Dataset Information

Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G₄ Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial.

ABSTRACT:

Purpose

Metastatic mucosal melanoma responds poorly to anti-programmed cell death-1 (PD-1) monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. The combination of VEGF inhibition and PD-1 blockade provides therapeutic opportunities for patients refractory to either therapy alone.

Patients and methods

We conducted a single-center, phase IB trial evaluating the safety and preliminary efficacy of toripalimab, a humanized immunoglobulin G₄ monoclonal antibody against PD-1 in combination with the VEGF receptor inhibitor axitinib in patients with advanced melanoma, including patients with chemotherapy-naïve mucosal melanomas (88%). Patients received toripalimab at 1 or 3 mg/kg via intravenous infusion every 2 weeks, in combination with axitinib 5 mg orally twice a day, 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.

Results

Thirty-three patients were enrolled. No dose-limiting toxicities were observed. Ninety-seven percent of patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were mild (grade 1 or 2) and included diarrhea, proteinuria, hand and foot syndrome, fatigue, AST or ALT elevation, hypertension, hypo- or hyperthyroidism, and rash. Grade 3 or greater TRAEs occurred in 39.4% of patients. By the cutoff date, among 29 patients with chemotherapy-naïve mucosal melanoma, 14 patients (48.3%; 95% CI, 29.4% to 67.5%) achieved objective response, and the median progression-free survival time was 7.5 months (95% CI, 3.7 months to not reached) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Conclusion

The combination of toripalimab plus axitinib was tolerable and showed promising antitumor activity in patients with treatment-naïve metastatic mucosal melanoma. Patients enrolled in this study were all Asian, and this combination therapy must be validated in a randomized phase III trial that includes a non-Asian population before it can become a standard of care.

SUBMITTER: Sheng X

PROVIDER: S-EPMC6839911 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G<sub>4</sub> Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial.

Sheng Xinan X Yan Xieqiao X Chi Zhihong Z Si Lu L Cui Chuanliang C Tang Bixia B Li Siming S Mao Lili L Lian Bin B Wang Xuan X Bai Xue X Zhou Li L Kong Yan Y Dai Jie J Wang Kai K Tang Xiongwen X Zhou Huaning H Wu Hai H Feng Hui H Yao Sheng S Flaherty Keith T KT Guo Jun J

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20190812 32

<h4>Purpose</h4>Metastatic mucosal melanoma responds poorly to anti-programmed cell death-1 (PD-1) monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. The combination of VEGF inhibition and PD-1 blockade provides therapeutic opportunities for patients refractory to either therapy alone.<h4>Patients and methods</h4>We conducted a single-center, phase IB trial evaluating the safety and preliminary efficacy ...[more]

PMID: 31403867

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Project description:BackgroundTRC105 is an IgG1 endoglin monoclonal antibody that potentiates VEGF inhibitors in preclinical models. We assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC).Subjects, materials, and methodsHeavily pretreated mRCC patients were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg b.i.d. and then escalated per patient tolerance to a maximum of 10 mg b.i.d.) until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design.ResultsEighteen patients (median number of prior therapies = 3) were treated. TRC105 dose escalation proceeded to 10 mg/kg weekly without dose-limiting toxicity. Adverse event characteristics of each drug were not increased in frequency or severity when the two drugs were administered concurrently. TRC105 and axitinib demonstrated preliminary evidence of activity, including partial responses (PR) by RECIST in 29% of patients, and median progression-free survival (11.3 months). None of the patients with PR had PR to prior first-line treatment. Lower baseline levels of osteopontin and higher baseline levels of TGF-β receptor 3 correlated with overall response rate.ConclusionTRC105 at 8 and 10 mg/kg weekly was well tolerated in combination with axitinib, with encouraging evidence of activity in patients with mRCC. A multicenter, randomized phase II trial of TRC105 and axitinib has recently completed enrollment (NCT01806064).Implications for practiceTRC105 is a monoclonal antibody to endoglin (CD105), a receptor densely expressed on proliferating endothelial cells and also on renal cancer stem cells that is implicated as a mediator of resistance to inhibitors of the VEGF pathway. In this Phase I trial, TRC105 combined safely with axitinib at the recommended single agent doses of each drug in patients with renal cell carcinoma. The combination demonstrated durable activity in a VEGF inhibitor-refractory population and modulated several angiogenic biomarkers. A randomized Phase II trial testing TRC105 in combination with axitinib in clear cell renal cell carcinoma has completed accrual.

Project description:PurposeOpen-label phase Ib/II study to investigate the safety and efficacy of LBL-007, an anti-LAG-3 antibody, plus toripalimab, an anti-PD-1 antibody, in patients with previously treated advanced nasopharyngeal carcinoma (NPC) and other solid tumors.MethodsPatients with advanced tumors refractory to prior standard therapies were enrolled. In phase Ib, patients received LBL-007 200 mg or 400 mg and toripalimab 240 mg intravenously once every 3 weeks. In phase II, all patients received LBL-007 at the recommended phase II dose (RP2D) and toripalimab 240 mg intravenously once every 3 weeks. The primary end points were safety in phase Ib and objective response rate (ORR) in phase II. The exploratory end point was the predictive capability of LAG-3 and PD-L1 expression for efficacy.ResultsBetween November 30, 2021, and December 1, 2023, 80 patients were enrolled, including 30 (37.5%) with NPC and 50 (62.5%) with other tumors. Median follow-up was 26.0 months. In Phase Ib, LBL-007 was administered at 200 mg to four patients and 400 mg to six patients, with no dose-limiting toxicities observed. Therefore, the 400 mg dose of LBL-007 was established as the RP2D and administered to 70 patients in phase II. Nine (11.3%) of 80 patients had grade 3 or 4 treatment-related adverse events, the most common of which included anemia (2.5%), hyponatremia (2.5%), increased alanine aminotransferase (2.5%), increased aspartate aminotransferase (1.3%), and fatigue (1.3%). Eight patients (10.0%) had treatment-related serious adverse events. No treatment-related deaths were reported. In immunotherapy-naive NPC patients (n = 12), ORR was 33.3%, disease control rate (DCR) was 75%, and median progression-free survival (PFS) was 10.8 months (95% CI, 1.3 to not estimated). In IO-treated NPC patients (n = 17), ORR was 11.8%, DCR was 64.7%, and median PFS was 2.7 months (95% CI, 1.4 to 4.9). For other tumors, ORRs were 15.8% in immunotherapy-naive patients and 3.7% in immunotherapy-treated patients. Patients with ≥ 2 + LAG-3 expression had a higher ORR of 28.0%, compared to 7.7% in those with < 2 + LAG-3 expression.ConclusionLBL-007 plus toripalimab exhibited a manageable safety profile in patients with advanced solid tumors and demonstrated promising antitumor activity in NPC, especially in immunotherapy-naive patients. These findings warrant further validation in future studies.

Dataset Information

Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G₄ Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial.

Purpose

Patients and methods

Results

Conclusion

Publications

Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G<sub>4</sub> Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G4 Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial.

Purpose

Patients and methods

Results

Conclusion

Publications

Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G<sub>4</sub> Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G₄ Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial.