What side effects are associated with this type of intervention?

The combination of Pembrolizumab, Lenvatinib, and chemotherapy for esophageal cancer is associated with several side effects. Pembrolizumab can cause immune-related adverse events like fatigue, rash, diarrhea, and endocrine disorders such as hypothyroidism. Lenvatinib often leads to hypertension, proteinuria, diarrhea, and fatigue. Chemotherapy agents typically result in nausea, vomiting, myelosuppression, and neuropathy. When these treatments are combined, patients may experience overlapping toxicities, leading to a higher incidence of severe side effects such as hypertension, diarrhea, and fatigue.

What prior FDA approvals exist?

The FDA has approved pembrolizumab, a PD-1 inhibitor, for the treatment of esophageal cancer, particularly in cases where tumors express high levels of PD-L1. Pembrolizumab has shown superiority over traditional chemotherapy in improving overall survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma. While lenvatinib, a tyrosine kinase inhibitor, has been approved in combination with pembrolizumab for other cancers such as endometrial carcinoma, its combination with pembrolizumab and chemotherapy for esophageal cancer is currently under investigation. These approvals highlight the growing role of immunotherapy and targeted therapies in the treatment landscape for esophageal cancer.

What other types of research exist?

Promising alternatives to Pembrolizumab + Lenvatinib + Chemotherapy for esophageal cancer patients include: 1) Pembrolizumab + Chemotherapy (as shown in the KEYNOTE-590 study, which demonstrated improved overall survival and progression-free survival), and 2) Tislelizumab + Chemotherapy (as assessed in a phase II study for advanced esophageal squamous cell carcinoma and gastroesophageal junction adenocarcinoma). Both combinations have shown efficacy and safety in clinical trials.

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Fluoropyrimidine-based Chemotherapy

Pembrolizumab + Lenvatinib + Chemo for Esophageal Cancer

Phase 3

Recruiting

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 adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP≤150/90 millimeters of mercury (mm Hg) with no change in antihypertensive medications within 1 week prior to randomization

Has a histologically or cytologically confirmed diagnosis of metastatic squamous cell carcinoma of the esophagus

Must not have

Has had previous therapy for locally advanced unresectable or metastatic esophageal cancer

Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to ~53 months

Awards & highlights

Summary

This trial tests a new combination of drugs and chemotherapy for advanced esophageal cancer. It targets patients whose cancer has spread and who need effective first-line treatment. The treatment works by enhancing the immune system, blocking cancer growth, and killing cancer cells.

Who is the study for?

This trial is for adults with metastatic squamous cell carcinoma of the esophagus. Participants must have controlled blood pressure, adequate organ function, and agree to contraception if applicable. Exclusions include adenocarcinoma of the esophagus, significant bleeding risks, recent major surgery or radiotherapy, active infections like Hepatitis B/C or HIV, weight loss over 20% in last 3 months, and certain cardiovascular diseases.

What is being tested?

The study tests pembrolizumab plus lenvatinib with chemotherapy against pembrolizumab with chemotherapy alone in first-line treatment for metastatic esophageal cancer. The goal is to see which combination improves overall survival (OS) and progression-free survival (PFS) better.

What are the potential side effects?

Potential side effects may include allergic reactions to drugs used; high blood pressure from lenvatinib; immune-related issues such as inflammation in organs due to pembrolizumab; fatigue; digestive problems; increased risk of infection; and possible nerve damage.

Eligibility Criteria

Inclusion Criteria

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

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My blood pressure is 150/90 or lower, and my medication hasn't changed in the last week.

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My esophageal cancer is confirmed to be squamous cell and has spread.

Exclusion Criteria

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

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I have received treatment for advanced esophageal cancer that cannot be surgically removed.

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I have cancer that has spread to my brain or spinal cord.

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I have had serious heart problems in the last year.

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My cancer, which started in the esophagus, has spread to other parts of my body.

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I have trouble swallowing or an obstruction in my digestive tract.

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I have a history of Hepatitis B or an active Hepatitis C infection.

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I frequently need treatment for fluid buildup in my chest or abdomen.

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I have lost more than 20% of my weight in the last 3 months.

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I have another cancer that is getting worse or was treated in the last 3 years.

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My cancer has spread to nearby organs like the aorta or windpipe.

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I have frequent and uncontrollable diarrhea.

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My scans show my tumor is surrounding a major blood vessel or has holes.

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I am at risk for or have had significant GI bleeding.

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I have an immune system disorder, am on long-term steroids, or have had an organ transplant.

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I have had lung inflammation not caused by infection, treated with steroids.

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My cancer is in the esophagus and has not spread far.

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I have not had radiotherapy in the last 2 weeks or suffered from radiation pneumonitis.

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I have moderate to severe numbness, tingling, or pain in my hands or feet.

