Study of Rilvegostomig or Pembrolizumab Plus Chemotherapy for First-Line Treatment of Metastatic Squamous NSCLC Whose Tumors Express PD-L1

Phase 3

Not yet recruiting

• Conditions: Malignant neoplasm of unspecifiedpart of bronchus or lung,

• Registration Number: CTRI/2025/04/084960
• Lead Sponsor: AstraZeneca AB

Brief Summary

This is a Phase III, two-arm, randomized, double-blind, multicenter, global study to assess the efficacy and safety of rilvegostomig in combination with platinum-based chemotherapy compared with pembrolizumab in combination with platinum-based chemotherapy in participants with squamous mNSCLC and whose tumors express PD-L1 (TC greater than or equal 1%).

Approximately 1760 participants will be screened to achieve approximately 880 participants randomized into the study. Participants will be randomized in a 1:1 ratio to one of the following intervention arms:

·      Arm A (experimental arm): rilvegostomig 750 mg iv Q3W in combination with carboplatin AUC 6 iv Q3W and paclitaxel 200 mg/m2 iv Q3W or nab-paclitaxel 100 mg/m2 iv Day 1, 8, and 15 of each 3-week cycle for 4 cycles followed by rilvegostomig 750 mg iv Q3W. Use of carboplatin AUC 5 and/or paclitaxel 175mg/m2 is permitted per local practice.

·      Arm B (control arm): pembrolizumab 200 mg iv Q3W in combination with carboplatin AUC 6 iv Q3W and paclitaxel 200 mg/m2 iv Q3W or nab-paclitaxel 100 mg/m2 iv Day 1, 8, and 15 of each 3-week cycle for 4 cycles followed by pembrolizumab 200 mg iv Q3W.

 ·      Use of carboplatin AUC 5 and/or paclitaxel 175mg/m2 is permitted per local practice.

Participants will continue to receive study treatment until RECIST 1.1-defined PD (per investigator assessment), unacceptable toxicity, or until any other discontinuation criteria are met.

Randomization will be stratified by PD-L1 expression (TC 1% to 49% versus greater than or equal 50%), choice of chemotherapy (paclitaxel versus nab-paclitaxel) and region (China versus Asia [other] versus rest-of-world). Participants will be prospectively tested for PD-L1 expression for eligibility and stratification. Participants must have a tumor tissue sample available for PD-L1 IHC testing performed by a central reference laboratory during the screening period. PD-L1 status is required prior to randomization. PD-L1 status will be determined by VENTANA PD-L1 (SP263) Assay in the submitted tumor sample.

Participants in both experimental and control arms will receive iv infusion Q3W until RECIST 1.1-defined radiological progression as assessed by the investigator, unacceptable toxicity, or until any other intervention discontinuation criterion is met. Following radiological disease progression, participants may continue to receive blinded study treatment until confirmed with a subsequent scan (performed at least 4 weeks later) as long as they continue to show clinical benefit.

**Follow-up of Participants Post Discontinuation of Study Intervention:**

All participants will be followed up for safety assessments until 90 days ( ±7 days) after their last dose of study intervention. Participants who have discontinued study intervention for reasons other than disease progression will be followed up with tumor assessments as per the SoA.

All participants will be followed up for survival status and time to second progression or death (PFS2) every 12 weeks (±7 days) until death, withdrawal of consent, or the end of the study.

