What side effects are associated with this type of intervention?

The combination of Lenvatinib and Pembrolizumab for the treatment of advanced Hepatocellular Carcinoma is associated with several side effects. Common side effects of Lenvatinib include hypertension, diarrhea, weight loss, proteinuria, and palmar-plantar erythrodysesthesia syndrome. Pembrolizumab, an immune checkpoint inhibitor, can cause immune-related adverse events such as colitis, hepatitis, endocrinopathies, and pneumonitis. Both treatments can lead to grade ≥3 toxicities, which are severe and require careful management.

What prior FDA approvals exist?

The FDA has approved several treatments for Hepatocellular Carcinoma (HCC) that involve Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors. Sorafenib, a Tyrosine Kinase Inhibitor, was one of the first approved treatments for advanced HCC. More recently, the combination of Atezolizumab (an Immune Checkpoint Inhibitor) and Bevacizumab (an anti-VEGF antibody) has been approved based on the IMbrave150 trial, which demonstrated a survival benefit over Sorafenib. These treatments are similar to the combination of Lenvatinib and Pembrolizumab currently being studied, as they also target tumor growth and immune response.

What other types of research exist?

Promising novel alternatives to Lenvatinib and Pembrolizumab for Hepatocellular Carcinoma patients include: 1) Atezolizumab plus Bevacizumab, which has shown improved overall survival and progression-free survival in the IMbrave150 trial. 2) Cabozantinib, a tyrosine kinase inhibitor, which has demonstrated efficacy in advanced HCC. 3) Nivolumab plus Ipilimumab, an immune checkpoint inhibitor combination, which has shown promising results in terms of response rates and survival benefits.

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Tyrosine Kinase Inhibitor

Lenvatinib + Pembrolizumab for Liver Cancer

Q: What is the mechanism of action of this treatment?

The most common treatments for Hepatocellular Carcinoma (HCC) include Tyrosine Kinase Inhibitors (TKIs) and Immune Checkpoint Inhibitors (ICIs). TKIs, such as Lenvatinib, work by blocking specific enzymes (tyrosine kinases) involved in the signaling pathways that promote tumor growth and angiogenesis (formation of new blood vessels that supply the tumor). This inhibition can slow down or stop the progression of the cancer. On the other hand, ICIs like Pembrolizumab target immune checkpoints (e.g., PD-1/PD-L1) that cancer cells use to evade the immune system. By blocking these checkpoints, ICIs enhance the body's immune response against cancer cells. The combination of these therapies is particularly significant for HCC patients as it addresses both tumor growth and immune evasion, potentially leading to improved outcomes compared to monotherapy.

Phase 3

Waitlist Available

Research Sponsored by Merck Sharp & Dohme Corp.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach

Has a diagnosis of hepatocellular carcinoma confirmed by radiology, histology, or cytology

Must not have

Has significant cardiovascular impairment within 12 months of the first dose of study intervention such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident stroke, or cardiac arrhythmia associated with hemodynamic instability

Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to approximately 41 months

Awards & highlights

Pivotal Trial

Summary

This trial is testing a combination of two drugs, lenvatinib and pembrolizumab, against lenvatinib alone. The study focuses on adults with advanced liver cancer. Lenvatinib works by stopping cancer cells from growing, while pembrolizumab helps the immune system fight the cancer. The goal is to see if this combination improves survival and delays cancer progression better than lenvatinib alone. Lenvatinib combined with pembrolizumab has shown promising results in early phase studies for hepatocellular carcinoma (HCC).

Who is the study for?

Adults over 18 with advanced hepatocellular carcinoma (a type of liver cancer) who haven't had certain treatments like anti-PD-1 or systemic chemotherapy for HCC in the past 3 years. They should be physically capable (ECOG status 0-1), have a life expectancy over 3 months, and not have conditions that could affect study participation or drug absorption.

What is being tested?

The trial is testing if combining lenvatinib, a cancer medication, with pembrolizumab, an immunotherapy drug, is more effective than lenvatinib alone for first-line treatment of liver cancer. The main goal is to see if this combination improves survival without the disease getting worse.

What are the potential side effects?

Possible side effects include high blood pressure, fatigue, diarrhea, decreased appetite and weight loss from lenvatinib; pembrolizumab may cause immune system-related side effects such as inflammation in organs like lungs or intestines.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My liver cancer is at a stage where it can't be cured with surgery or local treatments.

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My liver cancer diagnosis was confirmed through imaging or lab tests.

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My liver is functioning well.

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I am fully active or restricted in physically strenuous activity but can do light work.

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I have a liver cancer lesion that can be measured.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I haven't had major heart problems or strokes in the last year.

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I have had pneumonitis treated with steroids or have it now.

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I have been treated with specific immune therapy for cancer.

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I have been treated for an autoimmune disease in the last 2 years.

