RESUMO
Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.
Assuntos
Carcinoma Ductal Pancreático/genética , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Neoplasias Pancreáticas/genética , Células Estreladas do Pâncreas/metabolismo , Evasão Tumoral/efeitos dos fármacos , Aloenxertos , Animais , Antineoplásicos/farmacologia , Carbono/imunologia , Carbono/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Linhagem Celular Tumoral , Formiatos/imunologia , Formiatos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Interferon gama/genética , Interferon gama/imunologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Oximas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Células Estreladas do Pâncreas/efeitos dos fármacos , Células Estreladas do Pâncreas/imunologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Serina/imunologia , Serina/metabolismo , Serina/farmacologia , Transdução de Sinais , Sulfonamidas/farmacologia , Triptofano/imunologia , Triptofano/metabolismo , Triptofano/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologiaRESUMO
BACKGROUND: The combination of the checkpoint inhibitor (CPI) pembrolizumab and platinum-based chemotherapy is effective frontline therapy for advanced non-small cell lung cancer (NSCLC) lacking targetable mutations. Indoleamine 2,3- dioxygenase 1 (IDO1), an enzyme involved in kynurenine production, inhibits immune responses. Inhibition of IDO1 may restore antitumor immunity and augment CPI activity. This trial evaluated addition of epacadostat, a potent and highly selective IDO1 inhibitor, to pembrolizumab and chemotherapy for metastatic NSCLC. METHODS: ECHO-306/KEYNOTE-715 was a partial double-blind, randomized phase II study of adults with treatment-naïve stage IV NSCLC not indicated for EGFR-, ALK-, or ROS1-directed therapy. Patients were randomized to one of three treatment arms: epacadostat-pembrolizumab-chemotherapy (E + P + C; blinded), epacadostat-pembrolizumab (E + P; open-label) or placebo-pembrolizumab-chemotherapy (PBO + P + C; blinded). Stratification was by PD-L1 tumor proportion score (< 50% vs. ≥ 50%) and tumor histology (non-squamous vs. squamous). A protocol amendment closed enrollment in the open-label E + P group, excluding it from efficacy analyses. Intravenous pembrolizumab (200 mg) was administered every 21 days and epacadostat 100 mg or matching placebo (oral) twice daily (BID) for ≤ 35 3-week cycles. The primary objective was objective response rate (ORR) for E + P + C vs. PBO + P + C. RESULTS: 178 patients were randomized to E + P + C (n = 91) or PBO + P + C (n = 87); 55 were enrolled in the E + P group. The E + P + C group had a lower confirmed ORR (26.4%; 95% CI 17.7-36.7) than the PBO + P + C group (44.8%; 95% CI 34.1-55.9), with a difference of - 18.5% (95% CI - 32.0 - (- 4.3); one-sided P = 0.9948). The E + P + C group had a numerically higher percentage of confirmed responders with extended response ≥ 6 months (29.2% vs. 15.4%). Circulating kynurenine levels at C1D1 were similar to those at C2D1 in all treatment groups and were not reduced to normal levels with epacadostat 100 mg BID plus P + C. The safety profile of E + P + C was consistent with that for PBO + P + C. CONCLUSIONS: Addition of epacadostat 100 mg BID to pembrolizumab and platinum-based chemotherapy was generally well tolerated but did not improve ORR in patients with treatment-naïve metastatic NSCLC. Evaluating epacadostat doses that normalize circulating kynurenine in combination with CPIs may help determine the clinical potential of this combination. TRIAL REGISTRATION: NCT03322566. Registered October 26, 2017.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Método Duplo-Cego , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Adulto , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , OximasRESUMO
BACKGROUND: Pembrolizumab is a first-line therapy for certain patients with advanced/metastatic non-small cell lung cancer (NSCLC). Combining pembrolizumab with other immunotherapies may enhance tumor cell killing and clinical outcomes. Epacadostat is a selective inhibitor of indoleamine 2,3-dioxygenase 1, an immuno-regulatory enzyme involved in tryptophan to kynurenine metabolism that inhibits T cell-mediated immune responses. METHODS: In this randomized phase II study, patients with metastatic NSCLC expressing high (≥ 50%) programmed death-ligand 1 (PD-L1) levels received pembrolizumab 200 mg every 21 days plus oral epacadostat 100 mg twice daily (combination) or matching placebo (control). The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety/tolerability. RESULTS: 154 patients were randomized (77 per group). Median (range) follow-up was 6.8 months (0.1-11.4) and 7.0 months (0.2-11.9) in the combination and control groups, respectively Confirmed ORR was similar between groups (combination: 32.5%, 95% CI 22.2-44.1; control: 39.0%, 95% CI 28.0-50.8; difference: - 6.5, 95% CI - 21.5 to 8.7; 1-sided P = 0.8000). Median (range) DOR was 6.2 months (1.9 + to 6.5 +) and not reached (1.9 + to 8.6 +) in the combination and control groups, respectively. Although not formally tested, median PFS was 6.7 and 6.2 months for the combination and control groups, respectively, and median OS was not reached in either group. Circulating kynurenine levels increased from C1D1 to C2D1 (P < 0.01) in the control group and decreased from C1D1 to C2D1 (P < 0.01) in the combination group but were not normalized in most patients. The most frequent serious adverse events (AEs) (≥ 2%) were pneumonia (4.0%), anemia (2.7%), atelectasis (2.7%) and pneumonitis (2.7%) in the combination group and pneumonia (3.9%), pneumonitis (2.6%) and hypotension (2.6%) in the control group. Two deaths due to drug-related AEs were reported, both in the control group. CONCLUSIONS: Addition of epacadostat to pembrolizumab therapy for PD-L1-high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03322540. Registered 10/26/2017.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Sulfonamidas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Método Duplo-Cego , Antígeno B7-H1/antagonistas & inibidores , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Adulto , Oximas/administração & dosagem , Oximas/uso terapêutico , Oximas/efeitos adversos , Idoso de 80 Anos ou mais , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. METHODS: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. RESULTS: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. CONCLUSIONS: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03260894 .
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais , Indazóis , Neoplasias Renais , Pirimidinas , Sulfonamidas , Sunitinibe , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Sunitinibe/uso terapêutico , Sunitinibe/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Masculino , Feminino , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Idoso , Indazóis/administração & dosagem , Indazóis/uso terapêutico , Adulto , Idoso de 80 Anos ou mais , OximasRESUMO
BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%. METHODS: ECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Target enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35-48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67-29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent. CONCLUSIONS: Epacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03374488. Registered 12/15/2017.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Sulfonamidas , Humanos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Pessoa de Meia-Idade , Método Duplo-Cego , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Oximas/administração & dosagem , Oximas/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Idoso de 80 Anos ou mais , Adulto , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC. METHODS: ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1). RESULTS: A total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%). CONCLUSIONS: Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Sulfonamidas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Cisplatino/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Método Duplo-Cego , Pessoa de Meia-Idade , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Adulto , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , OximasRESUMO
BACKGROUND: Targeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment. METHODS: The open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors. RESULTS: The most common treatment-related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)-naïve patients (16.1%) compared with patients who had received previous CPI (4.1%). Epacadostat pharmacodynamics were evaluated by comparing baseline kynurenine levels with those on therapy at various time points. Only the 300-mg epacadostat dose showed evidence of kynurenine modulation, albeit unsustained. CONCLUSIONS: Epacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. ORR was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested >300 mg epacadostat twice daily is needed to ensure sufficient drug effect. CLINICAL TRIAL INFORMATION: A study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO-203) (NCT02318277).
