1621 - Phase 1 Study of the Arginase Inhibitor INCB001158 (1158) Alone and in Combination with Pembrolizumab (PEM) in Patients (Pts) with Advanced/Metastatic (Adv/Met) Solid Tumors

Background

Arginase (Arg), an enzyme secreted by myeloid-derived suppressor cells and neutrophils in the tumor milieu, suppresses T-cell activity via arginine depletion. This phase 1 study is evaluating 1158, an oral small molecule Arg inhibitor, as monotherapy (MT) and in combination (CT) w/ the PD-1 inhibitor PEM in checkpoint inhibitor (CPI) refractory and naïve adv/met solid tumors.

Methods

Dose escalation of 1158 MT and CT w/ PEM (200 mg Q3W) was followed by tumor expansion cohorts to evaluate safety/activity at the recommended phase 2 dose (RP2D) using a Simon 2 Stage design. Primary objective is safety/tolerability. Data cutoff: April 23, 2019.

Results

73 pts were enrolled in MT/CT dose escalation, 68 across 3 MT expansion cohorts (colorectal carcinoma [CRC], non-small cell lung cancer, basket) and 94 to date across 8 CT expansion cohorts (4 CPI refractory, 4 CPI naïve). Median age was 63 yrs (32-92), w/ median 3 prior therapies (1-11). No maximum tolerated dose of 1158 was reached up to 150 mg BID; RP2D was 100 mg BID. Plasma arginase inhibition was seen at all doses as were dose-related elevations in plasma arginine. Clinically significant urea cycle inhibition (on-target toxicity), defined as concomitant rise in urine orotic acid and plasma ammonia, was not seen. Immune-related adverse events (irAEs) in MT were G3 colitis and G2 malaise (1 each). Overall frequency/severity of irAEs for CT was similar to PEM MT. AEs were generally manageable and reversible. CRC expansion cohorts are most mature; MT CRC and CT MSS CRC cohorts met response criteria to advance to Simon Stage 2. Partial responses were seen in efficacy evaluable MSS CRC pts in MT and CT with overall response (ORR)/disease control rate (ORR + stable disease) of 3%/28% (n = 32) and 6%/37% (n = 35), respectively. Other expansion cohorts are ongoing in Stage 1.

Conclusions

Early data indicate that 1158 MT and CT w/ PEM was well tolerated and showed responses as MT and CT in pretreated MSS CRC pts. Updated safety and efficacy data will be presented.

Clinical trial identification

NCT02903914 Posted to clinicaltrials.gov: September 16, 2016.

Editorial acknowledgement

Medical writing support was provided by Ingrid Koo, PhD, and funded by Calithera Biosciences and Incyte Corporation.

Legal entity responsible for the study

Calithera Biosciences, Inc., and Incyte Corp.

Funding

Calithera Biosciences, Inc., and Incyte Corp.

