Frontline sigvotatug vedotin plus pembrolizumab vs pembrolizumab for non-small cell lung cancer with PD-L1 tumor proportion score ≥50%: phase III study design

ABSTRACT

Integrin beta-6 (IB6) is a tumor-associated membrane protein involved in many cellular processes, including wound healing and tissue remodeling. While IB6 expression is constitutively low in healthy tissues, high IB6 expression in numerous cancers, including non-small cell lung cancer (NSCLC), is associated with poor outcomes. In a phase I study, the novel IB6-directed vedotin-based antibody-drug conjugate sigvotatug vedotin (SV) showed manageable safety and encouraging efficacy as a monotherapy and in combination with pembrolizumab in patients with advanced solid tumors, including NSCLC. Based on those results, the phase III Sigvie-003 study is evaluating SV plus pembrolizumab compared with pembrolizumab monotherapy as first-line treatment in adult patients with locally advanced, unresectable, or metastatic NSCLC with high programmed cell death ligand 1 expression (tumor proportion score ≥50%). Here, we describe the design of the Sigvie-003 study, which is an open-label, randomized, controlled phase III study. Approximately 714 patients will be randomized 1:1. The dual primary endpoints are progression-free survival as assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; secondary endpoints include additional efficacy, safety and tolerability, pharmacokinetics, and immunogenicity endpoints.

Clinical trial registration: NCT06758401 (https://clinicaltrials.gov/study/NCT06758401).

Plain Language Summary

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Integrin beta-6 (IB6) is a protein found in small amounts on the surface of healthy cells and in larger amounts on some types of cancer cells, including NSCLC. Sigvotatug vedotin (SV) is a medicine that works by binding to IB6 and delivering a toxic substance to kill cells. Pembrolizumab is a medicine that targets and blocks a protein on the surface of immune system cells, which may help the immune system kill cancer cells. Sigvie-003 is a clinical trial investigating SV combined with pembrolizumab in participants with NSCLC that has spread beyond the lungs (advanced or metastatic disease) and has not been treated since spreading beyond the lungs. The trial is evaluating if the combination of SV and pembrolizumab increases the length of time a participant is alive after the start of treatment (overall survival) or alive without their cancer getting worse (progression-free survival) compared with pembrolizumab alone. Participants are also monitored for side effects and to see if their cancer has shrunk or disappeared. We describe the design of Sigvie-003.

1. Introduction

1.1. Background

1.1.1. Non-small cell lung cancer

Lung cancer is the most common cancer globally, with nearly 2.5 million new cases diagnosed in 2022 [1]. Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancer cases [2]. Most patients are diagnosed at advanced or metastatic stages and have poor prognosis [3,4]. However, the discovery of biomarkers and corresponding targeted therapies has improved patient outcomes. Guidelines recommend that patients receive a full biomarker panel, including genomic alterations in EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, METex14 skipping, RET, and ERBB2 (HER2) and programmed cell death ligand 1 (PD-L1) expression [5,6]. If an actionable genomic alteration (AGA) is found, guidelines recommend that the patient receive the corresponding approved therapy. For patients without AGAs, treatment options include immunotherapy and chemotherapy as monotherapy or in combination [7].

Pembrolizumab, a programmed cell death protein 1 inhibitor, was the first immunotherapy approved for first-line treatment of metastatic NSCLC [8]. In the US and Europe, pembrolizumab is indicated as a first-line treatment for patients with metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥1% (US) or ≥50% (Europe) and no EGFR or ALK alterations [9,10]. Support for these approvals came from the phase III KEYNOTE-024 (NCT02142738) and KEYNOTE-042 (NCT02220894) studies [9–15]. In KEYNOTE-024, after 5 years of follow-up in patients with previously untreated advanced NSCLC and PD-L1 TPS ≥50%, pembrolizumab (versus chemotherapy) improved median progression-free survival (PFS; 7.7 versus 5.5 months) and median overall survival (OS; 26.3 versus 13.4 months) [13]. Expansion of the first-line treatment recommendation to patients with PD-L1 TPS ≥1% was based on the KEYNOTE-042 study, which showed longer median OS with pembrolizumab versus chemotherapy (16.4 versus 12.1 months) [15,16].

Various combinations of immunotherapy and chemotherapy, including pembrolizumab-based regimens, have been approved for patients with metastatic NSCLC [9,17]. KEYNOTE-189 compared first-line treatment with either pembrolizumab or placebo plus pemetrexed and platinum-based chemotherapy in patients with nonsquamous NSCLC with any level of PD-L1 expression [18]. After over 5 years of follow-up, the addition of pembrolizumab versus chemotherapy alone improved median PFS (9.0 versus 4.9 months) and median OS (22.0 versus 10.6 months). This trend was consistent across PD-L1 subgroups, including the subgroup of patients with PD-L1 TPS ≥50% (median PFS: 11.3 versus 4.8 months; median OS: 27.7 versus 10.1 months). However, real-word and meta-analysis studies have reported conflicting results about whether pembrolizumab plus chemotherapy improves survival compared with pembrolizumab monotherapy for patients with NSCLC and high PD-L1 (TPS ≥50%) [19,20].

