Cesalatamig Monotherapy Shows Dose-Dependent Activity in PD-(L)1 Inhibitor–Experienced NSCLC

Cesalatamig (AI-081), an investigational PD-1 x VEGF bispecific antibody, produced dose-dependent responses and disease control as monotherapy in patients with actionable genomic alteration (AGA)–negative, PD-(L)1 inhibitor–experienced non–small cell lung cancer (NSCLC), according to pooled data from the phase 1/2 BiPAVE-001 (NCT06635785) and BiPAVE-001 CN (CTR20253261) trials presented at the 2026 SITC Annual Meeting.^1,2

Data demonstrated that evaluable patients treated at 1 mg/kg (n = 10), 3 mg/kg (n = 24), and 10 mg/kg (n = 21) every 3 weeks (Q3W) experienced objective response rates (ORRs) of 10%, 21%, and 33%, respectively.¹ The respective disease control rates (DCRs) were 40%, 67%, and 90%. The corresponding 6-month progression-free survival (PFS) rates were 22%, 40%, and 67%.

Exposure-response analyses showed that the probability of disease control rose with cesalatamig exposure at cycle 1, with statistically significant associations for maximum concentration (P = .018) and area under the curve (P = .026), supporting selection of 10 mg/kg Q3W as the provisional dose for a pivotal trial.

“Patients whose NSCLC progresses after immunotherapy and chemotherapy have limited effective treatment options,” Kai He, MD, PhD, principal investigator of the US BiPAVE-001 trial and presenter of the study, stated in a news release.² “The responses and disease control observed with cesalatamig monotherapy are encouraging. Together with the manageable safety profile observed in these studies, these findings support further clinical evaluation in this setting.”

How were the BiPAVE-001 studies designed?

Cesalatamig is engineered to overcome liabilities of first-generation PD-1/VEGF bispecific agents, which the investigators described as low VEGF avidity and effector-mediated T-cell clearance.¹ Compared with ivonescimab, cesalatamig has 46-fold higher affinity for VEGF and 2.2-fold higher affinity for PD-1, and it carries additional L234A, L235A, and G237A Fc mutations intended to silence Fc effector function and spare effector T cells.

The global program, which has enrolled more than 400 patients, began with phase 1 dose escalation of cesalatamig at 1, 3, 10, and 20 mg/kg Q3W in patients with advanced or metastatic solid tumors, followed by expansion cohorts in NSCLC, colorectal cancer, and other solid tumors. The phase 2 dose-optimization portion evaluated monotherapy at 1, 3, and 10 mg/kg Q3W in patients with PD-(L)1–refractory or –resistant NSCLC in the second-line or later setting.

The NSCLC population (n = 126) included patients treated at 1 mg/kg (n = 18), 3 mg/kg (n = 31), 10 mg/kg (n = 56), and 20 mg/kg (n = 21). The median age was 63 years (range, 31-87), 63% of patients were male, and 46% were Asian. Overall, 71% of patients had nonsquamous histology, 78% had an ECOG performance status of 1, and the median time from initial diagnosis to first dose was 24 months (interquartile range, 12-39). Fifty-seven percent of patients had received 1 to 2 prior systemic regimens, and 41% had received at least 3; 85% had received a prior anti–PD-(L)1 agent, 85% had received platinum-based chemotherapy, and 13% had received bevacizumab (Avastin) or ramucirumab (Cyramza).

Efficacy was assessed in patients with at least 1 post-treatment assessment as of October 14, 2026. Data for the 20-mg/kg Q3W cohort were immature and not reported.

What did the safety analysis show?

As of the October 8, 2026, data cutoff, the rates of grade 3 treatment-related adverse effects (TRAEs) among patients with NSCLC who had received 1 to 5 prior lines of systemic therapy were 22%, 29%, and 36% at the 1-, 3-, and 10-mg/kg Q3W doses, respectively.

Across all patients with NSCLC, the most common TRAEs were hypertension (grade 1-2, 11%; grade 3, 14%), proteinuria (grade 1-2, 18%; grade 3, 3%), hypoalbuminemia (grade 1-2, 15%; grade 3, 0%), increased aspartate aminotransferase (AST) levels (grade 1-2, 13%; grade 3, 0%), decreased appetite (grade 1-2, 11%; grade 3, 1%), and increased alanine aminotransferase (ALT) levels (grade 1-2, 10%; grade 3, 1%). In the 10-mg/kg Q3W cohort, grade 3 TRAEs included hypertension (16%), proteinuria (7%), and decreased appetite, increased ALT levels, diarrhea, and hemoptysis (2% each).

What are the next steps for cesalatamig?

OncoC4 plans to initiate a phase 3 trial of cesalatamig in second-line NSCLC in 2027. In September 2026, the FDA granted fast track designation to cesalatamig for patients with NSCLC whose disease progressed following PD-(L)1–targeted immunotherapy and platinum-based chemotherapy.³

Ongoing phase 2 cohorts are also evaluating cesalatamig at 10 vs 20 mg/kg Q3W in the frontline setting for PD-L1–positive NSCLC, in combination with chemotherapy or targeted therapies in frontline NSCLC, and with chemotherapy in the perioperative setting for high-risk NSCLC.¹ Additional cohorts are exploring the agent in microsatellite stable colorectal cancer and ovarian cancer.

References

1. He K, Yang J, Li M, et al. Safety and clinical activities of a novel PD-1/VEGF bispecific antibody cesalatamig as monotherapy in PD-(L)1-resistant/refractory NSCLC: results of global, multi-center, open-label phase 1/2 studies. Presented at: 2026 Society for Immunotherapy of Cancer Annual Meeting; November 4-8, 2026; Phoenix, AZ. Abstract 1187.
2. OncoC4 reports encouraging phase 1/2 data for cesalatamig monotherapy in previously treated non-small cell lung cancer at SITC 2026. News release. OncoC4. November 6, 2026. Accessed November 8, 2026. https://www.oncoc4.com/en/news-resources/news/oncoc4-reports-encouraging-phase-12-data-for-cesalatamig-monotherapy-in-previously-treated-non-small-cell-lung-cancer-at-sitc-2026/
3. OncoC4 receives FDA fast track designation for cesalatamig, an investigational PD-1/VEGF bispecific antibody. News release. OncoC4, Inc. September 16, 2026. Accessed November 8, 2026. https://oncoc4.com/en/news-resources/news/oncoc4-receives-fda-fast-track-designation-for-cesalatamig-an-investigational-pd-1vegf-bispecific-antibody/