What is the recommended treatment for a patient with poorly differentiated metastatic uterine cancer that is triple negative (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor 2 negative), desmin (muscle marker) negative, CD10 (common acute lymphoblastic leukemia antigen) negative, and PD-L1 (programmed death-ligand 1) negative?

Treatment for Poorly Differentiated Metastatic Uterine Cancer (Triple Negative, Desmin Negative, CD-10 Negative, PD-L1 Negative)

For this patient with poorly differentiated metastatic uterine cancer that is PD-L1 negative, the recommended first-line treatment is carboplatin/paclitaxel combination chemotherapy, as immunotherapy is not an option without PD-L1 positivity. 1

First-Line Systemic Therapy

Preferred regimen: Carboplatin/paclitaxel combination 1

• This is the category 1 preferred option for metastatic endometrial cancer with high-risk histologies 1
• The carboplatin/paclitaxel doublet achieves approximately 40% response rate with median overall survival of approximately 13 months 1
• This regimen is better tolerated than the more toxic cisplatin/doxorubicin/paclitaxel triplet, which showed only marginal survival improvement (15 vs 12 months) with significantly increased toxicity 1

Enhanced regimen consideration: Carboplatin/paclitaxel/bevacizumab triplet 1

• A retrospective analysis showed collective median PFS of 20 months with median OS of 56 months 1
• Overall response rate of 82.8% was noted with this triplet combination 1
• A phase II randomized study demonstrated OS improvement from 29.7 to 40 months compared with the doublet regimen 1
• A meta-analysis of 3 studies concluded the triplet combination increased OS and PFS at 12 months with an ORR of 76% 1

Why Immunotherapy Is NOT Recommended

PD-L1 negativity excludes checkpoint inhibitor therapy 1, 2

• Dostarlimab, nivolumab, and avelumab are only recommended for dMMR/MSI-H endometrial tumors that have progressed on prior platinum-containing therapy 1
• Even in triple-negative breast cancer (a different disease but with similar immunotherapy principles), checkpoint inhibitor monotherapy in later lines is not recommended due to low response rates 1
• For PD-L1-negative disease, immunotherapy has not demonstrated benefit and should not be used outside clinical trials 1, 2

Critical Biomarker Testing Required

Before finalizing treatment, the following must be assessed:

• Mismatch repair (MMR) status or microsatellite instability (MSI) testing 1
  • If dMMR/MSI-H is present, this changes the treatment paradigm after first-line platinum failure
  • Dostarlimab showed 43.5% response rate at 16.3 months in dMMR/MSI-H endometrial cancer 1
• NTRK gene fusion testing 1
  • If NTRK fusion-positive, larotrectinib or entrectinib are category 2B options for recurrent/advanced disease 1
• HER2 testing 1
  • If HER2-positive (particularly in uterine serous carcinoma or carcinosarcoma), carboplatin/paclitaxel/trastuzumab is the preferred regimen 1
  • This triplet showed median PFS of 17.9 vs 9.3 months (P=0.013) for stage III/IV disease 1

Second-Line Treatment Options After Progression

If multiagent chemotherapy regimens are contraindicated or after progression:

• Single-agent options include cisplatin, carboplatin, doxorubicin, liposomal doxorubicin, paclitaxel, albumin-bound paclitaxel, topotecan, cabozantinib, and docetaxel (category 2B) 1
• Paclitaxel is the most active single agent in second-line setting with response rates ranging from 4% to 27% 1
• Bevacizumab monotherapy showed 13.5% response rate with OS of 10.5 months in persistent or recurrent endometrial cancer 1

If dMMR/MSI-H status is confirmed:

• Dostarlimab, nivolumab, or avelumab monotherapy becomes an option after prior platinum-containing therapy 1

Treatment Algorithm Summary

1. Confirm histology and complete biomarker panel (MMR/MSI, NTRK, HER2) 1
2. First-line: Carboplatin/paclitaxel ± bevacizumab 1
   • Consider triplet with bevacizumab for enhanced response rates and survival benefit 1
3. Monitor for progression with imaging every 2-3 cycles 1
4. At progression on first-line therapy:
   • If dMMR/MSI-H: Consider dostarlimab, nivolumab, or avelumab 1
   • If dMMR/MSI-H negative: Single-agent chemotherapy (paclitaxel preferred) or bevacizumab 1
5. After failure of 2 chemotherapy regimens: Best supportive care or clinical trial enrollment 1

Common Pitfalls to Avoid

Do not use hormonal therapy in this patient 1

• Hormonal therapy is only for endometrioid histologies with estrogen/progesterone receptor-positive disease 1
• Poorly differentiated tumors are unlikely to respond to hormonal manipulation 1

Do not delay biomarker testing 1

• MMR/MSI status fundamentally changes treatment options after first-line therapy 1
• HER2 status changes the first-line regimen entirely if positive 1

Do not use immunotherapy without appropriate biomarker selection 1, 2

• PD-L1 negativity predicts lack of benefit from checkpoint inhibitors 2
• Immunotherapy outside of dMMR/MSI-H context has not shown benefit in endometrial cancer 1