In a patient with advanced, recurrent, or metastatic endometrial cancer who has progressed after surgery, radiation, and chemotherapy, what immunotherapy regimen should be selected based on tumor microsatellite instability‑high (MSI‑H)/mismatch repair deficient (dMMR) versus microsatellite stable (MSS)/mismatch repair proficient (pMMR) status, including drug choice, dosing, and required monitoring?

Immunotherapy for Endometrial Cancer

Treatment Selection Based on MMR/MSI Status

For patients with advanced, recurrent, or metastatic endometrial cancer who have progressed after prior therapy, treatment selection must be guided by mismatch repair (MMR) status: patients with dMMR/MSI-H tumors should receive pembrolizumab or dostarlimab monotherapy, while patients with pMMR/MSS tumors should receive pembrolizumab 200 mg IV every 3 weeks plus lenvatinib 20 mg orally daily. 1, 2, 3

Essential Biomarker Testing

• All patients with advanced or recurrent endometrial cancer must undergo MMR immunohistochemistry (IHC) on tumor tissue as the first-line biomarker test to determine dMMR status, as this directly informs treatment selection between monotherapy versus combination approaches 1

• MSI testing and next-generation sequencing can serve as second-line biomarker tests when MMR IHC is unavailable or inconclusive 1

• PD-L1 expression should NOT be used to guide immunotherapy treatment decisions in endometrial cancer, as it has limited predictive value and shows heterogeneous expression regardless of molecular subgroup 1

• When MLH1 loss is detected on IHC, perform MLH1 promoter methylation testing immediately to distinguish sporadic (methylated) from hereditary Lynch syndrome (non-methylated) cases 4

Treatment Regimens for Previously Treated Disease

For dMMR/MSI-H Tumors (Monotherapy Options)

Pembrolizumab monotherapy:

• Dosing: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks 2
• Administer as IV infusion over 30 minutes 2
• Continue until disease progression or unacceptable toxicity 2
• Expected response rate: 46% objective response rate with durable responses 1
• No routine premedication required for pembrolizumab 5

Dostarlimab monotherapy (alternative):

• Expected response rate: 42.3% in dMMR tumors 1
• Provides similar efficacy to pembrolizumab in this biomarker-selected population 6

For pMMR/MSS Tumors (Combination Required)

Pembrolizumab plus lenvatinib combination:

• Pembrolizumab: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks 2, 3
• Lenvatinib: 20 mg orally once daily 3
• Continue until disease progression or unacceptable toxicity 3
• This combination demonstrated superior outcomes compared to chemotherapy: median PFS 6.6 months versus 3.8 months (HR 0.60, p<0.0001) and median OS 17.4 months versus 12 months (HR 0.68, p=0.0001) 1
• Take lenvatinib at the same time each day, with or without food 3
• If a lenvatinib dose is missed and cannot be taken within 12 hours, skip that dose and resume at the usual time 3

Rationale for MMR-Based Treatment Selection

The distinction between dMMR and pMMR tumors is critical because:

• dMMR/MSI-H tumors are hypermutated (median 541 predicted neoantigens) with high tumor mutational burden, making them highly responsive to immune checkpoint inhibitor monotherapy 1

• pMMR/MSS tumors have low mutational burden (median 70.5 predicted neoantigens) and show underwhelming efficacy with single-agent immune checkpoint inhibitors, requiring combination with anti-angiogenic therapy to enhance response 1, 7

• MMR status is the preferred biomarker over tumor mutational burden (TMB) for treatment selection, despite exploratory data showing TMB-H tumors respond better regardless of MSI status 1

Required Monitoring and Toxicity Management

Expected Toxicity Profile

For pembrolizumab plus lenvatinib combination:

• Grade ≥3 adverse events occur in approximately 63-70% of patients 5
• Most common toxicities: hypertension, fatigue, diarrhea, decreased appetite, nausea, hypothyroidism 3
• Immune-related adverse events: hypothyroidism, rash, and less commonly colitis, hepatitis, pneumonitis, or nephritis 5

For pembrolizumab monotherapy:

• Generally better tolerated than combination therapy 6
• Monitor for immune-related adverse events including thyroid dysfunction, rash, colitis, hepatitis, pneumonitis 5

Monitoring Requirements

• Monitor for immune-related adverse events throughout treatment, including thyroid function, liver enzymes, renal function, and pulmonary symptoms 5

• For lenvatinib: monitor blood pressure regularly (hypertension is common), assess for proteinuria, monitor thyroid function, and evaluate for cardiac dysfunction 3

• Dose modifications for lenvatinib are frequently required: withhold for Grade 3 hypertension persisting despite optimal antihypertensive therapy, resume at reduced dose when controlled to ≤Grade 2 3

Critical Clinical Pitfalls to Avoid

• Do not use single-agent pembrolizumab in pMMR/MSS tumors—these patients require combination therapy with lenvatinib for meaningful clinical benefit 1, 7

• Do not skip MMR testing—approximately 40% of patients with advanced recurrent endometrial cancer historically did not receive MMR/MSI screening, missing opportunities for appropriate immunotherapy selection 1

• Do not rely on PD-L1 expression to select patients, as it has proven unreliable across all molecular subtypes of endometrial cancer 1

• When MLH1 loss is detected, do not skip MLH1 methylation testing—this distinguishes sporadic from hereditary Lynch syndrome cases and prevents unnecessary germline testing 4

• Ensure adequate antiemetic coverage beyond standard premedications when using combination therapy, as significant nausea is expected; consider 5-HT3 antagonists and NK1 receptor antagonists 5

Emerging Context: First-Line Treatment

While not FDA-approved at the time of the 2023 SITC guideline publication, two phase III trials demonstrated positive results combining immune checkpoint inhibitors with carboplatin and paclitaxel chemotherapy in previously untreated stage III/IV or first recurrent endometrial cancer 1. These combinations showed particular benefit in dMMR tumors for progression-free survival 8. However, for patients who have already progressed after surgery, radiation, and chemotherapy (as specified in the clinical scenario), the FDA-approved regimens described above remain the standard approach.