FDA Approves Keytruda (pembrolizumab) Plus Lenvima (lenvatinib) Combination Therapy for Advanced Endometrial Carcinoma, Demonstrating Significant Survival Benefit

Endometrial cancer (Image source: womenworking.com)

July 22, 2021 /BioValleyBIOON/ --Merck & Co. and its partner Eisai recently jointly announced that the U.S. Food and Drug Administration (FDA) Approved anti-PD-1 therapyKeytruda (Keruida, generic name: pembrolizumab, pembrolizumab)with oral multi-receptor tyrosine kinase inhibitorLenvima (Lenvima, generic name: lenvatinib, lenvatinib)Combination regimen, for the treatment of patients with disease progression following prior systemic therapy in any setting, who are not candidates for curative surgery or radiation therapy,Confirmed by testing to be negative for microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR)patients with advanced endometrial cancer (EC). Here, "not MSI-H or not dMMR"Also known as "non-microsatellite instability-high (non-MSI-H) or proficient mismatch repair (pMMR)".

This approval was based on data from the pivotal Phase 3 KEYNOTE-775/Study 309 trial (NCT03517449). The trial evaluated the efficacy and safety of the Keytruda plus Lenvima regimen in patients with advanced, metastatic, or recurrent endometrial cancer whose disease had progressed following platinum-based chemotherapy. Results showed that, compared with chemotherapy (investigator's choice: doxorubicin or paclitaxel),The Keytruda + Lenvima regimen demonstrated statistically significant and clinically meaningful improvements in the primary endpoints of overall survival (OS) and progression-free survival (PFS), as well as in the secondary endpoint of objective response rate (ORR).

In the population with approved indications (non-MSI-H or non-dMMR), specifically, the data show that compared with chemotherapy, the Keytruda + Lenvima regimen: (1) significantly improved overall survival (OS), and will32% reduction in risk of death(HR=0.68 [95% CI: 0.56-0.84]; p=0.0001); (2) significantly improved progression-free survival (PFS), will40% reduction in the risk of disease progression or death（HR=0.60[95%CI:0.56-0.72]；p＜0.0001）；（3）Significantly improved the objective response rate (ORR: 30% vs 15%), the Keytruda + Lenvima group had a complete response (CR) rate of 5% and a partial response (PR) rate of 25%, while the chemotherapy group had a CR rate of 3% and a PR rate of 13%. In this study, the safety profile of the Keytruda + Lenvima combination therapy was generally consistent with previously reported studies.

The Phase 3 KEYNOTE-775/Study 309 trial is a confirmatory trial of the Phase II KEYNOTE-146/Study 111 trial (NCT02501096). Based on data from the latter Phase II trial, in September 2019, the United StatesFDAAccelerated approval of the Keytruda + Lenvima combination regimen for the treatment of patients with advanced endometrial carcinoma that is non-MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation therapy. This accelerated approval is based onTumorResponse rate and duration of response data. Under the accelerated approval provisions, continued approval for this indication is contingent upon verificationClinical TrialVerification and description of clinical benefits.Data from the Phase 3 KEYNOTE-775/Study 309 trial confirmed the clinical benefit required for this accelerated approval.

Endometrial cancer (EC) is the most common type of uterine corpus cancer, with over 90% of uterine corpus cancers originating in the endometrium. It is estimated that in 2020, there were over 417,000 newly diagnosed cases of uterine corpus cancer worldwide, with more than 97,000 deaths. In the United States, it is estimated that there will be over 66,000 new cases and nearly 13,000 deaths in 2021. The disease-specific survival rate for endometrial cancer varies byDiagnosis...varies depending on the stage at diagnosis, the 5-year survival rate for metastatic endometrial cancer (Stage IV) is only 17%, indicating a very poor prognosis.

Dr. Vicky Makker, a medical oncologist at Memorial Sloan Kettering Cancer Center and principal investigator of the KEYNOTE-775/Study 309 trial, stated: “The prognosis for patients with advanced endometrial cancer who are not candidates for curative therapy is poor, particularly for those whose disease has progressed after prior systemic therapy, with very limited treatment options. This approval is to help these patients fight this refractoryTumoran important step in this regard. The Keytruda plus Lenvima regimen will provide a treatment option that can significantly improve survival outcomes.”

KEYNOTE-775/Study 309 is a multicenter, randomized, open-label Phase 3 trial evaluating the efficacy and safety of combination therapy with Keytruda and Lenvima in patients with advanced endometrial cancer who have received at least one prior platinum-based regimen. The study enrolled 827 patients, of whom 697 had non-microsatellite instability-high (non-MSI-H) or proficient mismatch repair (pMMR) tumors, and 130 patientsTumorHigh microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). In the study, patients were randomized in a 1:1 ratio to receive either: (1) Keytruda (200 mg via intravenous [IV] infusion every 3 weeks) for 35 cycles (approximately 2 years) in combination with Lenvima (20 mg orally once daily); or (2) chemotherapy (treatment of physician's choice [TPC]: doxorubicin [60 mg/m² IV] every 3 weeks up to a cumulative dose of 500 mg/m²; or paclitaxel [80 mg/m² IV] on a 28-day cycle [paclitaxel administered once weekly for 3 weeks followed by 1 week off]).

