Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors

Jian Li, Yanhong Deng, Weijie Zhang, Ai-Ping Zhou, Weijian Guo, Jianwei Yang, Ying Yuan, Liangjun Zhu, Shukui Qin, Silong Xiang, Haolan Lu, John Gong, Ting Xu, David Liu, Lin Shen, Jian Li, Yanhong Deng, Weijie Zhang, Ai-Ping Zhou, Weijian Guo, Jianwei Yang, Ying Yuan, Liangjun Zhu, Shukui Qin, Silong Xiang, Haolan Lu, John Gong, Ting Xu, David Liu, Lin Shen

Abstract

Background: Monoclonal antibodies targeting programmed death ligand 1 (PD-L1) signaling currently approved for defective mismatch repair (dMMR)/microsatellite instability high (MSI-H) tumors must be delivered by intravenous infusion. Envafolimab, a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment, represents a potential advance because it can be conveniently administered subcutaneously.

Methods: This open-label, single-arm, phase 2 study evaluated the efficacy and safety of envafolimab in patients with previously treated advanced dMMR/MSI-H tumors from 25 clinical sites across China. Adults with histologically confirmed locally advanced or metastatic malignant dMMR/MSI-H solid tumors received weekly 150 mg subcutaneous envafolimab injections in a 28-day treatment cycle. The primary efficacy endpoint was the objective response rate (assessed by a blinded independent review committee). Secondary efficacy outcomes were disease control rate, duration of response, progression-free survival, and overall survival.

Results: One hundred and three patients (65 with colorectal cancer, 18 with gastric cancer, and 20 with other solid tumors) were enrolled. Median follow-up was 11.5 months. The objective response rate was 42.7% (95% confidence interval [CI] 33.0-52.8), and the disease control rate was 66.0% (95% CI 56.0-75.1). Median duration of response was not reached; the duration of response rate at 12 months was 92.2% (95% CI 77.5-97.4). Median progression-free survival was 11.1 months (95% CI 5.5 to not evaluable). Overall survival at 12 months was 74.6% (95% CI 64.7-82.1). Sixteen patients (16%) had at least one grade 3 or 4 related treatment-emergent adverse event. No grade 5 treatment-emergent adverse events related to envafolimab were reported. Injection site reactions, all grade 1-2, were reported in nine patients (9%), but there were no infusion reactions. Eight patients (8%) had grade 3 or 4 immune-related adverse events.

Conclusions: This is the first pivotal phase 2 study to examine the efficacy and safety of a single-domain immune checkpoint antibody in the treatment of cancer. Envafolimab was effective and had acceptable safety in the treatment of previously treated advanced dMMR/MSI-H solid tumors. As the first single-domain PD-L1-targeting antibody administered by rapid subcutaneous injection, envafolimab has the potential to be a significant advance in the treatment of cancer. Trial registration ClinicalTrials.gov, NCT03667170. Registered 10 September 2018-Retrospectively registered, https://ichgcp.net/clinical-trials-registry/NCT03667170 .

Keywords: Envafolimab; PD-L1; Subcutaneous injection; dMMR/MSI-H.

Conflict of interest statement

SX, HL, JG, and DL are employees of and own stock in 3D Medicines Co., Ltd. JG and DL have leadership roles at 3D Medicines Co., Ltd. LS has received research funding from 3D Medicines Co., Ltd. XT is an employee of Alphamab Co., Ltd, where he has a leadership role and owns stock. The other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Patient disposition. CRC, colorectal cancer; dMMR, defective mismatch repair; GC, gastric cancer; MSI-H, microsatellite instability high; PEP, primary efficacy population
Fig. 2
Fig. 2
Time to event outcomes for the primary efficacy population and the overall study population. a Duration of response, assessed by the blinded independent review committee. b Overall survival

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