Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors

Abstract

Background: Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors.

Methods: Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1.

Results: Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer.

Conclusions: Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted.

Trial registration number: NCT04047290.

Keywords: antibodies, neoplasm; clinical trials as topic.

Figure 1

Patient flow diagram. (A) In dose escalation phase, one patient each in 10 mg/kg and 20 mg/kg dropped off within the first cycle and thus deemed non-DLT evaluable. One patient in 10 mg/kg experienced recurrent colitis. Although the event did not meet the DLT definition; DEC deemed it as a notable TRAE and determined to enroll more patients in 10 mg/kg dose escalation cohort before further escalation. (B) In dose expansion phase, 10 mg/kg every 2 weeks was initially expanded for additional enrolment in patients with pMMR colorectal cancer given the one responder observed at 3 mg/kg. Considering the efficacy signal observed in dose escalation cohorts, ovarian cancer, endometrial cancer and mesothelioma was recommended for further expansion by DEC in both 20 mg/kg and 10 mg/kg to select the optimal dose moving forward. AE, adverse event; DLT, dose-limiting toxicity; pMMR, mismatch repair proficient; TRAE, treatment-related adverse event; DEC, dose escalation committee.

Figure 2

(A) Maximum change from baseline of target lesions in all evaluable patients. Four patients discontinued before any disease assessment and are not included in the plot. (B) Duration of treatment in all evaluable patients. (01)=adenocarcinoma, (02)=anus cancer, (03)=chondrosarcoma, (04)=colorectal cancer, (05)=endometrial cancer, (06)=epithelial ovarian cancer, (07)=esophageal cancer, (08)=granulosa cell tumor, (09)=HNSCC, (10)=hepatocellular carcinoma, (11)=medullary thyroid cancer, (12)=mesothelioma, (13)=NSCLC, (14)=pancreatic cancer, (15)=renal oncocytoma, (16)=small cell ovarian cancer. Epithelial ovarian cancer: (1) high-grade serous; (2) clear cell; (3) mucinous; (4) endometrioid; (5) serous (grade unknown). *Previous bevacizumab; +Previous immunotherapy. NSCLC, non-small cell lung cancer; HNSCC, head and neck squamous cell carcinoma.

Figure 3

(A) Serum concentration-time curve after the first dose of ivonescimab. (B) Serum concentration-time curve after the fifth dose of ivonescimab. Visit days are presented on the x-axis, ivonescimab concentration on the y-axis, data represent the mean and SD of patients.

Figure 4

(A) Receptor occupancy (RO) following multiple doses of ivonescimab. (B) Percentage change from baseline in serum free VEGF level following multiple doses of ivonescimab. Visit days are presented on the x-axis, percentage of RO on the y-axis in (A), percentage change from baseline in serum free VEGF on the Y axis in (B), data represent the mean+SD for each dose cohort. VEGF, vascular endothelial growth factor.