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I have a condition that affects how my body absorbs medication.

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I have a severe fistula.

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My heart's pumping ability is below normal.

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I have received an organ or tissue transplant from another person.

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I had major liver surgery less than 4 weeks ago.

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I have active tuberculosis.

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I have had bleeding from varices in my esophagus or stomach in the past 6 months.

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I have an immune system disorder or have been on steroids or other immune-weakening medicines recently.

Select...

I have or had cancer spread to my brain or spinal cord.

Select...

I have not had chemotherapy for liver cancer or any cancer in the last 3 years.

Select...

I have a serious wound or broken bone that is not healing.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to approximately 41 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to approximately 41 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to approximately 41 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Overall Survival (OS)

Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

Secondary study objectives

Disease Control Rate (DCR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)

Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

Duration of Response (DOR) Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)

+11 more

Side effects data

From 2024 Phase 3 trial • 794 Patients • NCT03713593

47%

Diarrhoea

45%

Hypertension

42%

Hypothyroidism

37%

Decreased appetite

34%

Palmar-plantar erythrodysaesthesia syndrome

33%

Proteinuria

32%

Fatigue

30%

Weight decreased

29%

Aspartate aminotransferase increased

26%

Blood bilirubin increased

25%

Platelet count decreased

23%

Alanine aminotransferase increased

23%

Nausea

22%

Arthralgia

21%

Dysphonia

18%

Abdominal pain

18%

Asthenia

17%

Pruritus

17%

Constipation

16%

Gamma-glutamyltransferase increased

16%

Rash

16%

Oedema peripheral

15%

Hypoalbuminaemia

14%

Lipase increased

14%

Back pain

13%

Cough

13%

Vomiting

12%

Headache

12%

Blood alkaline phosphatase increased

12%

Anaemia

11%

Abdominal pain upper

11%

Pyrexia

11%

Hyponatraemia

11%

Dyspnoea

10%

Amylase increased

10%

Blood creatinine increased

10%

Stomatitis

Hypokalaemia

Insomnia

Neutrophil count decreased

Urinary tract infection

Hyperthyroidism

Dyspepsia

Abdominal distension

White blood cell count decreased

Haematuria

Ascites

Hypertriglyceridaemia

Myalgia

Dizziness

Toothache

Mucosal inflammation

Hyperglycaemia

Hypomagnesaemia

Epistaxis

Hypophosphataemia

Pain in extremity

Dysgeusia

Oropharyngeal pain

Hepatic encephalopathy

Neutropenia

Dry mouth

Malaise

Hyperkalaemia

Pneumonia

General physical health deterioration

Tumour haemorrhage

Pancreatitis

Pneumonia klebsiella

Hepatic pain

Septic shock

Hepatic failure

Angina pectoris

Myocardial infarction

Gastric ulcer haemorrhage

Gastrointestinal haemorrhage

Hepatorenal syndrome

COVID-19

COVID-19 pneumonia

Atrial fibrillation

Immune thrombocytopenia

Acute myocardial infarction

Adrenal insufficiency

Hypophysitis

Colitis

Gastric haemorrhage

Haemorrhoidal haemorrhage

Death

Multiple organ dysfunction syndrome

Immune-mediated hepatitis

Sepsis

Dehydration

Diabetic ketoacidosis

Hypoglycaemia

Tumour lysis syndrome

Cerebrovascular accident

Depressed level of consciousness

Ischaemic stroke

Seizure

Acute kidney injury

Pemphigoid

100%

80%

60%

40%

20%

Study treatment Arm

Lenvatinib + Placebo

Lenvatinib + Pembrolizumab

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: lenvatinib plus pembrolizumabExperimental Treatment2 Interventions

Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight \<60 kg) orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.

Group II: lenvatinib plus placeboActive Control2 Interventions

Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight \<60 kg) orally QD plus saline placebo by IV infusion on Day 1 Q3W. Saline placebo will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

lenvatinib

2018

Completed Phase 3

~1950

pembrolizumab

2017

Completed Phase 3

~5890

0 / 20Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Hepatocellular Carcinoma (HCC) include Tyrosine Kinase Inhibitors (TKIs) and Immune Checkpoint Inhibitors (ICIs). TKIs, such as Lenvatinib, work by blocking specific enzymes (tyrosine kinases) involved in the signaling pathways that promote tumor growth and angiogenesis (formation of new blood vessels that supply the tumor). This inhibition can slow down or stop the progression of the cancer. On the other hand, ICIs like Pembrolizumab target immune checkpoints (e.g., PD-1/PD-L1) that cancer cells use to evade the immune system. By blocking these checkpoints, ICIs enhance the body's immune response against cancer cells. The combination of these therapies is particularly significant for HCC patients as it addresses both tumor growth and immune evasion, potentially leading to improved outcomes compared to monotherapy.

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma.