A Prospective, Single-center, Non-randomized, Interventional Study on the Effectiveness and Safety of Combined Immunotargeted Therapy in Patients With Metastatic Non-small Cell Cancer With a RET Gene Translocation (LPR-2)

LPR-2: A Prospective, Single-center, Non-randomized, Interventional Study on the Effectiveness and Safety of Combined Immunotargeted Therapy in Patients With Metastatic Non-small Cell Cancer With a RET Gene Translocation

This interventional study will evaluate the effectiveness, safety, and tolerability of pembrolizumab in combination with lenvatinib in adults with metastatic non-small cell lung cancer (NSCLC) who have a confirmed RET gene rearrangement and whose disease has progressed after one or more previous systemic treatments.

Participants will receive pembrolizumab intravenously once every 3 weeks in combination with lenvatinib taken by mouth daily until disease progression, unacceptable side effects, or treatment discontinuation. Tumor response will be assessed using imaging studies according to RECIST 1.1, and participants will be monitored for treatment-related side effects, progression-free survival, and overall survival. The study will also evaluate clinical and tumor characteristics, RET rearrangement variants, and the diagnostic methods used to confirm RET-positive status.

Study Overview

• Status: Recruiting
• Conditions: NSCLC (Non-small Cell Lung Cancer)R
• Intervention / Treatment: Combination product: lenvatinib pembrolizumab

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sergey Orlov, Doctor of Medical Sciences, Pr; Phone Number: +7 918 603 48 38; Email: orloff-sv@mail.ru
• Study Contact Backup: Name: Maria Sviridenko, MD; Phone Number: +79215990021; Email: sviridenko944@gmail.com

Study Locations

• Russia
  • Saint Petersburg, Russia, 197022
    • Recruiting
    • EuroCityClinic LLC
    • Contact: Maria Sviridenko, MD; Phone Number: +7 921 599 00 21; Email: sviridenko944@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Be able and willing to sign a written informed consent form before taking part in the study.
2. Be 18 years of age or older.
3. Have a confirmed diagnosis of metastatic non-small cell lung cancer (NSCLC), established by examination of a tumor tissue sample, with cancer that has spread to distant parts of the body.
4. Have a confirmed RET gene rearrangement, identified using a validated molecular test, such as next-generation sequencing (NGS), polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or another validated method.
5. Have previously received treatment for metastatic NSCLC and have experienced disease progression during or after at least one previous line of standard systemic chemotherapy or targeted therapy.
6. Have previously received platinum-containing chemotherapy for metastatic NSCLC and have experienced disease progression during or after this treatment.
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, meaning that the participant is fully active or able to perform light daily activities.
8. Have at least one tumor lesion that can be measured on imaging according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
9. Have an expected life expectancy of at least 3 months.

10. Have adequate blood cell counts at screening, defined as:

    • absolute neutrophil count of at least \(1.5 \times 10^9/L\);
    • platelet count of at least \(100 \times 10^9/L\);
    • hemoglobin level of at least 90 g/L.

    The participant must not have received a blood transfusion or transfusion of blood components within 14 days before starting study treatment.

11. Have adequate liver function at screening, defined as:

    • total bilirubin no higher than 1.5 times the upper limit of normal (ULN); participants with Gilbert syndrome may have a total bilirubin level up to 3 times the ULN;
    • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels below 3 times the ULN; for participants with liver metastases, levels below 5 times the ULN are allowed;
    • alkaline phosphatase (ALP) level below 3 times the ULN; for participants with liver and/or bone metastases, a level below 5 times the ULN is allowed.

12. Have adequate kidney function at screening, defined as:

    • serum creatinine no higher than 1.5 times the ULN; or
    • creatinine clearance of at least 50 mL/min if the serum creatinine level is higher than 1.5 times the ULN.

    Creatinine clearance will be calculated according to local medical standards. If no local standard is available, it may be calculated using the Cockcroft-Gault formula. Estimated glomerular filtration rate (eGFR) may also be used instead of serum creatinine or creatinine clearance, according to the study protocol.

13. Have a thyroid-stimulating hormone (TSH) level within the normal range at screening. At the investigator's discretion, a participant with a TSH level outside the normal range may still be eligible if the triiodothyronine (T3) and free thyroxine (free T4) levels are within the normal range.

