Tivantinib (ARQ 197) versus placebo in patients (Pts) with hepatocellular carcinoma (HCC) who failed one systemic therapy: Results of a randomized controlled phase II trial (RCT).

Abstract

4006 Background: Tivantinib (T) is a selective, oral inhibitor of c-Met, the tyrosine kinase receptor for hepatocyte growth factor involved in tumor cell migration, invasion, proliferation and angiogenesis. T has shown promising results in HCC in phase 1 studies as monotherapy and in combination with sorafenib. Methods: This multi-center RCT, enrolled pts with unresectable HCC, 1 failed systemic therapy, ECOG PS <2. Child-Pugh B-C were excluded. Pts were randomized 2:1 to oral T {360 mg bid (A), 240 mg bid (B)} or placebo (P), stratifying by PS and vascular invasion (VI). Treatment continued until disease progression (PD) or unacceptable toxicity. RECIST 1.1 response was evaluated by CT / MRI every 6 weeks. Crossover to open-label T was allowed after PD. Primary endpoint was time to tumor progression (TTP) in the intent-to-treat (ITT) population by central radiology review. Other endpoints included disease control rate (DCR), PFS, OS, efficacy in Met+ (Met ≥ 2+ in >50% of tumor at immunohistochemistry) pts, safety. Results: Characteristics of the 107 enrolled HCC pts (A= 38, B= 33, P= 36) in T/P: 58/28 male; median age 70/68; PS 0 41/21; VI 22/13; Met+ 22/15; Met- 27/13. Dose A was reduced to B in all pts due to G≥3 neutropenia (NEUT) rate. Major TTP, DCR and PFS benefits were obtained in Met+ pts, with preliminary OS trend favoring T (HR=0.47) and no detrimental effect in Met- pts. DCR (95% CI) in T/P was 44 (31-56) / 31(16-48)% for ITT and 50 (28-72) / 20 (4-48)% in Met+ pts. Most common AEs in T were asthenia (26.8%), NEUT (25.4%), low appetite (25.4%); most common drug-related AEs were NEUT (25.4%), anemia (15.5%). Most frequent drug-related serious AE was neutropenic sepsis (4.2%). Efficacy was similar in A / B with less frequent NEUT in B (21.1% / 6.1%). Final OS, PK, biomarker data will be presented. Conclusions: Compared to P, T significantly benefited second-line HCC pts, especially if Met+, with manageable safety profile at 240 mg BID. [Table: see text]

Emerging Targeted Strategies in Advanced Hepatocellular Carcinoma

“…Most recently, randomized phase II data of the cMET inhibitor, tivantinib, has demonstrated activity in a subset of patients with advanced HCC that have progressed on sorafenib and had elevated expression of cMET by immunohistochemistry. 35 There has been considerable interest in targeting peptide growth factor signaling via the EGFR and IGFR axis, which is suggested by elevated levels of these receptors in HCC. 36,37 The increasing awareness of the association of insulin resistance, diabetes, obesity, and nonalcoholic steatohepatitis (NASH) in the development of cirrhosis and HCC also is evidence that the IGFR pathway might have a causal role in this process.…”

“…39 The most recent clinical data relating to these novel agents, their combinations, and ongoing trials are outlined in ►Tables 1 and 2. 35,…”

“…Early efficacy results of novel targeted therapies in advanced development in hepatocellular carcinoma35,[40][41][42][43][44][45][46][47][48][49][50][51] …”

Systemic targeted therapy beyond sorafenib

“…The recent results observed with the randomized phase II trial comparing tivantinib (n ¼ 71) with placebo (n ¼ 36) in patients with advanced HCC who failed one prior systemic therapy met its primary endpoint of improving TTP. 25 Tivantinib treatment has a manageable safety profile and significantly benefited second-line HCC patients. A randomized phase III study with tivantinib as a second-line treatment is planned.…”

Selecting the right patients for testing novel agents in hepatocellular carcinoma: who, when and how?

“…Although the driver mutations of HCC are not yet clearly understood, sequencing studies in both tissue and plasma samples have already deciphered some potential druggable molecular defects of HCC . In fact, recent phase II data on novel agents including c‐Met inhibitors and histone deacetylase inhibitors show that biomarkers could potentially identify responding patients for HCC . Conventionally, biopsy tissue of HCC is usually not required or even not recommended in the design of clinical trials.…”