Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

Mitchell, Tara C.; Hamid, Omid; Smith, David C.; Bauer, Todd M.; Wasser, Jeffrey S.; Olszanski, Anthony J.; Luke, Jason J.; Balmanoukian, Ani Sarkis; Schmidt, Emmett V.; Zhao, Yufan; Gong, Xiaomeng; Maleski, Janet; Leopold, Lance; Gajewski, Thomas F.

doi:10.1200/jco.2018.78.9602

Cited by 307 publications

(210 citation statements)

References 30 publications

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“…In human patients, epacadostat monotherapy was not effective (163,164), while combined administration with PD-1 or cytotoxin T-lymphocyte-associated protein 4 (CTLA-4) inhibitors showed promising clinical activity in phase I/II studies (165)(166)(167)(168). Unfortunately, a recent trial with combined administration of epacadostat with pembrolizumab found no superiority over pembrolizumab alone (169).…”

Section: Immune Tolerance Related To Indoleamine 23-dioxygenase 1 Acmentioning

confidence: 99%

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

et al. 2020

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Many patients with cancer suffer from anemia, depression, and an impaired quality of life (QoL). These patients often also show decreased plasma tryptophan levels and increased kynurenine concentrations in parallel with elevated concentrations of Th1 type immune activation marker neopterin. In the course of anti-tumor immune response, the pro-inflammatory cytokine interferon gamma (IFN-γ) induces both, the enzyme indoleamine 2,3-dioxygenase (IDO) to degrade tryptophan and the enzyme GTP-cyclohydrolase I to form neopterin. High neopterin concentrations as well as an increased kynurenine to tryptophan ratio (Kyn/Trp) in the blood of cancer patients are predictive for a worse outcome. Inflammation-mediated tryptophan catabolism along the kynurenine pathway is related to fatigue and anemia as well as to depression and a decreased QoL in patients with solid tumors. In fact, enhanced tryptophan breakdown might greatly contribute to the development of anemia, fatigue, and depression in cancer patients. IDO activation and stimulation of the kynurenine pathway exert immune regulatory mechanisms, which may impair anti-tumor immune responses. In addition, tumor cells can degrade tryptophan to weaken immune responses directed against them. High IDO expression in the tumor tissue is associated with a poor prognosis of patients. The efficiency of IDO-inhibitors to inhibit cancer progression is currently tested in combination with established chemotherapies and with immune checkpoint inhibitors. Inflammation-mediated tryptophan catabolism and its possible influence on the development and persistence of anemia, fatigue, and depression in cancer patients are discussed.

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Section: Immune Tolerance Related To Indoleamine 23-dioxygenase 1 Acmentioning

confidence: 99%

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

et al. 2020

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“…13 The genetic differences between acral and mucosal melanomas and cutaneous melanomas may contribute to the IDO expression levels in tumors and in the peritumoral stroma. Although anti-PD-1 inhibitor/IDO-1 inhibitor combination therapy in phase I/II trials had encouraging antitumor activity in metastatic melanomas, 26 the results of the phase 3 study did not detect the efficacy of them. 27 Because our results showed the varying IDO expression profiles between major melanoma subtypes, anti-PD-1 inhibitor/IDO-1 inhibitor combination therapy targeted for specific strata of melanoma patients may merit consideration.…”

Section: Discussionmentioning

confidence: 99%

Variable indoleamine 2,3‐dioxygenase expression in acral/mucosal melanoma and its possible link to immunotherapy

