Phase III Randomized Study of Rilvegostomig vs. Pembrolizumab Monotherapy in PD-L1-high Metastatic Non-small Cell Lung Cancer
- Trial ID
- 2024-517780-24-00
- Protocol
- D702GC00001
- Sponsor
- AstraZeneca AB
Trial statistics
Objectives
The primary objective of this Phase III, randomized, double-blind, multicenter study is to demonstrate the efficacy of **rilvegostomig** relative to **pembrolizumab** by assessing overall survival (OS) and progression-free survival (PFS) in patients with PD-L1-high metastatic non-small cell lung cancer (NSCLC). This is clinically relevant as it aims to establish a potentially more effective first-line treatment option for this patient population, which could improve survival outcomes.
Secondary objectives include:
- Characterizing the efficacy of rilvegostomig relative to pembrolizumab by assessing OS rates, PFS rates, overall response rate (ORR), duration of response (DoR), and PFS2.
- Assessing the pharmacokinetics (PK) and immunogenicity of rilvegostomig.
- Evaluating patient-reported outcomes, including physical functioning, global health status/quality of life (GHS/QoL), and lung cancer symptoms specific to NSCLC.
Participants
The clinical trial involves a total of **617 participants** diagnosed with **lung cancer**, specifically non-small cell lung cancer (NSCLC) at Stage IV, which is not amenable to curative treatment. The study population includes both male and female subjects, aged 18 years and older, with a **World Health Organization/Eastern Cooperative Oncology Group (WHO/ECOG) performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on their ability to provide informed consent and meet specific health criteria, including adequate organ and bone marrow function, a minimum body weight of 30 kg, and a minimum life expectancy of 12 weeks. The trial includes individuals from all races, genders, and ethnic groups, with no significant deterioration in health over the two weeks prior to baseline screening. Lifestyle considerations such as contraceptive use are required to align with local regulations, and participants must not have any sensitizing EGFR mutations or ALK and ROS1 rearrangements. The trial does not exclude vulnerable populations, and tumor PDL1 expression must be confirmed prior to randomization. The sponsor has not provided additional information regarding specific lifestyle factors such as diet or physical activity.
Plans and Procedures
The clinical trial is a **Phase III**, randomized, double-blind, multicenter study designed to evaluate the efficacy of **rilvegostomig** compared to **pembrolizumab** monotherapy in patients with PD-L1-high metastatic non-small cell lung cancer. The primary objective is to assess overall survival (OS) and progression-free survival (PFS). The trial is expected to commence recruitment on July 26, 2025, and conclude by January 25, 2031. Participants will be randomly assigned to receive either rilvegostomig or pembrolizumab, both administered as a solution for infusion via intravenous use.
The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, organ function, and tumor characteristics. Participants must be at least 18 years old, have adequate organ and bone marrow function, and a minimum body weight of 30 kg. The screening visit will also include a negative pregnancy test for female participants of childbearing potential. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of OS, PFS, and adverse events. The end-of-study visit will occur after the final dose of the study drug, with additional follow-up to assess long-term outcomes.
Participant involvement is expected to last until the end of the study, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial will also monitor secondary endpoints such as overall response rate, duration of response, and quality of life measures. The study is not classified as low intervention, and all races, genders, and ethnic groups are eligible to participate. The trial will adhere to strict ethical guidelines, including informed consent and compliance with local contraceptive regulations.
Treatment
The clinical trial involves the administration of **Rilvegostomig**, an experimental medication, which is a **solution for infusion**. The active substance, Rilvegostomig, is a bispecific IgG1 monoclonal antibody targeting PDCD1 and TIGIT. It is administered via **intravenous use**. The maximum daily dose is 750 mg, with a total maximum dose of 3000 mg. The treatment period is not explicitly limited, allowing for extended administration as required by the study protocol. Participant compliance is monitored through regular assessments and infusion records.
