Merck & Eisai's Keytruda + Lenvima Achieves Success in Pivotal Phase 3 Trial for Advanced Endometrial Cancer with Targeted and Immunotherapy Combination

December 17, 2020 /BioValleyBIOON/ -- Merck & Co. and its partner Eisai recently announced that the pivotal Phase 3 KEYNOTE-775/Study 309 trial (NCT03517449), evaluating the anti-PD-1 therapy Keytruda® (pembrolizumab) in combination with the oral multi-receptor tyrosine kinase inhibitor Lenvima® (lenvatinib) for the treatment of patients with advanced endometrial cancer, yielded positive results. The data showed thatCompared with chemotherapy, the Keytruda + Lenvima combination significantly prolonged overall survival (OS) and progression-free survival (PFS), and significantly improved the overall response rate (ORR).

Currently, MSD and Eisai are conducting 20 trials across 13 different types of tumors through the LEAP clinical program.Clinical Trial, including the Phase 3 LEAP-001 trial evaluating first-line treatment in patients with advanced endometrial cancer. Data from this program show that the Keytruda + Lenvima combination has been used in multiple typesTumorDemonstrated robust efficacy!

KEYNOTE-775/Study 309 was a multicenter, randomized, open-label Phase 3 trial conducted in patients with advanced endometrial cancer who had received at least one prior platinum-containing regimen, to evaluate the efficacy and safety of combination therapy with Keytruda and Lenvima. The study enrolled 827 patients, including 697 patients with non-microsatellite instability-high (non-MSI-H) or proficient mismatch repair (pMMR) tumors, and 130 patientsTumorwith high 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 intravenous [IV] infusion every 3 weeks) for 35 cycles (approximately 2 years) in combination with Lenvima (20 mg orally once daily); or (2) chemotherapy (physician’s choice of treatment [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 [weekly paclitaxel for 3 weeks followed by 1 week off]).

The results showed that the study met both primary endpoints of overall survival (OS) and progression-free survival (PFS), as well as the secondary efficacy endpoint of objective response rate (ORR). These positive results were observed in the mismatch repair proficient (pMMR) subgroup and in the intent-to-treat (ITT) study population. The ITT population included patients with advanced endometrial cancer who were pMMR or MSI-H/dMMR.

According to an analysis conducted by the Independent Data Monitoring Committee, the Keytruda + Lenvima treatment group demonstrated statistically and clinically significant improvements in OS, PFS, and ORR compared with the chemotherapy group (TPC: doxorubicin or paclitaxel). In this study, the safety profile of the Keytruda + Lenvima combination was consistent with previously reported studies. MSD and Eisai will discuss these data with regulatory authorities worldwide and plan to submit marketing applications based on these data, with plans to present at upcoming medicalMeetingpublish these results on.

Endometrial Cancer (Image source: womenworking.com)

MSD Research LaboratoriesTumorDr. Gregory Lubiniecki, Vice President of Clinical Research, stated: “Patients with advanced endometrial cancer face high mortality and limited treatment options following initial systemic therapy. This is a Phase 3 study of combination regimens, including immunotherapy, for advanced endometrial cancer.”Clinical Trialinitial results: Compared with chemotherapy, the combination regimen demonstrated significant improvements in OS, PFS, and ORR. MSD and Eisai are committed to continuing research on the Keytruda and Lenvima combination and discovering new approaches to address unmet medical needs in devastating diseases such as endometrial cancer.”

EisaiTumorDr. Takashi Owa, Chief Drug Development Officer and Vice President, Chief Discovery Officer of the Business Group, stated: “We are encouraged by the data observed in the KEYNOTE-775/Study 309 trial, which represent a potential significant step forward for patients with advanced endometrial cancer and support the results from the advanced endometrial cancer cohort in the KEYNOTE-146/Study 111 trial. As more clinical data from the LEAP program are disclosed, we are energized by the trajectory of our collaboration with Merck Sharp & Dohme and the benefits we hope to deliver together to patients. Most importantly, we thank the patients and healthcare professionals who participated in this trial for their trust.”

The KEYNOTE-775/Study 309 trial is a confirmatory study of the phase II KEYNOTE-146/Study 111 trial (NCT02501096). Based on data from the latter phase II trial, the U.S. FDA granted accelerated approval in mid-September 2019 to the combination regimen of Keytruda and Lenvima for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (non-MSI-H) or mismatch repair deficient (dMMR), who have experienced disease progression following prior systemic therapy and are not candidates for curative surgery or radiation therapy. This accelerated approval was based on tumor response rate and durability of response data, marking the first approval under the Orbis Project. The Orbis Project is an initiative of the FDA Oncology Center of Excellence designed toFDAand its international cooperation regulatory agencies provide a targetedTumorCollaborative Framework for Joint Submission and Review of Products. Under the Orbis Initiative, Health Canada and the Australian Therapeutic Goods Administration (TGA) granted conditional and provisional approval, respectively, for this indication.

Notably, endometrial cancer also marks the first U.S. regulatory approval for the combination of Keytruda and Lenvima. Previously,FDAThe combination therapy has been granted three Breakthrough Therapy Designations (BTD) for: (1) the treatment of advanced and/or metastatic microsatellite stable (MSS)/proficient mismatch repair (pMMR) endometrial cancer (EC); (2) the treatment of advanced and/or metastatic renal cell carcinoma (RCC); and (3) first-line treatment of advanced unresectable hepatocellular carcinoma (HCC) in patients ineligible for locoregional therapy.

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

Lenvima is an oral multi-receptor tyrosine kinase (RTK) inhibitor with a novel binding mode, inhibiting not only those involved in tumor angiogenesis, tumor progression, andTumorIn addition to other pro-angiogenic and oncogenic signaling pathway-related receptor tyrosine kinases (RTKs) involved in immune modulation, including platelet-derived growth factor (PDGF) receptors 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).

Keytruda is an anti-PD-1 tumor immunotherapy that helps detect and combat tumor cells by enhancing the capability 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 activatingTumorT lymphocytes of cells and healthy cells.

Currently, MSD and Eisai are conducting clinical development for 13 different types through the LEAP (LEnvatinib and Pembrolizumab) programTumor(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-negativeBreast Cancer) 20 itemsClinical Trialscontinue to study the Keytruda + Lenvima combination in China.

Data from two trials of the LEAP program released this September show that the Keytruda + Lenvima combination in seven typesTumorAll showed efficacy. (Bioon.com)

Original Source: KEYTRUDA® (pembrolizumab) Plus LENVIMA® (lenvatinib) Combination Demonstrated Statistically Significant Improvement in Overall Survival, Progression-Free Survival and Objective Response Rate Versus Chemotherapy in Patients With Advanced Endometrial Cancer