et al. 2019

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Immune checkpoint inhibitors have improved the prognosis of advanced melanoma. Although anti–programmed death ligand‐1 (PD‐L1) is a well‐studied biomarker for response to anti–programmed death‐1 PD‐1 therapy in melanoma, its clinical relevance remains unclear. It has been established that the high expression of indoleamine 2,3‐dioxygenase (IDO) is correlated to a response to anti–CTLA‐4 treatment in melanoma. However, it is still unknown whether the IDO expression is associated with response to anti–PD‐1 therapy in advanced melanoma. In addition, acral and mucosal melanomas, which comprise a great proportion of all melanomas in Asians, are genetically different subtypes from cutaneous melanomas; however, they have not been independently analyzed due to their low frequency in Western countries. To evaluate the association of IDO and PD‐L1 expression with response to anti–PD‐1 antibody in acral and mucosal melanoma patients, we analyzed 32 Japanese patients with acral and mucosal melanomas treated with anti–PD‐1 antibody from the perspective of IDO and PD‐L1 expression levels by immunohistochemistry (IHC). Multivariate Cox regression models showed that the low expression of IDO in tumors was associated with poor progression‐free survival (HR = 0.33, 95% CI = 0.13‐0.81, P = 0.016), whereas PD‐L1 expression on tumors was not associated with progression‐free survival. Significantly lower expression of IDO in tumors was found in non–responders compared to responders. Assessment of the IDO expression could be useful for the identification of suitable candidates for anti–PD‐1 therapy among acral and mucosal melanomas patients. Further validation study is needed to estimate the clinical utility of our findings.

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“…In a phase I study, epacadostat monotherapy did not show any objective responses among patients with colon cancer, melanoma, or renal cell carcinoma . In a phase I/II study using epacadostat and pembrolizumab for solid cancers, the ORR for melanoma was 55% . Of the 2 patients with HNSCC, one achieved a partial response .…”

Section: Combination Therapy For Hnsccmentioning

confidence: 94%

“…In a phase I/II study using epacadostat and pembrolizumab for solid cancers, the ORR for melanoma was 55% . Of the 2 patients with HNSCC, one achieved a partial response . Two phase I/II trials used epacadostat with nivolumab and pembrolizumab in patients with HNSCC (Table ).…”

Section: Combination Therapy For Hnsccmentioning

confidence: 99%

“…79,80 However, several analyses showed that ORR may not be a reliable surrogate for OS. 81,82 For example, two important anti-PD1/PD-L1 phase III combination studies were conducted based on their high ORR in earlier phase trials-epacadostat and pembrolizumab for melanoma, 55,56 and atezolizumab-cobimetinib for colon cancer. 83 Both regimens showed encouraging ORR in early phase I/II trials 56,83 ; however, confirmatory phase III trials of both regimens reported a lower ORR than expected.…”

Section: Concurrent Radiation With Anti-pd1/pd-l1 Therapy For Hnsccmentioning

confidence: 99%

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Immune checkpoint inhibitors for head and neck squamous cell carcinoma: Current landscape and future directions

Kao

Lou

2019

Head & Neck

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Background Immune checkpoint inhibitors (ICIs) can reinvigorate T cells and activate the immune system to eliminate cancer cells. Head and neck squamous cell carcinoma (HNSCC) is a malignancy with a poor prognosis. The roles of ICIs for HNSCC treatments are emerging. Method We reviewed the study results of Programmed‐Death 1 (PD‐1) and PD‐ligand‐1 (PD‐L1) monoclonal antibodies for HNSCC. The ongoing trials of anti‐PD‐1 and anti‐PD‐L1 were also reviewed. Results Nivolumab showed a significant overall survival benefit in platinum‐refractory HNSCC patients. For platinum‐sensitive or first‐line patients, pembrolizumab monotherapy (patients with PD‐L1 Combined Positive Score ≥ 20) or pembrolizumab‐platinum‐fluorouracil improved overall survival vs the EXTREME (cetuximab‐platinum‐fluorouracil). Many HNSCC studies have combined anti‐PD1/PD‐L1 therapy with various anticancer agents or radiotherapy to improve treatment efficacy. Conclusion ICIs demonstrate their efficacies for R/M HNSCC patients. The incorporation of ICIs showed a great impact on the treatment landscape of HNSCC.

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Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

Cited by 307 publications

References 30 publications

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

Variable indoleamine 2,3‐dioxygenase expression in acral/mucosal melanoma and its possible link to immunotherapy

Immune checkpoint inhibitors for head and neck squamous cell carcinoma: Current landscape and future directions

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