lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed and are posted here as part of a 12-month trial. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

Axitinib in Combination with Toripalimab, a Humanized IgG4 mAb Against Programmed Death-1 (PD-1) in Patients with Metastatic Mucosal Melanoma: A Non-Randomized, Open-Label, Dose-Finding, and Cohort-Expansion Phase 1b Trial

148 Pages Posted: 24 Jan 2019

See all articles by Xinan Sheng

Xinan Sheng

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Xieqiao Yan

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Zhihong Chi

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Lu Si

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Chuanliang Cui

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Bixia Tang

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Siming Li

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Lili Mao

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Bin Lian

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Xuan Wang

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Xue Bai

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Li Zhou

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Yan Kong

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Jie Dai

Peking University - Key Laboratory of Carcinogenesis and Translational Research

Kai Wang

OrigiMed

Xiongwen Tang

Shanghai Junshi Biosciences Co., LTD

Huaning Zhou

Shanghai Junshi Biosciences Co., LTD

Hai Wu

Shanghai Junshi Biosciences Co., LTD

Hui Feng

Shanghai Junshi Biosciences Co., LTD

Sheng Yao

Shanghai Junshi Biosciences Co., LTD

Keith T. Flaherty

Harvard University - Medical School; Massachusetts General Hospital, Cancer Center

Jun Guo

Peking University - Key Laboratory of Carcinogenesis and Translational Research

More...

Abstract

Background: Metastatic mucosal melanoma responds poorly to anti-PD-1 monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. Combination therapy of VEGF inhibition with PD-1 blockade provides therapeutic opportunities for patients otherwise refractory to either monotherapy.

Methods: We conducted a single center phase Ib trial evaluating the safety and preliminary clinical efficacy of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in combination with VEGFR inhibitor axitinib in chemotherapy naive advanced mucosal melanoma patients. Patients received toripalimab at 1 mg/kg or 3 mg/kg via IV infusion once every two weeks, in combination with 5 mg axitinib orally BID in a dose-escalation and cohort-expansion study until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary objective was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, immunogenicity and tumor tissue biomarkers.

Findings: Thirty-three patients were enrolled in the study. No dose-limiting toxicities (DLTs) were observed. 97% of patients experienced treatment-related adverse events (TRAE). The most common TRAE were mild (grade 1/2), including diarrhea, proteinuria, hand and foot syndrome, fatigue, AST/ALT elevation, hypertension, hypo- or hyper-thyroidism, bilirubin elevation, and rash. Grade 3 and above TRAE occurred in 39.4% subjects. By the data cutoff date, 20 (60.6%; 95% CI 42.1-77.1) patients achieved an objective response (complete or partial response) and median progression-free survival was 9.1 months (95% CI 3.9 to NE).

Interpretation: The treatment combination of toripalimab plus axitinib was tolerable and showed promising anti-tumor activity in patients with treatment-naïve metastatic mucosal melanoma. A randomized phase III trial of toripalimab with axitinib versus standard of care is needed to validate the combination as a first-line treatment option for advanced mucosal melanoma.

Trial Registration Number: Clinical trial (NCT03086174)

Funding Statement: Study is sponsored by Shanghai Junshi Biosciences Co., LTD, Shanghai, China. This work was supported by grants from National Natural Science Foundation of China (81672696; 81772912), Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding support (ZYLX201603), and Beijing Municipal Science & Technology Commission (Z161100000516062).

Declaration of Interests: Kai Wang is employed by OrigiMed. Xiongwen Tang, Huaning Zhou, Hai Wu, Hui Feng and Sheng Yao are employed by Shanghai Junshi Bioscience. The rest of authors
have no disclosures of potential conflicts of interests.

Ethics Approval Statement: The study was approved by Peking University Cancer Hospital institutional review board and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Each subject provided written informed consent.

Keywords: Mucosal, Melanoma, anti-PD-1 antibody, Axitinib

Suggested Citation

Sheng, Xinan and Yan, Xieqiao and Chi, Zhihong and Si, Lu and Cui, Chuanliang and Tang, Bixia and Li, Siming and Mao, Lili and Lian, Bin and Wang, Xuan and Bai, Xue and Zhou, Li and Kong, Yan and Dai, Jie and Wang, Kai and Tang, Xiongwen and Zhou, Huaning and Wu, Hai and Feng, Hui and Yao, Sheng and Flaherty, Keith T. and Guo, Jun, Axitinib in Combination with Toripalimab, a Humanized IgG4 mAb Against Programmed Death-1 (PD-1) in Patients with Metastatic Mucosal Melanoma: A Non-Randomized, Open-Label, Dose-Finding, and Cohort-Expansion Phase 1b Trial (January 17, 2019). Available at SSRN: https://ssrn.com/abstract=3320203

Xinan Sheng

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Xieqiao Yan

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Zhihong Chi

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Lu Si

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Chuanliang Cui

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Bixia Tang

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Siming Li

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Lili Mao

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Bin Lian

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Xuan Wang

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Xue Bai

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Li Zhou

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Yan Kong

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Jie Dai

Peking University - Key Laboratory of Carcinogenesis and Translational Research

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Kai Wang

OrigiMed ( email )

Shanghai
China

Xiongwen Tang

Shanghai Junshi Biosciences Co., LTD

Shanghai
China

Huaning Zhou

Shanghai Junshi Biosciences Co., LTD

Shanghai
China

Hai Wu

Shanghai Junshi Biosciences Co., LTD

Shanghai
China

Hui Feng

Shanghai Junshi Biosciences Co., LTD

Shanghai
China

Sheng Yao

Shanghai Junshi Biosciences Co., LTD

Shanghai
China

Keith T. Flaherty

Harvard University - Medical School

25 Shattuck St
Boston, MA 02115
United States

Massachusetts General Hospital, Cancer Center

Boston, MA 02114
United States

Jun Guo (Contact Author)

Peking University - Key Laboratory of Carcinogenesis and Translational Research ( email )

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Click here to go to TheLancet.com

Paper statistics

Abstract Views
128
Downloads
31