Lenvatinib Plus Nivolumab Demonstrates Antitumor Activity in Unresectable HCC


Lenvatinib in combination with nivolumab demonstrated promising antitumor activity in patients with unresectable hepatocellular carcinoma with no new safety signals reported.

Lenvatinib (Lenvima) in combination with nivolumab (Opdivo) demonstrated promising antitumor activity in patients with unresectable hepatocellular carcinoma (HCC). In addition, there were no new safety signals and the combination was generally well-tolerated, according to a phase Ib trial reported at the 2020 Gastrointestinal Cancers Symposium.

At the data cutoff date of June 28, 2019, 30 patients had been enrolled into both parts of the study. Part 1 (n = 6) determined the tolerability of the combination, then additional patients were enrolled in part 2 (n = 24). Treatment remained ongoing in 18 patients (60%) at the data cutoff. The median duration of treatment was 5.49 months for lenvatinib and 5.06 months for nivolumab in the overall population. No dose-limiting toxicities were observed in part 1 of the study.

The investigator-assessed objective response rate (ORR) was 76.7% in the overall patient population, according to modified RECIST (mRECIST) criteria. The median time to response by mRECIST in patients enrolled in part 2 was 1.87 months (95% CI, 1.87-3.65), and the median duration of response in this group was not evaluable (NE; 95% CI, 2.07-NE).

Overall, 3 patients who were all treated in part 2 achieved a complete response (CR; 10.0%); 20 achieved a partial response (PR; 66.7%), including 4 patients from part 1 and 16 patients from part 2. Six patients had stable disease (SD; 20.0%), 4 of whom were from part 2. Only 1 patient from part 2 had progressive disease (PD; 3.3%). The ORR was 66.7% in the cohort of patients from part 1 (95% CI, 22.3%-95.7%) and 79.2% from part 2 (95% CI, 57.8%-92.9%).

Based on independent review of patients in part 2 comparing mRECIST versus RECIST 1.1 response criteria, 14 (58.3%) versus 11 (45.8%) cases of PR were reported; 6 (25.0%) versus 9 (37.5%) case of SD; and 2 with had CR and PD, respectively. The ORR was 66.7% per mRECIST and 54.2% per RECIST 1.1 criteria in this part of the study, as well.

Overall, 2 patients (6.7%) experienced treatment-emergent adverse events (TEAEs) that led to discontinuation of treatment with lenvatinib, and 4 patients (13.3%) experienced TEAEs that led to discontinuation of nivolumab. Dose reductions due to TEAEs were required for lenvatinib in 17 patients (56.7%) and for nivolumab in 15 patients (50.0%). Seven patients (23.3%) had a dose interruption due to TEAEs from nivolumab.

Any grade treatment-related TEAEs were observed in all patients. Eighteen patients (60.0%) experienced TEAEs of grade 3 or greater. Serious AEs occurred in 11 patients (36.7%), and 1 patient (3.3%) experienced a fatal AE.

The most common TEAEs of any grade included palmar-plantar erythrodysesthesia syndrome in 18 patients (60.0%), dysphonia in 16 patients (53.3%), decreased appetite in 14 patients (46.7%), diarrhea in 14 patients (46.7%), and proteinuria in 12 patients (40.0%). The most common grade 3 or greater TEAEs included aspartate aminotransferase level increased in 3 patients (10.0%); proteinuria in 2 patients (6.7%); and palmar-plantar erythrodysesthesia syndrome, dysphonia, decreased appetite, and diarrhea in 1 patient each (3.3%).

Overall, the toxicities were manageable with lenvatinib with dose modifications, dose interruptions, and supportive medications.

Most patients experienced a reduction in tumor size, and those reductions appeared durable for most patients, noted the investigators, who were led by Masatoshi Kudo, of Kindai University in Osaka, Japan. Data for progression-free survival (PFS) were immature at the time of data collection, with a median PFS in patients treated in part 2 of 7.39 months (95% CI, 3.71-NE).

In the open-label study, patients with unresectable HCC received lenvatinib orally based on body weight and nivolumab every 2 weeks intravenously at 240 mg. For patients of weighing 60 kg or less, lenvatinib was administered at 8 mg per day, and patients who weighed more than 60 kg received 12 mg per day.

Patients had to have unresectable HCC and at least 1 measurable target lesion to be included in the study. They had to have Barcelona Clinic Liver Cancer stage B disease (not applicable for TACE) or stage C disease, Child Pugh class A, and an ECOG performance status of 0 or 1. Patients in part 1 were those with no other available treatment options, and patients in part 2 had no prior systemic therapy for the disease.

In the overall population, the median age of patients was 70 years (range, 36-81), and 24 were male (80%). Two patients had an ECOG performance status of 1, and 28 had an ECOG of 0. The majority of patients had not received prior radiotherapy (27; 90.0%) and had no prior lines of anticancer medications (26; 86.7%). However, 3 patients had 1 prior line of anticancer medication (10.0%), 1 had received at least 3 (3.3%), and 3 patients (10.0%) had previous radiotherapy. Fifteen patients had 1 to 3 prior lines of anticancer procedures (50.0%), and 14 had 4 or more (46.7%).


Kudo M, Ikeda M, Motomura K, et al. A phase 1b study of lenvatinib plus nivolumab in patients with unresectable hepatocellular carcinoma (Study 117).J Clin Oncol. 2020;38(suppl 4;abstr 513). meetinglibrary.asco.org/record/182285/abstract.

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