Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an ...immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling
. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8
T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.
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Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) ...signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody–containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee–assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ≥1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval CI, 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ≥3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit–risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628.
•Single-agent ibrutinib induced durable remissions (ORR 48%) with a favorable benefit–risk profile in patients with previously treated MZL.•Inhibition of BCR signaling with ibrutinib provides a treatment option without chemotherapy for an MZL population with high unmet need.
The two major subtypes of diffuse large B cell lymphoma (DLBCL)--activated B cell-like (ABC) and germinal center B cell-like (GCB)--arise by distinct mechanisms, with ABC selectively acquiring ...mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling. The ABC subtype has a ∼40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies. We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling. In a phase 1/2 clinical trial that involved 80 subjects with relapsed or refractory DLBCL, ibrutinib produced complete or partial responses in 37% (14/38) of those with ABC DLBCL, but in only 5% (1/20) of subjects with GCB DLBCL (P = 0.0106). ABC tumors with BCR mutations responded to ibrutinib frequently (5/9; 55.5%), especially those with concomitant myeloid differentiation primary response 88 (MYD88) mutations (4/5; 80%), a result that is consistent with in vitro cooperation between the BCR and MYD88 pathways. However, the highest number of responses occurred in ABC tumors that lacked BCR mutations (9/29; 31%), suggesting that oncogenic BCR signaling in ABC does not require BCR mutations and might be initiated by non-genetic mechanisms. These results support the selective development of ibrutinib for the treatment of ABC DLBCL.
Type 2 Diabetes Mellitus (T2DM) is characterized by impaired glycemic control caused by insulin resistance and progressive beta cell failure. Menin, a scaffold protein, drives beta cell proliferation ...when inhibited. We have reported BMF-219, an oral covalent menin inhibitor, elicits durable glycemic control following a short treatment in a ZDF Rat model. COVALENT-111, a randomized, double-blind, placebo-controlled study is evaluating BMF-219 in healthy adults and adults with T2DM diagnosed ≤15 yrs (NCT05731544). Here we report initial results from the first cohort of T2DM patients treated with BMF-219. Patients with poor glycemic control (HbA1C ≥7%) on their current antidiabetic regimen were enrolled. Twelve patients were randomized 5:1 (10 BMF-219, 2 placebo) to receive 100 mg QD for 4 weeks while continuing their existing treatment. BMF-219 was well tolerated; no subjects discontinued treatment or exited the trial during the 4-week treatment and all subjects continue in follow-up to assess durability of the treatment effect. There were no dose reductions, SAEs, or severe AEs. All TRAEs were mild and observed in 3 of 12 subjects. No subjects showed symptomatic hypoglycemia. These data demonstrate preliminary proof of concept for the novel disease-modifying effect of BMF-219 in T2DM. Enrollment is ongoing at higher doses; additional follow-up data will be presented.
Disclosure
J. E. Rodriguez: None. A. Abitbol: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Dexcom, Inc., Novo Nordisk Canada Inc., Janssen Pharmaceuticals, Inc., Research Support; Abbott Diabetes, Lilly Diabetes, Zucara Therapeutics, Novo Nordisk Canada Inc., Moderna, Inc., Senseonics, Speaker's Bureau; Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Amgen Canada, Dexcom, Inc., Novo Nordisk Canada Inc., HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi. F. Abuzgaya: None. C. Perez: None. S. Mourya: Employee; Biomea Fusion, Inc. B. Munneke: Employee; Biomea Fusion, Inc., Corvus Pharmaceuticals. S. W. Morris: Employee; Biomea Fusion, Inc. T. Butler: Board Member; Biomea Fusion, Inc., Employee; Biomea Fusion, Inc., Stock/Shareholder; Biomea Fusion, Inc.
Funding
Not applicable
Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia (CLL) but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved ...response and progression-free survival (PFS) when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/small lymphocytic lymphoma (SLL), prolymphocytic leukemia, or Richter's transformation who failed ≥2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n = 27), concurrent start (group 2; n = 20), or ofatumumab lead-in (group 3; n = 24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates in CLL/SLL patients (n = 66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFSs for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib and with durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01217749.
•Ibrutinib combined with ofatumumab in relapsed CLL had had an ORR of 83% with median time to response of <3 months in all groups.•All 3 sequences of administration were acceptably tolerated and active; responses were durable, and median PFS was not yet reached.
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Background:
Marginal zone lymphoma (MZL) accounts for approximately 10% of cases of non-Hodgkin's lymphoma (NHL). Rituximab in combination with chemotherapy has substantially improved treatment ...outcomes, but relapse is common. Although therapies for indolent NHL are FDA approved, no agents are specifically approved for the treatment of MZL. Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase (BTK), is indicated by the US FDA for the treatment of patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including CLL/SLL with del17p, mantle cell lymphoma with at least one prior therapy, and Waldenstrom's macroglobulinemia, and allows for treatment without chemotherapy. MZL is often linked to chronic infection, which can induce B-cell receptor signaling, resulting in aberrant B-cell growth and survival. By blocking BTK, a critical component of B-cell receptor signaling, ibrutinib may be an ideal therapy for the treatment of MZL. This study evaluated the efficacy and safety of single-agent ibrutinib in pts with relapsed/refractory (R/R) MZL.