1.1.2. Integrin beta-6

In addition to established cancer biomarkers, integrins are emerging as potential biomarkers [21]. Integrins are a large family of transmembrane receptors that facilitate bidirectional communication between the extracellular matrix and the cytoskeleton [22,23]. Integrins have numerous roles in cellular processes, such as proliferation, migration, and apoptosis. Each integrin is a heterodimer formed from 1 of 18 alpha chains and 1 of 8 beta chains. Integrin beta-6 (IB6), which is formed from integrin subunit beta-6 and its only dimerization partner, integrin subunit alpha-v, is of particular interest in cancer biology due to its role in wound healing and tissue remodeling, especially its ability to activate transforming growth factor-β, promote the epithelial to mesenchymal transition, and protect against anoikis (Figure 1) [23–27]. Through increased expression of IB6, cancer cells may exploit these processes to facilitate invasion into healthy tissues [24,28,29]. The characteristic cytoplasmic tail of integrin subunit beta-6, which interacts with the cytoskeleton and signaling pathways, plays a unique role in cancer progression [23,30,31]. The current understanding of how IB6 expression contributes to cancer progression is derived from studies spanning various cancer types [23]. In lung cancer in particular, a preclinical study showed that IB6 expression was positively correlated with interleukin-8 levels [32]. IB6 promoted lung cancer proliferation and metastasis, at least in part through upregulation of interleukin-8–mediated MAPK/ERK signaling.

Figure 1.

Overview of IB6 (A) in cells and (B) key roles in oncogenic processes.

Abbreviations: ECM, extracellular matrix; IB6, integrin beta-6; IL, interleukin; LAP, latency-associated peptide; MMP, matrix metalloproteinase; TGF, transforming growth factor.

Additionally, while IB6 expression is constitutively low in epithelial tissues, it is upregulated in numerous cancers, including NSCLC, with positive IB6 expression (weak, moderate, or strong in > 1% of cells) in 90% of NSCLC tumors [23,24,26,33]. In a real-world study, high IB6 expression (2+ staining in ≥50% of cells) was found in 75% of NSCLC tumor samples, including 79% of nonsquamous samples and 59% of squamous samples [34]. IB6 expression has been associated with poor prognosis in various cancers, such as NSCLC [35–39]. The high level of IB6 expression in tumors compared to within healthy tissues and the negative prognostic indication makes IB6 a promising therapeutic target [23,24,36,37]. A wide range of approaches has been taken to target specifically IB6 in cancer treatment, such as antibodies blocking IB6 function, photodynamic therapy, radiotherapeutics, and antibody-drug conjugates (ADCs) [24,25,40–43]. However, many of these approaches have not advanced beyond the preclinical stage. There are several ongoing clinical studies of sigvotatug vedotin (SV), a novel IB6-directed vedotin-based ADC [33,44–47].

1.1.3. Sigvotatug vedotin

SV consists of a humanized monoclonal antibody that binds specifically to IB6, linked to the cytotoxic agent monomethyl auristatin E (MMAE) via a protease-cleavable linker [24]. MMAE is released in cells that have internalized SV, disrupting microtubule dynamics and leading to cell cycle arrest and apoptosis [24,48]. In preclinical studies, SV showed antitumor activity across various cancer models, including NSCLC, both squamous cell and adenocarcinoma histologic subtypes, and across a range of IB6 expression levels [24].

In parts A and B of the SGNB6A-001 phase I study (NCT04389632), SV monotherapy was evaluated in patients with heavily pretreated advanced NSCLC (N = 117) [46,49,50]. The recommended SV dosing regimen was 1.8 mg/kg adjusted ideal body weight on Days 1 and 15 of a 28-day cycle [46]. SV demonstrated encouraging efficacy in patients with heavily pretreated advanced NSCLC, with an objective response rate (ORR) of 19%, median duration of response (DOR) of 11.3 months, median PFS of 3.5 months, and median OS of 11.2 months. The highest antitumor activity was found in a subpopulation of patients with nonsquamous, taxane-naïve NSCLC (ORR, 31%; median DOR, 11.6 months; median PFS, 6.4 months; median OS, 16.3 months). Overall, SV monotherapy demonstrated manageable safety, with any-grade and grade ≥3 treatment-related adverse events (AEs) reported in 80% and 17% of patients, respectively. The most common any-grade treatment-emergent AEs were fatigue (49%), peripheral sensory neuropathy (37%), nausea (35%), and diarrhea (31%). Treatment-related AEs led to SV discontinuation in 9% of patients. Based on these results from the phase I SGNB6A-001 study, a randomized, phase III trial (Sigvie-002; Be6A Lung-01; NCT06012435) is evaluating SV versus docetaxel in patients with advanced, nonsquamous, taxane-naïve NSCLC who received prior therapy per standard of care [33].

1.2. Rationale for combination of SV and pembrolizumab

In addition to evaluating SV monotherapy, the phase I SGNB6A-001 study is exploring SV plus pembrolizumab with or without platinum-based chemotherapy in parts C and D [51]. The rationale for this combination is linked to the proposed mechanism of action of SV, namely its potential ability to induce immunogenic cell death (ICD), a type of cell death that elicits an immune response [24,51–53]. The ability of SV to induce ICD was demonstrated in a preclinical study that identified key hallmarks of ICD in tumor cells treated with SV [54,55]. This mechanism has been observed with other vedotin-based ADCs; the disruption of microtubules by MMAE can trigger endoplasmic reticulum stress, resulting in ICD and subsequent upregulation of immune function [24,52,53]. Therefore, vedotin-based ADCs may enhance antitumor activity when used in conjunction with an immunotherapy, such as pembrolizumab [52–54]. Prior clinical studies have shown encouraging activity and manageable safety of other vedotin-based ADCs combined with immunotherapy [56–58]. A preclinical study demonstrated increased antitumor activity when SV was investigated in combination with immunotherapy [54,55]. Initial results from the phase I study demonstrated antitumor activity of SV plus pembrolizumab as a first-line treatment for patients with advanced NSCLC, with encouraging ORRs between 50% and 61.5% in patients with PD-L1 TPS < 1% (n = 13; 50.0%) or ≥1% (n = 8; 61.5%) [51]. Overall, safety of the combination was generally manageable, with any-grade and grade ≥3 treatment-related AEs reported in 80% and 37% of patients, respectively. The most common any-grade treatment-emergent AEs were decreased appetite (39%), alopecia (37%), nausea (33%), and fatigue (31%). AEs of special interest (any grade; grade ≥3) included peripheral neuropathy (31%; 2%), hepatotoxicity (20%; 4%), hyperglycemia (6%; 0%), and ILD/pneumonitis (8%; 0%). These data support further investigation of the combination as a first-line treatment for patients with advanced NSCLC.

We report the design of the Sigvie-003 study (Be6A Lung-02; NCT06758401; EudraCT: 2024-517968-36), an open-label, randomized, controlled phase III study evaluating SV in combination with pembrolizumab compared with pembrolizumab monotherapy as first-line treatment in adult patients with locally advanced, unresectable, or metastatic NSCLC with high PD-L1 expression (TPS ≥50%), based on protocol version A03, 20 May 2025.

2. Methods

2.1. Key eligibility criteria

To be eligible for the study, patients must be aged ≥18 years with untreated, pathologically confirmed, advanced or metastatic NSCLC (stage IIIB or IIIC and ineligible for surgical resection or definitive chemoradiation; stage IV NSCLC) with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Table 1). Patients with nonsquamous histology are required to have documented negative test results for EGFR, ALK, and ROS1 AGAs; no known AGAs identified in NTRK, BRAF, RET, or MET; and no other AGAs with approved frontline therapies per local standard of care. Patients must have PD-L1 TPS of ≥50% as determined by local testing. As retrospective central confirmation will be conducted using a PD-L1 immunohistochemistry assay, patients must either have an acceptable tumor sample available from within the prior 6 months or be willing to undergo a biopsy procedure.

Table 1.

Key eligibility criteria.

Key inclusion criteria

Age ≥18 years* ECOG PS 0 or 1 Adequate baseline hematologic, hepatic, and renal function Pathologically confirmed stage IIIB or IIIC (not candidate for surgical resection or definitive chemoradiation) or stage IV disease per AJCC version 8.0 and UICC staging system 8th edition For patients with nonsquamous histology: documented negative test results for EGFR, ALK, and ROS1 AGAs; no known AGAs in NTRK, BRAF, RET, or MET; no other AGAs with approved frontline therapies per local standard of care Eligible for pembrolizumab monotherapy per local guidelines PD-L1 expression in ≥50% of tumor cells (TPS ≥50%) as determined by local testing with retrospective central confirmation using a PD-L1 IHC assay† Measurable disease based on RECIST v1.1 per investigator‡