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I have an autoimmune disease but haven't needed strong medication for it in the last 2 years.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to ~53 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to ~53 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to ~53 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

Part 1 (FP and TP Safety Run-in): Number of Participants With Adverse Events (AEs)

Part 1 (FP and TP Safety Run-in): Number of Participants With Dose Limiting Toxicities (DLTs)

Part 1 (FP and TP Safety Run-in): Number of Participants who Discontinued Study Treatment Due to an AE

+1 more

Secondary study objectives

Part 2 (Main Study): Change From Baseline in HRQoL Score Using EORTC Quality of Life Questionnaire-Oesophageal Module (QLQ-OES18)

Part 2 (Main Study): Change From Baseline in Health-related Quality of life (HRQoL) Score Using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)

Part 2 (Main Study): DOR per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10

+10 more

Side effects data

From 2012 Phase 3 trial • 256 Patients • NCT01005680

51%

Neutropenia

47%

Leukopenia

46%

Nausea

43%

Vomiting

35%

Anaemia

31%

Decreased appetite

26%

Haemoglobin decreased

26%

Fatigue

25%

Constipation

25%

White blood cell count decreased

24%

Neutrophil count decreased

19%

Alanine aminotransferase increased

13%

Platelet count decreased

12%

Rash

10%

Aspartate aminotransferase increased

10%

Thrombocytopenia

Blood sodium decreased

Hypokalaemia

Insomnia

Pyrexia

Hyponatraemia

Blood creatinine increased

Lymphopenia

Diarrhoea

Dyspepsia

Red blood cell count decreased

Cough

Dizziness

Bone marrow failure

Cerebral infarction

Dyspnoea

Ischaemic stroke

Pulmonary embolism

Embolism venous

Superior vena cava syndrome

100%

80%

60%

40%

20%

Study treatment Arm

Gemcitabine Plus Cisplatin (GC)

Pemetrexed Plus Cisplatin (PC)

Trial Design

3Treatment groups

Experimental Treatment

Active Control

Group I: Part 2: Pembrolizumab + Lenvatinib + ChemotherapyExperimental Treatment8 Interventions

In the induction phase, participants receive pembrolizumab 400mg intravenously (IV) every 6 weeks (Q6W) for 2 cycles (each cycle length = 6 weeks) plus Lenvatinib 8 mg orally (PO) once daily (QD) plus chemotherapy with FP (cisplatin 80 mg/m\^2 and 5-FU 4000 mg/m\^2) or TP (paclitaxel 175 mg/m\^2 and cisplatin 75 mg/m\^2) IV every 3 weeks for 4 administrations or mFOLFOX6 (oxaliplatin 85 mg/m\^2, 5-FU 400 mg/m\^2 followed by 2400 mg/m\^2, and leucovorin 400 mg/m\^2 \[or levoleucovorin 200 mg/m\^2\] once every 2 weeks \[Q2W\] for 6 administrations at the investigator's discretion (approximately 12 weeks). In the consolidation phase, participants receive pembrolizumab 400 mg IV Q6W for 16 cycles (each cycle length = 6 weeks) and Lenvatinib 20 mg PO until progressive disease or discontinuation (approximately 96 weeks).

Group II: Part 1: Pembrolizumab + Lenvatinib + ChemotherapyExperimental Treatment5 Interventions

In the induction phase, participants receive pembrolizumab 400mg intravenously (IV) every 6 weeks (Q6W) for 2 cycles (each cycle length = 6 weeks) plus Lenvatinib 8 mg orally (PO) once daily (QD) plus chemotherapy with FP (cisplatin 80 mg/m\^2 and 5-FU 400 mg/m\^2 followed by 2400 mg/m\^2) or TP (paclitaxel 175 mg/m\^2 and cisplatin 75 mg/m\^2) IV every 3 weeks for 4 administrations at the investigator's discretion (approximately 12 weeks). In the consolidation phase, participants receive pembrolizumab 400 mg IV Q6W for 16 cycles (each cycle length = 6 weeks) and Lenvatinib 20 mg PO until progressive disease or discontinuation (approximately 96 weeks).

Group III: Part 2: Pembrolizumab + ChemotherapyActive Control6 Interventions

Participants receive pembrolizumab 400 mg IV every 6 weeks for 18 cycles (each cycle length = 6 weeks, approximately 2 years) plus chemotherapy with FP (cisplatin 80 mg/m\^2 IV Q3W for up to 6 administrations \[up to \~18 weeks\] and 5-FU 4000 mg/m\^2 IV Q3W for up to 35 administrations \[up to \~2 years\]) or TP (paclitaxel 175 mg/m\^2 and cisplatin 75 mg/m\^2 Q3W for up 6 administrations \[up to \~18 weeks\]) or in combination with mFOLFOX6 (oxaliplatin 85 mg/m\^2, 5-FU 400 mg/m\^2 followed by 2400 mg/m\^2 and leucovorin 400 mg/m\^2 \[or levoleucovorin 200 mg/m\^2\] IV Q2W for up to 52 administrations \[approximately 2 years\]).

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Oxaliplatin

2011

Completed Phase 4

~2890

Levoleucovorin

2019

Completed Phase 2

~20

Lenvatinib

2017

Completed Phase 4

~2040

Cisplatin

2013

Completed Phase 3

~2360

5-FU

2014

Completed Phase 3

~3420

Leucovorin

2005

Completed Phase 4

~6010

Paclitaxel

2011

Completed Phase 4

~5810

Pembrolizumab

2017

Completed Phase 2

~2070

0 / 21Eligibility 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 esophageal cancer include PD-1 inhibitors like pembrolizumab, tyrosine kinase inhibitors like lenvatinib, and cytotoxic chemotherapy. PD-1 inhibitors work by blocking the programmed death-1 (PD-1) pathway, which cancer cells use to evade the immune system, thereby allowing the immune system to recognize and attack the cancer cells. Tyrosine kinase inhibitors target specific enzymes (tyrosine kinases) involved in the signaling pathways that promote cancer cell growth and survival, effectively inhibiting tumor growth. Cytotoxic chemotherapy uses drugs that kill rapidly dividing cells, including cancer cells, by damaging their DNA or interfering with cell division. These treatments are crucial for esophageal cancer patients as they offer a multi-faceted approach to controlling and potentially reducing tumor burden, improving overall survival and progression-free survival.

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.