Cellular Therapy Approaches
O35 The transcription factor Myb enhances CD8+ T cell stemness and polyfunctionality to promote curative antitumor immunity
Sanjivan Gautam1, Yun Ji1, Wei Zhu2, Jessica Fioravanti1, Jinhui Hu1, Neal Lacey1, James D Hocker1, John Le Gall1, Nga Voong1, William G Telford1, Philip Brohaun2, Avinash Bhandoola3, Hai-Hui Xue4, Rahul Roychoudhuri4, Nicholas P Restifo1, Brandon Higgs2, Timothy P Bender5, Luca Gattinoni1
1National Cancer Institute, Bethesda, MD, USA; 2Medimmune, Gaithersburg, MD, USA; 3Carver College of Medicine, University of Iowa, Iowa City, IA, USA; 4Cambridge University, Cambridge, UK; 5Univeristy of Virginia, Charlottesville, VA, USA
Correspondence: Luca Gattinoni (Luca_Gattinoni@nih.gov)
Following antigen encounter, CD8+ T cells differentiate into effector and memory T cells to mediate pathogen clearance and provide life-long immunity. Although our understanding of the molecular mechanisms regulating CD8+ T cell fate has expanded dramatically over recent years, the precise transcriptional programs underlying this process remains incompletely resolved. Myb is a transcription factor known to play a major role in stem cell and progenitor renewal and homeostasis, but its function in mature T cell differentiation is unknown. In this study, we demonstrate the role of Myb in CD8+ T cell differentiation and antitumor function.
We employed CD8+ T cells isolated from pmel-1 mice (which recognize the shared melanoma-melanocyte differentiation antigen gp100) carrying loxP-flanked Myb alleles and a fusion of Cre recombinase and the estrogen receptor T2 moiety, which retains Cre in the cytosol until tamoxifen is administered (pmel-1 Mybfl/flCre-ERT2 cells). Treating these mice with tamoxifen for several days immediately prior to CD8+ T cell isolation ensured that pmel-1 Myb−/− T cells had undergone thymic development similar to their ERT2-Cre negative counterparts. pmel-1 Myb−/− or pmel-1 Myb+/+ cells were adoptively transferred into wild-type mice infected with a recombinant strain of vaccinia virus encoding gp100 and antigen-specific CD8+ T cell expansion and long-term persistence was monitored overtime. Evaluation of tumor treatment efficacy of CD8+ T cells was performed in the pmel-1 model of adoptive cell therapy in the treatment of large established B16 melanomas.
We demonstrate that Myb expression is progressively downregulated with T cell differentiation. We found that Myb deficient T cells were more prone to differentiate into short-lived KLRG1hi effector cells resulting in a severe impairment of CD62Lhi stem cell-like memory cell formation, indicating that Myb is an essential regulator of T cell stemness. Conversely, enforced expression of Myb enhanced generation of CD62Lhi memory cells, T cell polyfunctionality and recall responses, suggesting that these cells might be therapeutically superior for adoptive T cell therapy of tumors. Accordingly, Myb overexpressing T cells mediate enhanced antitumor immunity and promoted curative and long-lasting responses against large established vascularized tumors.
These findings identify Myb as a master regulator of CD8+ T cell stemness and highlight the remarkable therapeutic potential of maneuvers aimed at increasing Myb activity in CD8+ T cells.
Clinical Trials (Completed)
O36 First in human study with the CD40 agonistic monoclonal antibody APX005M in subjects with solid tumors
Melissa Johnson1, Marwan Fakih2, Johanna Bendell1, David Bajor3, Mihaela Cristea2, Thomas Tremblay4, Ovid Trifan4, Robert Vonderheide5
1Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA; 2City of Hope, Duarte, CA, USA; 3Case Western Reserve University School of Medicine, Cleveland, OH, USA; 4Apexigen, Inc., San Carlos, CA, USA; 5Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Correspondence: Ovid Trifan (email@example.com)
Immune activating antibodies are being explored as the next generation of immuno-oncology therapeutics. Activation of CD40 can stimulate both innate and adaptive immune responses against cancer, making it an ideal target for the immune activating approach. CD40 engagement with its ligand CD154 leads to antigen presentation, maturation and expression of co-stimulatory molecules and cytokine production by antigen presenting cells (APC), which are requisite for optimal antigen-specific T-cell activation. Apexigen is developing APX005M – a humanized IgG1 CD40 agonistic antibody that binds with high affinity to human CD40 (Kd=0.12nM) and carries an S267E mutation in the Fc region. APX005M recognizes a unique epitope that overlaps with the CD40 ligand binding sites and uses FcRγIIb to cluster and activate CD40 thus mimicking CD154 engagement.
In a “first in human” Phase 1 dose escalating clinical trial, APX005M was administered every 21 days at doses ranging from 0.0001 mg/kg to 1 mg/kg to 30 adult subjects with solid tumors. Primary objectives were to evaluate the safety of APX005M, and to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D).
APX005M demonstrated a dose-dependent APC activation (increases in expression of CD54, CD70, CD80, CD86, HLA-DR), dose dependent T cell activation and increases in circulating levels of IL-12, INF-γ, TNFα and IL-6. Five subjects had prolonged stable disease. Overall APX005M has been well tolerated; the majority of AEs were mild to moderate in severity, and the majority of serious AEs were considered unrelated to APX005M. The dose limiting toxicity of grade ≥ 3 cytokine release syndrome was observed in subjects receiving doses ≥ 0.6 mg/kg. The maximum administered dose of APX005M was 1 mg/kg. The dose of 0.3 mg/kg of APX005M was selected as the RP2D and represents the dose with maximum pharmacodynamic effects without grade > 2 toxicities. Increases in the dose of APX005M led to approximately dose-proportional increases in maximum serum concentration (Cmax) and area under the curve (AUC). No accumulation of APX005M was observed with every 21 day dosing.
APX005M produces dose-dependent activation of APCs and T cells at doses that are well tolerated. Toxicities generally associated with the on-target cytokine release are observed at doses above the doses that are required to activate APCs and T-cells. APX005M exhibits a highly differentiated and ideal profile for further clinical development as a single agent or in combination with other treatment modalities including immunomodulatory agents.
Clinical Trials (In Progress)
O37 Nivolumab in mismatch-repair deficient (MMR-d) cancers: NCI-MATCH Trial (Molecular Analysis for Therapy Choice) arm Z1D preliminary results
Nilofer Azad1, Michael Overman2, Robert Gray3, Jonathan Schoenfeld4, Carlos Arteaga5, Brent Coffey6, David Patton7, Shuli Li8, Lisa McShane7, Larry Rubenstein7, Lyndsay Harris7, Robert Comis9, Jeffrey Abrams6, Paul M. Williams6, Edith Mitchell11, James Zweibel6, Elad Sharon7, Howard Streicher7, Peter J. Dwyer12, Stanley Hamilton2, Barbara Conley7, Alice P. Chen13, Keith Flaherty14
1Johns Hopkins University, Baltimore, MD, USA; 2MD Anderson, Houston, TX, USA; 3Dana Farber Institute, Boston, MA, USA; 4Brighan and Women's Cancer Center, Boston, MA, USA; 5Vanderbilt, Nashville, TN, USA; 6National Institute of Health, Rockville, MD, USA; 7NCI, Rockville, MD, USA; 8Harvard, Boston, MA, USA; 9ECOG-ACRIN, Philadelphia, PA, USA; 11Thomas Jefferson University, Philadelphia, PA, USA; 12University of Pennsylvania, Philadelphia, PA, USA; 13DTC National Cancer Institute, Bethesda, MD, USA; 14Massachusetts General Hospital, Boston, MA, USA
Correspondence: Nilofer Azad; Stanley Hamilton (firstname.lastname@example.org)
The NCI-MATCH (Molecular Analysis for Therapy Choice) trial is the largest national study to date (1173 sites) for patients with relapsed/refractory solid tumors, lymphomas and myelomas, assigning rational targeted therapy based on individual tumor molecular alterations. Patients with mismatch repair-deficiency (MMR-d) may benefit from immune checkpoint inhibitor therapy secondary to increased mutational burden compared to MMR-proficient tumors. The anti-PD-1 inhibitor nivolumab has previously shown antitumor activity in MMR-d colorectal cancer; we hypothesized that nivolumab would have activity in patients with non-colorectal MMR-d cancers.
Eligibility for NCI-MATCH included relapsed/refractory cancers, good end-organ function, and ECOG performance status of ≤ 1. Patients enrolled were screened for molecular alterations by centralized testing on fresh biopsy tissue. MMR-d was defined by loss of nuclear expression of MLH1 or MSH2 by immunohistochemistry. Patients with MMR-d colorectal cancer were excluded. Patients received nivolumab 3 mg/kg q2weeks (28-day cycles) and 480 mg q4weeks past cycle 4. Disease reassessment was performed q2cycles. The primary endpoint of the study was RECIST 1.1 overall response rate (ORR). 35 enrolled patients were planned with the ORR compared against a null value of 5%. If the observed ORR was ≥5/31 (16%), the agent would be considered promising and worthy of further testing. The proposed design had power of 91.8% to find an agent promising assuming true OR rate was 0.25.
4864 enrolled patients had interpretable results for MMR-d. 99 patients were MMR-d, 63 patients were assigned to nivolumab treatment, and 47 patients were treated (35:preplanned and 12:expansion). We report the preliminary results of the first 35 enrolled (70% MLH1 loss, 30% MSH2 loss). Minimum follow-up time for all patients was >6 months, median age was 60 y/o, and median prior therapies was 3. Common histologies included endometrioid endometrial (EEA: 10), prostate (6), and breast (3) cancer. 10 pts remain on treatment; 7 stopped treatment for AEs; 12 for progressive disease. The confirmed ORR was 24% (8/33 patients) with an additional 9/33 (27%) patients with stable disease. Three additional patients had unconfirmed responses [PD at next scan(1), off study prior to reassessment(1), and no follow-up scan yet(1)]. The disease histologies for the PR were prostate(3), EEA(2), breast(1), parathyroid(1), and gallbladder cancer(1). Estimated 6-month PFS was 43% and median OS has not been reached at this early time-point. Toxicity was predominantly low-grade.
We report the first results of a substudy of the NCI-MATCH trial. Nivolumab has promising activity in MMR-d, non-colorectal cancers.
O38 Nivolumab + Ipilimumab (N+I) vs Sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (aRCC): results from CheckMate 214, including overall survival by subgroups
Robert J. Motzer1, Nizar M. Tannir2, David F. McDermott3, Osvaldo Arén Frontera4, Bohuslav Melichar5, Elizabeth R. Plimack6, Philippe Barthelemy7, Saby George8, Victoria Neiman9, Camillo Porta10, Toni K. Choueiri11, Thomas Powles12, Frede Donskov13, Pamela Salman14, Christian K. Kollmannsberger15, Brian Rini16, Sabeen Mekan17, M. Brent McHenry17, Megan Wind-Rotolo17, Hans J. Hammers18, Bernard Escudier19
1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2University of Texas, MD Anderson Cancer Center Hospital, Houston, TX, USA; 3Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA; 4Centro Internacional de Estudios Clinicos, Santiago, Chile; 5Palacky University, and University Hospital Olomouc, Olomouc, Czech Republic; 6Fox Chase Cancer Center, Philadelphia, PA, USA; 7Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 8Roswell Park Cancer Institute, Buffalo, NY, USA; 9Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel, and Tel Aviv University, Tel Aviv, Israel; 10IRCCS San Matteo University Hospital Foundation, Pavia, Italy; 11Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA; 12Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London, UK; 13Aarhus University Hospital, Aarhus, Denmark; 14Fundación Arturo López Pérez, Santiago, Chile; 15British Columbia Cancer Agency, Vancouver, British Columbia, Canada; 16Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 17Bristol-Myers Squibb, Princeton, NJ, USA; 18Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA; 19Gustave Roussy, Villejuif, France
Correspondence: Robert J. Motzer (email@example.com)
We report results from the phase III CheckMate 214 study of N+I versus S for treatment-naïve aRCC.
Adults with clear-cell aRCC, measurable disease, Karnofsky performance status ≥70, and available tumor tissue were eligible. Patients were randomized 1:1 (stratified by IMDC score; region) to N 3 mg/kg + I 1mg/kg every 3 weeks for four doses followed by N 3 mg/kg every 2 weeks, or S 50 mg daily orally for 4 weeks (6-week cycles). Co-primary endpoints were objective response rate (ORR), progression-free survival (PFS) per independent committee (IRRC), and overall survival (OS), all in intermediate- and poor-risk patients. Overall α for treatment effect was 0.05 (allocated as 0.001 ORR, 0.009 PFS, 0.04 OS).
