Treatment with the investigational, potential first-in-class integrin beta-6 (IB6)–directed antibody-drug conjugate (ADC) sigvotatug vedotin did not produce a statistically significant improvement in overall survival (OS) vs docetaxel in patients with locally advanced, unresectable or metastatic nonsquamous non–small cell lung cancer (NSCLC) who had received at least 1 prior line of therapy, missing the primary end point of the phase 3 SigVie-002 trial (NCT06012435).
Although the study missed the primary end point in the overall population, a stronger trend was seen in favor of sigvotatug vedotin for OS and progression-free survival (PFS) in the two-thirds of patients who had received 1 prior line of therapy. An exploratory analysis revealed no evidence that associated IB6 expression with magnitude of response.
The safety profile of the ADC was manageable and comparable with the adverse effect profile reported in prior studies. Complete results from the trial will be submitted for presentation at an upcoming medical meeting.
“Patients with previously treated advanced NSCLC are a historically difficult-to-treat population, and there is clearly more work to be done to improve the outcomes for this population,” Jeff Legos, PhD, MBA, chief oncology officer of Pfizer, stated in a news release. “Although the overall study results did not demonstrate superiority over docetaxel, it is encouraging that second-line patients treated with sigvotatug vedotin achieved strong efficacy outcomes compared [with] an established standard of care, alongside a manageable safety profile. This observed clinical benefit, along with our phase 1 combination data in the first-line setting, reinforces our confidence in the potential of the sigvotatug vedotin program, including an ongoing phase 3 trial in combination with pembrolizumab [Keytruda] in first-line advanced NSCLC.”
IB6 is highly expressed in NSCLC in approximately 90% of cases. Without effective inhibition of the target, patients can expect poor prognosis. Sigvotatug vedotin is a novel and highly selective IB6 ADC crafted for rapid internalization and minimized binding to other integrins that may be more commonly expressed in healthy tissues, potentially resulting in less off-target toxicity.
Phase 3 SigVie-002 Trial Misses OS End Point in Previously Treated Nonsquamous NSCLC
- The investigational, IB6-directed ADC sigvotatug vedotin failed to produce a statistically significant improvement in OS vs docetaxel in patients with locally advanced, unresectable, or metastatic nonsquamous NSCLC who had received at least 1 prior line of therapy, missing the primary end point of the SigVie-002 trial.
- Although the OS end point in the overall population fell short, exploratory analyses pointed to a more encouraging trend in the two-thirds of patients treated in the second-line setting, where sigvotatug vedotin appeared to offer a clinically meaningful survival advantage over docetaxel alongside a manageable safety profile.
- Investigators remain optimistic about sigvotatug vedotin’s potential in earlier treatment settings, citing promising phase 1 combination data with pembrolizumab and an ongoing phase 3 evaluation in first-line PD-L1–positive NSCLC, where the ADC’s ability to induce immunogenic cell death may be better leveraged.
The ongoing, global, open-label, randomized, SigVie-002 trial is evaluating sigvotatug vedotin vs docetaxel in adult patients with previously treated locally advanced, unresectable or metastatic NSCLC.1,2 Patients were randomly assigned to receive intravenous (IV) sigvotatug vedotin on days 1 and 15 of every 28-day cycle or IV docetaxel on day 1 of every 21-day cycle.
Investigators enrolled 703 patients to the study. Descriptive, secondary end points include PFS, confirmed objective response rate and duration of response per RECIST 1.1 criteria according to blinded independent central review, safety, and quality of life.
“It is important not to underestimate the activity of docetaxel as a comparator in this setting. Patients enrolled in this trial were heavily pretreated, with most having previously received both platinum-based chemotherapy and immunotherapy, yet docetaxel continues to provide meaningful clinical benefit.1 Although the study did not meet its OS end point, in second-line patients, the data suggest a clinically meaningful survival benefit for sigvotatug vedotin over docetaxel, supporting continued scientific evaluation of sigvotatug vedotin in earlier lines in combination with immunotherapy,” Solange Peters, MD, PhD, chair of Medical Oncology & Thoracic Cancers Clinic at Lausanne University Hospital in Switzerland, and honoree in the lung cancer category of the OncLive Giants of Cancer Care® awards, added in the news release.
Ongoing trials evaluating the ADC include the phase 3 Be6A Lung-02 trial (NCT06758401) of sigvotatug vedotin plus pembrolizumab as first-line therapy in patients with PD-L1–positive (tumor proportion score ≥ 50%) NSCLC, as well as the phase 1/2 Symbiotic-Lung-20 trial (NCT07227298), which is investigating the agent in combination with the novel PD-1 and VEGF bispecific antibody PF-08634404 in patients with NSCLC.
“The ability of sigvotatug vedotin to induce immunogenic cell death provides a strong rationale for combination approaches with immunotherapy, particularly in earlier treatment settings where immune competence is better preserved. In this context, the promising phase 1 efficacy signals observed in treatment-naive patients with high PD-L1 expression warrant further evaluation and may represent a more effective clinical application of this strategy,” Peters concluded.
References
- Pfizer announces topline phase 3 results for sigvotatug vedotin in previously treated metastatic non-squamous non-small cell lung cancer. News release. Pfizer. June 22, 2026. Accessed June 23, 2026. https://investors.pfizer.com/Investors/news-events/News/news-details/2026/Pfizer-Announces-Topline-Phase-3-Results-for-Sigvotatug-Vedotin-in-Previously-Treated-Metastatic-Non-Squamous-Non-Small-Cell-Lung-Cancer/default.aspx
- A study of SGN-B6A versus docetaxel in previously treated non-small cell lung cancer. ClinicalTrials.gov. Updated May 27, 2026. Accessed June 23, 2026. https://clinicaltrials.gov/study/NCT06012435