Assuntos
Segunda Neoplasia Primária , Neoplasias , Adulto , Humanos , Oximas , Sulfonamidas , Anticorpos Monoclonais/efeitos adversos , Neoplasias/patologia , Segunda Neoplasia Primária/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Epacadostat, an oral, selective inhibitor of IDO1, has shown activity when administered with pembrolizumab. We evaluated the addition of chemotherapy to epacadostat and pembrolizumab in patients with advanced or metastatic solid tumors. One proposed mechanism of resistance to PD-1 checkpoint inhibition is through immunosuppression mediated by L-kynurenine. IDO1, indoleamine-2,3-dioxygenase 1 is the rate-limiting enzyme catalyzing the conversion of L-tryptophan to L-kynurenine. If IDO1 is a mechanism of tumor escape from checkpoint inhibition, then addition of an IDO1 inhibitor with a PD-1 checkpoint inhibitor could enable tumor response to immunotherapy. METHODS: Patients received one of 7 tumor-appropriate chemotherapy regimens. Pembrolizumab 200 mg was infused intravenously every 3 weeks. Epacadostat 100 mg was administered orally twice daily. The primary objectives of phase I were determining safety/tolerability and defining the maximum tolerated or pharmacologically active dose of epacadostat. Phase II of the study was designed to enroll efficacy-expansion cohorts and to assess changes in the tumor and tumor microenvironment via mandatory-biopsy cohorts. RESULTS: A total of 70 patients were enrolled. Twelve patients were enrolled in the phase II mandatory-biopsy cohorts. Due to early study closure, efficacy expansion did not enroll. Grades 3 and 4 treatment-emergent adverse events (TEAEs) occurred in 78.6% of patients. Neutropenia and disease progression were the only grades 3 and 4 TEAEs reported in ≥10.0% of patients. One treatment-related death was reported. The ORR was 31.4% across all treatment groups. CONCLUSION: The combination of epacadostat 100 mg bid with pembrolizumab and chemotherapy had an acceptable safety profile. This regimen showed antitumor activity across multiple types of advanced or metastatic solid tumors (ClinicalTrials.gov Identifier: NCT03085914).
Assuntos
Cinurenina , Neoplasias , Humanos , Cinurenina/uso terapêutico , Receptor de Morte Celular Programada 1/uso terapêutico , Neoplasias/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Microambiente TumoralRESUMO
Dendritic cells (DCs) are key regulators of the immune system that shape T cell responses. Regulation of T cell induction by DCs may occur via the intracellular enzyme indoleamine 2,3-dioxygenase 1 (IDO), which catalyzes conversion of the essential amino acid tryptophan into kynurenine. Here, we examined the role of IDO in human peripheral blood plasmacytoid DCs (pDCs), and type 1 and type 2 conventional DCs (cDC1s and cDC2s). Our data demonstrate that under homeostatic conditions, IDO is selectively expressed by cDC1s. IFN-γ or TLR ligation further increases IDO expression in cDC1s and induces modest expression of the enzyme in cDC2s, but not pDCs. IDO expressed by conventional DCs is functionally active as measured by kynurenine production. Furthermore, IDO activity in TLR-stimulated cDC1s and cDC2s inhibits T cell proliferation in settings were DC-T cell cell-cell contact does not play a role. Selective inhibition of IDO1 with epacadostat, an inhibitor currently tested in clinical trials, rescued T cell proliferation without affecting DC maturation status or their ability to cross-present soluble antigen. Our findings provide new insights into the functional specialization of human blood DC subsets and suggest a possible synergistic enhancement of therapeutic efficacy by combining DC-based cancer vaccines with IDO inhibition.
Assuntos
Células Dendríticas/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Linfócitos T/imunologia , Vacinas Anticâncer , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Apresentação Cruzada , Regulação da Expressão Gênica , Homeostase , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Ativação Linfocitária , Terapia de Alvo Molecular , Especificidade de Órgãos , Oximas/farmacologia , Fenótipo , Sulfonamidas/farmacologiaRESUMO
PURPOSE: Part A of the open-label, phase I KEYNOTE-434 study evaluated the safety and tolerability of epacadostat, an indoleamine 2,3-dioxygenase-1 inhibitor, alone and in combination with pembrolizumab in Japanese patients with advanced solid tumors. METHODS: Japanese patients with refractory/recurrent metastatic or locally advanced tumors were enrolled. Cohort 1 received oral epacadostat 25 mg or 100 mg twice daily (BID) and subsequently received epacadostat in combination with intravenous pembrolizumab 200 mg every 3 weeks. Cohort 2 received epacadostat 25 mg or 100 mg BID with pembrolizumab 200 mg every 3 weeks. The primary objective was evaluation of safety and tolerability using a modified toxicity probability interval method. Secondary objectives were pharmacokinetic (PK) and pharmacodynamic profiles of epacadostat alone and in combination with pembrolizumab. RESULTS: Six patients were enrolled in cohort 1 (epacadostat 25 mg, n = 3; epacadostat 100 mg, n = 3); none experienced dose-limiting toxicities (DLTs). Nine patients were enrolled in cohort 2 (epacadostat 25 mg and pembrolizumab, n = 3; epacadostat 100 mg and pembrolizumab, n = 6); one patient receiving epacadostat 100 mg and pembrolizumab experienced grade 4 rhabdomyolysis-a DLT. Grade 3 or 4 treatment-related adverse events occurred in two patients (13.3%). There were no treatment-related deaths. Pembrolizumab had no impact on epacadostat PK and vice versa. The PK profile of pembrolizumab in the current study was comparable with historical pembrolizumab PK data. CONCLUSION: Epacadostat in combination with pembrolizumab was generally safe and well tolerated among Japanese patients with advanced solid tumors. Clinical trial registration NCT02862457.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Oximas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Relação Dose-Resposta a Droga , Humanos , Japão , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Oximas/administração & dosagem , Oximas/efeitos adversos , Oximas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinéticaRESUMO
S-epacadostat (S-EPA) is an efficient and selective small-molecule inhibitor of indoleamine 2,3-dioxygenase 1. It is an EPA analog with a sulfur atom instead of a nitrogen atom at the furazan C3 position. This study documents the pharmacokinetics of S-EPA in dogs and its metabolic pathway. After an oral administration of 15 mg/kg of S-EPA in dogs, the time to peak concentration was 0.80 h, the mean elimination half-life was 7.3 h, and the absolute bioavailability was 55.8%. Furthermore, we identified S-EPA metabolites in dog plasma and dog liver microsomes by UPLC-Q Exactive Orbitrap HRMS. In dog plasma, we found five metabolites, which came from glucuronidation (M1 and M2), deoxygenation (the amidine M4), glucuronidation of M4 (M3), and desulfonamidation and oxidation of M4 (the carboxylic acid M5). In dog liver microsomes, we identified three major metabolites, namely, the glucuronide conjugate (M6), a mono-oxidation product (M7), and a desulfonamidation and oxidation product (M8). Gut microbiota may cause the differences between in vivo and in vitro oxidation metabolisms. Contrary to EPA, S-EPA did not undergo dealkylation, suggesting that substituting the nitrogen with sulfur affects the metabolism of the adjacent alkyl side chain.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Oximas/sangue , Oximas/farmacocinética , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Animais , Cães , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Limite de Detecção , Modelos Lineares , Masculino , Microssomos Hepáticos/metabolismo , Oximas/química , Oximas/metabolismo , Reprodutibilidade dos Testes , Sulfonamidas/química , Sulfonamidas/metabolismo , Espectrometria de Massas em Tandem/métodosRESUMO
Immuno-oncology (IO) is an emerging option to treat cancer malignancies. In the last two years, IO has accounted for more than 90% of the new active drugs in various therapeutic indications of oncology drug development. Bioanalytical methods used for the quantitation of various IO small molecule drugs have been summarized in this review. The most commonly used are HPLC and LC-MS/MS methods. Determination of IO drugs from biological matrices involves drug extraction from the biological matrix, which is mostly achieved by simple protein precipitation, liquid-liquid extraction and solid-phase extraction. Subsequently, quantitation is usually achieved by LC-MS/MS, but HPLC-UV has also been employed. The bioanalytical methods reported for each drug are briefly discussed and tabulated for easy access. Our review indicates that LC-MS/MS is a versatile and reliable tool for the sensitive, rapid and robust quantitation of IO drugs.
