high-dose corticosteroid treatment should be started.

5. Eye Side Effects and Protective Measures

   • Use artificial tear drops to prevent dry eye.
   • If eye pain, light sensitivity, or blurred vision occurs, consult an ophthalmologist.

6. General Monitoring and Proactive Management

   • Recognizing and reporting early signs of side effects is important.
   • Regular blood tests and organ function checks are required.
   • Early intervention for side effects should help make continued treatment possible.

These measures can help EV + Pembro combination therapy continue safely and effectively.