Lenvatinib Shows Efficacy in Advanced HCC Post-Progression on Atezolizumab/Bevacizumab

Lenvatinib (Lenvima) showcased clinically meaningful efficacy outcomes with acceptable safety in patients with advanced hepatocellular carcinoma (HCC) who experienced disease progression on frontline atezolizumab (Tecentriq) plus bevacizumab (Avastin), according to data from a phase 2 KCSG HB23-04 study (NCT06138769) presented during the 2024 ESMO Asia Congress.1

The median progression-free survival (PFS) with second-line lenvatinib (n = 50) was 5.4 months (95% CI, 5.3-5.6) by investigator assessment and RECIST 1.1 criteria, which met the study’s primary end point. At the time of the presentation, overall survival (OS) data were not mature. With 13 OS events reported, the median OS was 8.6 months (95 CI, 8.1-not applicable) but the data require further follow-up.

Moreover, second-line lenvatinib induced an objective response rate (ORR) of 12%, which comprised a partial response rate of 12%; 72% of patients achieved stable disease and 12% experienced disease progression. Two patients were not evaluable for response. The disease control rate (DCR) with the agent was 84%.

“This is the first prospective study on the efficacy and safety of lenvatinib after prior atezolizumab plus bevacizumab,” Changhoon Yoo, MD, PhD, of the Department of Oncology at Asian Medical Center, University of Ulsan College of Medicine, in Seoul, Korea, said in a presentation of the data. “Lenvatinib may be considered a treatment option after frontline atezolizumab/bevacizumab.”

For patients with unresectable HCC, immune checkpoint inhibitor (ICI)–based combinations such as atezolizumab plus bevacizumab and tremelimumab (Imjudo) and durvalumab (Imfinzi) are becoming standard treatment for the first-line setting. Other regimens such as ipilimumab (Yervoy) plus nivolumab (Opdivo) and camrelizumab plus rivoceranib have also demonstrated superior activity over single-agent multikinase inhibitors, according to Yoo. Patients who receive an ICI-based regimen in the first line and progress are commonly administered a multikinase inhibitor although few prospective data support that approach.

“Lenvatinib is a VEGFR TKI approved for first-line therapy prior to the era of ICIs, and one of the widely used agents in the real-world post-ICI setting,” Yoo said. “But there are no prospective data in this setting.”

The investigator-initiated, multicenter, single-arm, phase 2 study enrolled patients with unresectable HCC who experienced disease progression after frontline atezolizumab/bevacizumab after at least cycle 2 and who had not received other systemic treatment. Patients were required to have at least 1 measurable lesion by RECIST 1.1 criteria, have Child-Pugh class A disease, an ECOG performance status of 0 or 1, and acceptable organ function.

Participants received 12 mg or 8 mg of lenvatinib until clinical benefit was lost or they experienced intolerable toxicity. They were assessed for responses every 8 weeks. In addition to the primary efficacy objective being investigator-assessed PFS, key secondary objectives included OS, ORR, and DCR. Investigators also examined adverse effects, which were graded by CTCAE v5.0 criteria.

A total of 50 patients were needed to improve median PFS from 2 months to 4.5 months with the consideration of a 1-sided alpha of 0.1, power of 80%, and 10% of follow-up loss, Yoo explained. The data lock for the primary analysis of the study was September 1, 2024, and the median duration of follow-up of 5.0 months (95% CI, 2.5-12.7). At this time point, 44% of the 50 patients were still receiving lenvatinib. The data lock for the final analysis is planned for June 1, 2025.

For the analysis shared during the meeting, the median patient age was 66 years (range, 32-86). Most patients were male (82%) and had an ECOG performance status of 1 (82%). Regarding etiology, 70% of patients had viral hepatitis B and 2% had hepatitis C; 28% of patients had non-viral disease. More than half of patients had a CP score of 5 (76%) and Barcelona-Clinic Liver Cancer stage C disease (76%). Forty-four percent of patients had an alpha-fetoprotein above 400 ng/mL. Previous local therapy received included surgery (40%) and transarterial chemoembolization (58%). The number of cycles of frontline atezolizumab plus bevacizumab received was 7.5 (interquartile range, 3.3-18.0).

“Second-line lenvatinib PFS was not associated with TTP with prior first-line atezolizumab/bevacizumab” Yoo reported.

The most common treatment-related adverse effects reported with lenvatinib in the second-line setting included diarrhea (grade 1, 20%; grade 2, 12%; grade 3, 0%), anorexia (6%; 18%; 6%), hypothyroidism (10%; 20%; 0%), hand-foot syndrome (12%; 10%; 0%), hypertension (0%; 14%; 8%), fatigue (12%; 6%; 2%), nausea (8%; 12%; 0%), proteinuria (0%; 14%; 6%), abdominal pain (2%; 12%; 4%), weight loss (4%; 8%; 2%), hyperbilirubinemia (2%; 8%; 4%), pruritus (8%; 4%; 0%), rash (10%; 2%; 0%), general weakness (2%; 10%; 0%), thrombocytopenia (0%; 10%; 0%), and elevated aspartate aminotransferase level (0%; 4%; 6%).

“No new safety signal of lenvatinib was observed in the population with prior use of atezolizumab plus bevacizumab,” Yoo concluded.

Disclosures: Dr Yoo serves in an advisory or consulting role or received honoraria from Servier, Bayer, AstraZeneca, Merck Sharp & Dohme, Eisai, Celgene, Bristol Myers Squibb, Novartis, Boryung, Roche, Qurient, Abbisko, Boehringer Ingelheim, HLB bio, and Elevar Therapeutics. Research support was provided by Servier, Bayer, AstraZeneca, Eisai, Ipsen, Boryung, CKD Pharm, Boehringer Ingelheim, Natera, and Lunit Inc.

Reference

Yoo C, Kim H-D, Chon HJ, et al. Multicenter phase 2 trial of lenvatinib in patients with advanced hepatocellular carcinoma after progression on first-line atezolizumab plus bevacizumab (KCSG HB23-04). Ann Oncol. 2024;35(suppl 4):S1450. doi:10.1016/j.annonc.2024.10.149