1,096 patients were randomized (N+I: n=550; S: n=546); 425 (N+I) and 422 (S) with intermediate/poor risk. With ~17.5 months minimum follow-up, confirmed ORR in intermediate/poor-risk patients was 41.6% (9.4% complete response [CR]) vs 26.5% (1.2% CR) for N+I vs S (P<0.0001); median duration of response was not reached (NR; 95% CI, 21.82-NR) vs 18.2 months (95% CI, 14.82-NR), respectively (Table 1). Median PFS with N+I vs S in intermediate/poor-risk patients was 11.6 vs 8.4 months (hazard ratio [HR] 0.82, P=0.0331, Table 1). At the first prespecified interim OS analysis, the Data Monitoring Committee recommended stopping the study early for statistically significant superiority in OS with N+I vs S (median not reached vs 26.0 months [HR 0.63], P<0.0001, Table 1). ORR favored N+I over S in intermediate/poor-risk patients irrespective of baseline tumor PD-L1 expression, while a PFS benefit with N+I vs S was seen only in patients with PD-L1 ≥1%. OS favored N+I over S across all prespecified subgroups (data to be presented), including baseline PD-L1 expression status. In all treated patients, drug-related AEs occurred in 509/547 (93% any grade, 46% grade 3-4) with N+I vs 521/535 (97% any grade, 63% grade 3-5) with S, including 22% vs 12% with AEs leading to discontinuation. Death occurred in 159 N+I arm patients (7 [1%] drug-related) and 202 S arm patients (4 [1%] drug-related).
This phase III study showed statistically significant OS benefit, significantly higher ORR, and numerically longer PFS for N+I vs S with a manageable safety profile in intermediate- and poor-risk patients with aRCC, supporting the use of N+I as a new first-line standard-of-care treatment option for these patients. OS benefit with N+I was seen irrespective of baseline PD-L1 status and was observed consistently across other subgroups.
ClinicalTrials.gov Identifier: NCT02231749
O39 Phase I study of E7046, a novel PGE2 receptor type 4 inhibitor, in patients with advanced solid tumors with high myeloid infiltrate: effects on myeloid- and T-lymphoid cell-mediated immunosuppression
Aurelien Marabelle1, Aparna Parikh2, Geoffrey Shapiro3, Andrea Vargas1, Aung Naing4, Funda Meric-Bernstam4, Larisa Reyderman5, Xingfeng Bao5, Terri Binder5, Min Ren5, Amy Siu5, Lucy Xu5, Mingjie Liu5, Satish Dayal5, Vijay Bhagawati-Prasad5, Ilian Tchakov5, Takashi Owa5, Chean Eng. Ooi5, David Sanghyun Hong4
1Gustave Roussy Institute, Villejuif, France; 2Massachusetts General Hospital, Boston, MA, USA; 3Dana-Farber Cancer Institute, Boston, MA, USA; 4The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5Eisai Inc., Woodcliff Lake, NJ, USA
Correspondence: Larisa Reyderman (firstname.lastname@example.org)
E7046 is a selective inhibitor of the prostaglandin E2 (PGE2) receptor-type-4, EP4, which transduces potent immunosuppressive activity of PGE2 in both myeloid cells and T-lymphoid cells in the tumor microenvironment. In preclinical studies, E7046 reversed PGE2-mediated inhibition of monocyte differentiation towards anti-tumorigenic antigen presenting cells and facilitated tumoral recruitment and activation of cytotoxic T-cells. Here, we present initial clinical, pharmacokinetic and pharmacodynamic results from a first-in-human study of single agent E7046 in patients with selected cancer types having high myeloid cell infiltration.
E7046 was administered orally, once-daily, in 21-day cycles in sequential dose-escalating cohorts of 6 pts each at 125, 250, 500 and 750mg. Tumor responses were evaluated by irRECIST and metabolic responses by 18FDG-PET. Modulation of immune response was assessed in pre- and post-treatment tumor biopsies by immunohistochemistry, and in blood samples by TaqMan Low Density Array and Meso Scale Discovery assays. Blood samples were collected for PK analysis.