Disclosure

A. Naing: Research grant / Funding (institution): NCI; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Healios Onc. Nutrition; Research grant / Funding (institution): Atterocor; Research grant / Funding (institution): Amplimmune; Research grant / Funding (institution), Travel / Accommodation / Expenses: ARMO Biosciences; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Incyte; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): CytomX Therapeutics; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): TopAlliance Bioscences; Research grant / Funding (institution): Kymab, PsiOxus; Spouse / Financial dependant: Immune Deficiency Foundation. T. Bauer: Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Leap Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy, Research grant / Funding (institution): Moderna; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Loxo; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Immunogen; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Phosplatin Therapeutics; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Koltan Pharmaceuticals; Research grant / Funding (institution): Principa Biopharma; Research grant / Funding (institution): Peleton; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Alleron Therapeutics; Research grant / Funding (institution): Bristol-Meyer Squibb; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Onyx, Sanofi, Boehringer-Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance Bioscience, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Foundation Medicine, ARMO Biosciences. K.P. Papadopoulos: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Curegenix; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): 3D Medicines; Research grant / Funding (institution): Formation Biologics; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Syros Pharmaceuticals; Research grant / Funding (institution): Mersana, OncoMed, MabSpace Biosciences, Jounce Therapeutics. O. Rahma: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Merck; Advisory / Consultancy: Celgene; Advisory / Consultancy: Five Prime; Advisory / Consultancy: GFK; Advisory / Consultancy: Defined Health INC; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Puretech; Advisory / Consultancy: Leerink; Advisory / Consultancy: PRMA Consulting; Licensing / Royalties, Patent pending: Methods of using Pembrolizumab and trebananib: Patent; Speaker Bureau / Expert testimony: BMS. F. Tsai: Shareholder / Stockholder / Stock options: Salarius Pharmaceuticals; Advisory / Consultancy: Tempus Lab; Licensing / Royalties: Caremission LLC. E. Garralda: Advisory / Consultancy, Research grant / Funding (institution): F. Hoffmann-La Roche; Advisory / Consultancy: Ellipses Pharma; Advisory / Consultancy: Neomed Therapeutics1 Inc; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Janssen Global Services; Speaker Bureau / Expert testimony: Bristol-Meyers Squibb; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Research grant / Funding (institution), Travel / Accommodation / Expenses: Glycotope; Travel / Accommodation / Expenses: Menarini; Research grant / Funding (self), Scitron Project - VHIÓS Technology Platform to study tumor clonal evolution and Resistance to Immune and Targeted Therapies.: Novartis; Research grant / Funding (institution): Principia Biopharma Inc; Research grant / Funding (institution): Lilly, S.A; Research grant / Funding (institution): Novartis Farmacéutica, S.A; Research grant / Funding (institution): Genentech, Inc; Research grant / Funding (institution): Loxo Oncology; Research grant / Funding (institution): Symphogen A/S; Research grant / Funding (institution): Incyte Biosciences International, Pharma Mar S.A.U., Kura Oncology Inc, Macrogenics Inc, Pierre Fabre Medicameng, Cellestia Biotech, Menarini Ricerche Spa, Blueprint Medicines Corporation, Beigene USA Inc, Sierra Oncology Inc, Genmab B.V.; Non-remunerated activity/ies, ImCORE Translational Committee Member since 2017: Roche/Genentech; Non-remunerated activity/ies: ESMO, SEOM, AACR, ASCO, Cancer Core Europe; Leadership role: ESMO Women For Oncology - W40. J. Naidoo: Honoraria (self): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Roche/Genentech; Research grant / Funding (institution): Merck. M.K. Gibson: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Non-remunerated activity/ies, Author: NCCN. I. Rybkin: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): Beyond Spring Pharmaceutical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Mirati Therapeutical Inc.; Research grant / Funding (institution): Nilogen, Inc.; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Polaris Group; Research grant / Funding (institution): Syndax Inc.; Research grant / Funding (institution): Xcovery Inc.; Research grant / Funding (institution): BerGenBio AS; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Amgen. D.F. McDermott: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Array BioPharm; Advisory / Consultancy, Research grant / Funding (institution): Genentech BioOncology; Advisory / Consultancy, Research grant / Funding (institution): Alkermes, Inc.; Advisory / Consultancy: Jounce Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): X4 Pharma; Advisory / Consultancy, Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Eli Lilly and Company; Research grant / Funding (institution): Prometheus Laboratories. M. de Miguel: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Incyte/INC Research; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Menarini; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pharmamar; Research grant / Funding (institution): Roche. Y. Jenkins: Shareholder / Stockholder / Stock options, Full / Part-time employment: Calithera Biosciences; Spouse / Financial dependant: Second Genome. H. Kallender: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. S. Gogov: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. E. Kuriakose: Shareholder / Stockholder / Stock options, Full / Part-time employment: Calithera Biosciences, Inc. M. Pishvaian: Speaker Bureau / Expert testimony: Sirtex; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Speaker Bureau / Expert testimony: Caris; Advisory / Consultancy: Rafael; Advisory / Consultancy, Research grant / Funding (institution): ARMO; Advisory / Consultancy: Eisai; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Merrimack; Shareholder / Stockholder / Stock options: Perthera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Fibrogen; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bavarian Nordic, Novartis, Pfizer, BMS, Abbvie, Halozyme, Karyopharm, Bayer, Regeneron, Curegenix, Calithera, Pharmacyclics. All other authors have declared no conflicts of interest.