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Evaluation of Novel Immunotherapy Combinations Versus Pembrolizumab in PD-L1-High Non-Small Cell Lung Cancer: A Phase 2 Randomized Open-Label Study

Trial ID: 2023-505057-40-00
Protocol: 213824
Sponsor: Glaxosmithkline Research & Development Limited

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Diseases & Conditions

Non-small cell lung cancer

Objectives

The primary objective of this study is to evaluate the **antitumor activity** of novel immunotherapy combinations compared with pembrolizumab in participants with PD-L1-high (TC/TPS ≥50%) non-small cell lung cancer (NSCLC). This is clinically relevant as it aims to determine the efficacy of new treatment regimens in a specific subset of NSCLC patients, potentially offering more effective therapeutic options.

Secondary objectives include:

Assessing the dose-response relationship of novel immunotherapy combinations across a range of the novel components' dose levels and fixed dostarlimab dose.
Further assessing the clinical activity of novel immunotherapy combinations compared with pembrolizumab in participants with PD-L1-high NSCLC.
Evaluating the antitumor activity of novel immunotherapy combinations via treatment arm comparisons to assess the contribution of components for the combination regimens.
Further characterizing the safety of novel immunotherapy combinations.
Determining the immunogenicity of individual agents comprising novel immunotherapy combinations.
Characterizing the pharmacokinetic (PK) properties of novel immunotherapy combinations.

Participants

The clinical trial involves a total of **166 participants** diagnosed with **non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, who have a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic NSCLC. Participants are required to have a **PD-L1-high** tumor expression (TC/TPS ≥50%) and must not have received prior systemic therapy for their condition. The trial excludes individuals with small-cell or neuroendocrine elements in their tumors. Participants are expected to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The selection process ensures that participants have adequate organ function and measurable disease based on RECIST 1.1 criteria. The trial does not include vulnerable populations, and both genders are represented without specific lifestyle considerations such as diet or physical activity being highlighted.

Plans and Procedures

The clinical trial is a **Phase 2**, randomized, open-label, platform study designed to evaluate novel immunotherapy combinations in participants with previously untreated, locally advanced or metastatic **non-small cell lung cancer** (NSCLC) with high PD-L1 expression. The trial aims to assess the antitumor activity of these combinations compared to **pembrolizumab**. The study is expected to run from February 2023 to October 2028, with a maximum treatment period of approximately 1111 days for each participant.

Participants will be randomly assigned to receive either the investigational immunotherapy combinations or pembrolizumab. The trial will involve multiple study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and organ function. Participants must provide a tumor tissue sample and have measurable disease based on RECIST 1.1 criteria. The screening visit will also include a review of the participant's medical history and a physical examination.

Following the screening, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments such as imaging studies, laboratory tests, and evaluations of adverse events. The primary endpoint is the overall response rate (ORR), defined as the percentage of participants achieving complete or partial response. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and duration of response (DOR).

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent. Participants will be involved in the study for the duration of the treatment period and follow-up, with the possibility of early exit if specific criteria are met.

Treatment

The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. **Pembrolizumab**, marketed as KEYTRUDA, is provided as a 25 mg/mL concentrate for solution for infusion. It is administered via **intravenous use**. The pharmaceutical form is a solution for infusion, and it is not a pediatric formulation. The maximum treatment period for pembrolizumab is 1111 days, with no specified maximum daily or total dose amount. The product is secondary packaged and labeled according to the investigational medicinal product dossier.

Another experimental medication used in the trial is a **human IgG1 kappa monoclonal antibody against TIGIT**, identified by the sponsor product code GSK4428859. This medication is also provided as a solution for infusion and administered through intravenous use. It is not a pediatric formulation, and the maximum treatment period is 1111 days, with no specified maximum daily or total dose amount. The product is developed by GlaxoSmithKline.

The trial also includes the administration of **GSK6097608**, which is provided as a solution for infusion. This medication is administered via **intravenous infusion**. Similar to the other experimental treatments, it is not a pediatric formulation, and the maximum treatment period is 1111 days, with no specified maximum daily or total dose amount. The product is developed by GlaxoSmithKline.

**Dostarlimab**, marketed as JEMPERLI, is included in the trial as a 500 mg concentrate for solution for infusion. It is administered via intravenous use. The pharmaceutical form is a solution for infusion, and it is not a pediatric formulation. The maximum treatment period for dostarlimab is 1111 days, with no specified maximum daily or total dose amount. The product may be tested, packaged, labeled, imported, and QP released at registered facilities, and the use of a closed system transfer device is permitted for its administration. Compatibility details are provided within the investigational medicinal product dossier.

Efficacy

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the Objective Response Rate (ORR), defined as the percentage of participants achieving a Complete Response (CR) or Partial Response (PR) as per RECIST 1.1 criteria, evaluated by investigator assessment. Secondary endpoints include Progression-Free Survival (PFS), Overall Survival (OS), and Duration of Response (DOR), all assessed per RECIST 1.1 by investigator evaluation. PFS is defined as the time from randomization to the first documented progression of disease or death from any cause. OS is the time from randomization to death from any cause, and DOR is the time from the first documented objective response to the first documented progression of disease or death.

Additional secondary endpoints include the incidence of Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESI), as well as the incidence of TEAEs/SAEs leading to dose modifications or discontinuation of the study intervention. The trial will also assess the Anti-Drug Antibody (ADA) incidence for individual agents in the novel immunotherapy combinations and plasma pharmacokinetic (PK) parameters, including maximum concentration (Cmax) and minimum concentration (Cmin) for each novel immunotherapy, as data permit.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Is capable of giving signed informed consent as described in the protocol which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Is, at the time of signing the ICF, at least 18 years old or the legal age of consent in the jurisdiction in which the study is taking place.
Has a histologically or cytologically confirmed diagnosis of locally advanced unresectable NSCLC not eligible for curative surgery and/or definitive radiotherapy with or without chemotherapy or metastatic NSCLC (squamous or nonsquamous). Mixed tumors will be categorized by the predominant cell type; if small-cell or neuroendocrine elements are present, the participant is ineligible.
Has not received prior systemic therapy for their locally advanced or metastatic NSCLC.
Provides a tumor tissue sample obtained at the time of or after the initial diagnosis of locally advanced or metastatic NSCLC. Although a fresh tumor tissue sample obtained during screening is preferred, an archival tumor specimen (collected within 2 years prior to screening*) is acceptable. Tumor tissue must be from a site not previously irradiated. Biopsies obtained prior to the administration of any systemic therapy administered for the treatment of a participant’s tumor (such as neoadjuvant/adjuvant therapy) are not acceptable. Needle or excisional biopsies or resected tissue is required. Cytological specimens such as fine needle aspirates, bone marrow samples, or cell blocks are not acceptable, nor are bone specimens.
Has a PD-L1-high (TC/TPS >/=50%) tumor.
Has measurable disease based on RECIST 1.1 as determined by the investigator.
Has an ECOG PS of 0 or 1.
Has adequate organ function as defined in the protocol
If of childbearing potential, female participants must be willing to use adequate contraception. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: Is a woman of non-childbearing potential (WONCBP) as defined in the protocol or Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective as described in the protocol during the study intervention period and for at least 4 months after the last dose of study intervention. Female participant agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. A woman of childbearing potential (WOCBP) must not be pregnant; this will generally be confirmed via a negative highly sensitive serum pregnancy test within 7 days before the first dose of study intervention.