Assuntos
Antineoplásicos Imunológicos/análise , Antineoplásicos Imunológicos/isolamento & purificação , Cromatografia Líquida , Espectrometria de Massas em Tandem , Animais , Antineoplásicos Imunológicos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Humanos , Extração Líquido-Líquido , Camundongos , Neoplasias/tratamento farmacológico , Extração em Fase SólidaRESUMO
Epacadostat is a potent and highly selective inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1). Here we report results from the open-label, dose-escalation, Phase 1b ECHO-110 study evaluating epacadostat plus atezolizumab in patients with previously treated Stage IIIB/IV nonsmall cell lung cancer (NSCLC). Eligible patients had received ≥1 prior line of platinum-based chemotherapy (≥2 cycles) and no prior checkpoint/IDO inhibitors treatment. Oral epacadostat (25, 50, 75, 100, 200 or 300 mg) was administered twice daily (BID) with intravenous atezolizumab 1,200 mg every 3 weeks (Q3W). Primary endpoints were safety, tolerability and dose-limiting toxicities (DLTs). Twenty-nine patients received ≥1 dose of treatment. The maximum tolerated dose of epacadostat was not reached. Two patients had DLTs: one patient with Grade 3 dehydration and hypotension (epacadostat 200 mg BID); one patient with Grade 3 hyponatremia and Grade 4 autoimmune encephalitis (epacadostat 300 mg BID). Twenty-three patients (79%) had treatment-related adverse events (AEs); seven patients (24%) experienced Grade 3/4 events; five patients (17%) discontinued treatment due to treatment-related AEs. No fatal treatment-related AEs occurred. One patient achieved a partial response (objective response rate, 3%), which was maintained for 8.3 months; eight patients had stable disease. Baseline tumoral programmed cell death ligand 1 (PD-L1) and IDO expression were low among patients with evaluable samples (1 of 23 expressed PD-L1; 5 of 17 expressed IDO). Epacadostat pharmacokinetics was comparable to historical controls. Epacadostat, at doses up to 300 mg BID, combined with atezolizumab 1,200 mg Q3W was well tolerated in patients with previously treated NSCLC, although clinical activity was limited.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Oximas/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Intravenosa , Administração Oral , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oximas/efeitos adversos , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
It was previously reported that the activation of antitumor immune response by photodynamic therapy (PDT) is crucial for its therapeutic outcome. Excessive PDT-mediated inflammation is accompanied by immunosuppressive mechanisms that protect tissues from destruction. Thus, the final effect of PDT strongly depends on the balance between the activation of an adoptive arm of immune response and a range of activated immunosuppressive mechanisms. Here, with flow cytometry and functional tests, we evaluate the immunosuppressive activity of tumor-associated myeloid cells after PDT. We investigate the antitumor potential of PDT combined with indoleamine 2,3-dioxygenase 1 (IDO) inhibitor in the murine 4T1 and E0771 orthotopic breast cancer models. We found that the expression of IDO, elevated after PDT, affects the polarization of T regulatory cells and influences the innate immune response. Our results indicate that, depending on a therapeutic scheme, overcoming IDO-induced immunosuppressive mechanisms after PDT can be beneficial or can lead to a systemic toxic reaction. The inhibition of IDO, shortly after PDT, activates IL-6-dependent toxic reactions that can be diminished by the use of anti-IL-6 antibodies. Our results emphasize that deeper investigation of the physiological role of IDO, an attractive target for immunotherapies of cancer, is of great importance.
Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/efeitos adversos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Inflamação/complicações , Interleucina-6/efeitos adversos , Fotoquimioterapia/métodos , Animais , Feminino , Humanos , CamundongosRESUMO
Epacadostat (EPA), a new and promising anti-cancer small molecule is firmly established as selective inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). The X-Ray structure of the human CA IX mimic in complex with EPA is investigated here for the first time and compared to previously reported EPA-CA II adduct. The structural information obtained are all in agreement with the in vitro kinetic data which accounted for a selective inhibition of the CA IX over the CA II isoform.
Assuntos
Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Oximas/química , Oximas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Antígenos de Neoplasias/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/química , Cristalografia por Raios X , Humanos , Simulação de Acoplamento MolecularAssuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Sulfonamidas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Sulfonamidas/uso terapêutico , Neoplasias/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Piperidinas/uso terapêutico , OximasRESUMO
PURPOSE OF REVIEW: This review focuses on the recent clinical development of indolamine-2,3-dioxygenase-1 (IDO-1) inhibitors. RECENT FINDINGS: IDO-1 alters tryptophan metabolism in a manner enhancing T-regulatory cell activity, but pre-clinical data show that its role in tumorigenesis is context-dependent on host and tumor interaction, highlighting some challenges in understanding the molecular oncology of this enzymatic drug target. Because results from phase I/II trials of IDO-1 inhibitor monotherapy have been disappointing, current clinical trials employ IDO-1 inhibitors in combination strategies with other immunotherapy agents or with chemotherapy ± radiation. Combinations with anti-PD-1/PD-L1 antibodies are already showing promise, and related strategies are under active evaluation. While further research is needed to elucidate the precise role of IDO-1 in tumor development, its mechanisms of action appear sufficiently distinct from other immunotherapy targets to warrant inclusion in combination immunotherapy regimens, an approach where multiple clinical trials are currently underway.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Humanos , Neoplasias/enzimologia , Neoplasias/imunologia , Neoplasias/patologia , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
1. S-EPA is a sulfur-substitution analog of epacadostat (EPA), an effective small molecule indoleamine 2,3-dioxgenase1 (IDO) inhibitor. By in vitro and in vivo experiments, pharmacokinetic differences of two closely related analogs, S-EPA and EPA was investigated in this study. 2. Liver microsomes clearance experiments showed S-EPA had comparable metabolic stability with EPA in rat and human liver microsomes. The whole blood distribution experiments showed the distribution ratio of S-EPA in blood cells to plasma in mice, rats, dogs and monkey was 1.2, 4.8, 2.2 and 40.6, respectively. While the distribution ratio of EPA ranged from 0.94 to 1.30 in mice, rats, dogs and was 3.1 in monkeys. 3. The pharmacokinetic study in rats showed the exposure (AUClast) of S-EPA in plasma and blood cells was 1.7-fold and 3.9-fold higher than that of EPA, respectively. Moreover, the exposure ratio of S-EPA in blood cells to plasma was 3.7, while the ratio of EPA was 1.6. 4. In CT26 tumor bearing mice, the IDO inhibition of S-EPA and EPA on plasma or tumor kynurenine was generally consistent. And the inhibition ratio could reach at more than 50% at 3 h after single dose, at least lasting up to 8 h.
