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Keytruda+Lenvima: “Immune + Targeted” treatment of uterine body cancer!

Keytruda+Lenvima: “Immune + Targeted” treatment of uterine body cancer! The Merck/Eisai Keytruda+Lenvima program submits an application in Japan: Significantly extend the patient survival!

Keytruda+Lenvima: "Immune + Targeted" treatment of uterine body cancer!

2 Eisai and its partner Merck & Co have recently announced that they have submitted an application in Japan for the oral multi-receptor tyrosine kinase inhibitor Lenvima (Leweima, generic name: lenvatinib, Lenvatinib Vatinib) combined with anti-PD-1 therapy Keytruda (generic name: pembrolizumab, pembrolizumab) for the treatment of patients with advanced uterine body cancer.

Previously, the Lenvim+Keytruda program has been granted Orphan Drug Designation (ODD) for the treatment of uterine body cancer by the Ministry of Health, Labour and Welfare (MHLW) of Japan. Under this system, this application will be subject to priority review.

It is worth mentioning that this is the second application in Japan for the “immune + targeted” combination therapy Keytruda + Lenvima. In March of this year, the two parties submitted their first application in Japan to use the Lenvim+Keytruda program for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

It is estimated that there will be more than 417,000 new cases of uterine body cancer diagnosed worldwide in 2020, and the death toll will be close to 97,000. In Japan, there are more than 17,000 new cases and more than 3,000 deaths in 2020.

Endometrial cancer is the most common type of uterine body cancer. It is believed that more than 90% of uterine body cancers occur in the endometrium. The survival rate of patients is highly dependent on the stage at diagnosis. The 5-year survival rate for metastatic disease is 17%, and the prognosis is very poor.

The application of the Keytruda+Lenvima regimen for the treatment of uterine body cancer is based on the results of the key phase 3 KEYNOTE-775/Study 309 trial (NCT03517449). The study was carried out in patients with advanced endometrial cancer (in Japan, advanced endometrial cancer) who had received at least one platinum-containing regimen.

The results showed that compared with chemotherapy (doctors’ choice of doxorubicin or paclitaxel), the Keytruda+Lenvima regimen has significantly improved overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).

The specific data are: in the entire study population, compared with chemotherapy, the Keytruda+Lenvima program:

(1) Reduced the risk of death by 38% and significantly prolonged the overall survival (median OS: 18.3 months vs. 11.4 months), Regardless of the mismatch repair status;

(2) Reduced the risk of disease progression or death by 44% and significantly extended progression-free survival (median PFS: 7.2 months vs. 3.8 months);

(3) Significantly improved overall remission Rate (ORR: 31.9% vs 13.7%).

Currently, Merck and Eisai are passing the LEAP clinical project, conducting 20 clinical trials in 13 different types of tumors, including the Phase 3 trial LEAP-001, which is the first-line evaluation of patients with advanced endometrial cancer. The data from this project shows that the combination of Keytruda+Lenvima has shown a strong effect in many types of tumors!

Keytruda+Lenvima: "Immune + Targeted" treatment of uterine body cancer!

Endometrial cancer (Image source: womenworking.com)

KEYNOTE-775/Study 309 is a multi-center, randomized, open-label phase 3 trial, carried out in patients with advanced endometrial cancer who have received at least one platinum-containing regimen, and evaluated the efficacy and effectiveness of Keytruda and Lenvima combination therapy safety. The study enrolled 827 patients, of which 697 patients had tumors with high non-MSI-H (non-MSI-H) or normal mismatch repair (pMMR), and 130 patients had tumors with high microsatellite instability ( MSI-H) or mismatch repair defect (dMMR).

In the study, patients were randomly assigned at a 1:1 ratio and received: (1) Keytruda (200 mg once every 3 weeks, intravenous [IV] infusion) for 35 cycles (approximately 2 years), and Lenvima (once a day) 20mg, orally); (2) Chemotherapy (doctor’s option [TPC]: doxorubicin [60mg/m2 IV] once every 3 weeks with a maximum cumulative dose of 500mg/m2; or paclitaxel [80mg/m2 IV] for 28 days /Cycle [Taxol treatment once a week for 3 weeks, stopping for a week]).

The results of the study were announced for the first time at the 52nd American Society of Gynecological Oncology (SGO) Women’s Cancer Annual Meeting in 2021. The data showed that the study reached the dual primary endpoints of overall survival (OS) and progression-free survival (PFS).

And objective response rate (ORR) secondary efficacy endpoint. These positive results were observed in the normal mismatch repair (pMMR) subgroup and the intention-to-treat (ITT) study population.

The ITT population includes pMMR and dMMR patients with advanced endometrial cancer. The median follow-up time for both the ITT population and the pMMR subgroup was 11.4 months.

——In the ITT population, PFS has a statistically significant and clinically significant improvement. Compared with the chemotherapy group (n=416), the Keytruda+Lenvima group (n=411) reduced the risk of disease progression or death by 44% (HR=0.56) [95%CI: 0.47-0.66]; p<0.0001), PFS was significantly prolonged (median: 7.2 months vs 3.8 months). In addition, the OS of the ITT population also had a statistically significant and clinically significant improvement.

Compared with the chemotherapy group, the risk of death in the Keytruda+Lenvima group was reduced by 38% (HR=0.62[95%CI:0.51-0.75]; p<0.0001), OS was significantly prolonged (median: 18.3 months vs 11.4 months). The safety of Keytruda+Lenvima is basically the same as the known safety of each drug.

In the ITT population, the ORR of the Keytruda+Lenvima treatment group was 31.9% (95%CI: 27.4-36.6), the complete response rate (CR) was 6.6%, and the partial response rate (PR) was 25.3%; the ORR of the chemotherapy group was 14.7% (95%CI: 11.4-18.4), CR rate was 2.6%, PR rate was 12.0% (ORR difference: 17.2%, p<0.0001).

For patients in remission, the median duration of remission (DOR) in the Keytruda+Lenvima group was 14.4 months (range: 1.6-23.7), while that in the chemotherapy group was 5.7 months (range: 0.0-24.2).

-The results of the pMMR subgroup are similar to those of the ITT population. In the pMMR subgroup, compared with the chemotherapy group, the risk of disease progression or death in the Keytruda+Lenvima group was reduced by 40% (HR=0.60[95%CI:0.50-0.72]; p<0.0001), and PFS was significantly prolonged (median : 6.6 months vs 3.8 months).

Compared with the chemotherapy group, the risk of death in the Keytruda+Lenvima group was reduced by 32% (HR=0.68[95%CI:0.56-0.84]; p=0.0001) and OS was significantly prolonged (median: 17.4 months vs 12.0 months) .

In the pMMR subgroup, the ORR of the Keytruda+Lenvima treatment group was 30.3% (95%CI: 25.5-35.5), the CR rate was 5.2%, and the PR rate was 25.1%; the ORR of the chemotherapy group was 15.1% (95%CI: 11.5- 19.3), CR rate was 2.6%, PR rate was 12.5% (ORR difference: 15.2%; p<0.0001). For patients in remission, the median duration of remission (DOR) in the Keytruda+Lenvima group was 9.2 months (range: 1.6-23.7), while that in the chemotherapy group was 5.7 months (range: 0.0-24.2).

In this study, the safety of the Keytruda+Lenvima combination is consistent with previously reported studies. Merck and Eisai will discuss these data with regulatory agencies around the world and plan to submit listing applications based on these data.

Lenvima+Keytruda combination therapy is part of the strategic cooperation between Merck and Eisai Oncology. In March 2018, the two parties signed a cooperation agreement totaling US$5.8 billion to develop a single drug of Lenvima and a combination with Keytruda for the treatment of multiple types of tumors.

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

Keytruda is an anti-PD-1 tumor immunotherapy that helps detect and fight tumor cells by improving 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 T lymphocytes that may affect tumor cells and healthy cells.

Currently, Merck and Eisai are conducting the LEAP (LEnvatinib and Pembrolizumab) clinical development project in 13 different types of tumors (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 and triple-negative breast cancer) continue to study the Keytruda+Lenvima combination in 20 clinical trials.

The data from this project shows that the combination of Keytruda+Lenvima has shown a strong effect in many types of tumors!

(source:internet, reference only)

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