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Safety of the natural killer (NK) cell-targeted anti-KIR antibody, lirilumab (liri), in combination with nivolumab (nivo) or ipilimumab (ipi) in two phase 1 studies in advanced refractory solid tumors

Date

09 Oct 2016

Session

Poster display

Presenters

Neil Segal

Citation

Annals of Oncology (2016) 27 (6): 359-378. 10.1093/annonc/mdw378

Authors

N.H. Segal1, J.R. Infante2, R.E. Sanborn3, G.T. Gibney4, D.P. Lawrence5, N. Rizvi6, R. Leidner3, T.F. Gajewski7, E. Bertino8, W.H. Sharfman9, S. Cooley10, S.L. Topalian11, W.J. Urba12, J.D. Wolchok1, X. Gu13, C. Passey14, D. McDonald15, P. Aanur15, S. Srivastava14, F..S. Hodi16

Author affiliations

  • 1 Department Of Medicine, Memorial Sloan Kettering Cancer Center, NY 10065 - New York/US
  • 2 Department Of Medicine, Tennessee Oncology, PLLC, Nashville/US
  • 3 Department Of Medical Oncology, Chiles Research Institute, Providence Cancer Center, Portland/US
  • 4 Melanoma Disease Group, Lombardi Cancer Center Georgetown University, Washington/US
  • 5 Hematology/oncology, Massachusetts General Hospital, Boston/US
  • 6 Hematology And Oncology, Memorial Sloan-Kettering Cancer Center, New York/US
  • 7 Department Of Pathology And Department Of Medicine, Section Of Hematology/oncology, University of Chicago, Chicago/US
  • 8 Department Of Internal Medicine, Division Of Medical Oncology, Ohio State Univ Medical Center, Columbus/US
  • 9 Oncology And Dermatology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore/US
  • 10 Division Of Hematology, Oncology And Transplantation, University of Minnesota Masonic Cancer Center, Minneapolis/US
  • 11 Department Of Surgery, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore/US
  • 12 Providence Melanoma Program, Earle A. Chiles Research Institute-Providence Cancer Center, Portland/US
  • 13 Biostatistics, Bristol-Myers Squibb, 08543 - Princeton/US
  • 14 Oncology, Bristol-Myers Squibb, 08543 - Princeton/US
  • 15 Immuno-oncology, Bristol-Myers Squibb, 08543 - Princeton/US
  • 16 Oncology, Dana-Farber Cancer Institute, Boston/US
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Resources

Abstract 3429

Background

NK cells play a critical role in immune surveillance and control of tumor growth. Killer-cell immunoglobulin-like receptors (KIR) are important in regulating NK cell activation and blocking KIR function may be a key strategy potentiating anti-tumor immune response, particularly in combination with other immuno-oncology therapies. Here we report the safety of liri, a fully human mAb that blocks KIR on NK cells, in combination with anti-PD-1, nivo (CA223-001; NCT01714739) or anti-CTLA4, ipi (CA223-002, NCT01750580).

Methods

A phase 1 study evaluated escalating doses of liri 0.1–3 mg/kg every 4 wk + nivo 3 mg/kg every 2 wk up to 2 yr. A companion phase 1 study examined liri 0.1–3mg/kg every 3 wk + ipi 3 mg/kg every 3 wk for 4 doses then every 12 wk for 4 doses. Treatment continued until disease progression or toxicity. Both studies enrolled pts with advanced solid tumors. Primary endpoints were safety and maximum tolerated combined dose.

Results

Adverse events (AEs) occurred in 135/136 pts and 22/22 pts across all doses in the liri + nivo and liri + ipi studies, respectively. Treatment-related (TR) AEs are summarized in Table 1.