Assuntos
Inibidores Enzimáticos/farmacocinética , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Oximas/farmacocinética , Sulfetos/farmacocinética , Sulfonamidas/farmacocinética , Animais , Linhagem Celular Tumoral , Cães , Estabilidade de Medicamentos , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Humanos , Cinurenina/sangue , Cinurenina/metabolismo , Macaca fascicularis , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Transplante de Neoplasias , Oximas/sangue , Oximas/química , Ratos Sprague-Dawley , Sulfetos/sangue , Sulfetos/química , Sulfonamidas/sangue , Sulfonamidas/químicaRESUMO
OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months). The primary endpoint was investigator-assessed progression-free survival (PFS; RECIST v1.1). Secondary endpoints included CA-125 response (Gynecologic Cancer InterGroup criteria), overall survival, safety, and tolerability. RESULTS: The study was terminated primarily due to slow accrual and lack of evidence of superiority. Median PFS was 3.75months for epacadostat (n=22) versus 5.56months for tamoxifen (n=20; HR, 1.34 [95% CI, 0.58-3.14]; P=0.54). Of evaluable patients, 1 (5.0%) epacadostat and 3 (15.8%) tamoxifen patients had confirmed CA-125 responses. The most common treatment-emergent adverse event was fatigue (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%). Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known mechanism of action. IDO1 expression was observed in 94% of archival tumour samples. CONCLUSIONS: This first report of immunotherapy evaluation in biochemical-only relapse ovarian cancer and of IDO1 inhibitor monotherapy in ovarian cancer found no significant difference in efficacy between epacadostat and tamoxifen. Epacadostat was generally well tolerated.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Oximas/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Sulfonamidas/uso terapêutico , Tamoxifeno/uso terapêutico , Adulto , Idoso , Antineoplásicos Hormonais/efeitos adversos , Antígeno Ca-125/sangue , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Toxidermias/etiologia , Término Precoce de Ensaios Clínicos , Exantema/induzido quimicamente , Neoplasias das Tubas Uterinas/sangue , Neoplasias das Tubas Uterinas/química , Fadiga/induzido quimicamente , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/análise , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Epiteliais e Glandulares/química , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/química , Oximas/efeitos adversos , Oximas/farmacocinética , Neoplasias Peritoneais/sangue , Neoplasias Peritoneais/química , Prurido/induzido quimicamente , Recidiva , Critérios de Avaliação de Resposta em Tumores Sólidos , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Taxa de Sobrevida , Tamoxifeno/efeitos adversosRESUMO
A sensitive, specific and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of epacadostat in mouse plasma using tolbutamide as an internal standard (IS) as per regulatory guidelines. Sample preparation was accomplished through a protein precipitation. Chromatographic separation was performed on an Atlantis dC18 column using a binary gradient using mobile phase A (acetonitrile) and B (0.2% formic acid in water) at a flow rate of 0.90 mL/min. Elution of epacadostat and IS occurred at ~2.41 and 2.51 min, respectively. The total chromatographic run time was 3.2 min. A linear response function was established in the concentration range of 1.07-533 ng/mL. The intra- and inter-day accuracy and precision were in the ranges of 1.81-12.9 and 3.80-11.1%, respectively. This novel method has been applied to a pharmacokinetic study in mice.