Thirty patients were treated with no dose-limiting toxicities observed. The most common adverse events were fatigue (37%), diarrhea (33%), and nausea (30%). Grade 3/4 AEs in >1 patient were abdominal pain (3 patients, at 250 mg, 750 mg) and vomiting (2 patients, at 125 mg, 250 mg). Grade 3/4 treatment-related AEs occurred in 4 patients (rash in 2 patients, and diarrhea, allergic reaction, anaphylaxis, hypersensitivity, and hyperuricemia, in 1 patient each). Four patients discontinued treatment due to an AE (bowel obstruction, allergic reaction, abdominal pain, acute renal failure). No objective tumor responses were reported. Duration of treatment of ≥20 wks with best response of stable disease (SD) was observed in 5 patients, 3 of these had partial metabolic responses. E7046 exposure was dose-proportional up to the 500 mg dose with a plateau at 750 mg. Elimination half-life (11 hr) justified once-daily dosing. Treatment with E7046 significantly increased tumor CD3+ and CD8+ T-cell infiltration and expression of the T-effector cell-recruiting chemokine CXCL10 in blood. Gene expression analysis in blood showed modulation of EP4 signaling genes (including IDO1, EOMES, PD-L1). Longer duration of therapy with SD was associated with higher baseline tumor infiltrate of CD8+ T-cells and CD163+ macrophages.
E7046 demonstrated favorable tolerability profile with preliminary evidence of anti-tumor activity and immune modulation in tumor and peripheral blood. MTD was not reached. Further studies testing E7046 in combination with other agents are planned.
O40 Interim safety analysis of Cancer Immunotherapy Trials Network – 12 (CITN-12): A phase 1 study of Pembrolizumab in patients with HIV and relapsed, refractory or disseminated malignancies
Thomas S. Uldrick1, Priscila H. Gonçalves1, Steven P. Fling2, Karen Aleman1, Brinda Emu3, Marc S. Ernstoff4, Ashley Jackson4, Judith Kaiser2, Holbrook E. Kohrt5, Andreanne Lacroix2, Matthew Lindsley1, Lisa M. Lundgren2, Kathryn Lurain1, Matthew Madura3, James S. Outland6, Chris Parsons6, Elad Sharon1, Robert Yarchoan1, Martin A. “Mac” Cheever2
1National Cancer Institute, Bethesda, MD, USA; 2Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 3Yale University, New Haven, CT, USA; 4Roswell Park Cancer Institute, Buffalo, NY, USA; 5Stanford University, Palo Alto, CA, USA; 6Louisiana State University Health Science Center, New Orleans, LA, USA
Correspondence: Thomas S. Uldrick (email@example.com)
Anti-PD-1 and anti-PD-L1 antibodies are approved for multiple indications and are becoming mainstays of cancer therapy. However, patients with HIV have been excluded from clinical trials evaluating these agents largely due to safety concerns.
CITN-12 is a multicenter study of pembrolizumab in patients with HIV and advanced cancers not curable by standard therapies. Three parallel cohorts are accruing based on CD4+ counts; 1: 100-199, 2: 200-350, and 3: >350 cells/uL. Additional eligibility criteria: >4 weeks antiretroviral therapy (ART), HIV viral load <200 copies/mL, no uncontrolled infections including hepatitis B and C, ECOG performance status 0-1. Treatment: pembrolizumab 200mg intravenously every 3 weeks for up to 2 years. The primary objective is to assess safety and tolerability by summarizing adverse events (AEs) graded by CTCAEv4 and evaluating HIV viral load and CD4+ counts. Immune mediated adverse events are managed using standard guidelines. We performed an interim analysis of treatment emergent adverse events at least possibly related to pembrolizumab (rTEAEs), serious AEs, and HIV viral load and CD4+ counts on therapy.
