Phase 2 Randomized Double-Blind Study of Dostarlimab Plus Chemotherapy Versus Pembrolizumab Plus Chemotherapy in Metastatic Non-Squamous NSCLC Patients
- Trial ID
- 2023-505894-33-00
- Protocol
- 213403
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized, phase 2, double-blind study is to compare the **Objective Response Rate (ORR)** of the **PD-1 inhibitor** dostarlimab versus pembrolizumab, both administered in combination with chemotherapy. This evaluation is conducted using RECIST v1.1 criteria based on Blinded Independent Central Review (BICR) in participants with metastatic non-squamous non-small cell lung cancer (NSCLC) who have not received prior treatment for metastatic disease and do not have known EGFR, ALK, ROS-1, or BRAF V600E mutations or other genomic aberrations for which targeted therapy is available. The clinical relevance of this objective lies in determining the efficacy of dostarlimab compared to pembrolizumab, potentially guiding treatment decisions in this patient population.
Secondary objectives include: - Evaluating the following measures of clinical benefit of the PD-1 inhibitor administered in combination with chemotherapy: Overall Survival (OS) and Progression-Free Survival (PFS) evaluated using RECIST v1.1 based on Investigator assessment. - Evaluating the safety of the PD-1 inhibitor in combination with chemotherapy.
Participants
The clinical trial involves a total of **128 participants** diagnosed with **non-small cell lung cancer** (NSCLC), specifically the non-squamous type, without known mutations such as EGFR, ALK, ROS-1, or BRAF V600E. The study population includes both male and female subjects, aged 18 years and older, who have not received prior treatment for metastatic disease. Participants were selected based on their ability to understand study procedures and provide informed consent, as well as their documented PD-L1 status. The trial excludes individuals with predominantly squamous cell histology or small cell elements in their tumors. Participants are required to have a measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The study does not involve a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. Participants must have a life expectancy of at least three months and adequate organ function, with recovery from any prior treatment-related toxicities to Grade 1 or lower, except for Grade 2 alopecia. Contraceptive use is mandated for both male and female participants in accordance with local regulations to prevent pregnancy during and after the study treatment period.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **dostarlimab** plus chemotherapy versus **pembrolizumab** plus chemotherapy in patients with metastatic non-squamous non-small cell lung cancer (NSCLC). The trial aims to compare the overall response rate (ORR) of these treatments, assessed using RECIST v1.1 based on blinded independent central review (BICR). The study is expected to run from December 28, 2020, to October 29, 2025, with a maximum treatment period of 105 weeks for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of metastatic non-squamous NSCLC, and absence of specific genetic mutations. Following randomization, participants will receive either dostarlimab or pembrolizumab in combination with chemotherapy. Regular follow-up visits will be conducted to monitor treatment efficacy and safety, including assessments of clinical laboratory parameters, vital signs, and adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is up to 105 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Secondary endpoints include overall survival (OS) and progression-free survival (PFS), with additional assessments of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). The trial will ensure compliance with ethical standards, and participants will provide informed consent prior to enrollment.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Pemetrexed Pfizer** is provided as a 25 mg/ml concentrate for solution for infusion. It is administered via **intravenous infusion** with a maximum daily dose of 500 mg/m². The treatment period for Pemetrexed is up to 105 days. This medication is a chemical entity and is not a paediatric formulation.
**KEYTRUDA**, containing the active substance **pembrolizumab**, is a 25 mg/mL concentrate for solution for infusion. It is administered through **intravenous use** with a maximum daily dose of 200 mg. The treatment duration is also up to 105 days. Pembrolizumab is a recombinant protein and is not formulated for paediatric use. The commercial drug product is over-labelled with a country-specific investigational label for clinical trial purposes.
**JEMPERLI**, with the active substance **dostarlimab**, is a 500 mg concentrate for solution for infusion. It is administered via **intravenous use** with a maximum daily dose of 500 mg. The treatment period extends to 105 days. Dostarlimab is a recombinant protein, and the commercial drug product is packaged, labelled, and released at registered facilities. Compatibility with additional materials is detailed in the investigational medicinal product dossier.
**Carboplatin-Teva** is a 10 mg/ml concentrate for solution for infusion, administered through **intravenous infusion**. The maximum daily dose is 5 mg/ml, with a treatment period of up to 12 days. Carboplatin is a chemical entity and is not a paediatric formulation.
**Cisplatin** is provided as a 1 mg/ml concentrate for solution for infusion, administered via **intravenous infusion**. The maximum daily dose is 75 mg/m², with a treatment period of up to 12 days. Cisplatin is a chemical entity and is not formulated for paediatric use.