Exclusion Criteria:

1. They have previously received treatment with lenvatinib.
2. They have had a severe allergic or hypersensitivity reaction to pembrolizumab, lenvatinib, any component of the study medicines, or similar medicines, including human, humanized, or mouse monoclonal antibodies or immunoglobulin medicines.
3. They have an active autoimmune disease.
4. They have cancer that has spread to the central nervous system or has caused carcinomatous meningitis. Participants with brain metastases may be eligible if the brain metastases were adequately treated with radiation therapy and/or surgery and have remained stable on imaging studies.
5. They have a clinically significant heart condition, including uncontrolled high blood pressure, coronary artery disease or any type of angina, a previous heart attack or post-heart-attack heart damage, or heart failure classified as New York Heart Association (NYHA) class II or higher.
6. Imaging or clinical examination shows that the tumor has invaded blood vessels or is located close to major blood vessels, and the investigator believes that this could increase the risk of bleeding.
7. They have severe kidney or liver failure.
8. They have any known allergy to an ingredient in the study medicines.
9. They are pregnant or breastfeeding.
10. They have uncontrolled high blood pressure despite treatment, defined as systolic blood pressure above 150 mmHg and/or diastolic blood pressure above 100 mmHg. Participants with a hypertensive crisis or hypertensive encephalopathy are also excluded.
11. They have another serious medical condition that, in the investigator's opinion, could affect participation in the study or the safety of the participant.
12. They have ongoing side effects from previous treatment that are more severe than Grade 1.
13. Women who could become pregnant are not willing to use an effective method of contraception during the study and for at least 30 days after the last dose of the study medicines.
14. Men with partners who could become pregnant are not willing to use an effective method of contraception during the study and for at least 30 days after the last dose of the study medicines.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lenvatinib, Pembrolizumab	Combination product: lenvatinib pembrolizumab; Participants will receive pembrolizumab intravenously every 3 weeks in combination with lenvatinib, which is taken orally every day until disease progression, unacceptable side effects, or treatment is stopped.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented disease progression (PD) according to the investigator's assessment using RECIST v1.1 criteria, or to death from any cause-whichever happens first. Disease progression (PD) is recorded when the sum of diameters (SOD) of target lesions increases by at least 20% from the smallest SOD previously recorded, including the baseline. In addition to the 20% relative increase, there must also be an absolute increase in SOD of at least 5 mm.	Up to 48 months.
Objective Response Rate (ORR)	The objective response rate (ORR) is calculated as the proportion of participants whose best overall response (BOR) reaches either a complete (CR) or partial (PR) response for both target and non-target lesions. A complete response (CR) is defined as the disappearance of all target and non-target lesions, with any pathological lymph nodes (whether target or non-target) shrinking to less than 10 mm in short-axis diameter. A partial response (PR) is recorded when the sum of diameters of target lesions decreases by at least 30% from baseline. Tumor burden is assessed according to modified RECIST 1.1 criteria: up to five target lesions in total are considered, with no more than two lesions per organ.	Up to 48 months.
Disease Control Rate (DCR)	The disease control rate (DCR) is calculated as the proportion of participants who, according to the investigator's assessment based on RECIST v1.1 criteria, achieve the best overall response of complete response (CR), partial response (PR), or stable disease (SD). Stable disease (SD) is defined as not enough reduction in tumor burden to qualify as CR or PR, and at the same time not enough increase to qualify as disease progression (PD). A complete response (CR) is recorded when all target lesions disappear; any pathological lymph nodes must shrink to less than 10 mm in the short axis. A partial response (PR) is noted when the sum of diameters (SOD) of all target lesions decreases by at least 30% compared to the baseline SOD, without signs of a CR. Disease progression (PD) is defined as an increase in the SOD of target lesions by at least 20% compared to the smallest recorded SOD at previous time points (including baseline); in addition to the 20% relative increase, there also needs t	Up to 48 months.

Collaborators and Investigators

• Sponsor: EuroCityClinic LLC

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2030

Study Registration Dates

• First Submitted: August 26, 2026
• First Submitted That Met QC Criteria: September 4, 2026
• First Posted (Actual): September 9, 2026

Study Record Updates

• Last Update Posted (Actual): September 9, 2026
• Last Update Submitted That Met QC Criteria: September 4, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; Pembrolizumab; Lenvatinib; RET fusion
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: 08Вн/26

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data will not be routinely shared with other researchers. Study results will be reported in aggregate form in scientific publications and presentations. De-identified individual participant data may be considered for sharing only when required by applicable laws, regulations, institutional policies, or ethics committee requirements, and subject to protection of participant privacy and confidentiality.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No