FDA Approves Single Agent KEYTRUDA® for Advanced Endometrial Carcinoma

SUMMARY: The FDA on March 21, 2022 approved KEYTRUDA® (Pembrolizumab) as a single agent, for patients with advanced endometrial carcinoma that is MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting, and who are not candidates for curative surgery or radiation. The FDA also approved VENTANA MMR RxDx Panel (Ventana Medical Systems/Roche Tissue Diagnostics) as a companion diagnostic device to select patients with dMMR in solid tumors that are eligible for treatment with KEYTRUDA® The FDA previously approved the FoundationOne CDx (F1CDx, Foundation Medicine, Inc.) as a companion diagnostic device to select patients with MSI-H in solid tumors that are eligible for treatment with KEYTRUDA®.

The American Cancer Society estimates that approximately 65,950 new cases of uterine cancer will be diagnosed in 2022 and about 12,550 individuals will die of the disease. Endometrial carcinoma is the second most prevalent gynecologic cancer in women worldwide, and its incidence has been increasing. Risk factors include age, factors that influence hormone levels such as obesity and estrogen replacement therapy, family history, diet and exercise, drugs such as Tamoxifen, etc. Patients with advanced or recurrent endometrial cancer are often treated with a combination of Carboplatin and Paclitaxel. Treatment options following failure of first-line therapy for this patient group however are limited, with single agent response rates of 10-15% and 5-year survival rates of approximately 17%.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an increase in CD3-positive, CD8-positive, and Programmed Death-1 (PD-1) expressing Tumor Infiltrating Lymphocytes and Programmed Death Ligand-1 (PD-L1) expressing intraepithelial and peritumoral immune cells, compared with MicroSatellite Stable cancers. This results in an enhanced antitumor immune response.

MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system. Defective MMR can be a sporadic or heritable event and can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma-HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of Tumor Infiltrating Lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with Immune Checkpoint Inhibitors.

MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The FDA in 2017 granted accelerated approval to KEYTRUDA® for patients with advanced MSI-High or dMMR solid tumors, that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors. The FDA in 2021 also approved KEYTRUDA® in combination with the multireceptor Tyrosine Kinase Inhibitor LENVIMA® (Lenvatinib) for patients with advanced endometrial carcinoma, irrespective of tumor MSI status based on the KEYNOTE-146 study.

KEYNOTE-158 is a multicenter, nonrandomized, open-label, multicohort, Phase II trial of KEYTRUDA® evaluating predictive biomarkers, in patients with advanced unresectable and/or metastatic solid tumors, who had progressed on standard of care therapy. The present FDA approval was based on the results from a total of 90 patients with MSI-H/dMMR endometrial cancer, who were enrolled in cohort D (11 patients) and cohort K (79 patients) of KEYNOTE-158 trial. This group of previously treated patients received KEYTRUDA® 200 mg IV once every 3 weeks for 35 cycles. The median patient age was 64 years, 48% had received 2 or more lines of prior therapy, and the majority of patients (68%) had received prior radiation therapy. The median duration of treatment was 8.3 months. The Primary end point was Objective Response Rate (ORR) by independent central radiologic review. Secondary end points included Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), and Safety.

The Objective Response Rate was 48%, and median Duration of Response was not reached after a median follow up of 42.6 months. The median PFS was 13.1 months, and median Overall Survival was Not Reached. No new safety signals were identified and the immune-mediated adverse events or infusion reactions occurred in 28% of patients and 7% were Grades 3-4, with no fatal events.

It was concluded that KEYTRUDA® demonstrated robust and durable antitumor activity with manageable toxicity in patients with advanced MSI-H/dMMR endometrial cancer, and should be considered as a treatment option for patients with advanced MSI-H/dMMR endometrial cancer, following failure on prior therapy.

Pembrolizumab in Patients With Microsatellite Instability–High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. O’Malley DM, Bariani GM, Cassier PA, et al. DOI: 10.1200/JCO.21.01874 Journal of Clinical Oncology 40, no. 7 (March 01, 2022) 752-761. Published online January 06, 2022.

KEYTRUDA® (Pembrolizumab) in combination with LENVIMA® (Lenvatinib)

The FDA on July 21, 2021 approved KEYTRUDA® in combination with LENVIMA® for patients with advanced Endometrial carcinoma that is not MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting, and are not candidates for curative surgery or radiation. KEYTRUDA® is a product of Merck & Co. and LENVIMA® is a product of Eisai Co., Ltd.

KEYTRUDA® (Pembrolizumab) and LENVIMA® (Lenvatinib)

The FDA on September 17, 2019 granted accelerated approval to the combination of KEYTRUDA® and LENVIMA® for the treatment of patients with advanced Endometrial carcinoma that is not MicroSatellite Instability High (MSI-H) or MisMatch Repair deficient (dMMR), and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. KEYTRUDA® is a product of Merck & Co and LENVIMA® is a product of Eisai Inc.

Oral Bisphosphonates May Decrease the Risk of Postmenopausal Endometrial Cancer

SUMMARY: Cancer of the endometrium is the most common cancer of the female reproductive organs in the United States. The American Cancer Society estimates that for 2015, about 54,870 new cases of cancer of the body of the uterus will be diagnosed and 10,170 women will die of the disease. Risk factors include age, factors that influence hormone levels such as obesity and estrogen replacement therapy, family history, diet and exercise, drugs such as Tamoxifen, etc. Bisphosphonates such as DIDRONEL® (Etidronate) have been available in the US since the late 1970’s. Bisphosphonates inhibit bone resorption (loss of bone mass) and are indicated for the treatment of osteoporosis and related diseases. The risk of fractures in postmenopausal women with osteoporosis is significantly reduced with the use of bisphosphonates. Several bisphosphonate derivatives have been developed for the treatment of osteoporosis. Aminobisphosphonates such as AREDIA® (Pamidronate) and ZOMETA® (Zoledronic acid) are an integral part of patient management in oncology practice, when bone metastases are initially diagnosed and may have cytostatic, proapoptotic, and antimetastatic properties. An estimated 14.7 million prescriptions for oral bisphosphonates were dispensed in U.S. retail pharmacies in 2012. Previously published studies have shown an inverse relationship between bisphosphonate use and breast cancer risk. Endometrial cancers which are hormone mediated, share risk factors with breast cancer and women with a history of fractures have a lower risk of endometrial cancers. The association between bisphosphonate use and endometrial cancer has remained unclear except for a few, small retrospective studies, which have shown an inverse relationship. To further explore this observation, the authors conducted a large prospective study which included 89,918 postmenopausal women participating in the Women’s Health Initiative (WHI). Following a health information interview conducted at baseline, the use of bisphosphonate was ascertained at baseline and over the follow up period. All women had an intact uterus at the time of enrollment and the most common type of bisphosphonate used was FOSAMAX® (Alendronate). During the study median follow up of 12.5 years, 1,123 women were diagnosed with incident invasive endometrial cancer. Ever use of bisphosphonates was inversely associated with age-adjusted endometrial cancer risk (HR=0.76; P=0.01). There was no evidence of statistically significant interactions with age at baseline, BMI (Body Mass Index), or hip fracture probability score. In this large prospective cohort of postmenopausal women, the authors concluded that bisphosphonate use was associated with a statistically significant reduction in endometrial cancer risk, in postmenopausal women. Oral Bisphosphonate Use and Risk of Postmenopausal Endometrial Cancer. Newcomb PA, Passarelli MN, Phipps AI, et al. J Clin Oncol 2015; 33: 1186-1190