**Pemetrexed Pfizer** is also available as a 100 mg powder for concentrate for solution for infusion. It is administered through **intravenous infusion** with a maximum daily dose of 500 mg/m², and the treatment period is up to 105 days. This formulation is a chemical entity and is not intended for paediatric use.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of these medications in combination with chemotherapy for the treatment of metastatic non-squamous non-small cell lung cancer.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, which will be evaluated using RECIST v1.1 criteria based on Blinded Independent Central Review (BICR). The ORR is defined as the proportion of participants achieving a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) within the analysis population. Secondary efficacy endpoints include Overall Survival (OS) and Progression-Free Survival (PFS). OS is defined as the time from randomization to death from any cause, while PFS is defined as the time from randomization to the date of disease progression or death, whichever occurs first, as evaluated by the investigator using RECIST v1.1.
Additional assessments will include the incidence of Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), immune-related Adverse Events (irAEs), TEAEs leading to death, and Adverse Events (AEs) leading to discontinuation. These will be monitored while participants are on treatment and up to 90 days after the last dose. Clinical laboratory parameters, including hematology, chemistry, thyroid function, and urinalysis, along with vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, ECG parameters, physical examinations, and concomitant medication usage, will be collected to support the efficacy assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be ≥18 years old, must be able to understand the study procedures, and agrees to participate in the study by providing written informed consent (as described in Appendix 4), which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- Participant has histologically- or cytologically-confirmed metastatic non-squamous NSCLC with documented absence of a sensitizing EGFR, ALK, ROS-1, or BRAF V600E mutation or other genomic aberration for which an approved targeted therapy is available. Mixed tumors will be categorized by the predominant cell type; if the tumor has predominantly squamous cell histology or if small cell elements are present, the participant is ineligible
- Participants must have measurable disease, i.e., presenting with at least 1 measurable lesion per RECIST v1.1 as determined by the local site Investigator/radiology assessment. Measurable lesions situated in a previously irradiated area may be considered target lesions if progression has been demonstrated in such lesions and if there are other target lesions. If there is only 1 target lesion that was previously irradiated, the participant is not eligible. See Appendix 1 for the definition of a measurable lesion.
- Participant has documented PD-L1 status by the 22C3 pharmDx assay (Agilent/Dako). If no prior PD-L1 result is available at the time of Screening, the participant can be tested locally using the stated method, or central PD-L1 testing can be completed. Results are needed for stratification and must be available prior to randomization.
- Participant has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
- Participant has a life expectancy of at least 3 months.
- Participant has adequate organ function as defined in Table 7. (Note: A complete blood count test should be obtained without transfusion or receipt of colony-stimulating factors within 2 weeks of obtaining the sample.)
- Participant has recovered to Grade ≤1 from any prior treatment-related toxicities at the time of randomization. A participant with Grade 2 alopecia is an exception to this criterion and may qualify for this study.
- Contraceptive use by male and female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a. Male participants are eligible to participate if they agree to the following during the Treatment Period and for at least 180 days after the last dose of study treatment. (Note: duration of contraceptive use after last dose of chemotherapy must be consistent with local requirements and local approved product labels; however, the minimum duration is 180 days after last dose of chemotherapy) Refrain from donating sperm PLUS, either: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR Must agree to use contraception/barrier as follows: Agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception, as a condom may break or leak) when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person. b. 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 Appendix 5. OR Is a WOCBP, as defined in Appendix 5, using a contraceptive method that is highly effective (with a failure rate of <1% per year and, preferably, with low user dependency, as described in Appendix 5) during the treatment Period and for at least 180 days after the last dose of study treatment and agrees not to donate eggs (ova or oocytes) for the purpose of reproduction during this period. (Note: duration of contraceptive use after last dose of chemotherapy may be longer than 180 days in order to comply with local requirements and local approved product labels). Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. The Investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance and recently initiated) in relationship to the first dose of study treatment. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local guidelines) within 72 hours before the first dose of study treatment. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Note: Additional requirements for pregnancy testing during and after study treatment are located in Section 7.4.7. Note: The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
Exclusion Criteria
- Participant has received prior systemic therapy for the treatment of metastatic NSCLC. Participants who have received neoadjuvant or adjuvant chemotherapy are eligible if the neoadjuvant/adjuvant therapy was completed at least 12 months prior to the development of metastatic disease.
- Participant has received prior therapy with a PD-(L)1 or PD-L2 inhibitor, a CTLA-4 inhibitor, a TIM-3 inhibitor, or any other immunotherapy agent (e.g., OX40) for the treatment of cancer.
- Participant has received radiation to the lung that is >30 Gy within 6 months of the first dose of study treatment.
