After displaying encouraging efficacy as monotherapy in heavily pretreated patients with non–small cell lung cancer (NSCLC) and in combination with pembrolizumab (Keytruda) in the frontline setting, sigvotatug vedotin (SGN-B6A) is being compared with docetaxel in patients with pretreated NSCLC in the phase 3 Be6A Lung-01 trial (NCT06012435).

“Sigvotatug vedotin is an antibody drug conjugate [ADC] which targets integrin beta-6,” Jyoti Malhotra, MD, MPH, explained in an interview with 

®. “The payload is the antitubulin chemotherapy monomethyl auristatin E. Because this is an ADC, it ensures a broader therapeutic index compared with standard of care chemotherapy, as well as more targeted delivery to cancer cells, making it [potentially] more efficacious than chemotherapies such as docetaxel.”

Malhotra is the interim division chief of Thoracic Medical Oncology, associate professor in the Department of Medical Oncology and Therapeutics Research, and the director of thoracic medical oncology at City of Hope in Duarte, California.

Prior Data Support Sigvotatug Vedotin Monotherapy and Combination Therapy in NSCLC

, investigators presented data from the phase 1 SGNB6A-001 study (NCT04389632), which examined sigvotatug vedotin in patients with NSCLC.

 The population was heavily pretreated, with a median of 3.0 (range, 1-10) prior lines of therapy; most patients received prior platinum-based therapy (87.2%) and a PD-1/PD-L1 inhibitor (92.3%).

Data from SGNB6A-001 revealed that patients with NSCLC treated across all dose groups (n = 116) achieved a confirmed overall response rate (ORR) of 19.0% (95% CI, 12.3%-27.3%), including a complete response (CR) rate of 2.6%. The median duration of response (DOR) was 11.3 months (95% CI, 2.4-24.9+) and the disease control rate (DCR) was 69.0% (95% CI, 59.7%-77.2%).

The median progression-free survival (PFS) and overall survival (OS) values were 3.5 months (95% CI, 2.7-5.3) and 11.2 months (95% CI, 8.3-13.7), respectively. The respective 12-month PFS and OS rates were 18.8% and 47.9%.

Notably, patients with nonsquamous, taxane-naive disease (n = 42) who received sigvotatug vedotin achieved a confirmed ORR of 31.0% (95% CI, 17.6%-47.1%), with a CR rate of 4.8%. The median DOR was 11.6 months (95% CI, 2.4-24.2+) and the DCR was 81.0% (95% CI, 65.9%-91.4%). The median PFS was 6.4 months (95% CI, 4.5-10.5) and the median OS was 16.3 months (95% CI, 11.5-not evaluable).

“We saw promising activity with sigvotatug vedotin in heavily pretreated patients with taxane-naive NSCLC,” Malhotra said. “The ORR was 31%, which is very promising in this setting.”

Patients in the safety population treated across all dose levels (n = 117) experienced any-grade treatment-emergent adverse effects (TEAEs) at a rate of 96.2%; any-grade treatment-related TEAEs occurred in 75.4% of patients. Grade 3 or higher TEAEs (50.5%), TEAEs leading to drug discontinuation (8.5%), and grade 5 TEAEs (2.2%) were all reported. The most common any-grade TEAEs occurring in at least 15% of patients included fatigue (48.7%), peripheral sensory neuropathy (36.8%), and nausea (35.0%).

Patients with NSCLC who received sigvotatug vedotin at 1.8 mg/kg adjusted ideal body weight (AiBW) every 2 weeks (n = 31) experienced any-grade TEAEs at a rate of 93.5%. Grade 3 or higher TEAEs occurred at a rate of 35.5% and there were no grade 5 TEAEs. Common any-grade TEAEs occurring in at least 15% of patients included nausea (51.6%), peripheral sensory neuropathy (48.4%), and decreased appetite (35.5%).

“We’ve seen the adverse effects [AEs] that we usually associated with microtubule inhibiting chemotherapy, but we haven’t seen any additional safety signals or an unexpected toxicity profile,” Malhotra commented.

There has also been interest in combining sigvotatug vedotin with immunotherapy in patients with NSCLC. Findings from an expansion cohort of SGNB6A-001 presented during the 

 revealed that sigvotatug vedotin in combination with pembrolizumab was safe and effective in patients with treatment-naive NSCLC.

Data from the expansion cohort showed that efficacy-evaluable patients with NSCLC with no known 

 mutations (n = 21) achieved a confirmed ORR of 42.9% (95% CI, 21.8%-66.0%) with the combination, including a CR rate of 9.5%. The DCR was 90.5% (95% CI, 69.6%-98.8%). At a median follow-up of 4.8 months (95% CI, 3.7-6.0), the median DOR was not reached.

“We we saw some promising results [with sigvotatug vedotin plus pembrolizumab] in treatment-naive patients [and] that’s something that needs to be explored further,” Malhotra said.

Be6A Lung-01 Is Underway in Pretreated NSCLC

Be6A Lung-01 is an ongoing open-label study that is evaluating sigvotatug vedotin vs docetaxel in adult patients with nonsquamous NSCLC (

 Patients are required to have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and a histologically or cytologically confirmed diagnosis of locally advanced, unresectable (stage IIIB or IIIC), or metastatic stage IV (M1a, M1b, or M1c) disease.

“[Nonsquamous histology] is an important consideration because sigvotatug vedotin is an ADC in which the payload is an antitubulin chemotherapy,” Malhotra said. “Patients who have already been treated with an antitubulin, such as a taxane, may not see the same efficacy as patients who are taxane naive. In squamous NSCLC, first-line treatment is usually with paclitaxel, unlike [nonsquamous] NSCLC where patients are taxane naive when they make it to the second-line setting. For that reason, [Be6A Lung-01] has been planned to include only patients with nonsquamous histology.”

Patients with known actionable genomic alterations are permitted to enroll if they have received at least 1 targeted therapy and/or received platinum-based combination therapy for the treatment of metastatic or recurrent disease or experienced disease progression within 6 months of the last dose of platinum-based chemotherapy in the adjuvant or neoadjuvant; these patients were also permitted to have received up to 1 PD-1/PD-L1 monoclonal antibody. Those without known actionable genomic alterations must have received platinum-based combination therapy for the treatment of metastatic or recurrent disease and a PD-1/PD-L1 monoclonal antibody, unless contraindicated, and/or have experienced disease progression within 6 months of the last dose of platinum-based chemotherapy in the adjuvant or neoadjuvant setting and received a PD-1/PD-L1 monoclonal antibody.

Eligible patients will be randomly assigned 1:1 to receive intravenous (IV) sigvotatug vedotin at 1.8 mg/kg AiBW on days 1 and 15 of each 28-day cycle or IV docetaxel at 75 mg/m

The coprimary end points are OS and ORR by blinded independent central review (BICR) per RECIST 1.1 criteria. The key secondary end points is PFS by BICR; additional secondary end points include investigator-assessed PFS, DOR by BICR and investigator assessment, all per RECIST 1.1 criteria, as well as safety and patient-reported outcomes.

“We don’t have a lot of effective options for patients with pretreated lung cancer right now, it’s usually single-agent chemotherapy, such as docetaxel or gemcitabine, which have a lot of AEs and are not as effective,” Malhotra said. “Any trial which shows significant results in that setting will be welcomed because we need to do better for our patients and improve outcomes.”

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).

. 2024;42(suppl 16):8521. doi:10.1200/JCO.2024.42.16_suppl.8521

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). 

. 2025;43(suppl 16):3010. doi:10.1200/JCO.2025.43.16_suppl.3010

A study of SGN-B6A versus docetaxel in previously treated non-small cell lung cancer. ClinicalTrials.gov. Updated July 18, 2025. Accessed August 12, 2025. https://clinicaltrials.gov/study/NCT06012435

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). 

. 2024;35(suppl 2):S875. doi:10.1016/j.annonc.2024.08.1453

Articles

Sigvotatug vedotin, an antibody-drug conjugate targeting integrin beta-6, is being evaluated against docetaxel in the phase 3 Be6A Lung-01 trial for pretreated non-small cell lung cancer (NSCLC). Previous studies demonstrated its efficacy as monotherapy and in combination with pembrolizumab, showing promising response rates and disease control. The ongoing trial focuses on patients with nonsquamous NSCLC, emphasizing the potential benefits of sigvotatug vedotin's targeted delivery and broader therapeutic index. The trial aims to improve outcomes for patients with limited treatment options in this setting.

Sigvotatug vedotin is being compared with docetaxel in patients with pretreated NSCLC in the phase 3 Be6A Lung-01 study.

Phase 3 Evaluation of Sigvotatug Vedotin Is Underway in Pretreated Nonsquamous NSCLC

Dr Sanborn on Early Efficacy and Safety Data With Sigvotatug Vedotin Plus Pembrolizumab in NSCLC

"[There was also] a phase 1 dose escalation and expansion study of single-agent sigvotatug vedotin, SGNB6A-001 [NCT04389632]. In that study, [among] patients with NSCLC, the confirmed ORR was [19.0%]. However, when looking at the patient population that had nonsquamous NSCLC and who were taxane naive, the ORR was 31.0%."

Rachel E. Sanborn, MD, 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, shared preclinical and early clinical data with the novel integrin beta-6 (IB6)–directed antibody-drug conjugate (ADC) sigvotatug vedotin (formerly SGN-B6A) for patients with non–small cell lung cancer (NSCLC).

Preclinical studies demonstrated that inhibition of IB6 enhanced tumor-infiltrating lymphocyte infiltration, including CD8-positive T cells, when combined with PD-1 blockade, Sanborn began. In vivo models also showed sigvotatug vedotin had antitumor activity across multiple tumor types, including NSCLC, pancreatic, pharyngeal, and bladder cancers, she reported.

Additionally, in the first-in-human, phase 1 SGNB6A-001 trial (NCT04389632), single-agent sigvotatug vedotin was evaluated across multiple dosing regimens, Sanborn continued. Among patients with NSCLC (n = 116), the ADC demonstrated a confirmed overall response rate (ORR) of 19.0% (95% CI, 12.3%-27.3%), including 3 complete responses (CRs) and 19 partial responses (PRs). In a subset of patients with nonsquamous, taxane-naive NSCLC (n = 42), the confirmed ORR was 31.0% (95% CI, 17.6%-47.1%), with 2 CRs and 11 PRs, and a median progression-free survival (PFS) of 6.4 months (95% CI, 4.5-10.5).

Treatment-related adverse effects (AEs) observed with sigvotatug vedotin in this study were generally consistent with the known chemotherapy-related toxicity of its monomethyl auristatin E payload, Sanborn stated. The most common grade 3 or higher AEs included dyspnea, fatigue, and neutropenia. Pneumonitis occurred in 3 patients but was not grade 3 or higher in severity.

, updated findings showed that in patients with untreated, advanced NSCLC (n = 21), frontline sigvotatug vedotin combined with pembrolizumab (Keytruda) led to a confirmed ORR of 42.9% (95% CI, 21.8%-66.0%), Sanborn added. This combination is being further explored in additional cohorts of the ongoing phase 1 trial, she noted.

Based on these findings, the randomized phase 3 Be6A Lung-01 trial (NCT06012435) is now evaluating sigvotatug vedotin vs docetaxel in previously treated NSCLC, with the goal of confirming clinical benefit in a larger population and further characterizing safety and efficacy of IB6-directed therapy, Sanborn concluded.

Videos

Rachel E. Sanborn, MD, discusses preclinical and early clinical data supporting the use of the IB6-directed ADC sigvotatug vedotin in patients with NSCLC. 

Dr Malhotra on the Future of Sigvotatug Vedotin in NSCLC 

“We don’t have a lot of options for patients with pretreated [NSCLC]. [Options] usually [include] single-agent chemotherapy such as docetaxel or gemcitabine, which we know have many toxicities and are not [very] effective. Any trial that shows significant results in this setting will be welcomed because we need to improve outcomes for our patients.”

Jyoti Malhotra, MD, MPH, interim division chief of Thoracic Medical Oncology, associate professor in the Department of Medical Oncology & Therapeutics Research, and the director of thoracic medical oncology at City of Hope, discussed future research directions for the antibody-drug conjugate sigvotatug vedotin (SGN-B6A) in non–small cell lung cancer (NSCLC).

Sigvotatug vedotin is currently being compared with docetaxel for patients with pretreated NSCLC in the phase 3 Be6A Lung-01 trial (NCT06012435). Malhotra noted that positive data from this study would be a welcome addition to the current body of research in pretreated NSCLC, as effective options for this patient population are limited. These patients are usually treated with single-agent chemotherapy, such as docetaxel or gemcitabine, which traditionally have limited efficacy and cause adverse effects, she added.

If sigvotatug vedotin shows significant efficacy and a tolerable safety profile in this pretreated patient population, there will likely be interest in moving it into frontline therapy, Malhotra noted. Sigvotatug vedotin could also be combined with immunotherapy in the first-line setting and compared with standard-of-care therapies in future clinical trials, she added. Prior safety data with sigvotatug vedotin in combination with pembrolizumab (Keytruda) have demonstrated that the combination was well tolerated, including in treatment-naive patients, warranting further investigation, she concluded.

Findings from the phase 1 SGNB6A-001 study (NCT04389632) presented during the 

 demonstrated that efficacy-evaluable patients with treatment-naive NSCLC (n = 21) achieved an overall response rate (ORR) of 57.1% (95% CI, 34.0%-78.2%) with sigvotatug vedotin plus pembrolizumab; the complete response rate was 9.5%. The confirmed ORR was 42.9% (95% CI, 21.8%-66.0%). At a median follow-up of 4.8 months (95% CI, 3.7-6.0), the median duration of response was not reached. The disease control rate was 90.5% (95% CI, 69.6%-98.8%).

Jyoti Malhotra, MD, MPH, discusses future research directions for sigvotatug vedotin in non–small cell lung cancer.

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).

 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 

 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).

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.

“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 

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.

: What is the background of IB6, and what makes it a viable target in NSCLC?

: 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%].

 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.

 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.

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). 

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). 

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).

Rachel E. Sanborn, MD, discusses the novel IB6-directed ADC sigvotatug vedotin for the treatment of patients with NSCLC.

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