A phase Ib study of lenvatinib (LEN) plus nivolumab (NIV) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): Study 117.

Abstract

513 Background: LEN, a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT with immunomodulatory activity, is approved in multiple countries for first-line treatment of uHCC. NIV is an anti-PD-1 monoclonal antibody approved in multiple countries as a second-line treatment for HCC. We report early results from a phase 1b trial of LEN + NIV in pts with uHCC. Methods: In this open-label study, pts with uHCC, BCLC stage B (not eligible for transarterial chemoembolization) or C, Child-Pugh class A, and ECOG PS ≤ 1 received LEN (bodyweight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) PO QD and 240 mg NIV IV Q2W. The primary endpoint was tolerability and safety of the combination. Objective response rate (ORR; mRECIST by investigator) was a secondary endpoint. Tolerability was evaluated by assessing dose-limiting toxicities (DLTs) during the first cycle in pts for whom no other appropriate therapy was available (Part 1). Once tolerability was confirmed, additional pts with no prior systemic therapy for uHCC were enrolled (Part 2). Results: At data cutoff (May 17, 2019), 30 pts had received LEN + NIV (Part 1: n=6; Part 2: n=24). Pts had BCLC stage B (n=17) or C (n=13) and Child-Pugh scores of 5 (n=23) or 6 (n=7). 4 pts in Part 1 (66.7%) had received prior anticancer medications (3 pts had 1; 1 pt had ≥3). No DLTs were reported in Part 1. TEAEs leading to discontinuation of LEN were reported in 2 (6.7%) pts; 4 (13.3%) pts had TEAEs leading to discontinuation of NIV. TEAEs occurred in all 30 pts; the most common were palmar-plantar erythrodysesthesia (56.7%) and dysphonia (53.3%). Adverse events were manageable. Efficacy outcomes are reported (Table). Conclusions: LEN + NIV was well tolerated with encouraging anti-tumor activity in pts with uHCC. Clinical trial information: NCT03418922. [Table: see text]

Gd-EOB-DTPA-MRI Could Predict WNT/β-Catenin Mutation and Resistance to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma

“…In other words, because MTA are expected to have a certain effect irrespectively of any immune class of HCC, sequential therapy using MTA [44][45][46][47][48][49][50][51] is extremely important in the treatment of the WNT/β-catenin mutation. Most interestingly, the PD rates in combination trials of pembrolizumab plus lenvatinib [23], and nivolumab plus lenvatinib [41], were considerably lower (7 and 8.3%, respectively) than those of nivolumab (37%) [20] or pembrolizumab monotherapy (32.4%) [21]. The PD rate of 7-8.3% is lower than the rate of the immune exclusion class with WNT-β-catenin mutation of 20-30% [10,11].…”

“…5, 7). Furthermore, the ORR (RECIST version 1.1) for pembrolizumab plus lenvatinib (36%) [23] and nivolumab plus lenvatinib (54.2%) [41] is higher than that of the phase 3 atezolizumab plus bevacizumab combination (IMbrave150; 27.3%). This could be attributed to the higher antitumor effect of lenvatinib over bevacizumab [42][43][44][45], specifically, a more effective induction of necrosis in cancer cells, enhanced induction of DC induced by an increased neoantigen release, and more potent trafficking and infiltration of CD8 + T cells into tumors.…”

Current progress and prospect of immune checkpoint inhibitors in hepatocellular carcinoma (Review)

“…At the ASCO-GI 2020 meeting, Kudo et al ( 63 ) reviewed the data of a phase IB trial that focused on the efficacy of nivolumab combined with lenvatinib in advanced HCC. The study enrolled 30 patients who were randomly divided into two groups: One group (n=6) had multidrug resistance and the other group (n=24) had no previous treatments.…”

Limited Impact of Anti-PD-1/PD-L1 Monotherapy for Hepatocellular Carcinoma

“…If the effects of anti-PD-1/PD-L1 plus anti-VEGF antibodies reported in the phase III IMbrave150 study are confirmed in future clinical studies of early and intermediate stages of HCC, this therapy should greatly extend patient survival. ICI monotherapy regimens that inhibit only CheckMate 459 [5] KEYNOTE-240 [6] phase 1b (arm F) [19] phase 1b (arm F) [19] IMbrave150 [7] phase 1b (arm A) [19] phase 1b [17] phase 1b [18] ORR, % 13.6 (12.1-14.9)…”