Lenvatinib and pembrolizumab trial results in unresectable hepatocellular carcinoma

Lenvatinib is an oral multi-receptor tyrosine kinase inhibitor invented by Eisai, and pembrolizumab is an anti-PD-1 therapy developed by Merck in the United States. Study 116/KEYNOTE-524 included patients with unresectable hepatocellular carcinoma (HCC) who had not received systemic therapy.

Study 116/KEYNOTE-524 (ClinicalTrials.gov, NCT03006926) is a Phase 1b, open-label, single-arm trial evaluating the combination of LENVIMA and KEYTRUDA in 100 patients with unresectable liver cancer who have not received systemic therapy. Patients take 8 or 12 mg LENVIMA (based on baseline body weight ˂60 kg or ≥60 kg) orally once daily and KEYTRUDA 200 mg intravenously every three weeks. The primary endpoints were ORR and duration of response (DOR) based on independent imaging (IIR) of mRECIST and RECIST v1. Secondary endpoints include progression-free survival (PFS), time to progression (TTP), and overall survival (OS). At the data cutoff date (October 31, 2019) and a median follow-up of 10.6 months (95% CI: 9.2-11.5), 37 patients were still receiving study treatment (LENVIMA+KEYTRUDA: n=34; LEN only VIMA: n=3), the median treatment duration of LENVIMA + KEYTRUDA combination was 7.9 months (range: 0.2-31.1)

Final analysis of the study's primary endpoint showed that using RECIST v1, the combination of LENVIMA and KEYTRUDA had an ORR of 36% (n=36) (95%CI: 26.6-46.2), a complete response rate of 1% (n=1), a partial response rate of 35% (n=35), and a median DOR of 12.6 months (95%CI: 6.9-not estimable [NE]). The LENVIMA plus KEYTRUDA combination demonstrated an ORR of 46% (n=46) (95%CI: 36.0-56.3), a complete response rate of 11% (n=11), a partial response rate of 35% (n=35), and a median DOR of 8.6 months (95%CI: 6.9-NE), as determined by independent imaging examinations (IIR) of mRECIST and RECIST v1.

Treatment-related adverse events (TRAEs) resulted in discontinuation of LENVIMA and KEYTRUDA in 6% of patients, LENVIMA in 14%, and KEYTRUDA in 10% of patients. Grade 3 TRAEs occurred in ≥67% of patients (Grade 3: 63%; Grade 4: 1%; Grade 5: 3%). There was 1 grade 4 TRAE (leukopenia/neutropenia) and 3 treatment-related deaths (acute respiratory failure/acute respiratory distress syndrome, intestinal perforation, and liver function abnormality; n=1 each). The most common treatment-related adverse events of any grade (≥20%) were hypertension (36%), diarrhea (35%), fatigue (30%), decreased appetite (28%), hypothyroidism (25%), palmar red blood cell dysesthesia syndrome (23%), weight loss (22%), dysphonia (21%), increased aspartate aminotransferase (20%), and proteinuria (20%).