Impact of Combination Therapy: Evaluating the Influence of Lenvatinib and Pembrolizumab in Relapsed Endometrial Cancer

Summary for Physicians: Interpretation of Findings From Existing and Upcoming Studies and Case Reports in Advanced EC

Dr Birrer to Dr Chan: Response to Lenvatinib and Pembrolizumab Combination Therapy in Pembrolizumab-Pretreated Relapsed EC (K. Mimura et al., Gyn Onc Reports, 2022)

• Study Overview:
  • Dr Chan would begin by discussing the 2022 study by K. Mimura et al., which investigates the combination of lenvatinib and pembrolizumab in patients with relapsed EC who have previously been treated with pembrolizumab monotherapy. These patients were not responsive to the initial pembrolizumab treatment, and the study examines whether combining lenvatinib (an antiangiogenic agent) with pembrolizumab can lead to a clinical benefit for these patients.
• Efficacy of the Combination:
  • Dr Chan would highlight that this study suggests the combination of lenvatinib and pembrolizumab can offer promising clinical responses in pembrolizumab-pretreated relapsed patients. The rationale behind this combination lies in dual targeting: Pembrolizumab restores immune system activity against the tumor, while lenvatinib disrupts the tumor's ability to maintain blood vessels, creating a more favorable environment for immune activity.
  • The study shows that the combination therapy could overcome immune resistance that some patients experience after progressing on single-agent pembrolizumab, making it a potentially effective second-line therapy for this group of patients.
    
• Clinical Implications:
  • Dr Chan would emphasize that this combination therapy is particularly useful in patients with mismatch repair deficiency (dMMR)/ microsatellite instability (MSI)-high (H) tumors, who are more likely to respond to immune-based therapies. The study’s findings could help clinicians personalize treatment plans, offering an effective second-line therapy for patients who do not respond to monotherapy.
  • The results also support the idea that immunotherapy can still be valuable after initial failure when combined with agents that target other aspects of the tumor’s microenvironment, such as angiogenesis.
    
• Safety and Toxicity:
  • Dr Chan would address the safety profile of this combination, which can include both immune-related adverse events (from pembrolizumab) and toxicity related to lenvatinib, such as hypertension and fatigue. Monitoring for these adverse effects is important, especially in the second-line treatment setting.
    
• Future Directions:
  • Dr Chan would discuss the need for further prospective studies to confirm the findings of this case series and determine the optimal patient population for this combination. Larger trials could help clarify the best sequencing of pembrolizumab and lenvatinib, as well as the long-term effects of combining these two agents.

Dr Birrer to Dr Naumann: Evaluation of Efficacy and Adverse Events After Second Immunotherapy Exposure in Endometrial and Cervical Carcinoma (M. Morton et al., Obstetrics & Gynecology, 2023)

• Study Overview:
  • Dr Naumann would introduce the 2023 study by M. Morton et al., which evaluates the efficacy and safety of second immunotherapy exposure in patients with endometrial and cervical carcinoma. This study focuses on patients who have relapsed or progressed after receiving first-line immunotherapy and examines the outcomes when second-line immunotherapy is reintroduced.
    
• Efficacy of Second-Line Immunotherapy:
  • Dr Naumann would highlight that the study demonstrates positive results for certain patients who are rechallenged with second-line immunotherapy after failure of first-line therapy. For some patients, particularly those with dMMR/MSI-H tumors, second-line exposure to immunotherapy shows that they can still derive significant benefit from this treatment. The response rates observed in these patients underscore the importance of biomarker-driven decisions when selecting candidates for second-line immune-oncology (IO) therapy.
    
• Safety and Adverse Events:
  • Dr Naumann would discuss the safety profile of second-line immunotherapy exposure, noting that immune-related adverse events (such as colitis, hepatitis, or pneumonitis) may increase with re-challenging treatment. This study offers crucial insights into the management of these toxicities, especially as patients who may already be immunocompromised following previous treatment cycles.
  • He would emphasize the importance of careful monitoring of patients receiving second-line immunotherapy, as immune-related adverse effects may be more severe or difficult to manage due to prior treatment exposure.
    
• Clinical Implications:
  • Dr Naumann would focus on the clinical implications of these findings, suggesting that second-line immunotherapy could become a valuable option for advanced EC patients who did not respond to initial IO therapy. It offers the potential for continued tumor regression and survival benefit, particularly in patients with dMMR/MSI-H disease.
  • The study also stresses the need for individualized treatment plans, as second-line therapy may not be suitable for all patients, and patient selection should rely on factors such as tumor biology and prior responses to therapy.
    
• Future Directions:
  • Dr Naumann would conclude by noting the need for further randomized clinical trials to confirm the safety and efficacy of second-line immunotherapy in endometrial and cervical cancers. These trials would help determine the optimal sequencing of immunotherapies and explore potential combinations with other therapeutic agents to improve outcomes.

Summary:

Both experts interpret findings from existing and upcoming studies that highlight second-line immunotherapy approaches in advanced EC:

• Dr Chan interprets the 2022 study by K. Mimura et al., which explores the combination of pembrolizumab and lenvatinib in pembrolizumab-pretreated patients. The study shows promising efficacy in overcoming resistance to pembrolizumab monotherapy, particularly in dMMR/MSI-H tumors, and underscores the importance of biomarker-driven treatment. However, careful monitoring for toxicity is required.
• Dr Naumann discusses the 2023 study by M. Morton et al., which evaluates the efficacy of second-line immunotherapy after failure of first-line treatment in endometrial and cervical cancer. The study highlights the potential benefits of rechallenging with immunotherapy in dMMR/MSI-H patients, although there is an increased risk of immune-related adverse events. Further studies are needed to confirm the optimal sequencing and patient selection.

Both discussions highlight the importance of personalized treatment strategies and biomarker-driven approaches to improve outcomes in patients with advanced EC, while also emphasizing the need for ongoing research to refine these therapies and their safe application.