TRAEs reported in >5% of pts or of Grade 3–4 from CA223-001 and CA223-002

CA223-001 Liri + Nivo (N = 136) CA223-002 Liri +Ipi (N = 22)
All Grades n (%) Grades 3–4 n (%) All Grades n (%) Grades 3–4 n (%)
Any TRAE 97 (71.3) 18 (13.2) Any TRAE 15 (68.2) 2 (9.1)
TRAE in >5% pts and all Grade 3–4
Pruritus 25 (18.4) 0 Fatigue 6 (27.3) 0
Fatigue 25 (18.4) 0 Diarrhea 5 (22.7) 0
Infusion-related reaction 25 (18.4) 0 Nausea 4 (18.2) 0
Rash, other 18 (13.2) 0 Decreased appetite 4 (18.2) 0
Diarrhea 12 (8.8) 1 (0.7) Vomiting 4 (18.2) 0
Rash maculopapular 11 (8.1) 2 (1.5) Chills 4 (18.2) 0
Amylase increased 10 (7.4) 3 (2.2) Rash, other 3 (13.6) 0
Nausea 8 (5.9) 0 Rash pruritic 3 (13.6) 0
Dry mouth 7 (5.1) 0 Pyrexia 3 (13.6) 0
Pyrexia 7 (5.1) 0 Hyperhidrosis 2 (9.1) 0
Arthralgia 7 (5.1) 0 Rash maculopapular 2 (9.1) 0
Lipase increased 6 (4.4) 4 (2.9) Headache 2 (9.1) 0
Leukopenia 4 (2.9) 1 (0.7) Pruritus 2 (9.1) 1 (4.5)
Hypophosphatemia 3 (2.2) 2 (1.5) Hypertension 2 (9.1) 0
Hypopituitarism 1 (4.5) 1 (4.5)
Rash erythematous 1 (4.5) 1 (4.5)
Of pts receiving liri + nivo, 10 (7.4%) pts developed serious TRAEs (n = 1 Grade 4 thrombocytopenia, n = 1 each Grade 3 pancreatitis or radiation skin injury). Two pts had DLTs (iridocyclitis and rash) with liri + ipi. No dose-related trends occurred in any AE up to the maximum tested dose of liri 3 mg/kg + nivo or ipi. No TR deaths occurred in either study.

Conclusions

Liri + nivo or ipi was tolerable in pts with advanced solid tumors. The larger number of pts treated with liri + nivo demonstrated safety consistent with nivo monotherapy, with the exception of increased infusion-related reactions, which were manageable. These data support ongoing evaluation of liri + nivo.

Clinical trial identification

Legal entity responsible for the study

Sponsored by Bristol-Myers Squibb

Funding

Sponsored by Bristol-Myers Squibb

Disclosure

R.E. Sanborn: Grants from Bristol-Meyers Squibb, during the conduct of the study; grants and other from Medimmune, other from Seattle Genetics, other from Peregrine Pharmaceuticals, other from Merck, outside the submitted work. G.T. Gibney: Personal fees from MERCK, personal fees from Novartis, outside the submitted work. N. Rizvi: Consulting for astrazeneca, merck, roche, novartis, lilly Co-founder and shareholder, gritstone oncology. W.H. Sharfman: Grants from BMS, during the conduct of the study; personal fees from Merck, personal fees from Castle Bioscience, outside the submitted work. S.L. Topalian: Grants from Bristol-Myers Squibb; personal fees from Five Prime Therapeutics, GlaxoSmithKline, ImaginAb, & Jounce Therapeutics, Melanoma Research Alliance; Patents with Bristol-Myers Squibb, MedImmune/AstraZeneca, and Potenza Therapeutics. W.J. Urba: Celldex and Medimmune. J.D. Wolchok: Dr. Wolchok reports grants from Bristol Myers Squibb, grants from Merck, grants from Medimmune, grants from Genentech, during the conduct of the study; other from BMS, other from Merck, other from Genentech, other from Medimmune. X. Gu, C. Passey, D. McDonald, P. Aanur, S. Srivastava: Employee of BMS. F.S. Hodi: Research support form Bristol-Myers Squibb to institution. All other authors have declared no conflicts of interest.

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