Key exclusion criteria

Prior or concomitant therapy: Prior systemic therapy for locally advanced, unresectable, or metastatic NSCLC (Neo)adjuvant anti–PD-(L)1 is allowed if recurrence or progression occurred ≥9 months after the last dose Other (neo)adjuvant or definitive therapy is allowed if recurrence or progression occurred ≥6 months after the last dose Prior radiotherapy to the lung received ≤6 months before first dose of study treatment Chemotherapy, biologics, and/or other antitumor immunotherapy not specifically prohibited that is completed ≤4 weeks prior to the first dose of study treatment (2 weeks for palliative radiotherapy)§ Current treatment with an investigational agent Any prior therapy with an immune-oncology agent directed toward a stimulatory or co-inhibitory T-cell receptor Any prohibited concomitant therapy within 21 days of the first dose of study intervention║ Presence of the following respiratory conditions: Evidence of noninfectious or drug-induced ILD or pneumonitis that: Was previously diagnosed and required systemic steroids, or Is currently diagnosed and managed, or Is suspected on radiologic imaging at screening Known diffusing capacity of the lung for carbon monoxide (adjusted for hemoglobin) < 50% predicted Any grade ≥3 pulmonary disease unrelated to underlying malignancy Known active CNS lesions, including leptomeningeal metastasis¶

*Or minimum age of consent in accordance with local regulations.

^†Archival tumor specimens collected within 6 months prior to the first dose of study intervention may be used. If no archival tissue is available, the patient must be willing and able to undergo a biopsy procedure to obtain a tumor tissue specimen.

^‡Patients with prior definitive radiotherapy must have measurable disease per RECIST v1.1 that is outside the radiation field or have unequivocal progression of previously irradiated lesions.

^§Must have recovered from all radiation-related toxicities that would otherwise prevent trial participation. Ongoing hormonal/antihormonal treatment (eg, for breast cancer or prostate cancer) is allowed if the patient meets other criteria.

^|Concomitant treatment determined necessary for patient’s wellbeing or palliative and supportive care for disease-related symptoms may be allowed per investigator’s discretion. Other investigational drugs, immunosuppressive medications, radiotherapy, or systemic antineoplastic therapy will not be allowed during the study.

^¶Patients with definitively treated brain metastases (surgery and/or radiotherapy) are eligible if CNS metastases are clinically stable for ≥14 days after definitive treatment completion and prior to beginning study treatment, no steroids have been required for symptom management for 7 days prior to beginning study treatment, and clinically inactive brain metastases have a longest diameter < 0.5 cm.

Abbreviations: AGA, actionable genomic alteration; AJCC, American Join Committee on Cancer; CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry; ILD, interstitial lung disease; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors; TPS, tumor proportion score; UICC, Union for International Cancer Control.

Exclusion criteria include detailed guidance for prior or concomitant therapies. Patients cannot have received prior systemic therapy for locally advanced, unresectable, or metastatic NSCLC. However, (neo)adjuvant anti-PD-(L)1 is allowed if recurrence or progression occurred >9 months after the last dose of an anti-PD-(L)1, or any other (neo)adjuvant therapy or curative-intent treatment for locally advanced disease if recurrence or progression occurred >6 months after the last dose. Prior treatment with an MMAE-based drug or an IB6-targeting therapy is not allowed. Patients are excluded if they have grade ≥2 peripheral neuropathy. Patients are excluded if they have certain respiratory conditions, including noninfectious or drug-induced interstitial lung disease (ILD) or pneumonitis or any grade ≥3 pulmonary disease unrelated to the underlying malignancy. Patients with active central nervous system (CNS) lesions, including untreated or symptomatic brain metastases and leptomeningeal disease, are ineligible. Patients with definitively treated brain metastases are allowed if they are stable ≥14 days after definitive treatment completion at the time of study entry, have not required steroids for symptom management for ≥7 days prior to study treatment initiation, and if applicable, the longest brain lesion diameter is <0.5 cm. All patients must provide written informed consent before enrollment.

2.2. Study design

In this study, approximately 714 patients will be enrolled at study sites in North America, Europe, South America, Australia, Middle East, and East Asia. Patients will be randomized 1:1 to receive either (A) SV plus pembrolizumab or (B) pembrolizumab monotherapy (Figure 2). Randomization will be done centrally with interactive response technology and will be stratified by histology subtype (squamous versus nonsquamous), Eastern Cooperative Oncology Group performance status (0 versus 1), region (East Asia versus rest of world), and brain metastasis (present versus absent at baseline). Patients in treatment arm A will receive SV 1.8 mg/kg adjusted ideal body weight intravenously on Days 1, 15, and 29 of a 42-day cycle (ie, every 2 weeks), and patients in both treatment arms will receive pembrolizumab 400 mg intravenously on Day 1 of a 42-day cycle (ie, every 6 weeks). In both treatment arms, pembrolizumab may be received for a maximum of 18 cycles, but SV monotherapy may be continued in arm A. Treatment will be administered until completion of the maximum number of cycles (applicable to pembrolizumab), disease progression, unacceptable toxicity, withdrawal of consent, end of study, or discontinuation for any other reason.

