Correction: Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression

Introduction: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. Methods: Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. Results: Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (n = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (n = 5 [22.7%]), and decreased appetite (n = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9–34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9–54.9%) per mRECIST for HCC. Conclusion: Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.

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Phase 1B study of enzalutamide (ENZA) with or without sorafenib (SORA) in patients (pts) with advanced hepatocellular carcinoma (HCC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.4083 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 4083-4083

Author(s):

James J. Harding ◽

Robin Kate Kelley ◽

Benjamin R. Tan ◽

Emily Iobst ◽

Chayma Boussayoud ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Advanced Hepatocellular Carcinoma ◽

Phase 1B

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First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4072 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4072-4072 ◽

Cited By ~ 18

Author(s):

Masatoshi Kudo ◽

Kenta Motomura ◽

Yoshiyuki Wada ◽

Yoshitaka Inaba ◽

Yasunari Sakamoto ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitor ◽

Objective Response ◽

Study Data ◽

Clinical Activity ◽

Advanced Hepatocellular Carcinoma ◽

Data Set ◽

Phase 1B ◽

Grade 3

4072 Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of advanced/metastatic (a/m) hepatocellular carcinoma (HCC). Avelumab is a human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a tyrosine kinase inhibitor selective for VEGF receptors 1/2/3. VEGF Liver 100 (NCT03289533) is a phase 1b study evaluating safety and efficacy of avelumab + axitinib in treatment-naive patients (pts) with HCC; interim results are reported here. Methods: Eligible pts had confirmed a/m HCC, ≥1 measurable lesion, a fresh or archival tumor specimen, ECOG PS ≤1, and Child-Pugh class A. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and objective response (RECIST v1.1; modified [m] RECIST for HCC). Results: Interim assessment was performed after a minimum follow up of 6 months based on the released study data set (clinical cut-off date: Aug 1, 2018). As of the cut-off date, 22 pts (median age: 68.5 y) were treated with avelumab (median: 20.0 wk) and axitinib (median: 19.9 wk). The most common grade 3 treatment-related adverse events (TRAEs) (≥10% of patients) were hypertension (50.0%) and hand-foot syndrome (22.7%); no grade 4/5 TRAEs were reported. Immune-related AEs (irAEs) (≥10% of pts) were hypothyroidism (31.8%) and hyperthyroidism (13.6%). No grade ≥3 irAEs were reported; no pts discontinued treatment due to TRAEs or irAEs. Based on Waterfall plot calculations, tumor shrinkage was observed in 15 (68.2%) and 16 (72.7%) pts by RECIST and mRECIST, respectively. ORR was 13.6% (95% CI, 2.9%-34.9%) and 31.8% (95% CI, 13.9%-54.9%) by RECIST and mRECIST, respectively. OS data were immature at data cutoff. Conclusions: The preliminary safety of avelumab + axitinib in HCC is manageable and consistent with the known safety profiles of avelumab and axitinib when administered as monotherapies. This study demonstrates antitumor activity of the combination in HCC. Follow-up is ongoing. Clinical trial information: NCT03289533. [Table: see text]

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Phase 1b/2 trial of tepotinib in sorafenibpretreated advanced hepatocellular carcinoma with MET overexpression

British Journal of Cancer ◽

10.1038/s41416-021-01334-9 ◽

2021 ◽

Author(s):

Thomas Decaens ◽

Carlo Barone ◽

Eric Assenat ◽

Martin Wermke ◽

Angelica Fasolo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Progression Free Survival ◽

Advanced Hepatocellular Carcinoma ◽

Phase 2 ◽

Once Daily ◽

Exact Test ◽

Primary Endpoints ◽

Phase 1B ◽

Risk Balance ◽

Grade 3

Abstract Background This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenibpretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression. Methods Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b (‘3 + 3’ design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2). Results In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5–74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%). Conclusions Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit–risk balance in sorafenibpretreated aHCC with MET overexpression. Trial Registration ClinicalTrials.gov: NCT02115373.

