FDA Rejects Merck/Eisai's Keytruda-Lenvima Combo for First-Line Hepatocellular Carcinoma Following Roche's Approval of Tecentriq-Avastin
Jul 09, 2020 15:25
CST Updated
15:35
MSD
Pharmaceutical R&D and Manufacturer
Eisai
Pharmaceutical Product R&D and Manufacturer
FDA
U.S. Food and Drug Administration
July 09, 2020 News /BioonBIOON/ -- Merck & Co. and its partner Eisai recently announced jointly that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) in response to the respective applications of both parties, which CRL pertains to: the combination therapy of the anti-PD-1 agent Keytruda (brand name: Keytruda; generic name: pembrolizumab) with the oral multi-receptor tyrosine kinase inhibitor Lenvima (brand name: Lenvima; generic name: lenvatinib) as first-line treatment for patients with unresectable hepatocellular carcinoma (HCC).
The applications from both parties are based on data from the single-arm, open-label Phase Ib KEYNOTE-524/Study 116 trial. The data demonstrated clinically meaningful efficacy of Keytruda plus Lenvima in patients with unresectable hepatocellular carcinoma (HCC) who had not previously received systemic therapy: an overall response rate (ORR) of 36% and a median duration of response (DOR) of 12.6 months. These data were presented in May at the 2020 ASCO Annual Meeting and supportFDABreakthrough Therapy Designation (BTD) granted in July 2019.
However, prior to the Prescription Drug User Fee Act (PDUFA) action dates for the applications filed by MSD and Eisai, another combination therapy was approved based on a randomized controlled trial that demonstrated an overall survival (OS) benefit.
According to articles retrieved from Bioon, the other combination therapy referred to here is Roche’s anti-PD-L1 therapy Tecentriq (atezolizumab) in combination with Avastin (bevacizumab). This combination regimen was approved by the U.S. FDA in late May of this year as a first-line treatment for patients with hepatocellular carcinoma (HCC), specifically for those with unresectable or metastatic HCC who have not previously received systemic therapy.
Notably, the Tecentriq plus Avastin combination is the first and only cancer immunotherapy regimen approved for the treatment of unresectable or metastatic hepatocellular carcinoma (HCC). Data from the Phase III IMbrave150 study demonstrated that, compared with the standard-of-care drug sorafenib, the Tecentriq plus Avastin combination significantly prolonged overall survival (median OS: not estimable vs. 13.2 months) and progression-free survival (median PFS: 6.8 months vs. 4.3 months), reduced the risk of death by 42%, and reduced the risk of disease progression or death by 41%.
Major Breakthrough in Liver Cancer Over the Past Decade! Tecentriq + Avastin (Atezolizumab + Bevacizumab) First-Line Treatment Significantly Extends Overall Survival!
Therefore, the FDA pointed out in the CRL that the applications submitted by Merck Sharp & Dohme and Eisai did not provide evidence demonstrating a meaningful advantage of Keytruda + Lenvima combination therapy over currently available treatments (Tecentriq + Avastin) for the treatment of unresectable or metastatic hepatocellular carcinoma (HCC) in patients with advanced disease who had not previously received systemic therapy.
Since the application based on the KEYNOTE-524/Study-116 trials no longer meets the criteria for accelerated approval, the two companies plan toFDAcollaborate and take appropriate next steps, including conducting a well-controlledClinical Trialto demonstrate the efficacy and clinical benefits of the combination therapy. Currently, the Phase III trial LEAP-002, evaluating Keytruda + Lenvima as a first-line treatment for advanced HCC, is ongoing and has completed patient enrollment.
It should be noted that this CRL does not affect the currently approved indications for Keytruda and Lenvima. MSD and Eisai are currently conducting 18Clinical Trialin China to continue the combination therapy of Keytruda + Lenvima for 13 different typesTumorConduct an assessment, including the LEAP (Lenvatinib And Pembrolizumab) clinical program.
KEYNOTE-524/Study 116 Trial Design and Data:
KEYNOTE-524/Study 116 (NCT03006926) is an open-label, single-arm Phase Ib trial conducted in 100 patients with unresectable hepatocellular carcinoma (HCC) who had not previously received systemic therapy, to evaluate the efficacy and safety of the combination of Keytruda and Lenvima. In the study, patients received Keytruda 200 mg via intravenous infusion every 3 weeks, along with oral Lenvima 8 mg or 12 mg once daily (based on baseline body weight: <60 kg, ≥60 kg). The primary endpoints were overall response rate (ORR) and duration of response (DOR) assessed by independent imaging review (IIR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST v1.1. Secondary endpoints included progression-free survival (PFS), time to progression (TTP), and overall survival (OS).
At the data cutoff date (October 31, 2019) and with a median follow-up of 10.6 months (95% CI: 9.2–11.5), 37 patients remained in the study (Keytruda + Lenvima: n=34; Lenvima: n=3). The median duration of treatment with Keytruda + Lenvima combination therapy was 7.9 months (range: 0.2–31.1).
The final analysis of the primary endpoint showed: As assessed by the Independent Imaging Review (IIR) according to mRECIST criteria, the objective response rate (ORR) for Keytruda plus Lenvima combination therapy was 36% (n=36; 95% CI: 26.6–46.2), with a complete response (CR) rate of 1% (n=1), a partial response (PR) rate of 35% (n=35), and a median duration of response (DOR) of 12.6 months (95% CI: 6.9–not evaluable [NE]). As assessed by the IIR according to RECIST v1.1 criteria, the ORR for Keytruda plus Lenvima combination therapy was 46% (n=46; 95% CI: 36.0–56.3), with a CR rate of 11% (n=11), a PR rate of 35% (n=35), and a median DOR of 8.6 months (95% CI: 6.9–not evaluable [NE]).Treatment-related adverse events (TRAEs) led to discontinuation of Keytruda + Lenvima in 6% of patients, Keytruda in 10% of patients, and Lenvima in 14% of patients.
Keytruda is an anti-PD-1 cancer immunotherapy that helps detect and fight 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 activating T lymphocytes that may affect both tumor cells and healthy cells.
Lenvima is a targeted drug discovered and developed internally by Eisai. It is an oral multi-receptor tyrosine kinase (RTK) inhibitor with a novel binding mode, inhibiting not only those involved in tumor angiogenesis and tumor progression, but alsoTumorIn addition to other receptor tyrosine kinases (RTKs) associated with pro-angiogenic and oncogenic signaling pathways 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).
The Keytruda plus 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 a monotherapy and in combination with Keytruda for the treatment of various types of tumors. In addition to ongoing evaluations of the Keytruda and Lenvima combination for several different tumor types, including renal cell carcinoma, the partners have initiated new clinical studies through the LEAP clinical program and are currently assessing efficacy in 13 different tumor types: endometrial cancer, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, urothelial carcinoma, biliary tract cancer, triple-negative breast cancer, colorectal cancer, gastric cancer, glioblastoma, and ovarian cancer.(Bioon.com)