Rethinking Immunotherapy: A Case for Personalization in Advanced Endometrial Cancer

Featuring Sahana Somasegar, MD, MS

A guest researcher shares a compelling case study that challenges conventional assumptions about immunotherapy in endometrial cancer, revealing how personalized treatment and multidisciplinary care enabled long-term disease control despite significant toxicities.

Please share your name, title, and a brief overview of your professional history. 

My name is Sahana Somasegar, and I am a third-year Gynecologic Oncology fellow at Stanford University. I completed my residency in Obstetrics and Gynecology at the University of Chicago, where I developed a strong interest in treating gynecologic cancers and addressing health care disparities. My research focuses on endometrial cancer outcomes, specifically examining the molecular characteristics of tumors and evaluating the development of clinical trials to address disparities in cancer care. I am passionate about integrating technology and patient education tools to enhance communication between providers and patients, ultimately improving health equity in cancer prevention and treatment.

Please share an overview of your case report concerning the long-term treatment of advanced endometrial cancer with lenvatinib and pembrolizumab. 

Our case report describes a 49-year-old patient with recurrent, advanced endometrial cancer who achieved remarkable long-term disease control with lenvatinib and pembrolizumab, despite experiencing multiple treatment-related toxicities. After progressing following standard treatments, including surgery, chemotherapy, and radiation, she was initiated on lenvatinib and pembrolizumab. Over 5 years, her disease has remained stable with minimal residual lesions, despite experiencing adverse events such as hypertension, colitis, hypothyroidism, adrenal insufficiency, and ocular toxicity. Careful management of these side effects through dose adjustments, treatment interruptions, and supportive care allowed her to continue therapy. This case highlights the potential for prolonged disease control with this combination, even in patients with proficient mismatch repair (pMMR) and low tumor mutational burden.

How does this case study challenge or expand current clinical assumptions about immunotherapy suitability in endometrial cancer?

This case challenges the conventional assumption that immunotherapy, particularly pembrolizumab, is less effective in patients with pMMR and low tumor mutational burden (TMB). While pembrolizumab monotherapy is typically indicated for tumors with high TMB or microsatellite instability, our patient’s tumor was microsatellite stable (MSS) with a low TMB (4 mutations/megabase), characteristics that are usually associated with lower response rates to immunotherapy. However, the sustained response observed in this case suggests that certain molecular alterations, such as activating mutations in the PI3K/AKT/mTOR and Wnt/β-catenin pathways, may create a more favorable tumor microenvironment for immunotherapy when combined with lenvatinib. This highlights the need to consider individualized molecular profiling when assessing the potential benefit of combination therapies in endometrial cancer.

This case also expands our understanding of how long patients can remain on immunotherapy despite experiencing significant treatment-related toxicities. The conventional assumption is that severe adverse effects often necessitate treatment discontinuation, yet in this case, careful dose adjustments and supportive management allowed the patient to continue therapy and maintain disease stability for years. This raises questions about whether our current toxicity management guidelines could be optimized to help more patients stay on effective treatment rather than stopping therapy prematurely due to adverse effects. This case also calls into question the traditional definitions of treatment failure and progression. Many clinical trials and treatment algorithms define progression based on radiologic criteria alone, often leading to treatment discontinuation. However, in this case, despite some radiologic changes, the patient remained clinically stable and continued to benefit from treatment, suggesting that a more nuanced approach to assessing disease status—one that considers both imaging findings and clinical symptoms—may be warranted in certain cases.

What implications does this case study have for clinical practice and clinical pathways related to endometrial cancer?  

This case underscores the importance of maintaining flexibility in treatment plans for patients receiving lenvatinib and pembrolizumab, particularly when managing long-term toxicities. The case demonstrates that with appropriate dose adjustments, proactive management of side effects, and occasional treatment interruptions, patients can continue to derive significant clinical benefit even in the setting of persistent toxicities. This suggests that clinical pathways should allow for individualized dose-modification protocols rather than strictly adhering to fixed-dose regimens, especially when patients show continued response to treatment. The case also highlights the potential for prolonged treatment durations beyond what is typically recommended in clinical guidelines. While most trials define progression and treatment failure based on strict radiologic criteria, this case suggests that clinical stability and symptom control should also be factored into the decision-making process. In select cases where patients remain asymptomatic and have manageable disease, continuing therapy despite minimal radiologic progression may be warranted. 

Additionally, this case emphasizes the need for close multidisciplinary collaboration in the management of advanced endometrial cancer. Managing the adverse effects of lenvatinib and pembrolizumab requires coordination between oncologists, endocrinologists, gastroenterologists, and other subspecialists. As immunotherapy and targeted therapies become more prevalent, clinical pathways should incorporate structured protocols for managing immune-related and anti-angiogenic toxicities, enabling early intervention and reducing the risk of permanent discontinuation. 

Finally, this case highlights the potential for real-world data to inform and refine clinical pathways. While clinical trials provide a framework for initial treatment recommendations, real-world experiences such as this case demonstrate that some patients may benefit from prolonged treatment or modified dosing strategies that extend beyond standard protocols. Incorporating insights from such cases can help refine guidelines and optimize outcomes for a broader range of patients with advanced endometrial cancer.

Where do you think future research on this topic needs to focus? 

Future research should focus on identifying predictive biomarkers that can better stratify which patients with pMMR and low TMB endometrial cancers are likely to benefit from combination therapy with lenvatinib and pembrolizumab. Understanding the role of molecular alterations, such as those in the PI3K/AKT/mTOR and Wnt/β-catenin pathways, in modulating the immune response could help optimize patient selection and refine treatment strategies. Additionally, studies investigating the long-term effects of treatment on quality of life and the management of chronic toxicities are needed. Exploring strategies to mitigate adverse events while maintaining efficacy could improve the overall tolerability and adherence to therapy in this population.

Another critical area of research is the management of chronic treatment-related toxicities. Given the high rates of adverse events associated with lenvatinib and pembrolizumab, studies should evaluate strategies to mitigate toxicities without compromising efficacy. This includes investigating alternative dosing schedules, identifying early biomarkers of toxicity, and exploring the use of prophylactic interventions to minimize adverse effects. Long-term outcomes and quality of life data from real-world patients receiving prolonged immunotherapy and targeted therapies are also needed. Most clinical trials report outcomes over relatively limited durations, but cases like this demonstrate the potential for prolonged survival with continued treatment. Capturing data on quality of life, treatment burden, and long-term toxicity management in real-world settings will provide valuable insights to inform clinical decision-making and optimize patient care.

Is there anything else you’d like to add?  

This case highlights the importance of individualized care in the treatment of advanced endometrial cancer and demonstrates that prolonged disease control is achievable even in cases that may not initially be considered ideal candidates for immunotherapy. As clinical practice evolves, integrating molecular profiling and personalized management strategies will be essential in optimizing outcomes for patients with advanced endometrial cancer. Additionally, continued research on mechanisms of response and resistance to lenvatinib and pembrolizumab will help guide future therapeutic advancements.