. 2024 May 2;20(35):2709–2721. doi: 10.2217/fon-2022-1148

Table 1.

Eligibility criteria for the LEAP-014 study.

Inclusion criteria	Exclusion criteria
• Male or female • Aged ≥18 years • Histologically or cytologically confirmed diagnosis of metastatic squamous cell carcinoma of the esophagus • Willing to use adequate contraception methods throughout the study and for 7 days after the last dose of lenvatinib or 90 days after the last dose of chemotherapy, whichever comes last (males), or 120 days after the last dose of pembrolizumab, 30 days after the last dose of lenvatinib, or 180 days after the last dose of chemotherapy, whichever comes last (females) • Adequately controlled BP with or without antihypertensive medications, defined as ≤150/90 mm Hg, with no change in antihypertensive medication within 1 week of randomization • Adequate organ function	• Previous therapy for locally advanced, unresectable, or metastatic esophageal cancer • Diagnosed with locally advanced esophageal carcinoma or metastatic adenocarcinoma of the esophagus • Direct tumor invasion into adjacent organs such as the aorta or trachea (T4b disease)^† • Radiographic evidence of >90-degree encasement of a major blood vessel or of intratumoral cavitation • Diagnosed with an immunodeficiency or receiving chronic systemic steroid therapy (in dosing ≥10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study intervention • A known additional malignancy that is progressing or has required active treatment within the past 3 years, excluding basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that has undergone potentially curative therapy • Known active CNS metastases and/or carcinomatous meningitis • Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapy, such as thyroxine and insulin, is not considered a form of systemic treatment and is allowed) • A history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease • Poorly controlled diarrhea, defined as watery stool, uncontrollable bowel movement with drugs ≥grade 2, and number of defecations ≥5/day • Clinically significant CVD within 12 months from first dose of study intervention, including NYHA Class III or IV congestive heart failure, unstable angina, MI, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability • Peripheral neuropathy ≥grade 2 • A known history of HIV, HBV or HCV infection • Weight loss of >20% within the past 3 months • Perforation risks, such as a serious nonhealing wound, peptic ulcer or bone fracture, within 28 days before randomization • Significant bleeding disorders, vasculitis, or a significant bleeding episode from the GI tract within 12 weeks before randomization^† • Active hemoptysis, defined as at least 0.5 teaspoon of bright red blood, within 3 weeks before the first dose of study drug or tumor bleeding within 2 weeks before the first dose of study treatment • GI obstruction, poor oral intake or difficulty in taking oral medication^‡ • Major surgery, open biopsy or significant traumatic injury within 3 weeks before the first dose of study interventions, or anticipation of the need for major surgery during the course of study intervention • Received prior radiotherapy within 2 weeks of start of study intervention • Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention • Received prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, or an agent directed to another stimulatory or co-inhibitory T-cell receptor

Inclusion criteria

Exclusion criteria

• Male or female
• Aged ≥18 years
• Histologically or cytologically confirmed diagnosis of metastatic squamous cell carcinoma of the esophagus
• Willing to use adequate contraception methods throughout the study and for 7 days after the last dose of lenvatinib or 90 days after the last dose of chemotherapy, whichever comes last (males), or 120 days after the last dose of pembrolizumab, 30 days after the last dose of lenvatinib, or 180 days after the last dose of chemotherapy, whichever comes last (females)
• Adequately controlled BP with or without antihypertensive medications, defined as ≤150/90 mm Hg, with no change in antihypertensive medication within 1 week of randomization
• Adequate organ function

• Previous therapy for locally advanced, unresectable, or metastatic esophageal cancer
• Diagnosed with locally advanced esophageal carcinoma or metastatic adenocarcinoma of the esophagus
• Direct tumor invasion into adjacent organs such as the aorta or trachea (T4b disease)^†
• Radiographic evidence of >90-degree encasement of a major blood vessel or of intratumoral cavitation
• Diagnosed with an immunodeficiency or receiving chronic systemic steroid therapy (in dosing ≥10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study intervention
• A known additional malignancy that is progressing or has required active treatment within the past 3 years, excluding basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that has undergone potentially curative therapy
• Known active CNS metastases and/or carcinomatous meningitis
• Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapy, such as thyroxine and insulin, is not considered a form of systemic treatment and is allowed)
• A history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
• Poorly controlled diarrhea, defined as watery stool, uncontrollable bowel movement with drugs ≥grade 2, and number of defecations ≥5/day
• Clinically significant CVD within 12 months from first dose of study intervention, including NYHA Class III or IV congestive heart failure, unstable angina, MI, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability
• Peripheral neuropathy ≥grade 2
• A known history of HIV, HBV or HCV infection
• Weight loss of >20% within the past 3 months
• Perforation risks, such as a serious nonhealing wound, peptic ulcer or bone fracture, within 28 days before randomization
• Significant bleeding disorders, vasculitis, or a significant bleeding episode from the GI tract within 12 weeks before randomization^†
• Active hemoptysis, defined as at least 0.5 teaspoon of bright red blood, within 3 weeks before the first dose of study drug or tumor bleeding within 2 weeks before the first dose of study treatment
• GI obstruction, poor oral intake or difficulty in taking oral medication^‡
• Major surgery, open biopsy or significant traumatic injury within 3 weeks before the first dose of study interventions, or anticipation of the need for major surgery during the course of study intervention
• Received prior radiotherapy within 2 weeks of start of study intervention
• Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• Received prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, or an agent directed to another stimulatory or co-inhibitory T-cell receptor

^†

Because of the potential risk of major bleeding with lenvatinib treatment.

^‡

To be eligible for the study, patients must be able to swallow the lenvatinib capsule. Lenvatinib capsules can be dissolved (without breaking or crushing) in a small glass of liquid such as water, milk or apple juice if a participant is unable to swallow or has a feeding tube.

BP: Blood pressure; CNS: Central nervous system; CVD: Cardiovascular disease; GI: Gastrointestinal; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; PD-L1: Programmed death ligand 1.