**Pembrolizumab**, marketed as KEYTRUDA, serves as the comparator treatment in this study. It is provided as a 25 mg/mL concentrate for solution for infusion, also administered intravenously. The active substance, Pembrolizumab, is a monoclonal antibody with a maximum daily dose of 200 mg and a total maximum dose of 800 mg. The treatment duration is similarly flexible, with compliance monitored through infusion logs and patient follow-ups.
**Infliximab** is included as an auxiliary treatment, provided as a powder for concentrate for solution for infusion. It is administered via intravenous infusion, with a dosing regimen of 5 mg/kg. The total dose is not specified, and the treatment period is open-ended, subject to clinical judgment and patient response. Compliance is tracked through infusion records and clinical assessments.
**Mycophenolate mofetil** is another auxiliary treatment, available in capsule form for **oral use**. The maximum daily dose is 3 g, with no specified total dose limit. The treatment period is indefinite, allowing for long-term administration as needed. Compliance is monitored through pill counts and patient diaries, ensuring adherence to the prescribed regimen.
Efficacy
The efficacy of the investigational product, **rilvegostomig**, will be assessed in a Phase III, randomized, double-blind, multicenter, global study for the first-line treatment of patients with PD-L1-high metastatic non-small cell lung cancer. The primary endpoints for evaluating efficacy include overall survival (OS) and progression-free survival (PFS). Secondary endpoints encompass landmark OS rates, landmark PFS rates, overall response rate (ORR), duration of response (DoR), time to second progression or death (PFS2), and the concentration of rilvegostomig in serum. Additionally, the presence of anti-drug antibodies (ADAs), titer, and neutralizing antibodies for rilvegostomig will be measured.
Further secondary endpoints include the proportion of participants with maintained or improved physical functioning, time to deterioration (TTD) of global health status (GHS)/quality of life (QoL) and in pulmonary symptoms, as well as adverse events (AEs) graded by CTCAE version 5.0. Clinical laboratory assessments, vital signs, physical examinations, and Eastern Cooperative Oncology Group (ECOG) performance status will also be monitored. These parameters will be collected and analyzed at specified timepoints throughout the study to determine the efficacy of the treatment regimen.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be ≥ 18 at the time of signing the ICF.
- Histologically or cytologically documented NSCLC, including all histological subtypes.
- Stage IV mNSCLC (based on the American Joint Committee on Cancer Edition 8) not amenable to curative treatment.
- Absence of sensitizing EGFR mutations (including, but not limited to, exon 19 deletion and exon 21 L858R, exon 21 L861Q, exon 18 G719X, and exon 20 S768I mutations) and ALK and ROS1 rearrangements. Negative assay result is required for all non-squamous histology subtypes.
- Absence of documented tumor genomic mutation results from tests conducted as part of standard local practice in any other actionable driver oncogenes for which there are locally approved targeted 1L therapies.
- WHO/ECOG performance status of 0 or 1, with no deterioration over the previous 2 weeks prior to baseline at screening and prior to randomization.
- Minimum life expectancy of 12 weeks.
- Tumour PDL1 expression must be confirmed prior to randomization.
- At least one lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT or MRI and is suitable for accurate repeated measurements.
- Adequate organ and bone marrow function
- Minimum body weight of 30 kg.
- Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- Female participants of childbearing potential: (a) Must have negative pregnancy test at screening and prior to each Day 1 administration of study intervention. (b) If sexually active with a non-sterilized male partner, must use at least 1 highly effective method of birth control from screening to 4 months after the last dose of study intervention. (c) Non-sterilized male partners of female participants of childbearing potential must use a male condom plus spermicide (if not available, a male condom without spermicide is acceptable) from screening to 4 months after the last dose of study intervention. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. (d) Must not breastfeed and must not donate, or retrieve for their own use, ova from screening to 4 months after the last dose of study intervention.
- Non-sterilized male participants who are sexually active with a female partner of childbearing potential: (a) Non-sterilized male participants who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom plus spermicide (if not available, a male condom without spermicide is acceptable) from screening to 4 months after the last dose of study intervention. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. (b) Female partners (of childbearing potential) of a male participant also must use at least 1 highly effective method of contraception (see Appendix G of the Clinical Study Protocol) throughout their participation in the study, and until at least 4 months after their male partners last dose of study intervention. (c) Male participants must refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of study intervention.
- Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
- Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.
- All races, gender, and ethnic groups are eligible for this study.
Exclusion Criteria
- As judged by the investigator, any severe or uncontrolled systemic diseases, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
- History of organ transplant.
- Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
- History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease.
- Presence of small cell and neuroendocrine histology components.
- Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anticancer therapy, excluding alopecia.
- Spinal cord compression unless the participant received adequate local treatment. Participant must have stable neurological status for at least 2 weeks after completion of local treatment and at least 7 days have elapsed after completion of steroids prior to randomization.
- Brain metastases unless asymptomatic, stable, and not requiring steroids or anticonvulsants for at least 7 days prior to randomization. A minimum of 2 weeks must have elapsed between the end of local therapy (brain radiotherapy or surgery) and randomization. Participants must have recovered from the acute toxic effect of radiotherapy or surgery (eg, dizziness and signs of increased intracranial pressure) prior to randomization.
- Active primary immunodeficiency/active infectious disease(s): • Known active hepatitis A, chronic or active hepatitis B, or chronic or active hepatitis C infection: • Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load, CD4+ count of ≥ 350 cells/µL, no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications.
- Active tuberculosis infection
- History of clinically significant arrhythmia, cardiomyopathy of any etiology; symptomatic congestive heart failure (as defined by New York Heart Association class ≥ 3), history of myocardial infarction within the past 6 months.
- Any concomitant medication known to be associated with Torsades de pointes.
- Any prior systemic therapy received for advanced or mNSCLC.
- Any prior exposure to an anti-TIGIT therapy or any other anticancer therapy targeting immune-regulatory receptors or mechanisms.
- Any prior treatment with an anti-PD-1 or anti-PD-L1 agent.
- Any concurrent chemotherapy, radiotherapy, immunotherapy, investigational, or biologic or hormonal therapy for cancer treatment other than those under investigation in this study. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, insulin for diabetes, HRT, gonadotropin-releasing hormone analogs, and bisphosphonates) is acceptable.
- Palliative radiotherapy with a limited field of radiation within 2 weeks or with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks, prior to the first dose of study intervention.
- Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
- Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention is excluded. The following are exceptions to this criterion (see Appendix I).
- Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are excluded, see Appendix I.
- Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
- Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 12 months or the combination/comparator agent (unless the safety profile is known prior to randomization), or concurrent enrollment in another clinical study (unless the study is observational [non-interventional], or the participant is in the follow-up period of an interventional study).
- Participants with a known hypersensitivity to study intervention or any excipients of the products.
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
- Previous enrollment in the present study.
- For females only: Currently pregnant (confirmed with positive pregnancy test) or breast-feeding, or who are planning to become pregnant.
- Female participants should refrain from breastfeeding from screening throughout the study and until 4 months after last dose of study intervention.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 26 Jul 2025 | 16 |
 Bulgaria | Recruiting | 26 Jul 2025 | 14 |
 France | Recruiting | 26 Jul 2025 | 45 |
 Germany | Recruiting | 26 Jul 2025 | 80 |
 Greece | Recruiting | 26 Jul 2025 | 25 |
 Ireland | Recruiting | 26 Jul 2025 | 20 |
 Italy | Recruiting | 26 Jul 2025 | 72 |
 Portugal | Recruiting | 26 Jul 2025 | 28 |
 Romania | Recruiting | 26 Jul 2025 | 30 |
 Spain | Recruiting | 26 Jul 2025 | 53 |
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 |
|---|---|---|---|---|---|---|
Rilvegostomig | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 750 | 999999 | PRD10448215 |
INFLIXIMAB | Other | — | INTRAVENIOUS INFUSION | 5 | 999999 | SUB02681MIG |
MYCOPHENOLATE MOFETIL | Other | — | ORAL USE | 3 | 999999 | SUB03360MIG |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 200 | 999999 | PRD4323105 |