T-Cell Repertoire Sequencing: Assessing Pembrolizumab Efficacy in Advanced Non-small Lung Cancer

This is a single site, non-randomized trial for the assessment of intravenous (IV) pembrolizumab (also known as MK-3475) combined with pemetrexed/platinum-based chemotherapy in subjects with advanced or metastatic non-squamous non-small lung cancer (NSCLC) who have not previously received systemic therapy for advanced disease and in whom directed therapy is not indicated. Approximately 30 subjects will be enrolled in this trial to examine the clonality and diversity dynamics matched with disease response evaluated by RECIST 1.1.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-small Cell Lung Cancer Metastatic
• Intervention / Treatment: Drug: Pembrolizumab 50 MG Injection [Keytruda]

Detailed Description

Subjects will receive pembrolizumab 200 mg combined with pemetrexed and platinum (investigator's choice of cisplatin or carboplatin), as indicated below:

Pembrolizumab 200 mg + pemetrexed 500 mg/m2 (with vitamin supplementation) + cisplatin 75 mg/m2 OR carboplatin AUC 5, all on Day 1 every 3 weeks (Q3W) for 4 cycles followed by pembrolizumab 200 mg + pemetrexed 500 mg/m2 Q3W until progression.

Treatment with pembrolizumab and pemetrexed will continue until 35 trial treatments have been administered, documented disease progression or unacceptable adverse event(s).

Patients will be stratified according to clinical and histopathological parameters: 1. PD-L1 status (PD-L1 >/= 1 or <1) 2. Age < 65 vs => 65 3. Smoking history yes vs no 4. Platinum chemotherapy: cisplatin vs. carboplatin 5. Immune-related adverse events (irAEs).

TCR repertoire clonality and diversity will serve as an assessment measure for treatment response, along with PET/CT-scans, tumor exomal profile and ctDNA dynamics.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ari Raphael, M.D; Phone Number: +972-3-6973082; Email: arir@tlvmc.gov.il

Participation Criteria

Eligibility Criteria

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

Study Population

Histologically confirmed diagnosis of NSCLC non-squamous stage IV or stage III, according to AJCC v8 that are not amenable for definitive therapy will be enrolled in this study.

Patients have not previously received systemic therapy for advanced disease and in whom directed therapy is not indicated.

Description

Inclusion Criteria:

• Participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Archival tumor tissue sample or newly obtained [core, incisional or excisional] biopsy of a tumor lesion not previously irradiated has been provided.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Adequate organ function.

Exclusion Criteria:

• Pregnancy or breastfeeding
• Aberration in a known targetable molecular driver.
• Received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor.
• Received prior systemic anti-cancer therapy for metastatic disease.
• Received prior radiotherapy within 2 weeks of start of study intervention.
• Major surgery within 14 days.
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy.
• Known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated or asymptomatic brain metastases may participate provided they are radiologically stable.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• 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: Pembrolizumab + Carboplatin+ Pemetrexed	Drug: Pembrolizumab 50 MG Injection [Keytruda]; Chemo-immunotherapy combination; Other Names: Carboplatin; Pemetrexed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) per RECIST 1.1 - correlated to TCR repertoire data, such as clonality/diversity.	ORR defined as the percentage of participants who achieve a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 as assessed by the investigator. By integrating serial TCR repertoire sequencing (Rep-seq) of NSCLC patients treated with pembrolizumab and platinum-based chemotherapy regimens we aim to capture the temporal clonality and diversity dynamics with the disease response.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) correlated with circulating tumor DNA (ctDNA), by measurement of variant allele frequency (VAF).	To capture the VAF in ctDNA, and correlate it with response to therapy evaluated by ORR per RECIST 1.1. We will capture its dynamics throughout blood samples collected longitudinally (pre-and during treatment).	5 years

Collaborators and Investigators

• Sponsor: Ari Raphael
• Collaborators: Merck Sharp & Dohme LLC; Bar-Ilan University, Israel
• Investigators: Principal Investigator: Ari Raphael, M.D, Tel-Aviv University school of medicine

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: September 13, 2023
• First Submitted That Met QC Criteria: September 13, 2023
• First Posted (Actual): September 21, 2023

Study Record Updates

• Last Update Posted (Actual): June 3, 2024
• Last Update Submitted That Met QC Criteria: May 30, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: ctDNA; T-cell repertoire
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Folic Acid Antagonists; Carboplatin; Pembrolizumab; Pemetrexed
• Other Study ID Numbers: 0222-24 TLV

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes