Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study

被引：46

作者：

Atkins, Michael B. ^{[1
]}

Hodi, F. Stephen ^{[2
]}

Thompson, John A. ^{[3
]}

McDermott, David F. ^{[4
]}

Hwu, Wen-Jen ^{[5
]}

Lawrence, Donald P. ^{[6
]}

Dawson, Nancy A. ^{[1
]}

Wong, Deborah J. ^{[7
]}

Bhatia, Shailender ^{[3
]}

James, Marihella ^{[5
]}

Jain, Lokesh ^{[8
]}

Robey, Seth ^{[8
]}

Shu, Xinxin ^{[8
]}

Moreno, Blanca Homet ^{[8
]}

Perini, Rodolfo F. ^{[8
]}

Choueiri, Toni K. ^{[2
]}

Ribas, Antoni ^{[7
]}

机构：

[1] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA

[2] Dana Farber Canc Inst, Boston, MA 02115 USA

[3] Seattle Canc Care Alliance, Seattle, WA USA

[4] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[5] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[6] Massachusetts Gen Hosp, Boston, MA 02114 USA

[7] Univ Calif Los Angeles, Los Angeles, CA USA

[8] Merck & Co Inc, Kenilworth, NJ USA

来源：

CLINICAL CANCER RESEARCH | 2018年 / 24卷 / 08期

关键词：

INVESTIGATOR-CHOICE CHEMOTHERAPY; OPEN-LABEL; LUNG-CANCER; COMBINED NIVOLUMAB; ADJUVANT THERAPY; TUMOR; SURVIVAL; BLOCKADE; SAFETY; ALPHA;

D O I：

10.1158/1078-0432.CCR-17-3436

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if <= 6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced >= 1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEGIFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 mg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 mg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC. Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. (C) 2018 AACR.

引用

页码：1805 / 1815

页数：11

共 43 条

[21] Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial [J].

Long, Georgina V. ;

Atkinson, Victoria ;

Cebon, Jonathan S. ;

Jameson, Michael B. ;

Fitzharris, Bernie M. ;

McNeil, Catriona M. ;

Hill, Andrew G. ;

Ribas, Antoni ;

Atkins, Michael B. ;

Thompson, John A. ;

Hwu, Wen-Jen ;

Hodi, F. Stephen ;

Menzies, Alexander M. ;

Guminski, Alexander D. ;

Kefford, Richard ;

Kong, Benjamin Y. ;

Tamjid, Babak ;

Srivastava, Archana ;

Lomax, Anna J. ;

Islam, Mohammed ;

Shu, Xinxin ;

Ebbinghaus, Scot ;

Ibrahim, Nageatte ;

Carlino, Matteo S. .

LANCET ONCOLOGY, 2017, 18 (09) :1202-1210

[22] Interferon Alpha Adjuvant Therapy in Patients With High-Risk Melanoma: A Systematic Review and Meta-analysis [J].

Mocellin, Simone ;

Pasquali, Sandro ;

Rossi, Carlo R. ;

Nitti, Donato .

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2010, 102 (07) :493-501

[23] Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma [J].

Motzer, R. J. ;

Escudier, B. ;

McDermott, D. F. ;

George, S. ;

Hammers, H. J. ;

Srinivas, S. ;

Tykodi, S. S. ;

Sosman, J. A. ;

Procopio, G. ;

Plimack, E. R. ;

Castellano, D. ;

Choueiri, T. K. ;

Gurney, H. ;

Donskov, F. ;

Bono, P. ;

Wagstaff, J. ;

Gauler, T. C. ;

Ueda, T. ;

Tomita, Y. ;

Schutz, F. A. ;

Kollmannsberger, C. ;

Larkin, J. ;

Ravaud, A. ;

Simon, J. S. ;

Xu, L-A ;

Waxman, I. M. ;

Sharma, P. .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (19) :1803-1813

[24] Effects of interferon-α-transduced tumor cell vaccines and blockade of programmed cell death-1 on the growth of established tumors [J].

