In the realm of oncology, the landscape of cancer treatment is continuously evolving, with significant strides being made in the development of novel therapies that promise enhanced efficacy and improved tolerability. One such innovation that has garnered considerable attention in recent years is ADCs, marking a notable shift away from traditional chemotherapy regimens.

Sigvotatug vedotin (SGN-B6A) is an investigational ADC poised to revolutionize the management of solid tumors, particularly NSCLC. Comprising of three components—a monoclonal antibody targeting integrin beta-6 (IB6), the potent cytotoxic agent monomethyl auristatin E (MMAE), and a protease-cleavable linker—sigvotatug vedotin embodies the convergence of precision medicine and targeted therapy. Integral to its therapeutic prowess is the selective binding of the monoclonal antibody to IB6, a protein found to be highly expressed in over 90% of NSCLC tumors, underscoring its potential as a prime target for therapeutic intervention. By harnessing this specificity, sigvotatug vedotin effectively delivers its cytotoxic payload directly to cancer cells, maximizing efficacy while minimizing off-target effects.

The clinical landscape surrounding sigvotatug vedotin has been illuminated by compelling data, with pivotal findings unveiled at prestigious platforms. The culmination of these efforts has borne witness to a manageable safety profile, coupled with promising antitumor activity and sustained response durability, particularly in heavily pretreated patient cohorts. At ASCO 2023, it showed that the treatment-emergent adverse events were observed in 88.5% of patients, out of which, 50.7% were Grade ≥ 3. The ORR was 9 (ongoing).

Furthermore, the exploration of multiple dosing regimens during dose escalation endeavors (Part A) has laid the groundwork for ongoing dose expansion initiatives (Part B), encompassing diverse tumor types, including NSCLC. Venturing beyond monotherapy, the synergy between sigvotatug vedotin and immune checkpoint inhibitors, exemplified by its combination with pembrolizumab in NSCLC and Head and Neck Squamous Cell Carcinoma (HNSCC) (Parts C and D), holds immense promise in reshaping the treatment landscape. The confirmed ORR among all dose groups of NSCLC comprised 19.0% and  31% in the taxane-naive non-Sq NSCLC group.

Of particular note is the tantalizing glimpse into the future offered by evolving Phase I data, which not only reaffirms the favorable safety profile of sigvotatug vedotin but also underscores its potential as a cornerstone of combination therapy regimens. The tantalizing prospect of randomized Phase III trials, pitting Sigvotatug vedotin against standard-of-care agents such as docetaxel, stands as a testament to its transformative potential and heralds a new era in the armamentarium against cancer.

KOL insights

“There’s no doubt that these data likely contributed in some way to Pfizer’s decision to move forward at the price they did because this looks like it’s going to be a pretty compelling asset if this early data holds out.” – Expert Opinion.

“Previously reported data from the trial demonstrated a statistically significant and clinically meaningful response.” –Expert Opinion.

Conclusion

In February 2024, Pfizer highlighted its oncology strategy, targeting eight blockbuster cancer drugs by 2030. With this, Pfizer is focusing intently on cancer and increasing its exposure to ADCs. Pfizer increased its stake in oncology and strengthened its exposure to ADCs by purchasing Seagen for USD 43 billion. With this deal, Seagen brings an ADC called sigvotatug vedotin to Pfizer's oncology franchise. At present, Pfizer is currently relatively small in the lung/thoracic cancer space. The company is working to establish its third-generation ALK inhibitor LORBRENA in NSCLC space. 

Sigvotatug vedotin’s ASCO 2024 findings exemplifies the advancement of Pfizer's ADC strategy in oncology. Currently, patients are being enrolled in a global Phase III study (SGNB6A-002; NCT06012435) that is aimed at 2L–3L taxane-naïve non-squamous NSCLC. In 2026 or 2027, the trial’s data readout is projected. Learnings from evolving Phase I data strengthen this global Phase III pivotal program. Pfizer also plans to test the ADC as a first-line treatment in NSCLC.