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Phase 1b study of galunisertib and ramucirumab in patients with advanced hepatocellular carcinoma

Cancer Medicine ◽

10.1002/cam4.3880 ◽

2021 ◽

Author(s):

James J. Harding ◽

Richard K. Do ◽

Amin Yaqubie ◽

Ann Cleverly ◽

Yumin Zhao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Advanced Hepatocellular Carcinoma ◽

Phase 1B

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Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression

British Journal of Cancer ◽

10.1038/s41416-021-01380-3 ◽

2021 ◽

Author(s):

Baek-Yeol Ryoo ◽

Ann-Li Cheng ◽

Zhenggang Ren ◽

Tae-You Kim ◽

Hongming Pan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Primary Endpoint ◽

Objective Response ◽

Progression Free Survival ◽

Advanced Hepatocellular Carcinoma ◽

Phase 2 ◽

Open Label ◽

Asian Patients ◽

Open Label Phase ◽

Phase 1B

Abstract Background This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression. Methods In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP). Results In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib. Conclusions Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression. Trial registration ClinicalTrials.gov NCT01988493.

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P-24 A prospective phase 1b dose de-escalation open-label clinical study to evaluate the safety and efficacy of sorafenib with metformin and atorvastatin in advanced hepatocellular carcinoma (SMASH)

Annals of Oncology ◽

10.1016/j.annonc.2021.05.079 ◽

2021 ◽

Vol 32 ◽

pp. S104

Author(s):

P. Bhargava ◽

V. Ostwal ◽

A. Ramaswamy ◽

S. Srinivas ◽

S. Mandavkar ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Study ◽

Advanced Hepatocellular Carcinoma ◽

Open Label ◽

Safety And Efficacy ◽

Prospective Phase ◽

Phase 1B

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The DASH Study: A phase 1b study of dalantercept plus sorafenib in advanced hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.tps495 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. TPS495-TPS495

Author(s):

Ghassan K. Abou-Alfa ◽

Rebecca A. Miksad ◽

Martin Gutierrez ◽

Mohamedtaki Abdulaziz Tejani ◽

Manish Sharma ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dose Level ◽

Kinase Inhibitor ◽

Safety Data ◽

Tumor Growth Inhibition ◽

Preclinical Model ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

Phase 1B ◽

Dose Levels

TPS495 Background: The activin receptor-like kinase (ALK1) pathway is a novel target in angiogenesis that promotes blood vessel maturation and stabilization. ALK1 binds to the ligand bone morphogenetic protein 9 (BMP9) which is overexpressed in hepatocellular carcinoma (HCC) compared to normal hepatocytes. Dalantercept is an ALK1 receptor fusion protein that binds BMP9 and acts as a ligand trap. Sorafenib, a multi-kinase and vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI), is the standard therapy for advanced HCC. In a preclinical model of HCC, simultaneous blockade of ALK1 and VEGF signaling with dalantercept and sorafenib resulted in additive tumor growth inhibition. In a completed Phase 1 study in thirty-seven subjects with solid tumors, dalantercept monotherapy demonstrated preliminary anti-tumor activity and a safety profile that was generally non-overlapping with VEGFR TKIs. Methods: An open label, multi-center, dose escalating, phase 1b study to evaluate dalantercept plus sorafenib in subjects with advanced HCC is ongoing. The primary endpoint includes the evaluation of the safety and tolerability of dalantercept plus sorafenib and determination of the recommended phase 2 dose levels of the combination. Secondary endpoints include assessments of the pharmacokinetic profile of the combination, preliminary activity including response rate using RECIST 1.1 and time to progression, and pharmacodynamic biomarkers in the serum and tissue including ALK1 and BMP9 expression. In the first two cohorts of 3-6 subjects each, the dalantercept dose levels will be 0.6 and 0.9 mg/kg, respectively, administered subcutaneously (SC) every 3 weeks in combination with sorafenib 400 mg PO once daily. In cohort three, 3-6 subjects will receive dalantercept dose level 0.9 mg/kg SC every 3 weeks with sorafenib 400 mg PO twice daily. Patient safety data through day 22 will be evaluated prior to escalation to the next cohort. An expansion cohort will enroll 10-20 subjects at or below the maximum tolerated dose level. Key eligibility criteria: histologically confirmed advanced HCC, Child-Pugh A liver disease, ECOG performance status of 0-1, and no prior systemic therapy in the advanced setting. Clinical trial information: NCT02024087.

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