FDA Grants Breakthrough Designation to Frontline Pembrolizumab/Lenvatinib for HCC

The FDA has granted a breakthrough therapy designation to the combination of pembrolizumab and lenvatinib for the first-line treatment of patients with advanced unresectable hepatocellular carcinoma that is not amenable to locoregional therapy.

The FDA has granted a breakthrough therapy designation to the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) for the first-line treatment of patients with advanced unresectable hepatocellular carcinoma (HCC) that is not amenable to locoregional therapy.1

The designation is based on updated interim findings from the phase Ib KEYNOTE-524/Study 116 trial. Earlier interim data, which were presented at the 2019 AACR Annual Meeting, showed that the combination elicited an investigator-assessed overall response rate (ORR) of 36.7% via modified RECIST (mRECIST) criteria in patients with unresectable HCC.2

“As part of our ongoing collaboration with Eisai, we are committed to evaluating the potential of Keytruda plus Lenvima across a number of different types of cancer,” said Jonathan Cheng, MD, vice president, Oncology Clinical Research, Merck Research Laboratories, the developer of pembrolizumab. “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.”

In the multicenter, open-label, single-arm, phase Ib KEYNOTE-524/Study 116 trial, investigators evaluated the safety and efficacy of the combination of pembrolizumab and lenvatinib in patients with unresectable HCC. The PD-1 inhibitor was administered at 200 mg intravenously every 3 weeks and lenvatinib at 12 mg daily for patients weighing ≥60 kg, and 8 mg/day for patients weighing <60 kg.

Patients had Barcelona Clinic Liver Cancer (BCLC) stage B that was ineligible for transarterial chemoembolization or C, Child-Pugh class A, and an ECOG performance status of 0 or 1. The primary endpoints are tolerability and safety; secondary endpoints include overall survival (OS), ORR, progression-free survival (PFS) and time to progression (TTP) via mRECIST criteria. Moreover, tumors were assessed for complete response (CR) or partial response (PR) ≥4 weeks after initial response.

In the first part of the study, investigators assessed dose-limiting toxicities (DLTs) during the first cycle of treatment in patients for whom no other appropriate therapy was available. After tolerability was confirmed, additional patients with no prior systemic therapy for unresectable disease were enrolled in the expansion part of the trial, which is evaluating ORR and duration of response as measured by mRECIST and RECIST 1.1 criteria based on independent imaging review (IIR).

No DLTs were reported in part 1 of the study (n = 6), and 24 patients with no prior systemic treatment were enrolled in the expansion phase (part 2) of the trial.

Overall, patients had BCLC stage B (n = 9), stage C (n = 21), Child-Pugh score of 5 (n = 26), or 6 (n = 4). At the time of data cutoff, which was August 23, 2018, 60% of patients were still on study treatment. At a median follow-up of 9.7 months (95% CI, 7.6-12.2), the overall response rate was 36.7% by mRECIST per investigator, 50.0% by mRECIST per IIR, and 36.7% per RECIST 1.1 per IIR; the stable disease (SD) rate was 60.0%, 43.3%, and 53.3%, respectively.

Regarding safety, no new safety signals were identified. All-grade treatment emergent adverse events (TEAEs) occurred in 28 patients (93%), and included decreased appetite (63%) and hypertension (60%). Seven patients discontinued therapy due to TEAEs.

Due to these data, the trial protocol was amended to enroll up to 100 total patients to part 2 of the trial. Moreover, the ongoing phase III LEAP-002 trial (NCT03713593) is evaluating the combination of lenvatinib and pembrolizumab as a first-line treatment for patients with advanced HCC.

Pembrolizumab and lenvatinib are each approved as monotherapy in the HCC paradigm. In November 2018, the FDA granted an accelerated approval to pembrolizumab for the treatment of patients with HCC who have previously received treatment with sorafenib (Nexavar). In August 2018, lenvatinib was granted approval as a frontline therapy for patients with unresectable disease.

Previously, the FDA granted breakthrough therapy designations to this combination in advanced or metastatic renal cell carcinoma in January 2018 and advanced and/or metastatic non-microsatellite instability-high/proficient mismatch repair endometrial carcinoma in July 2018.

“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,” said Takashi Owa, MD, vice president, Chief Medicine Creation and Chief Discovery Officer, Oncology Business Group, Eisai, the manufacturer of lenvatinib. “We are dedicated to working together with Merck to potentially bring another important option to patients.”


  1. Merck and Eisai Receive Third Breakthrough Therapy Designation from FDA for KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) Combination Treatment. Merck. Published July 23, 2019. https://bit.ly/2Gq3nwi. Accessed July 23, 2019.
  2. Ikeda M, Sung MW, Kudo M, et al. Abstract CT061: a phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results. Cancer Res. 2019;79(13). doi: 10.1158/1538-7445.SABCS18-CT061.