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Pembrolizumab/Lenvatinib Combo Gets FDA Breakthrough Designation for Newly Diagnosed, Unresectable HCC

Lisa Astor
Published Online:5:01 PM, Tue July 23, 2019
Takashi Owa, PhD
Takashi Owa, PhD
The FDA has granted a breakthrough therapy designation for the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) for the treatment of patients with newly diagnosed, advanced, unresectable hepatocellular carcinoma (HCC) that is not amenable to locoregional treatment.1 This marks the third FDA breakthrough designation granted to this combination.

Interim results from the phase Ib KEYNOTE-524/Study 116 trial presented at the 2019 American Association for Cancer Research Annual Meeting supported the breakthrough designation in HCC.2

“We are excited that the FDA has recognized the potential of Keytruda plus Lenvima in combination in advanced unresectable hepatocellular carcinoma not amenable to locoregional treatment with this Breakthrough Therapy designation,” Takashi Owa, PhD, vice president, chief medicine creation and chief discovery officer, Oncology Business Group, Eisai, said in a joint press release. “We are dedicated to working together with Merck to potentially bring another important option to patients.”

Eisai and Merck are collaborating to jointly develop, manufacture, and commercialize lenvatinib as a single-agent and in combination with pembrolizumab, which is developed by Merck. The collaboration began in March 2018.

“With this breakthrough therapy designation from the FDA, we look forward to working with Eisai to potentially build upon our existing indications for this difficult-to-treat cancer, so that we can help patients through a combination approach,” Jonathan Cheng, MD, vice president, Oncology Clinical Research, Merck Research Laboratories, said in the press release.

The open-label, multicenter phase Ib trial enrolled 30 patients with unresectable HCC, Child-Pugh class A, and Barcelona Clinic Liver Cancer (BCLC) stage B or C disease who were not candidates for transarterial chemoembolization. The patients received daily lenvatinib doses according to body weight (≥60 kg, 12 mg/day; <60 kg, 8 mg/day) and 200 mg of intravenous pembrolizumab every 3 weeks.

The trial was focused on the tolerability and safety of the PD-1/multikinase inhibitor combination in the unresectable HCC patient population.

Six patients were enrolled in the first part of the study, which reported no dose-limiting toxicities. In the expansion part of the trial, 24 patients who had not received prior systemic therapy for HCC were enrolled and measured by modified RECIST (mRECIST) criteria and independent imaging review (IIR) for responses.

Of the 30 overall patients, 70% had BCLC stage C disease, and 87% had a Child-Pugh score of 5. Sixty percent of patients were still receiving treatment as of the data cutoff with a median follow-up of 9.7 months (95% CI, 7.6-12.2).

By investigator assessment using mRECIST criteria, the objective response rate (ORR) was 36.7%, consisting of 1 complete response (CR) and 10 partial responses (PRs). An additional 18 patients (60%) had stable disease (SD), and 1 patient was not evaluable.

By IIR using mRECIST criteria, the ORR was 50.0%, with 3 CRs and 12 PRs. Thirteen patients had SD and 1 patient each had progressive disease and was not evaluable. With RECIST 1.1 criteria, on the other hand, the ORR per IIR was 36.7% consisting of all PRs. Sixteen patients had SD, 2 patients had progressive disease, and 1 was not evaluable.

Any-grade treatment-emergent adverse events (TEAEs) were observed in 93% of patients, the most common events being decreased appetite in 63% and hypertension in 60%. Seven patients discontinued treatment due to TEAEs. No new safety signals were identified with the combination over what has been seen in previous studies, and the combination was considered to have an acceptable safety profile.

Following these positive results, the trial protocol was amended to allow for up to 100 patients to be enrolled in part 2 of the study.

Both lenvatinib and pembrolizumab have been approved by the FDA for the treatment of patients with HCC when used as single agents. Lenvatinib’s approval is in the frontline setting and pembrolizumab’s indication is in the second-line setting.

The 2 prior breakthrough designations for the pembrolizumab and lenvatinib combination were for the treatment of patients with advanced and/or metastatic renal cell carcinoma and for patients with metastatic non-microsatellite instability–high or proficient mismatch repair endometrial cancer.
  1. Merck and Eisai Receive Third Breakthrough Therapy Designation from FDA for KEYTRUDA

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