Figure 2.

Study design.

Abbreviations: AE, adverse event; AGA, actionable genomic alteration; AiBW, adjusted ideal body weight; BICR, blinded independent central review; CT, computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; MRI, magnetic resonance imaging; NCI, National Cancer Institute; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-1, programmed cell death 1 protein; PD-L1, programmed death 1 ligand 1; PFS, progression-free survival; Q2W, on Days 1, 15, and 29 of a 42-day cycle; Q6W, on Day 1 of a 42-day cycle; SV, sigvotatug vedotin; TPS, tumor proportion score.

The primary endpoints will be OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints will include ORR and DOR per RECIST v1.1 by both BICR and investigator, PFS per RECIST v1.1 by investigator, safety and tolerability, pharmacokinetics (PK), and immunogenicity. All primary and secondary endpoints are described in Table 2.

Table 2.

Study objectives and endpoints.

Primary objectives	Primary endpoints
To demonstrate that SV plus pembrolizumab is superior to pembrolizumab monotherapy in prolonging OS	OS
To demonstrate that SV plus pembrolizumab is superior to pembrolizumab monotherapy in prolonging PFS by BICR	PFS using RECIST v1.1 as assessed by BICR
Secondary objectives	Secondary endpoints
To compare ORR by BICR between treatment arms	Confirmed ORR using RECIST v1.1 as assessed by BICR
To evaluate additional measures of efficacy in the treatment arms	PFS using RECIST v1.1 as assessed by investigator
	Confirmed ORR using RECIST v1.1 as assessed by investigator
	DOR using RECIST v1.1 as assessed by BICR and investigator
To characterize the safety and tolerability profile in both treatment arms	Type, incidence, severity, seriousness, and relatedness of AEs
To characterize the PK of SV when administered in combination with pembrolizumab	Plasma concentration at end of infusion (CEOI) and plasma predose concentration (Cpredose) for ac-MMAE and unconjugated MMAE
To characterize the immunogenicity of SV when administered in combination with pembrolizumab	Incidence of ADAs
Exploratory objectives and endpoints
A number of exploratory objectives/endpoints will be assessed on study

Abbreviations: ac-MMAE, antibody-conjugated monomethyl auristatin E; ADA, antidrug antibody; AE, adverse event; BICR, blinded independent central review; DOR, duration of response; MMAE, monomethyl auristatin E; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; RECIST, Response Evaluation Criteria in Solid Tumors; SV, sigvotatug vedotin.

2.3. Efficacy assessments

Tumor response assessments will be performed by both BICR and investigator according to RECIST v1.1 criteria [59]. Treatment decisions will be based on assessments per investigator according to RECIST v1.1 and iRECIST [59,60]. Disease assessments will include computed tomography or magnetic resonance imaging at baseline, during treatment, whenever disease progression is suspected, and at the time of withdrawal from treatment. During treatment, imaging will be done every 6 (±1) weeks from the randomization date for 48 weeks and then every 12 (±1) weeks thereafter. Confirmation scans will be required at least 4 weeks after first documentation of complete or partial response.

Until BICR-confirmed progressive disease (PD), clinically stable patients may continue treatment at the investigator’s discretion unless progression is confirmed per iRECIST as assessed by investigator with confirmatory scans 4 to 8 weeks after initial PD date. For patients who discontinue study treatment for reasons other than BICR-confirmed PD or withdrawal of consent, assessments will continue every 6 (±1) weeks from the randomization date for 48 weeks and then every 12 (±1) weeks thereafter until BICR-confirmed PD, death, end of study, or withdrawal of consent, whichever occurs first.

Magnetic resonance imaging of the brain will be performed at screening for all patients. For patients with a history of CNS metastases, brain imaging should be repeated with the other scheduled imaging. Additional brain imaging may be done if clinically indicated or CNS progression is suspected. For patients with history or symptoms of skeletal metastases, positron emission tomography, computed tomography, or bone scan may be conducted at screening as clinically indicated.

2.4. Safety assessments

Safety will be assessed using the incidence and severity of AEs and serious AEs from the time the patient provides informed consent through a minimum of 28 days after the last dose of SV or 90 days after the last dose of pembrolizumab, whichever is later, or until new anticancer treatment is started.