17 patients; Cohort 1 (4), Cohort 2 (9), Cohort 3 (4); were accrued starting April 2016 and followed through May 2017. Characteristics: 1 woman, 16 men; median age 56 years (range 43-77); white (13), African American (3), Hispanic (1); HIV viral load <20 copies/mL (94%). Cancers: non-Hodgkin lymphoma (3), Kaposi sarcoma (1), anal cancer (5), head and neck (1), lung (2), bladder (1), hepatocellular (1), pancreatic (1), cholangiocarcinoma (1). Median number prior therapies 1 (range 0-4), prior radiation (71%). Safety observed over a total of 100 cycles, median 4 (range 1-20). 82 rTEAEs were observed and comparable between cohorts. 93% were grade 1-2. Ten primary serious AEs were observed, 2 possibly attributable to pembrolizumab, both occurring in the setting of progressive malignancy. Immune mediated AEs managed with levothyroxine or prednisone included subclinical hypothyroidism 6 (35%), pneumonitis (2) and liver test elevations (2). Median CD4+ counts increased over time, changes did not reach statistical significance. HIV remained suppressed on ART in all patients.
Pembrolizumab has an acceptable safety profile to date in CITN-12. Standard therapy with anti-PD1 is appropriate for FDA-approved indications in patients with HIV. Patients with HIV who meet appropriate immune eligibility criteria for a given cancer should be included in immunotherapy studies. Further evaluation of checkpoint inhibitors in HIV-associated tumors is justified.
Combination Therapy (IO/IO, IO/Standard of Care, IO/Other)
O41 Preliminary antitumor and immunomodulatory activity of BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, in combination with nivolumab in patients with advanced cancers
Jason J. Luke1, Karen Gelmon2, Russell K. Pachynski3, Jayesh Desai4, Victor Moreno5, Josep M. Tabernero6, Carlos A. Gomez-Roca7, Quincy Chu8, Paul Basciano9, Penny Phillips9, Li Zhu9, Zhaohui Liu9, Lillian L. Siu10
1University of Chicago Medical Center, Chicago, IL, USA; 2University of British Columbia, BC Cancer Agency, Vancouver, British Columbia, Canada; 3Washington University School of Medicine, St. Louis, MO, USA; 4Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia; 5START Madrid-FJD, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; 6Vall d’Hebron University Hospital, Barcelona, Spain; 7Institut Universitaire du Cancer, Oncopole, Toulouse, France; 8Cross Cancer Institute, University of Alberta/Alberta Health Services, Edmonton, Alberta, Canada; 9Bristol-Myers Squibb, Princeton, NJ, USA; 10Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Correspondence: Jason J. Luke (firstname.lastname@example.org)
Checkpoint inhibitors have transformed cancer care, but extending those benefits to more patients requires additional approaches. IDO1 allows tumor escape through kynurenine production, which decreases immune cell tumor infiltration/function and increases regulatory T-cell numbers. Anti─PD-1 treatment upregulates IDO1, supporting a rationale for combining nivolumab (anti–PD-1) with an IDO1 inhibitor. BMS-986205 is a selective, potent, once-daily, oral IDO1 inhibitor with a potentially best-in-class pharmacokinetic/pharmacodynamic/safety profile in combination with nivolumab that was previously disclosed (NCT02658890) . Here we present updated safety and preliminary efficacy and pharmacodynamic data.
Dose-escalation methods were previously described . During cohort expansion in this phase 1/2a open-label study, patients with advanced cancers were treated with BMS-986205 100 or 200 mg orally once daily + nivolumab 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety, preliminary antitumor activity, and pharmacodynamics (including immunomodulatory assays).
As of the July 20, 2017, data cutoff, safety data were available for 216 patients across the study. Maximum tolerated dose during escalation was 200 mg; at 400 mg, 2/4 patients experienced dose-limiting toxicities (grade 3 AST/ALT increased; grade 2 anemia, fatigue). Treatment-related AEs occurred in 47% of patients (11% grade 3/4), and 4 patients (2%) discontinued due to study drug toxicity; the safety profile was generally consistent with that previously reported for nivolumab monotherapy. In the bladder cancer cohort, among 15 heavily pretreated patients (39% received ≥2 prior regimens), 5 partial responses (PRs), 3 stable disease (SD), and 6 progressive disease (PD, including a patient with prior anti–PD-[L]1 therapy) were reported, with 1 death prior to assessment. In the cervical cancer cohort, among 17 heavily pretreated patients (52% received ≥2 prior regimens), 3 PRs, 5 SD, and 7 PD were reported, with 2 deaths prior to assessment. Within 39 paired pre- vs on-treatment tumor samples across various tumor types, BMS-986205 plus nivolumab decreased kynurenine and increased the percentage of proliferating CD8+ T cells.
