Alphamab Oncology presented phase II clinical data at the ESMO Immuno-Oncology Congress 2024, showcasing the potential of KN046, a PD-L1/CTLA-4 bispecific antibody, in combination with axitinib for treating advanced non-small cell lung cancer (NSCLC). The study, KN046-209, is a multi-center, open-label phase II clinical trial evaluating the efficacy, safety, and tolerability of this combination in advanced NSCLC patients.
The bispecific antibody KN046 targets both PD-L1 and CTLA-4 immune checkpoints to activate T cells and enhance antitumor effects. Axitinib, a tyrosine kinase inhibitor, targets VEGF receptors to inhibit angiogenesis and tumor progression. This combination aims to provide a synergistic effect in combating NSCLC.
Study Design and Patient Population
The KN046-209 trial (NCT05420220) enrolled Stage IIIB-IV NSCLC patients without driver mutations. Patients received KN046 (5mg/kg, IV, Q3W) and axitinib (5mg or 3mg, PO, BID). The primary endpoint was objective response rate (ORR), with secondary endpoints including safety, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).
The study included two cohorts: Cohort A consisted of previously untreated patients with PD-L1 TPS≥1%, while Cohort B included patients who had progressed on checkpoint inhibitors (CPIs).
Efficacy Results
As of September 1, 2024, 53 patients in Cohort A and 32 patients in Cohort B were evaluated. The median follow-up times were 14.6 months and 11.2 months, respectively. Key findings include:
- Cohort A (PD-L1 TPS≥1%): The ORR was 56.8% (95% CI: 41.0, 71.7), with a confirmed ORR of 54.5% (95% CI: 38.8, 69.6). The DCR was 90.9% (95% CI: 78.3, 97.5). The median DoR was 13.2 months (95% CI: 6.6, NE), and the median PFS was 8.3 months (95% CI: 6.8, 13.9). Median OS was not reached.
- Cohort A (PD-L1 TPS≥50%): The ORR was 73.3% (95% CI 44.9, 92.2), with a confirmed ORR of 66.7% (95% CI 38.4, 88.2). The DCR was 93.3% (95% CI 68.1, 99.8). The mDoR was not reached (95% CI 4.1, NE). The mPFS was 12.4 months (95% CI 4.9, NE).
- Cohort B (Progressed on CPIs): The ORR and confirmed ORR were both 9.4% (95% CI: 2.0, 25.0), and the DCR was 81.3% (95% CI: 63.6, 92.8). The median DoR was 7.4 months (95% CI: NE, NE), the median PFS was 5.6 months (95% CI: 2.8, 7.0), and the median OS was 11.9 months (95% CI: 9.9, NE).
Safety Profile
Treatment-related adverse events (TRAEs) of grade ≥3 were observed in 58.8% of patients. The most common grade ≥3 TRAEs included increased ALT and AST, hypertension (10.6%), PPE, and diarrhea (7.1%). Further exploration with a 3mg axitinib combination showed reduced grade 3 or higher adverse events without compromising efficacy.
Implications for NSCLC Treatment
The KN046-axitinib combination demonstrates promising efficacy and tolerability in advanced NSCLC, particularly in previously untreated patients with high PD-L1 expression. The results support further investigation in larger trials. The reduced toxicity observed with the lower dose of axitinib suggests a potential avenue for optimizing the therapeutic window of this combination.
