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).
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.
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)|
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
Sponsored by Bristol-Myers Squibb
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.