AEs of special interest related to SV include peripheral neuropathy, hepatotoxicity, ILD/pneumonitis, and hyperglycemia and will be followed up regardless of severity until resolution, return to baseline, events are adequately characterized, end of study, or patient withdrawal of consent. These AEs may be managed with dose modifications. For instance, SV will be withheld for grade 2 or 3 peripheral neuropathy until it resolves to grade ≤1 when SV may be resumed at a lower dose; however, SV must be permanently discontinued for grade 4 peripheral neuropathy. Rash and severe skin reactions have been previously reported in patients receiving the SV and pembrolizumab combination regimen in the phase I setting; exfoliative dermatologic conditions, including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, and suspected toxic epidermal necrolysis, are known risks with programmed cell death protein 1/PD-L1 blocking antibodies [52,61]. Starting in the first cycle and throughout treatment, patients must be closely monitored for skin reactions. Dose modification guidance for skin toxicities include consideration of appropriate treatment, such as topical corticosteroids and antihistamines for mild to moderate skin reactions, as clinically indicated. If Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms is suspected, both SV and pembrolizumab will be withheld immediately and the patient will be referred to a dermatologist/specialist for diagnosis and specialized care.

Physical examination and evaluation of vital signs, weight, and Eastern Cooperative Oncology Group performance status will be done at screening, before treatment administration on dosing days throughout treatment, and at the end-of-treatment (EOT) visit. Clinical laboratory assessments will be done at baseline and up to 1 day prior to dosing throughout treatment. Electrocardiograms will be performed at screening, when clinically indicated during treatment, and at the EOT visit.

2.5. Additional assessments

Characterization of the PK and immunogenicity of SV when administered in combination with pembrolizumab is a secondary endpoint that will be assessed in patients in arm A. Blood samples will be collected before and after SV administration on Days 1, 15, and 29 of Cycle 1 and Cycle 3 Day 1, Cycle 5 Day 29, Cycle 8 Day 15, and Cycle 11 Day 1. Blood samples for PK analysis will be used to measure plasma concentrations of antibody-conjugated MMAE and unconjugated MMAE.

Exploratory endpoints will aim to characterize the relationship between study treatment response and molecular characteristics, such as IB6 and PD-L1 expression levels by immunohistochemistry, of the patient’s disease. IB6 expression will be evaluated to understand its potential predictive value for future clinical applications and potential enrichment strategies. While, PD-L1 expression will be evaluated locally prior to enrollment, confirmation of PD-L1 will be done centrally. Both IB6 and PD-L1 assessments will be done retrospectively. Analysis of circulating tumor DNA in relation to treatment efficacy will be done with samples collected before and after treatment administration. Biomarker assessment will include evaluation of ctDNA molecular response, acquired potential resistance mechanisms, and AGAs. Tumor mutational burden and microsatellite instability can be assessed using ctDNA, and SV efficacy will be evaluated in the context of these patient subpopulations. Additional biomarker research will be conducted with those blood samples along with tumor samples, which are required at screening and are optional on treatment and at EOT. Gene expression research will be done with RNA isolated from tumor tissues; samples will be analyzed via targeted and/or transcriptomic profiling to evaluate gene expression levels, which may then be used to identify associations with response, resistance, and AEs.

Patient-reported outcome assessments will be completed upon patient arrival on Day 1 of each cycle, at EOT, and during follow-up. Those assessments include European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13, EQ-5D-5 L, and Patient Global Impression of Change and Patient Global Impression of Severity.

2.6. Sample size determination and planned analyses

Approximately 714 patients will be randomized to provide 90% power for each primary endpoint (PFS and OS). Planned analyses include an interim analysis of OS at 75% of the events and final analysis of PFS, planned to be conducted at the same time, and final analysis of OS.

2.7. Statistical analysis

All efficacy analyses will be performed in all patients randomized to one of the treatment arms. OS is defined as the time from the date of randomization to the date of death due to any cause. Patients without documented death will be censored on the last known alive date. PFS is defined as the time from the date of randomization to the date of the first documentation of PD per RECIST v1.1 or death due to any cause, whichever occurs first. Both OS and PFS will be compared between treatment arms using 1-sided log-rank tests stratified by randomization stratification factors. The Cox proportional hazards model stratified by randomization stratification factors will be fitted to estimate the treatment hazard ratio and the corresponding 95% CI. Kaplan-Meier estimates and corresponding 95% CIs will be used for median survival times and rates.

ORR point estimates and 95% CIs will be calculated using the Wilson score method. The odds ratio and the corresponding 95% CI will be calculated to contrast the treatment effects on ORR. The Cochran-Mantel-Haenszel test with randomization stratification factors will be used to compare ORR between the 2 treatment arms. DOR, which is defined as the time from the first documentation of objective response to the date of the first documentation of PD or death due to any cause, whichever occurs first, will be calculated in the subgroup of patients with confirmed objective tumor response. DOR will be summarized by treatment arm using Kaplan-Meier methods.

