Alphamab Oncology announced the results of four studies of PD-L1/CTLA-4 bispecific antibody KN046 at the European Society of Medical Oncology (ESMO) Annual Meeting, held October 20-24 in Madrid, Spain. KN046-201 is an open-label, multi-center, multi-cohort and single-arm phase II clinical trial designed to evaluate the efficacy, safety and tolerability of KN046 for the treatment of NSCLC. The company previously showed the efficacy and safety of KN046 plus chemotherapy in advanced NSCLC with EGFR sensitivity mutation who progressed after tyrosine kinase inhibitor(s) (TKIs) from Cohort D. Here, the company reported the updated survival and safety data.

In Cohort D, subjects with EGFR sensitivity mutation (Ex19del or L858R), who had failed from prior EFGR-TKIs without platinum-based chemotherapy were enrolled. All subjects enrolled received KN046 5mg/kg Q3W combined with chemotherapy (Pemetrexed, 500 mg/m2, Q3W and carboplatin AUC5, Q3W). From January 7, 2020 to December 17, 2021, 26 patients with metastatic NSCLC were enrolled.

The median follow-up was 17.8 months (95% CI, 13.0, 19.5) at the data cutoff of July 30, 2022. Among all 26 patients, the ORR was 26.9% (7/26, 95% CI, 11.6,47.8) and 5 pts had tumor shrink rate =50%. DCR was 84.6% (22/26, 95% CI, 65.1, 95.6%) with 7 PR and 15 SD.

The CBR was 38.5% (10/26, 95% CI, 20.2, 59.4). Median progression-free survival (mPFS) was 5.5 months (95% CI, 4.2, 6.8) and median overall survival (mOS) was 20.2 months (95% CI, 11.5, -). The 12-month OS rate was 65.29% (95% CI, 42.16, 81.02).

In terms of the treatment-related adverse event (TRAE), 15 (57.7%) out of the 26 subjects had experienced TRAE at grade 3 or higher levels due to chemotherapy or KN046. The most common (=10%) TRAEs were anemia (11/26 [42.3%]), AST increased (11/26 [42.3%]), ALT increased (9/26 [34.6%]), infusion-related reaction (8/26 [30.8%]), etc. KN046 showed encouraging efficacy result especially in OS benefit and a favorable safety profile in advanced NSCLC with EGFR sensitivity mutation who progressed after EGFR-TKI(s).

Further study is warranted to confirm the clinical results. KN046-CHN-001 and KN046-201 assessed the efficacy, safety and tolerability of KN046 in NSCLC. The company present the efficacy and safety outcomes of KN046 in this population from KN046-CHN-001 and Cohort C of KN046-201.

Eligible patients had NSCLC that progressed after ICI(s) and platinum-based chemotherapy. Patients with EGFR mutation and/or ALK translocation were excluded. All patients received KN046 (26 at 5 mg/kg Q2W, 2 at 5 mg/kg Q3W, 2 at 300mg Q3W and 1 at 3 mg/kg Q2W) by IV infusion.

Between April 19, 2019 and July 13, 2020, 31 pts with metastatic NSCLC who failed ICI(s) and platinum-based chemotherapy were enrolled. At the data cutoff of July 30, 2022 for KN046-201 and August 31, 2021 for KN046-CHN-001, the median follow-up was 25.0months (95% CI, 24.4, NE). Among all 31 pts, the ORR was 3.2% (1/31, 95% CI, 0.1, 16.7), disease control rate (DCR) was 38.7% (12/31, 95% CI, 21.8, 57.8), clinical benefit rate (CBR) was16.1% (5/31, 95% CI, 5.5, 33.7%).

Median progression-free survival (mPFS) was 2.8 months (95% CI, 1.8, 3.7) and median overall survival (mOS) was 13.3 months (95% CI, 6.5, 17.5). The 12-month OS rate was 54.8% (95% CI, 35.97, 70.26). In terms of the treatment-related adverse event (TRAE), 7(22.6%) out of the 31 subjects had experienced treatment-related adverse event (TRAE) at grade 3 or higher levels.

Commonly reported TRAEs of grade 3 or higher were anemia (9.7%), febrile neutropenia (3.2%), fatigue (3.2%) etc. KN046 was well tolerated and demonstrated encouraging OS benefit in NSCLC patients who had failed prior ICI(s) therapy. Further study is warranted to confirm the clinical results.

KN046 combined with platinum doublet chemotherapy as 1L treatment for metastatic NSCLC had shown promising efficacy and tolerability in the previous clinical trial. KN046-209 is an ongoing, multicenter, open-label, phase II study enrolled treatment-naive patients with PD-L1-positive (TPS=1%) locally advanced or metastatic non-small-cell lung cancer (NSCLC). To evaluate the efficacy and safety of KN046 combined with axitinib.

The primary endpoint was objective response rate (ORR). Herein, the company present the promising preliminary data of KN046 combination with axitinib as 1L treatment for NSCLC. 38 subjects were enrolled.

86.8% were male. 86.8 % (33/38) were stage IVa or IVb. The proportion of subjects with PD-L1 expression =50% was lower(26.3%) than previously reported(about 40%).

In the efficacy analysis set, The ORR was 58.6% (17/29, 95% CI: 38.936, 76.476). Subjects with higher PD-L1 expression had a higher objective response rate. The median PFS follow-up was 4.172 months (1.413, 6.867).

The mPFS was 8.345 months (95% CI: 5.454, NE), which is immature. The mOS was not reached. The incidence of KN046-related TRAE was 78.9% (30/38).

The incidence of irAE was 15.8% (6/38). Only 2 subjects had Grade =3 irAE. There was no KN046-related death.

The incidence of KN046-related CTCAE Grade =3 TRAE was 23.7% (9/38). The most frequent TRAE was AST increased 7.9% (3/38), ALT increased 5.3% (2/38), diarrhoea 5.3% (2/38). KN046 combined with axitinib is well tolerated and has shown very promising efficacy and safety signal in 1L treatment for advanced NSCLC. The 2nd stage of enrollment is ongoing and a phase III RCT for the 1st line NSCLC patient is planned to confirm the combination of KN046 and axitinb as a viable chemo free option.

KN046-205 was a prospective, muti-center, single-arm phase 2 clinical study, in order to evaluate the efficacy and safety of KN046 in patients with = 2l R/M thymic carcinoma. All the subjects would receive intravenously 5mg/kg Q2W dose, until tumor progression or unacceptable toxicity occurred. Tumor response was assessed every 8 weeks per RECIST 1.1, Objective response rate (ORR) as assessed by an Independent Review Committee (IRC) was the primary endpoint. By the cut-off date (30 August, 2023), 48 subjects were enrolled.

The median follow-up was 21.5 months (IQR: 16.7, 24.8). 45 subjects had tumor assessment after baseline. The objective response was 15.6% (95% CI: 6.5%, 29.5%), and the clinical benefit rate (CBR) was 31.1% (95%CI: 18.2%, 46.7%).

The median duration of response (mDoR) was 14.7 months (95%CI: 1.9, NE), and the progression-free survival was 3.9 months (95% CI: 1.3, 11.3). The overall survival was not reached, and the 12-months survival rate and 24-months survival rate was 92.4% (95%CI: 78.3%, 93.5%) and 72.1% (95%CI: 53.8%, 84.4%), respectively. There were 16 subjects with TPS = 1% enrolled in the trial.

The ORR and CBR were 18.8% (95% CI: 4.1%, 45.7%), respectively. The most common treatment-related adverse events (TRAE) of any grade include rash (18/48, 37.5%), AST increased (15/48, 31.3%), ALT increased (13/48,27.1%), and anemia (22.9%).