- Participant has completed palliative radiotherapy within 7 days of the first dose of study treatment.
- Participant is ineligible if any of the following hepatic characteristics are present: a. ALT >2.5×upper limit of normal (ULN) without liver metastases/tumor infiltration b. ALT >5×ULN with liver metastases/tumor infiltration c. Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%) d. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per Investigator assessment) Note: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis
- Participant has a corrected QT interval (QTc) >450 msec (or QTc >480 msec for participants with bundle branch block). Notes: The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or manually over-read. The specific formula that will be used to determine eligibility and discontinuation for an individual participant should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant from the study. For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used as specified in the Reporting and Analysis Plan (RAP).
- Participant has had major surgery within 3 weeks of the first dose of study treatment or has not adequately recovered from any AEs (Grade ≤1) and/or complications from any major surgery. Surgical implantation of a port catheter is not exclusionary.
- Participant has an additional malignancy or a history of prior malignancy, with the exception of adequately treated basal or squamous skin cancer, cervical carcinoma in situ, superficial bladder cancer without evidence of disease, other in situ cancers, or had a malignancy treated with curative intent and with no evidence of disease recurrence for 5 years since the initiation of that therapy
- Participant has known active brain metastases and/or leptomeningeal metastases. Participants who have received prior therapy for their brain metastases and have radiographically stable central nervous system disease may participate, provided they are neurologically stable for at least 2 weeks before study entry and must be off corticosteroids within 3 days prior to the first dose of study treatment. Stable brain metastases by this definition should be established prior to the first dose of study treatment. Participants with known untreated, asymptomatic brain metastases (i.e., no neurological symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and no lesions >1.5 cm) may participate, but will require regular imaging of the brain as a site of disease.
- Participant has tested positive for the presence of hepatitis B surface antigen or has a positive hepatitis C antibody test result at Screening, or within 3 months prior to first dose of study treatment.
- Participant has an active infection requiring systemic therapy within 1 week prior to the anticipated first dose of study treatment.
- Participant has known HIV (positive for HIV-1 or HIV-2 antibodies).
- Participant has active autoimmune disease that required systemic treatment in the past 2 years, is immunocompromised in the opinion of the Investigator, or is receiving systemic immunosuppressive treatment. (Note: Participants with splenectomy are allowed.) Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment.
- Participant has received systemic steroid therapy within 3 days prior to the first dose of the study treatment or is receiving any other form of immunosuppressive medication. Replacement therapy is not considered a form of systemic therapy. Use of inhaled corticosteroids, local steroid injection, or steroid eye drops is allowed.
- Participant has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment of these conditions (including therapeutic thoraco- or paracentesis) is eligible.
- Participant has current interstitial lung disease, current pneumonitis, or a history of pneumonitis that required the use of oral or IV glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.
- Participant has a history or current evidence of any medical condition, therapy, or laboratory abnormality that might confound the study results, interfere with their participation for the full duration of the study treatment, or indicate it is not in the best interest of the participant to participate, in the opinion of the Investigator.
- Participant has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or peritoneal carcinomatosis.
- Participant has pre-existing peripheral neuropathy that is Grade ≥2 by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 criteria.
- Participant has received a live vaccine within 30 days of the first dose of study treatment. Seasonal flu vaccines that do not contain live virus are permitted.
- Participant does not meet requirements per local prescribing guidelines for receiving treatment with either pemetrexed and cisplatin or carboplatin.
- Participant has sensitivity to any of the study treatments, or components thereof, or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation.
- Participant is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 28 Dec 2020 | 20 |
 Germany | Not Recruiting | 28 Dec 2020 | 25 |
 Italy | Not Recruiting | 28 Dec 2020 | 18 |
 Poland | Not Recruiting | 28 Dec 2020 | 20 |
 Romania | Not Recruiting | 28 Dec 2020 | 12 |
 Spain | Not Recruiting | 28 Dec 2020 | 19 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Pemetrexed Pfizer 25 mg/ml concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 500 | 105 | PRD8396784 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 200 | 105 | PRD4323105 |
Carboplatin-Teva 10 mg/ml Concentrate for Solution for Infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 5 | 12 | PRD675076 |
Cisplatin 1 mg/ml Concentrate for Solution for Infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 75 | 12 | PRD1168083 |
Pemetrexed Pfizer 100 mg powder for concentrate for solution for infusion | Other | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 500 | 105 | PRD3399795 |
JEMPERLI 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 500 | 105 | PRD8877508 |
Pemetrexed Pfizer 25 mg/ml concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 500 | 105 | PRD8396782 |
Pemetrexed Pfizer 25 mg/ml concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 500 | 105 | PRD8396780 |