Methods:
Pts had histologically confirmed MZL, ECOG PS of ≤2, life expectancy >3 months (mo) and had previously received ≥1 prior therapy including at least one CD20 monoclonal antibody (mAb)-containing regimen or monotherapy rituximab (RTX). All pts received ibrutinib 560 mg orally once daily until progression or unacceptable toxicity. The primary study endpoint was overall response rate (ORR) as assessed by an independent review committee (IRC) according to 2007 IWG criteria. ORR by investigator assessment is reported here, and ORR by IRC is forthcoming. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
Results:
Sixty-three pts (extranodal n=32, nodal n=17, and splenic n=14) were enrolled. Median age was 66 years (range, 30-92); 92% had ECOG PS of 0-1. Median number of prior systemic therapies was 2 (range, 1-9) with 35% receiving ≥3 prior therapies. Four (6%) pts had a prior splenectomy, and 9 (14%) pts received prior radiotherapy. Seventeen pts (27%) had received only monotherapy RTX, and 40 (64%) had received at least one CD20 mAb-containing chemoimmunotherapy regimen; 33% of the pts had bone marrow involvement. The median time on study was 16.6 mo, and the median duration of therapy 11.7 mo. Per investigator assessment, ORR was 51% (6 CRs and 26 PRs). Thirty-eight percent of total pts had stable disease (SD), and the clinical benefit rate (CR+PR+SD) was 89%, with 87% having some tumor reduction (Figure). The overall median DOR was 19 mo (95% CI: 8.0-not reached NR). The median time to initial response was 4.2 mo, and the median PFS was 18 mo (95% CI: 12.2-NR). The most common adverse events (AEs ≥20%) of any grade included: fatigue (44%), diarrhea (43%), anemia (35%), nausea and thrombocytopenia (25% each), peripheral edema (24%), cough and arthralgia (22% each), dyspnea and URTI (21% each). Grade ≥3 AEs occurred in 40 pts (63%). The most common events were anemia (14%), pneumonia (8%), and fatigue (6%). Serious AEs of any grade occurred in 28 pts (44%), with grade 3/4 pneumonia being the most common AE (5 pts 8%). Atrial fibrillation occurred in 4 pts (6%; all grade 1/2). Any-grade bleeding events occurred in 57% of pts, with 1 grade 3 event of hematemesis and 1 grade 5 cerebral hemorrhage. Three treatment-emergent AEs resulted in death due to disease progression, cerebral hemorrhage, and parainfluenza virus infection leading to multiple organ failure. Overall, 38 pts (60%) discontinued treatment (PD: 30%; AEs: 19%, pt decision: 5%; physician decision: 6%) and 40% continue treatment. The most common AE leading to treatment discontinuation was diarrhea in 2 pts (3%). At least 2 pts appeared to have experienced pseudoprogression at weeks 9 and 13, respectively, confirmed by further follow up.
Conclusions:
Single-agent ibrutinib achieved a high ORR and durable responses, and produced clinically meaningful tumor shrinkage yielding a high clinical benefit rate. Overall, the treatment was well tolerated. These results support BTK signaling blockade via single-agent ibrutinib as an effective, chemotherapy-free targeted strategy for R/R MZL.
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Noy:Pharmacyclics, LLC, an AbbVie Company: Other: travel, accommodations, expenses, Research Funding. Thieblemont:Roche: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Martin:Novartis: Consultancy; Celgene: Consultancy, Honoraria; Teva: Research Funding; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Gilead: Consultancy, Other: travel, accommodations, expenses; Acerta: Consultancy. Flowers:Infinity: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; NIH: Research Funding; Millenium/Takeda: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Mayo Clinic: Research Funding; ECOG: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Janssen: Honoraria; Gilead Sciences: Consultancy, Honoraria. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Ma:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding; Xeme: Research Funding; AbbVie: Research Funding. Coleman:Celgene: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Pfizer: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding; Immunomedies: Equity Ownership, Other: Leadership; AbbVie: Equity Ownership; Karyoharm: Research Funding. Peles:Takeda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Novartis: Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Celgene: Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Onyx: Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; SGN: Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Florida Cancer Specialists: Employment, Equity Ownership. Smith:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: travel, accommodations, expenses. Munneke:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: travel, accommodations, expenses. Dimery:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: travel, accommodations, expenses. Beaupre:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: travel, accommodations, expenses, Leadership, Patents & Royalties, Research Funding. Chen:Merck: Consultancy, Research Funding; Genentech: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau.