Uterine cancer is the second most prevalent gynecological cancer in the world and it has high incidence rates in developed countries. Over 90% of cases of uterine cancer are endometrial cancer. For advanced endometrial cancer, the standard of care continues to be surgical excision and chemotherapy. Despite recent advancements in targeted therapies and immunotherapies, there is still an unmet need for effective therapies that can improve survival outcomes in patients with metastatic and recurrent endometrial cancer .
Current perspective on endometrial cancer
At the time of diagnosis, 10-15% of endometrial cancer patients had advanced disease, and 20% of those with distant metastases had a relative 5-year survival rate. For advanced endometrial cancer, chemotherapy using carboplatin and paclitaxel or doxorubicin and cisplatin is advised as the gold standard of care. Pembrolizumab, an immune checkpoint inhibitor (ICI), can be used to treat advanced malignancies with high microsatellite instability (MSI) in patients with platinum-resistant tumors.
However, late-line treatments include either hormone therapy or chemotherapy with paclitaxel or doxorubicin when platinum-based chemotherapy and ICIs fail. However, at present, there is no universally accepted standard of care for the treatment of patients with advanced disease The limited number of effective treatment choices for advanced or recurrent diseases encourages the reuse of earlier treatments like a combination of pembrolizumab and lenvatinib .
Does lenvatinib in combination with pembrolizumab show promising outcomes?
Lenvatinib is an oral multi-kinase inhibitor that primarily inhibits the receptors for vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor receptor-α, and other receptor tyrosine kinases. However, pembrolizumab is an antibody that targets programmed cell death protein 1 (PD-1). PD-1 is essential for suppressing immunological responses and encouraging self-tolerance by regulating T-cell activity.
Thus, it may be effective to co-inhibit vascular endothelial growth factor and PD-1 signaling, as in the case of pembrolizumab, an immune checkpoint inhibitor, and lenvatinib, which inhibits angiogenesis and vascular endothelial growth factor-mediated immune suppression together. Recently it has been reported that combination therapies of lenvatinib with ICIs for different malignancies have shown encouraging outcomes .
Various clinical trials have examined the efficacy and safety of the combination of lenvatinib and pembrolizumab in patients with endometrial cancer. The outcomes of these trials are discussed below.
In a single-arm phase Ib/II KEYNOTE-146/ Study 111 (ClinicalTrials.gov identifier: NCT02501096) a combination of lenvatinib plus pembrolizumab was investigated in patients with certain solid tumors including endometrial carcinoma. This study demonstrated the encouraging antitumor activity of lenvatinib plus pembrolizumab in advanced endometrial carcinoma patients who had disease progression following prior systemic therapy. The toxicity profile of this combination therapy was also manageable .
In a confirmatory phase III Study 309/ KEYNOTE-775 (ClinicalTrials.gov identifier: NCT03517449) a combination of lenvatinib plus pembrolizumab demonstrated significant improvements in progression-free and overall survival than chemotherapy in pre-treated patients with advanced endometrial cancer .
Safety profile of a combination of lenvatinib and pembrolizumab
Kinase inhibitors (such as lenvatinib) and/or immunotherapies are frequently associated with adverse events such as hypertension, immunological responses, rashes, nausea, diarrhea, exhaustion, and musculoskeletal discomfort. As a result, the quality of life may suffer as a result of the therapy with these drugs. Kinase inhibitors and immunotherapies are used more often to treat endometrial cancer. Thus, it is critical to address the long-term impact of these therapies on patients’ health-related quality of life.
According to health-related quality of life outcomes from Study 309/KEYNOTE-775, lenvatinib plus pembrolizumab has a generally better benefit/risk profile than the physician's treatment of choice for the treatment of patients with advanced endometrial cancer. Lenvatinib plus pembrolizumab is therefore a new standard of care for people with advanced or recurrent endometrial cancer after receiving prior systemic therapy. It can also be thought of as the first choice for people with advanced endometrial cancer .
A combination of lenvatinib and pembrolizumab considerably improved survival rates and demonstrated tolerable safety in pre-treated patients with advanced endometrial cancer. But, the underlying mechanism of action is still unknown. Additional research on the efficacy and safety of this combination therapy may shed light on the effectiveness of cancer immunotherapy in uterine cancer.
1. Mimura, K. et al. 'Response to lenvatinib and pembrolizumab combination therapy in pembrolizumab-pretreated relapsed endometrial cancer'. Gynecol Oncol Rep. (2022) 44, 101084. DOI: 10.1016/j.gore.2022.101084.
2. Makker, V. et al. 'Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer'. J Clin Oncol. (2020) 38(26), 2981–2992. DOI: 10.1200/JCO.19.02627.
3. Makker, V. et al. 'Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer'. N Engl J Med. (2022) 386(5), 437–448. DOI: 10.1056/NEJMoa2108330.
4. Lorusso, D. et al. 'Health-Related Quality of Life in Patients With Advanced Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab or Treatment of Physician’s Choice'. Eur J Cancer. (2023) 186, 172–184. DOI: 10.1016/j.ejca.2023.03.015.