All safety analyses will use all randomized patients who received at least 1 dose of study treatment. AEs will be graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0. AEs and serious AEs will be summarized by Medical Dictionary for Regulatory Activities preferred term, grade, seriousness, and relationship to study treatment. AEs leading to death or treatment discontinuation will also be summarized.

2.8. Data monitoring

An external data monitoring committee independent of the sponsor will be appointed for this study to monitor the safety and scientific integrity of the human research intervention. The committee will review safety and may request to review efficacy data based on an observed safety signal. They will make recommendations to the sponsor. An adjudication committee for ILD and pneumonitis will also be appointed and blinded to treatment assignment to facilitate unbiased assessments. Additional safety adjudication committees may be established during the study to standardize safety assessments.

3. Ethics and dissemination

This study is being conducted in accordance with the protocol, legal and regulatory requirements, applicable guidelines from International Council for Harmonisation Good Clinical Practice, and ethical principles from international guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines. Prior to study initiation, the protocol, protocol amendments, and other relevant documents will be approved by the sponsors and the institutional review board and ethics committee. Protocol amendments will require institutional review board and ethics committee approval before incorporation into the study design, except for changes necessary to eliminate an immediate hazard to study participants. Written informed consent is being obtained from participants by investigators prior to enrollment.

To maintain patient anonymity, patients will be assigned a unique numerical code, and patient records will be securely stored at the study site. Any patient data that is transferred to the sponsor will include the patient’s numerical code in place of their name or any information that would be patient identifiable. Patient information will be protected following applicable laws.

Findings will be posted in a publicly accessible database (eg, ClinicalTrials.gov) in accordance with applicable laws, regulations, and guidelines. The results will also be disseminated through congress presentations and peer-reviewed publications.

4. Conclusion

While immunotherapy-based regimens are considered standard of care for first-line treatment of patients with metastatic NSCLC and PD-L1 TPS ≥50%, most patients experience disease progression and die of their disease within 2 to 3 years [15,18,62]. The phase III Sigvie-003 study aims to evaluate SV in combination with pembrolizumab compared with pembrolizumab monotherapy as first-line treatment for patients with locally advanced, unresectable, or metastatic NSCLC with high PD-L1 expression (TPS ≥50%). This study follows the encouraging efficacy demonstrated by the combination in the phase I SGNB6A-001 study [51]. The primary objectives of this study are to determine whether SV plus pembrolizumab improves PFS and OS compared with pembrolizumab monotherapy. If results are positive, SV plus pembrolizumab may become a first-line treatment option for patients with metastatic NSCLC with high PD-L1 expression (TPS ≥50%). For additional study information, please visit the NCT website (https://www.clinicaltrials.gov/study/NCT06758401).

Funding Statement

This manuscript was funded by Pfizer. The funder was involved in the study design and collaborated with the authors on the preparation of this manuscript.

Article highlights

• Integrin beta-6 (IB6) is a transmembrane protein with constitutively low expression in healthy tissues and high expression in tumors, including non-small cell lung cancer (NSCLC), which is linked to poor outcomes.

• IB6 is a promising anticancer therapeutic target, and several approaches have been investigated; however, few therapeutic approaches have moved beyond preclinical trials.

• Sigvotatug vedotin (SV) is a novel IB6-directed vedotin-based antibody-drug conjugate, which is composed of an antibody specific to IB6 linked to monomethyl auristatin E.

• In a phase I study, SV showed manageable safety and encouraging efficacy as a monotherapy and in combination with pembrolizumab in patients with advanced solid tumors, including NSCLC.

• Sigvie-003 is an open-label, randomized, controlled phase III study evaluating the efficacy of SV in combination with pembrolizumab compared with pembrolizumab monotherapy as first-line treatment in adult patients with locally advanced, unresectable, or metastatic NSCLC with programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS)≥50%.

• Approximately 714 patients will be randomized to receive either (A) SV 1.8 mg/kg adjusted ideal body weight intravenously on Days 1, 15, and 29 of a 42-day cycle (ie, every 2 weeks) and pembrolizumab 400 mg intravenously on Day 1 of a 42-day cycle (ie, every 6 weeks) or (B) only pembrolizumab 400 mg intravenously on Day 1 of a 42-day cycle (ie, every 6 weeks).

• The dual primary end points are progression-free survival as assessed by blinded independent committee review per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and overall survival; secondary endpoints include additional efficacy, safety and tolerability, pharmacokinetics, and immunogenicity endpoints.

