What is the recommended first‑line systemic therapy, dosing schedule, monitoring, toxicity management, and alternative options for an adult patient with metastatic or unresectable endometrial carcinoma who has progressed after or is unsuitable for conventional chemotherapy, regarding lenvatinib (Lenvima) plus pembrolizumab (Keytruda)?

Lenvatinib Plus Pembrolizumab for Metastatic Endometrial Carcinoma

Recommended Regimen and Patient Selection

For patients with advanced or metastatic endometrial carcinoma that is pMMR/MSS (not MSI-H or dMMR) who have progressed after prior platinum-based chemotherapy, pembrolizumab 200 mg IV every 3 weeks (or 400 mg every 6 weeks) combined with lenvatinib 20 mg orally once daily is the standard second-line treatment, demonstrating superior survival outcomes compared to chemotherapy. 1, 2

Critical Patient Selection Criteria

• MMR/MSI testing is mandatory before initiating therapy to determine appropriate treatment strategy 3
• This combination is specifically indicated for pMMR/MSS tumors that have progressed after platinum-containing therapy in any setting 1, 2
• For dMMR/MSI-H tumors, single-agent pembrolizumab or dostarlimab monotherapy is preferred over combination therapy 1, 3
• Patients must not be candidates for curative surgery or radiation 1

Common pitfall: Approximately 40% of patients with advanced endometrial cancer historically did not undergo MMR/MSI testing, resulting in missed opportunities for appropriate therapy selection 3. Do not rely on PD-L1 expression for treatment decisions, as it has limited predictive value 1, 3.

Dosing Schedule

Standard Dosing

• Pembrolizumab: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks 2
• Lenvatinib: 20 mg orally once daily, taken continuously 2, 4
• Duration: Continue until disease progression, unacceptable toxicity, or up to 24 months for pembrolizumab 2

Efficacy Data

The KEYNOTE-775 phase III trial demonstrated compelling survival benefits in previously treated pMMR/MSS endometrial cancer 1:

• Median PFS: 6.6 months vs 3.8 months with chemotherapy (HR 0.60,95% CI 0.50-0.72, p<0.0001) 1
• Median OS: 17.4 months vs 12 months with chemotherapy (HR 0.68,95% CI 0.56-0.84, p=0.0001) 1
• Objective response rate: 31.9% vs 14.7% with chemotherapy 1

In the phase Ib/II KEYNOTE-146 study, the ORR was 38% at week 24, with median PFS of 7.4 months and median OS of 16.7 months 1, 4. Responses occurred regardless of MSI status, PD-L1 status, or histology 1.

Toxicity Profile and Monitoring

Expected Adverse Events

Grade ≥3 adverse events occur in 63-70% of patients, with the most common being 3, 5:

• Hypertension (most frequent grade ≥3 toxicity)
• Fatigue
• Diarrhea
• Decreased appetite/weight loss
• Nausea

Hypothyroidism occurs in 51% of patients, primarily grade 2 severity (46%), representing a unique toxicity signal for this combination 5.

Monitoring Requirements

All selected adverse reactions have median time to onset within the first 10 weeks of treatment 5, requiring:

• Baseline and ongoing monitoring for:

  • Blood pressure (before each dose and weekly for first 8 weeks)
  • Thyroid function tests (baseline, then every 4-6 weeks)
  • Liver enzymes (ALT, AST, bilirubin)
  • Renal function (creatinine, proteinuria)
  • Complete blood count
  • Pulmonary symptoms assessment 3, 5

• Immune-related adverse events surveillance including:

  • Pneumonitis (withhold for grade 2, permanently discontinue for grade 3-4) 2
  • Colitis (withhold for grade 2-3, permanently discontinue for grade 4) 2
  • Hepatitis (withhold if AST/ALT >3-8× ULN or bilirubin >1.5-3× ULN) 2
  • Nephritis, endocrinopathies, dermatologic conditions 2

Toxicity Management Strategy

Dose modifications are common and expected: 65% of patients require dose reductions and 72% require dose interruptions 1.

Management approach 5:

• No dose reduction for pembrolizumab is recommended 2
• Lenvatinib dose reductions follow a stepwise approach: 20 mg → 14 mg → 10 mg → 8 mg daily
• Supportive medications are essential:
  • Antihypertensives (ACE inhibitors or ARBs preferred)
  • Antiemetics (5-HT₃ antagonists ± NK1 receptor antagonists for nausea prophylaxis) 3
  • Antidiarrheals
  • Thyroid hormone replacement as needed
  • Topical therapies for palmar-plantar erythrodysesthesia

For immune-related adverse events: Withhold pembrolizumab for severe (grade 3) reactions; permanently discontinue for life-threatening (grade 4) reactions or inability to taper corticosteroids to ≤10 mg prednisone equivalent daily within 12 weeks 2.

Alternative Treatment Options

For pMMR/MSS Tumors After Progression

If pembrolizumab-lenvatinib is not tolerated or contraindicated:

• Single-agent chemotherapy (doxorubicin or paclitaxel) 1
• Hormonal therapy with letrozole plus palbociclib for ER-positive endometrioid histology (median PFS 8.3 months) 1

For dMMR/MSI-H Tumors

Single-agent immunotherapy is preferred over combination therapy 1, 3:

• Pembrolizumab monotherapy: ORR 46% 1
• Dostarlimab monotherapy: ORR 42.3% 1, 6

Both agents demonstrate durable responses with median duration of response not reached in dMMR tumors 1.

Critical Clinical Pitfalls

1. Do not use single-agent pembrolizumab in pMMR/MSS disease—combination with lenvatinib is required for meaningful benefit 3

2. Do not use PD-L1 expression to select patients, as it is unreliable across molecular subtypes 1, 3

3. Anticipate early toxicity: Most adverse reactions manifest within 10 weeks, requiring proactive monitoring and early intervention 5

4. Manage hypertension aggressively: This is the most common grade ≥3 toxicity and requires weekly monitoring during the first 8 weeks 5

5. Provide adequate antiemetic prophylaxis from treatment initiation, as significant nausea is common 3

6. Monitor thyroid function regularly: Hypothyroidism occurs in over half of patients and is primarily a combination-specific toxicity 5