What are the side effects of pembrolizumab and lenvatinib?

Side Effects of Pembrolizumab and Lenvatinib Combination Therapy

The combination of pembrolizumab and lenvatinib causes significant adverse events in 82.4% of patients, with the most common being hypertension, fatigue, diarrhea, hypothyroidism, and musculoskeletal disorders—requiring dose modifications in approximately 68.8% of patients. 1

Most Common Adverse Events by Frequency

Very Common (≥30% incidence):

• Hypertension (42-61.1%)
• Fatigue (30-59.1%)
• Diarrhea (39-51.9%)
• Hypothyroidism (25-47%)
• Musculoskeletal pain/arthralgia/myalgia
• Decreased appetite (34%)
• Nausea
• Stomatitis 2

Common (20-30% incidence):

• Decreased weight (31%)
• Proteinuria (25%)
• Vomiting
• Rash
• Dysphonia
• Abdominal pain
• Palmar-plantar erythrodysesthesia syndrome
• Hemorrhagic events
• Headache
• Constipation 2

Serious Adverse Events Profile

Grade 3 or higher adverse events occur in 82.4% of patients receiving the combination, compared to 71.8% with sunitinib monotherapy. 1 This high rate necessitates vigilant monitoring and proactive management strategies.

Treatment Discontinuation Rates:

• Lenvatinib discontinuation: 25.6%
• Pembrolizumab discontinuation: 28.7%
• Both drugs discontinued: 13.4%
• Dose reductions required: 68.8% of patients 1

Critical Adverse Events Requiring Immediate Attention

Cardiovascular:

• Hypertension is the most frequent serious adverse event, occurring more commonly with lenvatinib than with pembrolizumab alone
• Monitor blood pressure regularly and initiate antihypertensive therapy promptly
• Grade 3 hypertension is particularly common in full-dose regimens 3

Hepatotoxicity:

• Monitor liver function tests prior to each treatment cycle
• Withhold or discontinue for Grade 3 or 4 hepatotoxicity
• Discontinue permanently for hepatic failure 2

Renal Complications:

• Proteinuria (25% incidence): Monitor urinary protein before treatment and periodically during therapy
• Withhold treatment if 24-hour urinary protein ≥2 grams
• Discontinue for nephrotic syndrome
• Acute kidney injury can occur 2

Hemorrhagic Events:

• Bleeding complications occur in approximately 20% of patients
• Important distinction: Hemorrhage and fistula events show stronger signals with lenvatinib monotherapy, while combination therapy increases tumor-related bleeding complications 4
• Small intestinal hemorrhage risk is specifically elevated with combination therapy 4

Gastrointestinal Toxicity Patterns

The gastrointestinal toxicity profile differs significantly between monotherapy and combination therapy. 5

Lenvatinib Monotherapy Pattern:

• Predisposes to acute bleeding and fistula formation
• Perforation events show strong positive signals
• Median onset: 27 days (earlier than combination)
• Female sex and low-dose medication are protective factors 5

Combination Therapy Pattern:

• Colitis and pancreatitis are unique to combination therapy
• Delayed tumor-related complications more common
• Median onset: 38 days (later than monotherapy)
• Most events occur within the first month regardless of regimen 5

Diarrhea management requires distinguishing between lenvatinib-induced diarrhea versus pembrolizumab-induced immune-related colitis, as treatment approaches differ fundamentally. 6

Immune-Related Adverse Events (Pembrolizumab Component)

Thyroid Dysfunction:

• Hypothyroidism occurs in 25-47% of patients
• Monitor TSH levels monthly
• Consider endocrinology consultation if TSH >10 mIU/L or >5 mIU/L on two separate occasions
• Initiate thyroid replacement therapy as needed 7, 6

Rare but Serious Immune-Related Events:

• Immune-related encephalopathy: Can occur as early as 6 days after initiation
• Presents with confusion, speech difficulty, gait disturbance
• Neuroimaging and CSF findings often unremarkable, making diagnosis challenging
• Requires immediate high-dose corticosteroids and drug discontinuation 8

Dose Modification Strategy

Successful adverse event management requires proactive dose adjustments rather than treatment discontinuation. 9

Stepwise Management Approach:

1. Prevention and Monitoring:

   • Baseline assessments: liver function, renal function, blood pressure, TSH, urinalysis
   • Monthly monitoring during treatment
   • Patient education on self-monitoring for symptoms

2. Early Intervention:

   • Hypertension: Initiate antihypertensives immediately; do not wait for dose modification
   • Diarrhea: Prompt antidiarrheal agents and hydration; distinguish from immune-related colitis
   • Stomatitis: Dental hygiene, avoid irritating foods, maintain hydration 6

3. Dose Interruption Triggers:

   • Grade 3 adverse events (most cases)
   • Proteinuria ≥2 grams/24 hours
   • QT interval >500 ms or ≥60 ms increase from baseline
   • Any Grade 4 adverse event 2

4. Dose Reduction Protocol:

   • Lenvatinib dose reductions are common and necessary (68.8% of patients)
   • Reduce rather than discontinue when possible to maintain therapeutic benefit
   • Lower relative dose intensity (≤70%) correlates with shorter PFS 7

Special Monitoring Requirements

Proteinuria Monitoring Algorithm:

• If dipstick shows 2+ or greater, obtain random urinary protein-to-creatinine ratio
• If ratio elevated, proceed to 24-hour urinary protein collection
• Interrupt lenvatinib if ≥2 grams/24 hours 7

Wound Healing Considerations:

• Withhold lenvatinib at least 1 week before elective surgery
• Do not administer for at least 2 weeks following major surgery
• Resume only after adequate wound healing confirmed 2

Osteonecrosis of the Jaw:

• Consider preventive dentistry prior to treatment initiation
• Avoid invasive dental procedures during treatment, particularly in high-risk patients 2

Critical Clinical Pitfalls to Avoid

1. Do not attribute all diarrhea to lenvatinib—pembrolizumab-induced colitis requires corticosteroids, not just antidiarrheals
2. Do not delay antihypertensive therapy—waiting for dose modification allows cardiovascular complications
3. Do not overlook early neurological symptoms—immune-related encephalopathy can occur within days and requires immediate intervention
4. Do not continue full doses in the face of Grade 3 toxicity—dose reduction maintains efficacy while improving tolerability
5. Intensive monitoring is mandatory during the first month—most gastrointestinal adverse events occur early 5

Gender and Dosing Considerations

Female patients and those receiving lower doses of lenvatinib have reduced risk of gastrointestinal adverse events. 5 Consider starting at reduced doses (18 mg vs 20 mg daily) in patients at higher risk for toxicity, though this must be balanced against potential efficacy reduction.