• Results from Sigvie-003 will provide insight into the efficacy and safety of SV plus pembrolizumab as a first-line treatment option for patients with metastatic NSCLC with PD-L1 TPS ≥50%.

Author contributions

Martin Reck: investigation; writing‒review & editing; Shun Lu: investigation; writing‒review & editing; Kenneth J. O’Byrne: investigation; writing‒review & editing; Carlos Barrios: investigation; writing‒review & editing; Dmitri Pavlov: writing‒review & editing; Fabian Tay: writing‒review & editing; Marcelo V. Negrao: investigation; writing‒review & editing.

Financial and competing interests disclosure

Dr Reck has received consulting fees, honoraria, and travel support from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, BeiGene, Daiichi Sankyo, GSK, Lilly, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Regeneron, and Roche.

Dr Lu has received consulting fees from AstraZeneca, Boehringer Ingelheim, Hutchison MediPharma, Simcere Pharmaceutical, Zai Lab, GenomiCare Biotechnology, and Roche; grant support from AstraZeneca, Roche, Hutchison MediPharma, Bristol Myers Squibb, and Hengrui Therapeutics; and lecture fees from AstraZeneca and Roche Hansoh Pharmaceutical.

Dr O’Byrne has received honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Merck Group, MSD, Pfizer/EMD Serono, Roche, Seagen, Takeda, and TriStar Technology Group; has had a consulting or advisory role for Amgen, AstraZeneca/MedImmune, BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Ipsen, MSD, Pfizer, Roche/Genentech, Sanofi, and Seagen; has received speaker fees from BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Janssen-Cilag, Merck Group, MSD, Pfizer, Roche, and Seagen; received travel support from Bayer Holding and Sanofi; has received payments to institution for being named on 4 active patents (2 published and 2 provisional); and has stock ownership in Carpe Vitae Pharmaceuticals, DGC Diagnostics, and RepLuca Pharmaceuticals.

Dr Barrios has received research funding to institution from Pfizer, Novartis, Amgen, AstraZeneca, Roche/Genentech, Lilly, Sanofi, Merck, Bristol Myers Squibb, Daiichi Sankyo, Exelixis, Janssen, Gilead Sciences, Regeneron, Aveo, Servier, OBI Pharma, Novocure, TRIO US, PharmaMar, PPD Global, Syneos Health, LabCorp, ICON Clinical Research, IQvia, Parexel, Nuvisan, PSI, Worldwide Clinical Trials, BioNTech SE, BMS Brazil, Dizal Pharma, FORTREA, GlaxoSmithKline, Samsung, Sandoz, Sremline, Takeda, and Taiho Pharmaceutical; has received honoraria from Novartis, Roche/Genentech, Pfizer, MSD, Lilly, AstraZeneca, Adium Pharma, Daiichi Sankyo/Astra Zeneca, and Gilead Sciences; has had a consulting or advisory role for Roche/Genentech, Novartis, Pfizer, AstraZeneca, MSD Oncology, Lilly, Daiichi Sankyo/Astra Zeneca, and Gilead Sciences; has received travel, accommodations, or other expenses from Roche/Genentech, Novartis, Pfizer, BMS Brazil, AstraZeneca, MSD Oncology, and Lilly; and has stock ownership in MedSIR, Thummi, and CPO.

Drs Pavlov and Tay are employed by and own stock in Pfizer.

Dr Negrao has received research funding to institution from Lilly, Mirati, BMS, Novartis, Alaunos, AstraZeneca, Pfizer, Genentech, Navire, and Frontier; has had a consultant or advisory role for Genentech, Sanofi, Pfizer, Lilly, AstraZeneca, and BMS; has had a speakers bureau role for OncLive, Ideology, BIO Brasil, Medscape, DAVA Oncology, and Targeted Oncology; has received travel and accommodation expenses from Ideology, DAVA Oncology, and Targeted Oncology; and has received writing support from ApotheCom and Ashfield Healthcare.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Editorial and medical writing support was provided by Caitlin Cash, PhD, of Nucleus Global, and was funded by Pfizer.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethical declaration

This study is being conducted in accordance with the protocol, legal and regulatory requirements, applicable guidelines from International Council for Harmonisation Good Clinical Practice, and ethical principles from international guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines. Prior to study initiation, the protocol, protocol amendments, and other relevant documents were approved by the sponsors and the institutional review board and ethics committee. Protocol amendments will require institutional review board and ethics committee approval before incorporation into the study design, except for changes necessary to eliminate an immediate hazard to study participants. Written informed consent is being obtained from participants by investigators prior to enrollment.

Data-sharing statement

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

Supplementary Information

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14796694.2025.2596228