BMS-986205 plus nivolumab was well tolerated, increased proliferating CD8+ T cells in tumors, and demonstrated preliminary antitumor activity. Updated efficacy, safety, and pharmacodynamic data will be presented.
1. Siu L, et al. AACR 2017, abstract CT116.
O42 First-in-human phase 1 dose escalation and expansion of a novel combination, anti–CSF-1 receptor (cabiralizumab) plus anti–PD-1 (nivolumab), in patients with advanced solid tumors
Zev Wainberg1, Sarina Piha-Paul2, Jason Luke3, Edward Kim4, John Thompson5, Nicklas Pfanzelter6, Michael Gordon7, Drew Rasco8, Amy Weise9, F. Stephen Hodi10, Sandeep Inamdar11, Serena Perna12, Christy Ma11, Janine Powers11, Michael Carleton12, Hong Xiang11, Lei Zhou11, Helen Collins11, Yeonju Lee11, James Lee13, Jennifer Johnson14, Carolyn Britten15, Majid Ghoddusi11
1UCLA School of Medicine, Santa Monica, CA, USA; 2The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3The University of Chicago Medicine, Chicago, IL, USA; 4UC Davis Comprehensive Cancer Center, Sacramento, CA, USA; 5Seattle Cancer Center Alliance, Seattle, Washington, CA, USA; 6Rush University Medical Center, Chicago, IL, USA; 7HonorHealth Scottsdale Shea Medical Center, Scottsdale, AZ, USA; 8South Texas Accelerated Research Therapeutics, San Antonio, TX, USA; 9Karmanos Cancer Center, Detroit, MI, USA; 10Dana-Farber Cancer Institute, Boston, MA, USA; 11FivePrime Therapeutics, South San Francisco, CA, USA; 12Bristol-Myers Squibb, Lawrenceville, NJ, USA; 13University of Pittsburg Medical Center, Pittsburg, PA, USA; 14Thomas Jefferson University Hospital, Philadelphia, PA, USA; 15Medical University of South Carolina, Charleston, SC, USA
Correspondence: Sandeep Inamdar (email@example.com)
Resistance to immunotherapy may be related to activity of several immunosuppressive cell types. Depletion of tumor-associated macrophages (TAMs) may promote a pro-inflammatory state, increasing antitumor T-cell responses. Cabiralizumab, a humanized IgG4 monoclonal antibody, binds to CSF-1 receptor and blocks cytokine signaling that is needed for TAM activation and survival, leading to TAM depletion. The combination of cabiralizumab plus anti–PD-1 may work synergistically by modifying the immunosuppressive tumor environment while simultaneously suppressing the PD-1 checkpoint pathway. This is the first clinical disclosure of safety, pharmacokinetics, and pharmacodynamics of this novel combination, along with preliminary evidence of antitumor activity in pancreatic cancer (NCT02526017).
In phase 1a dose escalation, patients with advanced solid tumors were treated with cabiralizumab 1, 2, 4, and 6 mg/kg alone or combined with nivolumab 3 mg/kg, both given IV Q2W, in a 3+3+3 design.
As of August 1, 2017, 205 patients were treated with the combination. Most received cabiralizumab 4 mg/kg Q2W plus nivolumab 3 mg/kg Q2W. Cabiralizumab, alone or with nivolumab, demonstrated target-mediated clearance and dose-dependent increase in exposure, and pharmacodynamic activity as evidenced by reduced circulating CD14+ CD16+ nonclassical monocytes. Grade 3–5 treatment-related AEs (TRAEs) attributed to cabiralizumab occurred in 43% of patients, with 13% of patients discontinuing due to AEs. Elevations in creatinine phosphokinase (14%) and AST (5%) were among the most common grade 3 TRAEs but were secondary to cabiralizumab’s depletion of macrophages, which would otherwise metabolize these enzymes, and were reversible without significant clinical sequelae. Among the cohort of prior chemotherapy–treated and immunotherapy-naive patients with pancreatic cancer, 31 were efficacy evaluable. There were 3 confirmed partial responses in microsatellite-stable patients (293, 275+, and 168+ days on study) and 1 prolonged stable disease (182 days); 1 patient treated beyond progressive disease experienced >40% reduction in baseline target lesions (247 days on study). The 6-month disease control rate was 13%, and objective response rate was 10%. Studies in a larger pancreatic cohort and other tumor types are ongoing, and preliminary translational biomarker data will be presented.
