The novel integrin beta-6 (IB6)–directed antibody-drug conjugate (ADC) sigvotatug vedotin (formerly SGN-B6A) demonstrated early efficacy data alone and in combination with pembrolizumab (Keytruda) in patients with non–small cell lung cancer (NSCLC), warranting further study, according to Rachel E. Sanborn, MD.
Findings from the phase 1 SGNB6A-001 trial (NCT04389632) revealed that sigvotatug vedotin led to a confirmed overall response rate (ORR) of 19.0% (95% CI, 12.3%-27.3%) as monotherapy in patients with NSCLC (n = 116).1 Overall responses consisted of 3 complete responses (CRs) and 19 partial responses (PRs). Among patients with nonsquamous, taxane-naive NSCLC (n = 42), the confirmed ORR was 31.0% (95% CI, 17.6%-47.1%), which consisted of 2 CRs and 11 PRs. Additional findings presented at the 2025 ASCO Annual Meeting illustrated a confirmed ORR of 42.9% (95% CI, 21.8%-66.0%) when pembrolizumab was added to sigvotatug vedotin for the frontline treatment of patients with NSCLC (n = 21).2
Sigvotatug vedotin is now being further evaluated in the phase 3 Be6A Lung-01 trial (NCT06012435) in which patients with previously treated NSCLC will be randomly assigned to treatment with the ADC or docetaxel.3
“Preclinical studies have shown that blocking IB6 can lead to a blockade of downstream signaling pathways, which can inhibit tumor migration as well as invasion. There are also preclinical studies that show that IB6 inhibition can increase potentiation to anti–PD-1 checkpoint inhibition, hence why this becomes an attractive scientific target in cancer,” Sanborn explained during an interview with OncLive®.
In the interview, Sanborn discussed the viability of IB6 as a target in NSCLC, the mechanism of action of sigvotatug vedotin, and early efficacy and safety data from the phase 1 study. She also shared the objectives of the phase 3 Be6A Lung-01 trial and potential future implications of sigvotatug vedotin’s development.
Sanborn is the medical director of the Thoracic Oncology Program and the Phase I Clinical Trials Program at the Earle A. Chiles Research Institute at Providence Cancer Institute in Portland, Oregon.
OncLive: What is the background of IB6, and what makes it a viable target in NSCLC?
Sanborn: If we’re talking about understanding IB6, [it’s important] to first think about what integrins are. They are transmembrane proteins, and they act as signaling between the cells and the cellular surroundings. The surface [of an integrin] includes a cell surface receptor, there is also a transmembrane helix, and then an intracellular cytoplasmic tail. These proteins then function in multiple different signaling pathways. They function in cell survival, migration, cell proliferation, differentiation, metastasis, and tumor invasion. The integrins consist of both alpha and beta subunits, and they combine in different ways, which can create multiple different integrin protein heterodimers.
IB6 is one of these integrin proteins. It is minimally expressed in healthy adult tissues; however, it is upregulated during embryogenesis as well as in tissue repair and carcinogenesis. Upregulated IB6 levels have been associated with poor prognosis in many kinds of cancers, and they’re also associated with tumor progression and higher-grade, more aggressive tumors. IB6 can also activate the TGF-beta complex and convert this to tumor-promoting signaling pathways, and can also facilitate tumor invasion as well as epithelial to mesenchymal transition in cancer cells. IB6 has been shown to be increased with increased expression in many different types of cancer cells, especially in NSCLC, but also in head and neck carcinomas, gastrointestinal primaries, and others as well.
What is the mechanism of action of sigvotatug vedotin, and how is it different from standard agents for patients with pretreated NSCLC, such as docetaxel?
Sigvotatug vedotin is an ADC, and it is specifically directed to IB6 and has an MMAE payload, which is the cytotoxic component. Although ADCs have [adverse] effects [AEs] that predominantly reflect the chemotherapy drug payload, the overall goal of any ADC technology is to try to attempt to more specifically target the cancer cells with maximum [efficacy] and try to have a relative reduction of toxicity to the normal tissues. In terms of chemotherapy agents like docetaxel, they demonstrate valid yet relatively minimal efficacy in the later-line settings in cancer treatment in general. We all realize that so much needs to be done to improve disease control as well as survival and quality of life. It’s hoped that the more specific treatments are going to be able to help improve outcomes over a broader application of a chemotherapy agent. There’s also the consideration of the potentiation of sigvotatug vedotin with checkpoint inhibition to potentially improve T-cell recognition of tumors, and that may provide us with the scientific rationale for further exploration to see if we can obtain better outcomes in combination with immune therapy and hopefully then, even more prolonged disease control.
Based on preclinical and early clinical data, has the agent improved efficacy and simultaneously reduced toxicity?
It’s very important to consider the preclinical data when thinking about ongoing clinical investigations with IB6, IB6 inhibition, sigvotatug [vedotin], or any other agent. [Regarding] the preclinical studies with IB6, when an inhibitor of IB6 was combined with checkpoint inhibition, improvements in CD8-positive T-cell infiltration or tumor-infiltrating lymphocyte infiltration were demonstrated. There were also in vivo models of sigvotatug vedotin, which demonstrated activity in multiple different types of cancers, including NSCLC, and in other cancers, including pancreatic, pharyngeal, and bladder cancers.