Omori, R. ;

Eguchi, J. ;

Hiroishi, K. ;

Ishii, S. ;

Hiraide, A. ;

Sakaki, M. ;

Doi, H. ;

Kajiwara, A. ;

Ito, T. ;

Kogo, M. ;

Imawari, M. .

CANCER GENE THERAPY, 2012, 19 (09) :637-643

[25] Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma [J].

Ribas, Antoni ;

Hamid, Omid ;

Daud, Adil ;

Hodi, F. Stephen ;

Wolchok, Jedd D. ;

Kefford, Richard ;

Joshua, Anthony M. ;

Patnaik, Amita ;

Hwu, Wen-Jen ;

Weber, Jeffrey S. ;

Gangadhar, Tara C. ;

Hersey, Peter ;

Dronca, Roxana ;

Joseph, Richard W. ;

Zarour, Hassane ;

Chmielowski, Bartosz ;

Lawrence, Donald P. ;

Algazi, Alain ;

Rizvi, Naiyer A. ;

Hoffner, Brianna ;

Mateus, Christine ;

Gergich, Kevin ;

Lindia, Jill A. ;

Giannotti, Maxine ;

Li, Xiaoyun Nicole ;

Ebbinghaus, Scot ;

Kang, S. Peter ;

Robert, Caroline .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2016, 315 (15) :1600-1609

[26] Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial [J].

Ribas, Antoni ;

Puzanov, Igor ;

Dummer, Reinhard ;

Schadendorf, Dirk ;

Hamid, Omid ;

Robert, Caroline ;

Hodi, F. Stephen ;

Schachter, Jacob ;

Pavlick, Anna C. ;

Lewis, Karl D. ;

Cranmer, Lee D. ;

Blank, Christian U. ;

O'Day, Steven J. ;

Ascierto, Paolo A. ;

Salama, April K. S. ;

Margolin, Kim A. ;

Loquai, Carmen ;

Eigentler, Thomas K. ;

Gangadhar, Tara C. ;

Carlino, Matteo S. ;

Agarwala, Sanjiv S. ;

Moschos, Stergios J. ;

Sosman, Jeffrey A. ;

Goldinger, Simone M. ;

Shapira-Frommer, Ronnie ;

Gonzalez, Rene ;

Kirkwood, John M. ;

Wolchok, Jedd D. ;

Eggermont, Alexander ;

Li, Xiaoyun Nicole ;

Zhou, Wei ;

Zernhelt, Adriane M. ;

Lis, Joy ;

Ebbinghaus, Scot ;

Kang, S. Peter ;

Daud, Adil .

LANCET ONCOLOGY, 2015, 16 (08) :908-918

[27] Tumor Immunotherapy Directed at PD-1 [J].

Ribas, Antoni .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (26) :2517-2519

[28] Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206 [J].

Rini, Brian I. ;

Halabi, Susan ;

Rosenberg, Jonathan E. ;

Stadler, Walter M. ;

Vaena, Daniel A. ;

Archer, Laura ;

Atkins, James N. ;

Picus, Joel ;

Czaykowski, Piotr ;

Dutcher, Janice ;

Small, Eric J. .

JOURNAL OF CLINICAL ONCOLOGY, 2010, 28 (13) :2137-2143

[29] SKIN TOXICITY [J].

Robert, C. .

ANNALS OF ONCOLOGY, 2014, 25

[30] Pembrolizumab versus Ipilimumab in Advanced Melanoma [J].

Robert, Caroline ;

Schachter, Jacob ;

Long, Georgina V. ;

Arance, Ana ;

Grob, Jean Jacques ;

Mortier, Laurent ;

Daud, Adil ;

Carlino, Matteo S. ;

McNeil, Catriona ;

Lotem, Michal ;

Larkin, James ;

Lorigan, Paul ;

Neyns, Bart ;

Blank, Christian U. ;

Hamid, Omid ;

Mateus, Christine ;

Shapira-Frommer, Ronnie ;

Kosh, Michele ;

Zhou, Honghong ;

Ibrahim, Nageatte ;

Ebbinghaus, Scot ;

Ribas, Antoni .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (26) :2521-2532

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