Pfizer's Seagen-derived ADC pipeline suffers a setback
One of the antibody-drug conjugates at the heart of Pfizer's $43 billion acquisition of Seagen three years ago has failed a keenly anticipated phase 3 trial in lung cancer.
The results of the SigVie-002 of IB6-directed sigvotatug vedotin as a second-line or later therapy for metastatic, non-squamous non-small cell lung cancer (NSCLC) failed to show an improvement with the ADC over docetaxel chemotherapy on overall survival, the study's primary endpoint.
Pfizer said that, despite the top-line failure, there were encouraging signs for the drug, with trends towards improved OS and progression-free survival (PFS) compared to docetaxel in patients who had only been treated with one prior line of therapy, accounting for around two-thirds of the 703 subjects in the study, as well as a "manageable" safety profile.
On the negative side, there was no clear relationship between the drug's efficacy and the expression of IB6 (integrin beta-6), which has become an attractive target because it is highly overexpressed in tumour cells, but virtually undetectable in healthy lung tissues.
Pfizer has previously held up sigvotatug vedotin as a core asset in its thoracic cancer franchise, and one that could deliver both long-term growth and an innovative breakthrough therapy to patients. Around 50,000 patients in the US, and more than 200,000 globally, fall into the second-line or later non-squamous, metastatic NSCLC category.
The company has said it wants its cancer pipeline to deliver eight or more blockbuster medicines by 2030.
After this second-line setback, Pfizer's focus will now shift to earlier use of the ADC as a first-line therapy, which is being tested in the ongoing phase 3 SigVie-003 trial, comparing sigvotatug vedotin in combination with MSD's PD-1 inhibitor Keytruda (pembrolizumab) to Keytruda alone in patients with PD-L1-positive 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," commented Solange Peters of Lausanne University Hospital, Switzerland, one of the SigVie-002 investigators.
"The promising phase 1 efficacy signals observed in treatment-naïve patients with high PD-L1 expression warrant further evaluation and may represent a more effective clinical application of this strategy," she added.
Meanwhile, Pfizer is looking at first-line studies of sigvotatug vedotin in combination with Keytruda and chemotherapy, a standard regimen for treatment-naïve NSCLC. It is also exploring combinations of the ADC with other drugs, such as PF-08044404, a novel bispecific antibody targeting PD-1 and VEGF, which had encouraging results at this year's ASCO, in early-stage lung cancers and other IB6-expressing solid tumours.
It is also developing a new generation of IB6-directed ADCs that use different cancer cell-killing payloads than sigvotatug vedotin, which deploys the monomethyl auristatin E payload used in most of Seagen's candidates.
Other ADCs from Seagen that have failed to deliver as hoped for Pfizer include B7-H4-directed felmetatug vedotin in solid tumours, including triple-negative breast cancer, and HER2-directed disitamab vedotin for bladder cancer.
Photo by Aakash Dhage on Unsplash