The results showed:The study met the dual primary endpoints of overall survival (OS) and progression-free survival (PFS), and the secondary efficacy endpoint of objective response rate (ORR).. These positive results were observed in both the non-MSI-H/pMMR subgroup and the intention-to-treat (ITT) study population. The ITT population included patients with advanced endometrial cancer who were non-MSI-H/pMMR or MSI-H/dMMR. The median follow-up time for both the ITT population and the pMMR subgroup was 11.4 months. In this study, the safety profile of Keytruda + Lenvima was generally consistent with the known safety profiles of each individual drug.

ITT Population Study Results:(1) Significant improvement in OS: Compared with the chemotherapy arm, the Keytruda + Lenvima arm demonstrated a 38% reduction in the risk of death (HR=0.62 [95% CI: 0.51-0.75]; p<0.0001) and significantly prolonged OS (median: 18.3 months vs. 11.4 months). (2) Significant improvement in PFS: Compared with the chemotherapy arm (n=416), the Keytruda + Lenvima arm (n=411) demonstrated a 44% reduction in the risk of disease progression or death (HR=0.56 [95% CI: 0.47-0.66]; p<0.0001) and significantly prolonged PFS (median: 7.2 months vs. 3.8 months). (3) Significant improvement in ORR: The ORR in the Keytruda + Lenvima arm was 31.9% (95% CI: 27.4-36.6), with a complete response (CR) rate of 6.6% and a partial response (PR) rate of 25.3%; the chemotherapy arm had an ORR of 14.7% (95% CI: 11.4-18.4), a CR rate of 2.6%, and a PR rate of 12.0% (difference in ORR: 17.2%, p<0.0001). (4) Among patients who achieved a response, the median duration of response (DOR) was 14.4 months (range: 1.6-23.7) in the Keytruda + Lenvima arm, compared with 5.7 months (range: 0.0-24.2) in the chemotherapy arm. (5)

non-MSI-H/pMMR Subgroup Results:(1) OS was significantly improved; compared with the chemotherapy group, the Keytruda + Lenvima group demonstrated a 32% reduction in the risk of death (HR=0.68 [95% CI: 0.56–0.84]; p=0.0001) and significantly prolonged OS (median: 17.4 months vs. 12.0 months). (2) PFS was significantly improved; compared with the chemotherapy group, the Keytruda + Lenvima group demonstrated a 40% reduction in the risk of disease progression or death (HR=0.60 [95% CI: 0.50–0.72]; p<0.0001) and significantly prolonged PFS (median: 6.6 months vs. 3.8 months). (3) ORR was significantly improved; the ORR in the Keytruda + Lenvima group was 30.3% (95% CI: 25.5–35.5), with a CR rate of 5.2% and a PR rate of 25.1%; in the chemotherapy group, the ORR was 15.1% (95% CI: 11.5–19.3), with a CR rate of 2.6% and a PR rate of 12.5% (difference in ORR: 15.2%; p<0.0001). (4) Among patients who achieved a response, the median duration of response (DOR) was 9.2 months (range: 1.6–23.7) in the Keytruda + Lenvima group, compared with 5.7 months (range: 0.0–24.2) in the chemotherapy group.

KEYNOTE-775 Clinical Study Subgroup Results (non-MSI-H/dMMR Endometrial Cancer)

The Keytruda+Lenvima combination therapy is part of a strategic oncology collaboration between MSD and Eisai. In March 2018, the two parties signed a collaboration agreement worth up to $5.8 billion to develop Lenvima as a monotherapy and in combination with Keytruda for various types ofTumortreatment.

Keytruda is an anti-PD-1 cancer immunotherapy that helps detect and fight tumor cells by enhancing the ability of the human immune system. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, thereby activating that may affectTumorT lymphocytes of cells and healthy cells.

Lenvima is an oral multi-receptor tyrosine kinase (RTK) inhibitor with a novel binding mode, in addition to inhibiting receptors involved in tumor angiogenesis, tumor progression, andTumorIn addition to other receptor tyrosine kinases (RTKs) associated with immunomodulation and pro-angiogenic and oncogenic signaling pathways (including platelet-derived growth factor (PDGF) receptor PDGFRα, KIT, and RET), it can also selectively inhibit the kinase activity of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3, FGFR4).

Currently, MSD and Eisai are, through the LEAP (Lenvatinib and Pembrolizumab) clinical development program, in 14 different tumor types (endometrial cancer, hepatocellular carcinoma,Melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, urothelial carcinoma, cholangiocarcinoma, colorectal cancer, gastric cancer, glioblastoma, ovarian cancer, pancreatic cancer, and triple-negativeBreast Cancer) of more than 20 itemsClinical Trialcontinue to study the Keytruda + Lenvima combination. Data from this project indicate that the Keytruda + Lenvima combination has been in various typesTumordemonstrated robust efficacy! (Bioon.com)

Original source:FDA Approves KEYTRUDA® (pembrolizumab) Plus LENVIMA® (lenvatinib) Combination for Patients With Certain Types of Advanced Endometrial Carcinoma