Detailed Description

Not available

Study Timeline

• Last Update Posted: 2025-04-14
• Study Start: 2025-05-05

Recruitment & Eligibility

• Status: Not Yet Recruiting
• Sex: All
• Target Recruitment: 880

Inclusion Criteria

• Inclusion criteria Participants are eligible to be included in the study only if all of the following criteria apply 1.
• Participant must be greater than or equal 18 at the time of signing the ICF.
• 2.Histologically or cytologically documented squamous NSCLC.
• 3.Stage IV mNSCLC (based on the American Joint Committee on Cancer Edition 8) not amenable to curative treatment.
• 4.Absence of documented tumor genomic mutation results from tests conducted as part of standard local practice in any actionable driver oncogenes for which there are locally approved targeted 1L therapies.
• 5.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.
• 6.Minimum life expectancy of 12 weeks.
• 7.Provision of acceptable tumor sample, as defined in the Pathology Manual and Laboratory Manual and summarized in Section 8.8, to confirm tumor PD-L1 expression TC greater than or equal 1% using the VENTANA PD-L1 (SP263) Assay at a Sponsor-designated central laboratory prior to randomization.
• Participants with unknown PD-L1 status or TC lesser than1% are not eligible for the study.
• 8.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 greater than or equal 10 mm in the longest diameter (except lymph nodes, which must have short axis greater than or equal 15 mm) with CT or MRI and is suitable for accurate repeated measurements.
• Adequate organ and bone marrow function as defined in below table.
• 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 blinded study treatment and 6 months after last dose of chemotherapy.
• (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 blinded study treatment and 6 months after last dose of chemotherapy.
• 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 blinded study treatment and 6 months after last dose of chemotherapy.
• 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 blinded study treatment and 6 months after last dose of chemotherapy.
• (b) Female partners (of childbearing potential) of a male participant also must use at least 1 highly effective method of contraception throughout their participation in the study, and until at least 4 months after their male partners last dose of blinded study treatment and 6 months after last dose of chemotherapy.
• (c) Male participants must refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of blinded study treatment and 6 months after last dose of chemotherapy.
• Capable of giving signed informed consent as described in Appendix A of the CSP 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 16.
• All races, gender, and ethnic groups are eligible for this study.

Exclusion Criteria

• Exclusion criteria Participants are excluded from the study if any of the following criteria apply Medical Conditions 1.
• As judged by the investigator, any severe or uncontrolled systemic diseases, including, but not limited to, uncontrolled hypertension, and active bleeding diseases, ongoing or active known infection; ILD (of any grade), serious chronic gastrointestinal conditions associated with diarrhea (eg, active inflammatory bowel disease), active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment, psychiatric illness/social situations, substance abuse, or significant cardiac conditions which, in the investigator’s opinion, 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 greater than or equal 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 greater than or equal 2) caused by previous anticancer therapy, excluding alopecia.
• Participants may be enrolled with the following chronic stable Grade 2 toxicities (defined as no worsening to greater than Grade 2 for at least 3 months prior to the first dose of study intervention and managed with SoC treatment) which the investigator deems related to previous anticancer therapy: (a) Chemotherapy-induced neuropathy.
• (c) Vitiligo.
• (d) Endocrine disorders, that are controlled with replacement hormone therapy.
• (e) Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss).
• Spinal cord compression.
• Brain metastases unless asymptomatic, stable, and not requiring steroids or anticonvulsants for at least 4 weeks prior to start of study intervention.
• A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and study enrollment.
• Participants must have recovered from the acute toxic effect of radiotherapy (eg, dizziness and signs of increased intracranial pressure).
• Active primary immunodeficiency/active infectious disease(s) Known active hepatitis A, chronic or active hepatitis B, or chronic or active hepatitis C infection Participants who have chronic HBV and are receiving suppressive antiviral therapy are allowed to be enrolled if viral load is controlled and ALT is normal.
• Controlled hepatitis B viral load is defined as serum HBV DNA lesser than 100 U/mL by PCR.
• Participants with controlled hepatitis B viral load must remain on antiviral therapy, per institutional practice, during the study treatment and follow-up period to ensure adequate viral suppression.
• Participants who have chronic HCV are allowed to be enrolled if ALT is normal and HCV RNA undetectable by PCR, either spontaneously or in response to a successful prior course of anti-hepatitis C therapy (Regev et al 2020).
• Controlled hepatitis C viral load is defined as undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-hepatitis C therapy 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, CD4pluse count of greater then 350 cell, 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 (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice) 11.
• History of clinically significant arrhythmia, cardiomyopathy of any etiology; symptomatic congestive heart failure (as defined by New York Heart Association class greater than or equal 3), history of myocardial infarction within the past 6 months.
• Prior/Concomitant Therapy 13.
• Any prior systemic therapy received for advanced or mNSCLC.
• Note: Prior systemic therapy in the neoadjuvant or adjuvant setting and/or definitive radio- or chemoradiotherapy for early-stage resectable disease are allowed, provided that recurrence or progression has occurred Grater then12 months after the end of treatment.
• 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 18.
• 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.
• Note: Local treatment of isolated lesions for palliative intent is acceptable 19.
• 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 Note: Local surgery of isolated lesions for palliative intent is acceptable.
• 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: (a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intraarticular injection).
• (b) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication), as premedication for chemotherapy, or a single dose for alliative purpose (eg, pain control).
• 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.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
• Note: Participants, if enrolled, should not receive live vaccine while receiving study intervention and up to 30 days after the last dose of study intervention.
• Prior/Concurrent Clinical Study Experience 23.
• 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.
• Other Exclusions 25.
• 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 27.
• 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 blinded study treatment and 6 months after last dose of chemotherapy.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To demonstrate the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessment of PFS	OS is defined as the time from randomization until the date of death due to any cause. | The analysis will include all randomized participants. All deaths will be included regardless of whether the participant withdraws from therapy or receives another anticancer therapy. | The measure of interest is the HR of OS | PFS is defined as the time from randomization until radiological progression per RECIST 1.1 as assessed by BICR, or death due to any cause (in the absence of progression). | The analysis will include all randomized participants. All events will be included regardless of whether the participant withdraws from therapy, receives another anticancer therapy or clinically progresses prior to radiographic progression per RECIST 1.1. However, if the participant progresses or dies immediately after 2 or more consecutive missed visits, the participant will be censored at the time of the latest evaluable assessment prior to the 2 missed visits. | The measure of interest is the HR of PFS.
To demonstrate the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessment of OS	OS is defined as the time from randomization until the date of death due to any cause. | The analysis will include all randomized participants. All deaths will be included regardless of whether the participant withdraws from therapy or receives another anticancer therapy. | The measure of interest is the HR of OS | PFS is defined as the time from randomization until radiological progression per RECIST 1.1 as assessed by BICR, or death due to any cause (in the absence of progression). | The analysis will include all randomized participants. All events will be included regardless of whether the participant withdraws from therapy, receives another anticancer therapy or clinically progresses prior to radiographic progression per RECIST 1.1. However, if the participant progresses or dies immediately after 2 or more consecutive missed visits, the participant will be censored at the time of the latest evaluable assessment prior to the 2 missed visits. | The measure of interest is the HR of PFS.

