A phase IIa study of afuresertib, an oral pan‐AKT inhibitor, in patients with Langerhans cell histiocytosis

Arceci, Robert J.; Allen, Carl E.; Dunkel, Ira J.; Jacobsen, Eric; Whitlock, James A.; Vassallo, Robert; Morris, Shannon R.; Portnoy, Alison; Reedy, Beth Ann; Smith, Deborah A.; Noble, Robert; Murnane, Amy A.; Cornfeld, Mark; Rodríguez‐Galindo, Carlos; Heaney, Mark L.; McClain, Kenneth L.; Vaiselbuh, Sarah R.

doi:10.1002/pbc.26325

Cited by 21 publications

(15 citation statements)

References 38 publications

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“…Notably, a recent report of a phase 2 clinical trial of pan-AKT inhibitor afuresertib for LCH patients, including 7 evaluable cases with pulmonary involvement, demonstrated that AKT inhibition exerts limited efficacy against pulmonary LCH patients. 54 Because AKT inhibition induces feedback activation of PI3K, 55 which could signal through AKT-independent downstream pathways, 56 AKT may not be an optimal target to suppress the PI3K pathway. Direct inhibition of PI3K isoform(s), rather than AKT inhibitors, would be warranted in future clinical trials for pulmonary LCH patients.…”

Section: Gr1mentioning

confidence: 99%

KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

Kamata

Giblett

Pritchard

2017

Blood

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Key Points• KRAS G12D expression in mouse lung myeloid cells induces pulmonary LCH-like neoplasms.• KRAS G12D -induced LCH-like neoplasms are sensitive to in vivo treatment with 3-hydroxy-3-methylglutaryl coenzyme A inhibitor atorvastatin. -induced LCH-like mouse with the cholesterol-lowering drug atorvastatin ameliorated the pathology, implicating statins as potential therapeutics against a subset of pulmonary LCH. (Blood. 2017;130(4):514-526)

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Section: Gr1mentioning

confidence: 99%

KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

Kamata

Giblett

Pritchard

2017

Blood

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“…One year later, the patient presented with painful right‐sided neck swelling and a biopsy of the lesion confirmed recurrence of LCH. The patient was then treated with the oral pan‐AKT inhibitor afuresertib as part of a clinical trial . The patient responded to afuresertib therapy and completed a total of 30 weeks of treatment (Figure A).…”

Section: Case Descriptionmentioning

confidence: 99%

“…The patient was then treated with the oral pan-AKT inhibitor afuresertib as part of a clinical trial. 17 The patient responded to afuresertib therapy and completed a total of 30 weeks of treatment ( Figure 1A). Several months later, the patient relapsed and was treated with cytarabine 150 mg/m 2 /day for a 5-day course.…”

Section: Case Descriptionmentioning

confidence: 99%

Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis

Azorsa

Lee

Wai

et al. 2018

Pediatric Blood & Cancer

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Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p.L98_K104 > Q deletion confirmed its effect on cellular activation of the ERK pathway and drug resistance.

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“…In the trial presented in this issue, Arceci et al. report on afuresertib, an oral, potent, highly selective, reversible pan‐AKT inhibitor at 125 mg/day administered to adult treatment‐naïve (n = 7) or relapsing/refractory LCH patients (n = 10) . The majority of patients were treated for more than 24 weeks, with four patients receiving treatment for more than 48 weeks.…”

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confidence: 99%

Targeting BRAK, MEK, mTOR, and now AKT in histiocytosis: The ongoing revolution of therapies in orphan diseases

Haroche¹

2017

Pediatric Blood & Cancer

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Barrett Rollins led the way in 2010 with the discovery of recurrent BRAF V600E mutation in Langerhans cell histiocytosis (LCH). 1 Soon, the same mutation was found in Erdheim-Chester disease (ECD) 2 with an overall frequency of 55-70%. Thereafter, LCH and ECD were gathered in the same group ("L") in the most recent classification of histiocytosis. 3 The understanding of such orphan histiocytic disorders has moved from inflammation driven by aberrant immune activation to recognition as myeloid neoplasms. Other recurrent somatic mutations of the MAP kinase and AKT pathways were also found, including N/KRAS, MAP2K1, along with other kinase alterations promoting MAP kinase signaling and PIK3CA. 4 In 2012, the French Histiocytosis Study Group, followed by the Memorial Sloan Kettering Cancer Center (MSKCC) in New York started targeted therapies (vemurafenib) 5,6 in adult patients with BRAF-mutated histiocytosis, with dramatic and highly consistent efficacy. This landscape of new targetable mutations for histiocytosis patients also provided important hope for children, with a major therapeutic breakthrough in 2015 by the French group that used vemurafenib for the first time. 7 More than 140 patients -including nearly 30 children -worldwide have been treated with BRAF inhibitors (mostly vemurafenib, occasionally dabrafenib). In 2015, in New York (MSKCC) as well as in Paris, MEK inhibitors (trametinib, cobimetinib) were rapidly effective in a four adult patients even more than we observed with BRAF inhibitors 3 years prior, leading to the development of clinical trials targeting BRAF wild-type adult histiocytosis. 8,9 Until recently, such targeted therapies have mainly been prescribed off-label, but clinical trials dedicated both to adult and pediatric patients are currently developed on both sides of the Atlantic. Of note, an Orphan Drug Designation status was obtained for vemurafenib in the European Union for LCH, and in the United States for ECD. Several trials are currently ongoing for adult histiocytic disorders: NIH (NCT02281760) trametinib + dabrafenib for BRAF V600E patients; LOVE study (NCT02089724) in Paris, a multicenter study of Abbreviations: ECD, Erdheim-Chester disease; LCH, Langerhans cell histiocytosis; MSKCC, Memorial Sloan Kettering Cancer Center the Long-term Outcome after Vemurafenib/BRAF inhibitor interruption in ECD; and MSKCC (NCT02649972) cobimetinib for BRAF wildtype or V600E patients with inability to access of BRAF inhibitor or prior treatment with a BRAF inhibitor discontinued due intolerable side effects or toxicity prior to progression. Last year, new light was shed on the mTOR-AKT pathway. The combination of the mTOR inhibitor sirolimus and prednisone had encouraging results in an open-label trial, in which 10 patients with ECD experienced stabilization or objective responses. 10 Interestingly, two patients with BRAF wild-type histiocytosis were recently reported with translocations involving KIF5B and ALK, 8 which are responsible for ALK hyperexpression and activation, suggesting that spec...

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A phase IIa study of afuresertib, an oral pan‐AKT inhibitor, in patients with Langerhans cell histiocytosis

Abstract: Afuresertib has clinical activity in some patients with newly diagnosed and advanced LCH.

Cited by 21 publications

References 38 publications

KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis

Targeting BRAK, MEK, mTOR, and now AKT in histiocytosis: The ongoing revolution of therapies in orphan diseases

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