[There was also] a phase 1 dose escalation and expansion study of single-agent sigvotatug vedotin, called the SGNB6A-001 trial. That study explored different dosing regimens of sigvotatug vedotin, and in patients with NSCLC, the confirmed ORR was [19.0%].2 However, when looking at the patient population that had nonsquamous NSCLC and who were taxane naive, the ORR was 31.0% and the median progression-free survival [PFS] in that group was 6.4 months [95% CI, 4.5-10.5]. In the phase 1 trial, the most common AEs that were grade 3 or higher with sigvotatug vedotin included dyspnea, fatigue, and neutropenia, and were reflective primarily of the chemotherapy toxicities from the payload when [used] in combination with pembrolizumab. Three patients also experienced pneumonitis; however, none were grade 3 or higher in that group.
Later cohorts now in that trial are exploring the combination of sigvotatug vedotin and pembrolizumab. Updates from the ongoing cohorts were presented at [the 2025 ASCO Annual Meeting and] demonstrated that there was early evidence of efficacy, but the study evaluation is still ongoing.
What are the methods and objectives of the phase 3 Be6A Lung-01 trial?
There is an ongoing phase 3 trial of sigvotatug vedotin in NSCLC, the phase 3 Be6A Lung-01 trial, which is an open-label, global, randomized trial [that enrolled patients] with nonsquamous NSCLC who have had prior treatment with 1 line of platinum-based chemotherapy and an anti–PD-1 or anti–PD-L1 [immune] checkpoint inhibitor.3 Patients with actionable genomic alterations are also permitted to enroll in the study. They are required to have received at least 1 line of appropriate targeted therapy, as well as platinum doublet chemotherapy. Prior anti-microtubule agents like taxane chemotherapies are not allowed for that trial. Sigvotatug vedotin [will be] administered on days 1 and 15 of a 28-day cycle and compared with standard of care docetaxel administered intravenously every 21 days. Patients are [randomly assigned] in a 1:1 fashion. The primary end point of the study is overall survival, and [secondary end points include] confirmed ORR and PFS, among others.
The eligibility criteria established that patients with pretreated, actionable genomic alterations are permitted on this study. What has helped set this precedent?
Multiple different considerations helped set this precedent that allowed patients with actionable genomic alterations to enroll in the trial. The agent itself and the target are not felt to be specific for the presence or absence of any particular actionable genomic alteration, and the ADC has the potential to offer activity that could be similar to, and it is hoped to be better than, traditional chemotherapy agents like docetaxel.
If the phase 3 trial results are positive, how could that affect the drug’s development and potential placement within the current armamentarium?
We are always optimistic, and we all want to see positive trials. It’s important to consider the context that we have extremely limited therapeutic options in this setting for patients who have such a significant need, so any agent that demonstrates a significant benefit over docetaxel in a randomized phase 3 trial is going to be met with enthusiasm. I would anticipate, in the event of a positive trial, that there would be significant enthusiasm to add [sigvotatug vedotin] to our therapeutic armamentarium. It’s also going to raise further questions about incorporation into earlier lines of therapy, such as with the ongoing Be6A Lung-02 trial [NCT06758401], which is a randomized phase 3 trial of sigvotatug vedotin plus pembrolizumab compared with pembrolizumab alone for the first-line treatment of patients with PD-L1–high, advanced NSCLC.
It’s really hoped that ADCs are going to offer greater efficacy than chemotherapy in the treatment of [patients with] lung cancer. So far, the effects have been muted compared with the hopes. However, the science is continuing to evolve, and we’re continuing to try to optimize these agents to make them better. ADCs on their own at this point don’t accomplish what our overall goal is, which is to cure [patients] with no or minimal toxicity. That’s what we all want. ADCs don’t offer that, [although] that’s a tall order for any treatment. [Nevertheless], ADCs are going to have roles to play, especially in combination with other treatments to enhance efficacy over broad-based chemotherapy alone as we continue to learn more.
References
- Sehgal K, Jaime JC, Powell SF, et al. Sigvotatug vedotin (SV), an investigational integrin beta-6 (IB6)–directed antibody‒drug conjugate (ADC), and pembrolizumab combination therapy: Initial results from an ongoing phase 1 study (SGNB6A-001). J Clin Oncol. 2025;43(suppl 16):3010. doi:10.1200/JCO.2025.43.16_suppl.3010
- Peters S, Hollebecque A, Sehgal K, et al. Efficacy and safety of sigvotatug vedotin, an investigational ADC, in NSCLC: updated phase 1 results (SGNB6A-001). J Clin Oncol. 2024;42(suppl 16):8521. doi:10.1200/JCO.2024.42.16_suppl.8521
- Peters S, De Cerqueira Mathias CM, Cheng ML, et al. Be6A Lung-01, a phase III study of sigvotatug vedotin (SV), an investigational antibody-drug conjugate (ADC) versus docetaxel in patients (pts) with previously treated non-small cell lung cancer (NSCLC). Ann Oncol. 2024;35(suppl 2):S875. doi:10.1016/j.annonc.2024.08.1453