Cabiralizumab plus nivolumab, a mechanistically novel immunotherapy combination, demonstrated a tolerable safety profile across several cohorts and promising preliminary antitumor activity in pancreatic cancer. These results also show a potential immunotherapeutic strategy to treat patients with tumors resistant to anti–PD-1 blockade.
Tumor Microenvironment (Mechanisms and Therapies)
O43 Monotherapy dose escalation clinical and translational data from first-in-human study in advanced solid tumors of IPI-549, an oral, selective, PI3K-gamma inhibitor targeting tumor macrophages
David Hong1, Anthony Tolcher2, Ryan Sullivan3, Geoffrey Shapiro4, Bartosz Chmielowski5, Antoni Ribas5, Les Brail6, Joseph Pearlberg6, Suresh Mahabhashyam6, Lucy Lee6, Claudio Dansky Ullmann6, Brenda O'Connell6, Jeffery Kutok6, Michael Postow7, Jedd Wolchok7
1UT MD Anderson Cancer Center, Houston, TX, USA; 2START, San Antonio, TX, USA; 3Massachusetts General Hospital, Boston, MA, USA; 4Dana Farber Cancer Institute, Boston, MA, USA; 5University of California, Los Angeles, Santa Monica, CA, USA; 6Infinity Pharmaceuticals, Inc., Cambridge, MA, USA; 7Memorial Sloan Kettering Cancer Center, New York, NY, USA
Correspondence: Jeffery Kutok (firstname.lastname@example.org)
IPI-549 is a potential first-in-class, oral, selective PI3K-gamma inhibitor being developed as an immuno-oncology therapeutic in multiple cancer indications. Preclinical research demonstrated that IPI-549 results in transcriptional reprogramming M2, pro-tumor macrophages to the M1, anti-tumor phenotype. In preclinical tumor models, IPI-549 was active as a monotherapy and was able to overcome checkpoint inhibitor (CPI) resistance in CPI-insensitive models. These preclinical data provide a strong rationale for the ongoing Phase 1/1b study.
This study (NCT02637531) is being conducted to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics to determine the recommended dose and activity of IPI-549 as monotherapy and in combination with nivolumab in patients with advanced solid tumors. The study design includes four parts: 1) monotherapy dose escalation 2) combination dose escalation of IPI-549 with nivolumab 3) monotherapy expansion, and 4) combination expansion in specific tumor types with de novo or acquired resistance to checkpoint inhibitors. Pre- and on-treatment blood samples are being obtained in all patients to perform flow cytometry, gene expression, and serum cytokine and chemokine analysis to better understand the biological effect of IPI-549 on immune cells and to identify correlations with any clinical response. Pre- and on-treatment biopsies are being mandated in the expansion cohorts to evaluate the effect of IPI-549 on the tumor microenvironment.
A total of 19 patients have been enrolled (18 evaluable) in the monotherapy dose escalation phase (10, 15, 20, 30, 40, 60 mg qd). No DLTs, or drug related SAEs have been observed. The majority of treatment-emergent adverse events were low grade (grade 1-2). The most common (≥2 patients) drug related treatment-emergent adverse events are alanine aminotransferase increase, rash maculo-papular, white blood cell count decrease, and headache. Durable clinical benefit has been observed, with 8 patients able to remain on treatment ≥16 weeks, including 2 patients on study for ≥52 weeks. The PK profile of IPI-549 has favorable characteristics including dose proportionality. PD analysis demonstrates full and sustained suppression of PI3K-γ at 60 mg qd. Translational studies performed on peripheral blood demonstrated increased activation of circulating myeloid cells in patient subsets, as well as, evidence of interferon-gamma mediated immune stimulation after IPI-549 treatment. Detailed PK, PD, translational, safety, and efficacy data will be presented.
The monotherapy dose escalation has completed enrollment, demonstrating favorable tolerability, evidence of immune modulation, and PK/PD defining 60 mg qd as the monotherapy expansion dose. The monotherapy expansion phase in solid tumors is actively enrolling.