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Exclusion Criteria

Has NSCLC with a tumor that harbors any of the following molecular alterations: a. EGFR mutations that are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19, exon 20 insertion mutation, and exon 21 [L858R] substitution mutation). All participants with nonsquamous histology must have been tested for EGFR mutation status using a tissue-based test; use of an approved test is strongly encouraged. Participants with squamous histology do not need to be tested for EGFR mutation status. Participants with nonsquamous histology and unknown or indeterminate EGFR status are excluded. b. ALK translocations that are sensitive to available targeted inhibitor therapy. All participants with nonsquamous histology must have been tested for ALK fusion mutation status using a tissue-based test; use of an approved test is strongly encouraged. Participants with squamous histology do not need to be tested for ALK mutation status. Participants with nonsquamous histology and with unknown or indeterminate ALK status are excluded. c. Any other known genomic aberrations or oncogenic driver mutations for which a locally approved targeted therapy is available for first-line treatment of locally advanced or metastatic NSCLC.
Has had major surgery within 4 weeks of the first dose of study intervention or has received lung radiation therapy of >30 Gy (for any purpose, including palliatively) within 6 months prior to the first dose of study intervention.
Has received prior therapy with any immune-checkpoint inhibitors, including antibodies or drugs targeting PD-1, PD-L1, CTLA-4, TIGIT, CD96, or other checkpoint pathways.
Has never smoked, defined as smoking <100 tobacco cigarettes in a lifetime
Has an invasive malignancy or history of invasive malignancy other than the disease under study within the last 5 years, except as noted below: a. Participants may be enrolled in the study with a history of any other invasive malignancy for which the participant was definitively treated, from which the participant has been disease-free for at least 2 years, and which, in the opinion of the principal investigator and sponsor/medical monitor, is not expected to affect the evaluation of the effects of the study intervention on the currently targeted malignancy. b. Participants with curatively treated basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, and/or in situ breast cancer may be enrolled in the study.
Has known brain metastases meeting any of the following criteria: a. Symptomatic b. Untreated (NOTE: asymptomatic brain metastases are exclusionary if untreated) c. Actively progressing d. Any leptomeningeal disease (regardless of symptomatology, treatment status, or stability). NOTE: Participants with non-leptomeningeal brain metastases who have received prior therapy for brain metastases and have radiographically stable CNS disease for at least 4 weeks (confirmed by 2 brain scans taken at least 4 weeks apart, with at least 1 scan collected after treatment of brain metastases) may participate, provided they are neurologically stable for at least 2 weeks following treatment for brain metastases (i.e., any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have returned to baseline or resolved) and prior to the first dose of study intervention. Corticosteroids must be discontinued at least 3 days prior to the first dose of study intervention.
Has autoimmune disease or syndrome (current or history thereof) that required systemic treatment within the past 2 years. Replacement therapies (e.g., insulin, thyroxine, or physiologic doses of corticosteroids for treatment of adrenal or pituitary insufficiency) are not considered systemic treatments and are allowed.
Has received systemic steroid therapy </=3 days prior to the first dose of study intervention or is receiving any other form of immunosuppressive medication. Replacement therapy is not considered a form of systemic therapy. Note the following: a. Corticosteroid use is allowed as premedication for hypersensitivity reactions (e.g., IV contrast allergies/reactions). b. Use of topical, inhaled, or intranasal corticosteroids, local steroid injection, or steroid eye drops is allowed. c. Participants who receive daily steroid replacement therapy are an exception to this criterion. Daily prednisone at doses of ≤10 mg is an example of replacement therapy. Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy.
Has received any live vaccine within 30 days prior to first dose of study intervention.
Has any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis.
Has symptomatic ascites, pleural effusion, or pericardial effusion. A participant who is clinically stable following treatment of these conditions (including therapeutic thoracentesis, paracentesis, or pericardiocentesis) is eligible if the participant otherwise meets entry criteria.
Has active inflammatory bowel disease, acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or peritoneal carcinomatosis.
Has a history or evidence of cardiac abnormalities, including: a. Recent history (i.e., within 6 months prior to the first dose of study intervention) of any of the following: i. Serious, uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities including second-degree (Type II) or third-degree AV block (including complete heart block). ii. Myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, bypass grafting, or newly diagnosed cardiomyopathy. iii. Symptomatic pericarditis. b. Congestive heart failure (Class III or IV) as defined by the New York Heart Association Functional Classification System [The Criteria Committee of the New York Heart Association, 1994]. c. Myocarditis of any grade.
Has QTcF >470 msec, or >480 msec for participants with bundle branch block.
Has current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
Has had a severe infection requiring IV antibiotics or requiring hospitalization for infection or complication of infection or has had severe pneumonia within 4 weeks prior to the first dose of study intervention.
Has active tuberculosis.
Has a known HIV infection.
Has a history of severe hypersensitivity to mAbs or to any of the excipients in the formulations of the components of the study interventions
Has any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric, or other condition that could, in the opinion of the investigator, interfere with participant’s safety, obtaining informed consent, or compliance with the study procedures
Is, at the time of signing the ICF, a regular user (including recreational use) of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol) that, in the opinion of the investigator, would interfere with the evaluation of the study intervention or interpretation of safety.
Has a positive test for the presence of HBsAg at Screening or within 3 months prior to first dose of study intervention.
Has a positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study intervention. NOTE: Participants with a positive hepatitis C antibody test due to prior resolved disease can be enrolled only if a confirmatory negative hepatitis C RNA test is obtained.
Has a positive hepatitis C RNA test result at Screening or within 3 months prior to first dose of study intervention. NOTE: Participants with a negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing.
Has advanced, symptomatic, or visceral spread and is considered to be at imminent risk of life-threatening complications
Is currently participating in or has participated in a study of an investigational therapy within 4 weeks prior to the first dose of study intervention.
Has a history of allogeneic tissue/stem cell transplant or solid organ transplant

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	09 Feb 2023	5
Finland	Not Recruiting	09 Feb 2023	12
France	Not Recruiting	09 Feb 2023	23
Germany	Not Recruiting	09 Feb 2023	17
Greece	Not Recruiting	09 Feb 2023	22
Hungary	Not Recruiting	09 Feb 2023	12
Italy	Not Recruiting	09 Feb 2023	22
The Netherlands	Not Recruiting	09 Feb 2023	—
Poland	Not Recruiting	09 Feb 2023	15
Portugal	Not Recruiting	09 Feb 2023	12

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Sites & Investigators

Research sites

Azienda Usl Toscana nord ovest Centre Hospitalier Intercommunal De Cornouaille Hospital Vall d’Hebron Farkasgyepui Tudogyogyintezet

Investigators

João G.Eleni F.Nóra B.Marta S.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Treatment Duration	EU MP Number
JEMPERLI 500 mg concentrate for solution for infusion	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS USE	1111	PRD8877508
KEYTRUDA 25 mg/mL concentrate for solution for infusion	Comparator	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS USE	1111	PRD4323105
KEYTRUDA 25 mg/mL concentrate for solution for infusion.	Comparator	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS USE	1111	PRD12081132