Secondary Outcome Measures

Name	Time	Method
To characterize the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessment of OS	OS is defined as the time from randomization until the date of death due to any cause.
To characterize the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessment of PFS	PFS is defined as the time from randomization until radiological progression per RECIST 1.1 as assessed by BICR, or death due to any cause (in the absence of progression).
To compare the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessment of PFS2	PFS2 is defined as the time from randomization until the earliest of the progression event (following the initial investigator-assessed progression event), after the start of the first subsequent therapy, or death from any cause, whichever occurs first. The date of the second progression will be recorded by the investigator in the eCRF and defined according to local standard clinical practice.
To investigate the immunogenicity of rilvegostomig	Presence ADAs, titer, and neutralizing antibodies for rilvegostomig.
To assess patient-reported physical Functioning	Proportion of participants with maintained or improved physical functioning as measured by PROMIS PF-SF 8c – 7 day at each time point.
To assess patient-reported GHS/QoL	To assess patient-reported lung cancer
o assess patient-reported lung cancer	symptoms of NSCLC
To assess the PK of rilvegostomig	Concentration of rilvegostomig in serum.
To characterize and compare the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessment of ORR	ORR is defined as the proportion of participants who have a confirmed CR or confirmed PR, as determined by BICR assessments using RECIST 1.1.
To characterize the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessment of DoR	DoR is defined as the time from the date of first documented response until the date of documented progression per BICR assessments using RECIST 1.1 or death due to any cause (in the absence of progression).

Trial Locations

Locations (10)

Aakash Healthcare Super Speciality Hospital; 🇮🇳 Delhi, DELHI, India

All India Institute of Medical Sciences; 🇮🇳 Delhi, DELHI, India

Apollo Multispecialty Hospitals Limited; 🇮🇳 Kolkata, WEST BENGAL, India

First Cure Hospital; 🇮🇳 Surat, GUJARAT, India

HCG Manavata Cancer Center; 🇮🇳 Nashik, MAHARASHTRA, India

Jawaharlal Institute of Postgraduate Medical Education Research (JIPMER); 🇮🇳 Pondicherry, PONDICHERRY, India

Mahamana Pandit Madan Mohan Malaviya Cancer Centre; 🇮🇳 Varanasi, UTTAR PRADESH, India

Meenakshi Mission Hospital & Research Centre; 🇮🇳 Madurai, TAMIL NADU, India

MVR Cancer Centre and Research Institute; 🇮🇳 Kozhikode, KERALA, India

Tata Memorial Centre; 🇮🇳 Mumbai, MAHARASHTRA, India

Aakash Healthcare Super Speciality Hospital

🇮🇳Delhi, DELHI, India

Dr Parveen Jain

Principal investigator

9811775324

drparveen1010@gmail.com