TY - JOUR
T1 - Phase I study of MK-4166, an anti-human glucocorticoid-induced tnf receptor antibody, alone or with pembrolizumab in advanced solid tumors
AU - Papadopoulos, Kyriakos P.
AU - Autio, Karen
AU - Golan, Talia
AU - Dobrenkov, Konstantin
AU - Chartash, Elliot
AU - Chen, Qiusheng
AU - Wnek, Richard
AU - Long, Georgina V.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - Purpose: In this first-in-human phase I study (NCT02132754), we explored MK-4166 [humanized IgG1 agonist mAb targeting glucocorticoid-induced TNF receptor (GITR)] with and without pembrolizumab in advanced solid tumors. Patients and Methods: MK-4166 was tested alone (0.0015. 900 mg i.v. every 3 weeks for four doses) or with pembrolizumab (200 mg i.v. every 3 weeks for ≤35 doses) in patients with metastatic solid tumors (dose escalation/confirmation) and advanced melanoma (expansion). Primary objectives were to evaluate the safety and tolerability and establish the MTD of MK-4166. Exploratory endpoints were objective response rate (ORR) and T cell-inflamed gene expression profile (GEP) analysis using RNA from baseline tumor samples. Results: A total of 113 patients were enrolled [monotherapy, n = 48; combination therapy, n = 65 (20 in the expansion)]. Fortysix patients (40.7%) had grade ≥3 adverse events, 9 (8.0%) of which were treatment related. No treatment-related deaths were observed. One dose-limiting toxicity event with monotherapy (bladder perforation in patient with neobladder) was considered related to study drug. MTD was not reached. MK-4166 pharmacodynamics showed decreased GITR availability on circulating T cells with increasing doses. One objective response (ORR, 2.2%) was achieved with combination therapy in the dose escalation/confirmation (n=45). In the expansion, 8 of 13 patients with immune checkpoint inhibitor (ICI)-naive melanoma achieved a response (ORR, 62%; 95% confidence interval, 32.86; 5 complete responses and 3 partial responses). None of the ICI-pretreated patients (n=7) responded. Highresponse rates were observed in ICI-naive patients irrespective of GEP status. Conclusions: MK-4166 900 mg i.v. every 3 weeks as monotherapy and with pembrolizumab was tolerable. Responses were observed with combination therapy, mostly in patients with ICI-naïve melanoma.
AB - Purpose: In this first-in-human phase I study (NCT02132754), we explored MK-4166 [humanized IgG1 agonist mAb targeting glucocorticoid-induced TNF receptor (GITR)] with and without pembrolizumab in advanced solid tumors. Patients and Methods: MK-4166 was tested alone (0.0015. 900 mg i.v. every 3 weeks for four doses) or with pembrolizumab (200 mg i.v. every 3 weeks for ≤35 doses) in patients with metastatic solid tumors (dose escalation/confirmation) and advanced melanoma (expansion). Primary objectives were to evaluate the safety and tolerability and establish the MTD of MK-4166. Exploratory endpoints were objective response rate (ORR) and T cell-inflamed gene expression profile (GEP) analysis using RNA from baseline tumor samples. Results: A total of 113 patients were enrolled [monotherapy, n = 48; combination therapy, n = 65 (20 in the expansion)]. Fortysix patients (40.7%) had grade ≥3 adverse events, 9 (8.0%) of which were treatment related. No treatment-related deaths were observed. One dose-limiting toxicity event with monotherapy (bladder perforation in patient with neobladder) was considered related to study drug. MTD was not reached. MK-4166 pharmacodynamics showed decreased GITR availability on circulating T cells with increasing doses. One objective response (ORR, 2.2%) was achieved with combination therapy in the dose escalation/confirmation (n=45). In the expansion, 8 of 13 patients with immune checkpoint inhibitor (ICI)-naive melanoma achieved a response (ORR, 62%; 95% confidence interval, 32.86; 5 complete responses and 3 partial responses). None of the ICI-pretreated patients (n=7) responded. Highresponse rates were observed in ICI-naive patients irrespective of GEP status. Conclusions: MK-4166 900 mg i.v. every 3 weeks as monotherapy and with pembrolizumab was tolerable. Responses were observed with combination therapy, mostly in patients with ICI-naïve melanoma.
UR - http://www.scopus.com/inward/record.url?scp=85104852114&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-2886
DO - 10.1158/1078-0432.CCR-20-2886
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C2 - 33355238
AN - SCOPUS:85104852114
SN - 1078-0432
VL - 27
SP - 1904
EP - 1911
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -