A phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results

Llovet, Josep M.; Shepard, Karen; Finn, RS; Ikeda, Masafumi; Sung, Max W.; Baron, Ari David; Kudo, Masatoshi; Okusaka, Takuji; Kobayashi, Masahiro; Kumada, Hiromitsu; Kaneko, Shuichi; Pracht, Marc; Мамонтов, К Г; Meyer, Tim; Mody, Kalgi; Kubota, Tomoki; Saitô, Kenichi; Siegel, Abby B.; Dubrovsky, Leonid; Zhu, Andrew X.

doi:10.1093/annonc/mdz247.073

Cited by 58 publications

(53 citation statements)

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“…With these data, the study reached both its primary endpoints, making a strong case for approval by drug administrations around the globe. These data are furthermore supported by competitors' results also suggesting high efficacy of lenvatinib and pembrolizumab in combination [9]. As a logical consequence, these combinations will now increasingly be utilized in treatment of aHCC.…”

Section: Introductionsupporting

confidence: 53%

“…With the combination of atezolizumab and bevacizumab reaching statistically significant and clinically meaningful improvements in OS and PFS compared with standard-of-care sorafenib, systemic therapy for aHCC is about to change [8]. Since a comparable combination of ICI and TKI by competing companies show comparable strong efficacy in early clinical trials [9], these combinations will most likely soon become standard first-line treatment upon approval by the drug administrations.…”

Section: Discussionmentioning

confidence: 99%

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Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure

Schulte

Zhan

et al. 2020

Z Gastroenterol

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In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy, and these drugs have already become essential for the treatment of various noncurable tumors. However, monotherapy in advanced hepatocellular carcinoma (aHCC) failed to show statistically significant improvement.Recently, the combination of atezolizumab and bevacizumab demonstrated efficacy of combining ICI and VEGF inhibition, further substantiating previous data on synergistic mechanisms among respective substance classes.As TKI treatment is currently standard of care for aHCC, and ICIs are approved by the FDA and available in many areas of the world, numerous patients may have been treated with monotherapy of those drugs. However, it remains unclear if failure to monotherapy has an impact on combination therapy. We therefore report a patient well responding to combination therapy despite previous failures to TKI and ICI monotherapy.

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Section: Introductionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure

Schulte

Zhan

et al. 2020

Z Gastroenterol

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“…22 In all studies, mRECIST ORR was superior to RECIST ORR (Table 1). Similarly, in single phase II studies, patients on nivolumab achieved an ORR of 19% by mRECIST (vs. 14% for RECIST), 48 while those on combination treatments with lenvatinib plus pembrolizumab, 54 or atezolizumab plus bevacizumab (n = 67) achieved ORRs of 42% or 34%, 55 both by mRECIST, respectively. Of note, most of the drugs approved by the FDA under the accelerated programme reported ORRs exceeding 30%.…”

Section: Assessment Of Objective Responsementioning

confidence: 93%

mRECIST for HCC: Performance and novel refinements

Llovet

Lencioni

2020

Journal of Hepatology

368

254

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In 2010, modified RECIST (mRECIST) criteria were proposed as a way of adapting the RECIST criteria to the particularities of hepatocellular carcinoma (HCC). We intended to overcome some limitations of RECIST in measuring tumour shrinkage with local and systemic therapies, and also to refine the assessment of progression that could be misinterpreted with conventional RECIST 1.1, due to clinical events related to the natural progression of chronic liver disease (development of ascites, enlargement of lymph nodes, etc.). mRECIST has served its purpose since being adopted or included in clinical practice guidelines (European, American and Asian) for the management of HCC; it has also been instrumental for assessing response and time-to-event endpoints in several phase II and III investigations. Nowadays, mRECIST has become the standard tool for measurement of radiological endpoints at early/intermediate stages of HCC. At advanced stages, guidelines recommend both methods. mRECIST has been proven to capture higher objective response rates in tumours treated with molecular therapies and those responses have shown to be independently associated with better survival. With the advent of novel treatment approaches (i.e. immunotherapy) and combination therapies there is a need to further refine and clarify some concepts around the performance of mRECIST. Similarly, changes in the landscape of standard of care at advanced stages of the disease are pointing towards progression-free survival as a potential primary endpoint in some phase III investigations, as effective therapies applied beyond progression might mask overall survival results. Strict recommendations for adopting this endpoint have been reported. Overall, we review the performance of mRECIST during the last decade, incorporating novel clarifications and refinements in light of emerging challenges in the study and management of HCC.

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“…7,21,22 Most of the recently reported early-phase trials of anti-PD-1/anti-PD-L1 plus antiangiogenic agents for advanced HCC were initially parts of basket trials testing the same regimen in multiple cancer types. [23][24][25][26][27] The HCC cohorts were selected for further development because of the promising antitumor activity demonstrated by these regimens, with ORRs of 10-50% and median PFS of more than 6 months ( Table 1). It was recently announced that the combination of atezolizumab and bevacizumab demonstrated superior OS and PFS compared to sorafenib in the first-line treatment of advanced HCC 158 .…”

Section: Promising Data On Immuno-oncology Combinations For Advanced Hccmentioning

confidence: 99%

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma

Cheng

Hsu

Chan

et al. 2020

Journal of Hepatology

362

339

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Immune checkpoint inhibitor (ICI) therapy targeting anti-programmed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is the backbone of numerous combination regimens aimed at improving the objective response and survival of patients with hepatocellular carcinoma (HCC). Clinical trials of immunooncology regimens in other cancer types have shed light on issues of study design, including how to choose candidate regimens based on early-phase trial results, statistical considerations in trials with multiple primary endpoints, and the importance of predictive biomarkers. In this review, the updated data from early-phase trials of combination immunotherapy for HCC are summarised. Since the most extensively tested combination regimens for advanced HCC comprise anti-PD-1/anti-PD-L1 agents plus antiangiogenic agents, the relative benefit and antitumor mechanism of antiangiogenic multikinase inhibitors versus specific VEGF/VEGFR inhibitors are discussed. Other critical issues in the development of combination immunotherapy, including optimal management of immune-related adverse events and the value of ICI therapy in combination with locoregional treatment for HCC, are also explored.

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A phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results

Cited by 58 publications

References 0 publications

Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure

Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure

mRECIST for HCC: Performance and novel refinements

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma

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