Endometrial cancer is the fourth most common cancer and sixth most common cause of death among women in the United States, with an estimated 67,880 new cases and 13,250 deaths in 2024. Approximately 10-15% of patients present with advanced-stage disease, and 5-year survival among patients with distant metastases is only 17%. While platinum-based chemotherapy combined with immune checkpoint inhibition is the standard first-line therapy, options for recurrent disease remain limited.
Lenvatinib is a multiple kinase inhibitor targeting VEGFR1-3, FGFR, PDGFR-alpha, c-Kit, and RET. In the KEYNOTE-146 study, the combination of lenvatinib and pembrolizumab showed an objective response rate of 39.8% with a median duration of response of 22.9 months. The KEYNOTE-775 trial confirmed that this combination significantly improved progression-free and overall survival compared to single-agent chemotherapy, establishing it as the standard treatment for pMMR recurrent endometrial cancer after platinum-based chemotherapy.
Despite the demonstrated efficacy, limited data exist on the optimal duration of lenvatinib and pembrolizumab treatment in clinical practice. Significant side effects can impact quality of life and lead to high discontinuation rates, creating a need for real-world evidence on long-term treatment outcomes.
The case involves a 49-year-old patient diagnosed with FIGO grade 3, stage IVB endometrioid adenocarcinoma with a BMI of 19 kg/m2. Germline genetic testing revealed no pathogenic variants associated with hereditary cancer syndromes. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy with optimal cytoreduction.
Tumor molecular profiling showed p53 wild-type status, positive estrogen and progesterone receptor expression, proficient mismatch repair (pMMR), microsatellite stability, low tumor mutational burden (4 mutations/megabase), and somatic mutations in ARID1A, CTNNB1, KDM6A, PIK3R1, PTEN, TP53, and U2AF1. Following surgery, the patient completed six cycles of carboplatin and paclitaxel, external beam radiation, vaginal brachytherapy, and radiation to supraclavicular and occipital metastases.
Post-adjuvant PET/CT revealed widespread metastatic disease including hypermetabolic osseous lesions, lymph node metastases, bilateral adrenal masses, pulmonary nodules, hepatic lesions, and subcutaneous scalp lesions. Treatment with lenvatinib 20 mg daily and pembrolizumab 200 mg every 3 weeks was then initiated.
Shortly after treatment initiation, the patient developed lenvatinib-induced hypertension requiring antihypertensive therapy. At two months, colitis developed requiring steroids and lenvatinib dose reduction to 14 mg daily. Hypothyroidism and adrenal insufficiency followed, prompting thyroid hormone replacement and further dose reduction to 10 mg daily.
At 18 months, disease progression in the right adrenal gland led to lenvatinib dose increase to 14 mg and subsequent laparoscopic bilateral adrenalectomy with steroid replacement. Ocular side effects including light sensitivity required steroid ocular injections and a two-month treatment interruption. Further interruptions occurred due to recurrent ocular symptoms, transaminitis with elevated liver enzymes, and left-sided otitis externa with ear canal ulcerations.
Each treatment interruption lasted approximately two months, after which therapy was resumed at reduced doses. The patient also experienced mild weight loss over time, though not severe enough to warrant discontinuation. This careful toxicity management through dose modifications, treatment pauses, and supportive care enabled continued long-term therapy.
At 10 months post-treatment initiation, PET/CT showed complete resolution of previously hypermetabolic lymph nodes, osseous lesions, soft tissue nodules, and left adrenal mass. Residual low-level uptake in osseous lesions was consistent with treated metastases, representing a significant treatment response.
PET/CT imaging performed five years after treatment initiation showed no metabolically active disease. Stable calcified sub-centimeter lymph nodes and scattered sclerotic osseous lesions with mild FDG uptake were noted, consistent with treated disease. The patient continues on lenvatinib and pembrolizumab with minimal and stable residual disease.
This response far exceeds the median outcomes from the KEYNOTE-775 trial, which reported median progression-free survival of 7.2 months and overall survival of 18.3 months. The longest reported duration of response in KEYNOTE-775 was 23.7 months in the pMMR population, making this patient's 5-year response truly exceptional.
The biological mechanisms underlying this exceptional response remain unclear, as the tumor was microsatellite stable with low tumor mutational burden -- characteristics typically associated with lower likelihood of response to immune checkpoint inhibitors. However, the tumor harbored activating mutations in PI3K/AKT/mTOR and Wnt/beta-catenin pathway genes that may explain the synergistic drug effects.
Mutations in PIK3R1 and PTEN dysregulate the PI3K/AKT/mTOR pathway, leading to enhanced cell proliferation and survival through constitutive pathway activation. Lenvatinib's inhibition of VEGFR and RET blocks key upstream signals in this pathway, potentially reducing cell proliferation, angiogenesis, and metastasis in tumors with these specific mutations.
The somatic CTNNB1 mutation may have activated the Wnt/beta-catenin pathway, which induces an immune-excluded tumor microenvironment. Lenvatinib can block beta-catenin-driven immunosuppression through VEGFR and FGFR inhibition, potentially enhancing immune cell infiltration and pembrolizumab-induced T-cell-mediated anti-tumor responses. These molecular insights suggest potential predictive biomarkers for individualized treatment selection.
Balancing disease control with quality of life was a key consideration throughout this patient's treatment course. While she experienced multiple treatment-related adverse effects requiring interventions including ocular injections, surgical procedures, and corticosteroid courses, she maintained treatment and daily activities without requesting permanent discontinuation.
Discontinuation rates due to adverse events were 17.7% in KEYNOTE-146 and 33.0% in KEYNOTE-775, highlighting the ongoing challenge of toxicity management. This patient's continued adherence over several years suggests that perceived treatment benefits outweighed the associated toxicities, though the absence of formal patient-reported outcome measures limits definitive conclusions.
In clinical trials, patients were discontinued at disease progression and surgical resection of metastases was not permitted. In clinical practice, treatment decisions are individualized, as demonstrated by this case where therapy continued post-progression based on maintained disease control, manageable toxicity, and patient preference.
This case demonstrates the potential for long-term disease control with lenvatinib and pembrolizumab in advanced endometrial cancer, even in patients with pMMR tumors and low tumor mutational burden. The over 5-year response with minimal stable residual disease represents an exceptional outcome that far exceeds reported trial medians.
Successful management of treatment-related toxicities through dose modifications, treatment interruptions, and supportive care was crucial to maintaining therapy continuity. Most side effects could be effectively mitigated with appropriate interventions, allowing prolonged treatment without permanent discontinuation.
Further research is needed to determine optimal treatment duration, identify biomarkers that predict exceptional responders, and develop strategies to mitigate long-term side effects. The molecular profile findings regarding PI3K/AKT/mTOR and Wnt/beta-catenin pathway mutations may inform future patient selection for this combination therapy.