Efficacy and safety of KN046 plus paclitaxel/cisplatin as first-line treatment for unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC).

Abstract

4062 Background: The prognosis of pts with advanced esophageal squamous cell carcinoma (ESCC) remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. Recently, the combination of PD-1/PD-L1 pathway blockades with chemotherapy has shown synergistic efficacy in a few clinical trials. KN046 is the world's first dual immune checkpoint inhibitor, which can block PD-1/PD-L1 and CTLA-4 pathways at the same time. The purpose of this ongoing phase II trial (NCT03925870) in China was to evaluate the efficacy and safety of KN046 monotherapy or combined with chemotherapy for unresectable locally advanced, recurrent or metastatic ESCC. Methods: This trial included 3 cohorts, one of which enrolled systemic treatment naïve pts with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who have ECOG PS of 0-1. Eligible subjects were given paclitaxel (135-175mg/m2, iv, d1, q3w) and cisplatin (75mg/m2, iv, d2-4, q3w) plus KN046 (5mpk, iv, d1, q3w) for 4̃6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with KN046 monotherapy (5mpk, iv, q2w) until progression or unacceptable toxicity. Tumour response was assessed according to RECIST 1.1 every 6 weeks. The primary endpoint was investigator-assessed ORR. Secondary endpoints included DCR, safety, PK profile, and immunogenicity. Results: As of December 14, 2020, 15 pts were enrolled, all of them were male, 52.3% ≥60 years, 64% ECOG 1, 80% with distant metastasis. Median exposure time to KN046 was 11.4 wks and average KN046 treatment was 2.4 cycles. 12 pts were included in the efficacy analysis and 15 pts in the safety analysis. The overall response rate (ORR) and disease control rate (DCR) were 58.3% and 91.6%, respectively. 7 pts (58.3%) had partial response (PR) including one complete response of target lesion. 4 pts (33.3%) had stable disease (SD) with 3 pts showing more than 20% of tumor burden reduction. The overall incidence of KN046 related adverse events was 80.0%, with 13.3% Gr 3 or above TRAE. Infusion-related adverse events occurred during 7.8% and most were mild. Immune related adverse events（irAE）were seen in 53.3% and the most common Gr 3 irAE were nausea (n＝1, 6.7%) and rash (n＝1, 6.7%). Conclusions: KN046 plus paclitaxel/cisplatin demonstrated clinical efficacy and acceptable safety as first-line treatment, and might be a favorable option for pts with advanced ESCC. Clinical trial information: NCT03925870. Research Sponsor: Jiangsu Alphamab Biopharmaceuticals Co., Ltd. Clinical trial information: NCT03925870.

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

“…Erfonrilimab is a symmetric full-length IgG1 PD-1×CTLA-4 bsAb. Combined with chemotherapy, erfonrilimab induced ORRs of 50.6%, 58.3%, and 55.6% in NSCLC, 390 ESCC, 391 and PDAC patients. 392 A similar ORR of 57% was also observed combining erfonrilimab and lenvatinib in HCC patients.…”

Potent molecular-targeted therapies for advanced esophageal squamous cell carcinoma

“… 256 A phase II KN046-204 trial (NCT03925870) of KN046 monotherapy or combined with chemotherapy in ESCC is ongoing, in which the ORR and DCR are 58.3% and 91.6%, respectively, in a cohort with KN046 plus first-line chemotherapy. 150 The treatment efficacy of a fully human immunoglobin G4 anti-PD-L1 mAb sugemalimab (CS1001) in combination with first-line chemotherapy is also assessing in a phase III trial (NCT04187352) ( Table 6 ).…”

The anti-PD-L1/CTLA-4 bispecific antibody KN046 in combination with nab-paclitaxel in first-line treatment of metastatic triple-negative breast cancer: a multicenter phase II trial

“…The first-inhuman study has demonstrated that KN046 monotherapy has an acceptable safety profile and is in line with previously reported safety data from other ICIs, and the preliminary efficacy results are promising 9 . Several clinical trials of KN046 monotherapy and combination therapy were conducted in different advanced solid tumors, including non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), pancreatic cancer, esophageal squamous cell carcinoma, and rare thoracic tumors, which have shown promising efficacy and well-tolerated toxicity [10][11][12][13][14] .…”