FDA Holds Off on Approval of Pembrolizumab/Lenvatinib for Frontline Unresectable HCC

The FDA has issued a complete response letter in regard to the applications for potential accelerated approval of pembrolizumab in combination with lenvatinib as treatment of patients with previously untreated, unresectable hepatocellular carcinoma.

The FDA has issued a complete response letter (CRL) in regard to the applications for potential accelerated approval of pembrolizumab (Keytruda) in combination with lenvatinib (Lenvima) as treatment of patients with previously untreated, unresectable hepatocellular carcinoma (HCC), according to a press release from Merck and Eisai.1

The companies had submitted applications for the potential accelerated approval of the combination regimen based on findings from the single-arm phase 1b KEYNOTE-524/Study 116 trial (NCT03006926). Findings from the study supported an FDA breakthrough therapy designation granted to the combination in July 2019.

Although clinically meaningful efficacy was achieved in the study, the FDA approved the combination of atezolizumab (Tecentriq) in combination with bevacizumab (Avastin) in May 2020for the treatment of patients with unresectable or metastatic HCC who have not received prior therapy for advanced disease.2 The atezolizumab/bevacizumab combination was approved based on findings from the phase 3 IMbrave150 trial (NCT03434379), which demonstrated an improvement in overall survival (OS) with the combination compared with standard-of-care sorafenib (Nexavar) alone in this patient population.

As a result, the pembrolizumab/lenvatinib did not show evidence of meaningful improvement over available therapies, which now included the atezolizumab/bevacizumab combination, for the treatment of patients with unresectable HCC who have not received prior therapy for advanced disease, and no longer met the criteria for accelerated approval. Earlier FDA-approved indications for the agents are not affected by the CRL though.

The companies plan to continue the evaluation of the combination in this setting to further demonstrate the clinical benefit of pembrolizumab plus lenvatinib. The multicenter, randomized, double-blind phase 3 LEAP-002 trial is continuing to explore the safety and efficacy of the pembrolizumab and lenvatinib combination in comparison with lenvatinib alone as frontline treatment for adult patients with advanced HCC (NCT03713593). The trial is ongoing but no longer enrolling patients.

About 750 patients were enrolled into the study and randomized patients to pembrolizumab/lenvatinib or lenvatinib/placebo. In the investigational arm, patients received 8 or 12 mg of lenvatinib, based on body weight, orally once daily in combination with 200 mg intravenous pembrolizumab on day 1 of each 3-week cycle. Treatment with pembrolizumab continued for up to 35 weeks.

Eligible patients had Barcelona Clinical Liver Cancer (BCLC) stage C disease, or stage B disease that was not amenable to or was refractory to locoregional therapy, a Child-Pugh class A score, an ECOG performance status of 0 or 1, and a life expectancy of more than 3 months. Patients with hepatitis B virus were able to participate in the trial if the virus was well controlled.

Primary end points of the study are progression-free survival (PFS) by RECIST 1.1 criteria and overall survival (OS). Secondary end points include objective response rate (ORR), duration of response (DOR), disease control rate (DCR), time to disease progression (TTP), and adverse events (AEs). The study is also exploring outcome measures by modified RECIST (mRECIST) criteria.

Results of KEYNOTE-524/Study 116

According to findings presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program,3 the ORR by RECIST criteria per independent imaging review was 36% (95% CI, 26.6%-46.2%). By mRECIST criteria, the ORR was 46% (95% CI, 36.0%-56.3%) per independent review and 41% (95% CI, 31.3%-51.3%) per investigator review. The DCR was 88% by both RECIST and mRECIST criteria with independent imaging review. The DCR per investigator review was 86%.

The median DOR was 12.6 months by RECIST criteria and independent review as well as by mRECIST criteria and investigator review. According to mRECIST criteria and independent review, the median DOR was 8.6 months.

Eighty-nine percent out of 93 and 83% of evaluable patients had reduction in tumor size by independent imaging review, which appeared to be durable.

The phase 1b study included an examination of dose-limiting toxicities in 6 patients ineligible for other treatments in part 1 and an expansion phase with 98 unresectable patients in part 2.

Eligible patients had unresectable HCC, BCLC stage B disease that was not amenable to transarterial chemoembolization or stage C disease, Child-Pugh class A score, ECOG performance status of 0 or 1, and at least 1 measurable target lesion by mRECIST criteria.

Primary end points for part 1 were safety and tolerability and for part 2 the primary end points were ORR and DOR by mRECIST and RECIST criteria. Secondary and exploratory end points included PFS, TTP, OS, pharmacokinetics, and antidrug antibodies for pembrolizumab.

Of the 100 patients included in the frontline analysis, the median age was 66.5 years, 81% were male, and 81% had a bodyweight of at least 60 kg at baseline. The majority of patients had an ECOG performance status of 0 (62%), BCLC stage C disease (71%), and a Child-Pugh score of 5 (71%). Additionally, 62% of patients had macroscopic portal vein invasion, extrahepatic spread, or both.

The median PFS by RECIST criteria was 8.6 months (95% CI, 7.1-9.7) and 9.3 months by mRECIST criteria (95% CI, 5.6-9.7). The median OS was 22.0 months (95% CI, 20.4-not evaluable).

The most common treatment-related AEs of any grade observed with the combination were hypertension (36%), diarrhea (35%), fatigue (30%), decreased appetite (28%), and hypothyroidism (25%). Treatment-related AEs led to discontinuation of lenvatinib in 14% of patients, of pembrolizumab in 10%, and of both agents in 6%.


1. Merck and Eisai Receive Complete Response Letter for KEYTRUDA® (pembrolizumab) plus LENVIMA® (lenvatinib) Combination as First-Line Treatment for Unresectable Hepatocellular Carcinoma. News release. Merck and Eisai. July 8, 2020. Accessed July 8, 2020. https://bwnews.pr/2Z89nmX

2. FDA Approves Genentech’s Tecentriq in Combination With Avastin for People With the Most Common Form of Liver Cancer. Published May 29, 2020. Accessed July 8, 2020. https://bit.ly/2Aneztc

3. Zhu AX, Finn RS, Ikeda M, et al. A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2020;38(suppl):4519. doi: 10.1200/JCO.2020.38.15_suppl.4519