Terms of use This work is brought to you by the University of Southern Denmark through the SDU Research Portal. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version T h e ne w e ngl a nd jou r na l o f m e dicine n engl j med 381;17 nejm.org

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When a series of individuals with private information announce public predictions, initial conformity can create an "information cascade" in which later predictions match the early announcements. This paper reports an experiment in which private signals are draws from an unobserved urn. Subjects make predictions in sequence and are paid if they correctly guess which of two urns was used for the draws. If initial decisions coincide, then it is rational for subsequent decision makers to follow the established pattern, regardless of their private information. Rational cascades formed in most periods in which such an imbalance occurred. (JEL C92, D8)In many economic situations, agents ob-arnples and some simple models of the cascade serve private signals of some underlying state process. They point out that the conformity of and make public decisions. Subsequent deci-followers in a cascade contains no informasion makers face a dilemma if their own ~r i -tional value. and in this sense. the cascade is vate signal is indicative of a state tha; is fragile and can be upset by the arrival of new unlikely given the previously observed deci-public information. sions. An "information cascade' ' occurs whenAs indicated above, an information cascade initial decisions coincide in a way that it is can result from rational inferences that others' optimal for each of the subsequent individuals decisions are based on information that domto ignore his or her private signals and follow inates one's own signal. Particularly interestthe established pattern. For example, suppose ing is the possibility of a reverse cascade; the that a worker is not hired by several potential initial decision makers are unfortunate to obemployers because of poor interview perfor-serve private signals that indicate the incorrect mances. Knowing this, an employer ap-state, and a large number of followers may join proached subsequently may not hire the the resulting pattern of "mistakes," despite worker even if the employer's own assess-the fact that their private signals are more ment is favorable, since this information may likely to indicate the correct state.' Even a be dominated by the unfavorable signals qualified worker will sometimes make a bad inferred from previous rejections.' sushi1 impression in an interview, and a series of Bikhchandani et al. (1992) discuss other ex-rejections can create a reverse cascade that eliminates many future job opportunities.'Cascade-like behavior might also arise in fiw nancial markets, where trading decisions come

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AA: African American; ADPKD: autosomal dominant polycystic kidney disease; HLA, human leukocyte antigen; PRA: panel reactivity antibody. Continuous variables represented as mean AE SD. Categorical variables as numbers (percentage). c l i n i c a l i n v e s t i g a t i o n M Fribourg et al.: T-cell exhaustion in transplantation

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220 Background: The RAS/RAF/MEK/ERK pathway plays a major role in cell growth and survival and is aberrantly activated in many cancers. MEK162 (ARRY-438162) is a potent, selective, ATP-uncompetitive inhibitor of MEK1/2. The objectives of this Phase 1 expansion study were to characterize the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of MEK162 in patients (pts) with biliary tract cancer (BTC). Methods: Pts with unresectable, locally advanced or metastatic BTC who had received ≤ 1 prior systemic therapy received oral MEK162 at 60 mg twice daily (BID). Mutation status of RAS, BRAF and other relevant genes were assessed from tumor samples. Tumor response was assessed every 6 weeks. Results: Twenty-eight pts, median age 64 years (range 30-86) with gallbladder (7), intrahepatic (14) or extrahepatic (7) cholangiocarcinoma (CC) were enrolled. All pts were ECOG 0-1 and 43% received previous first-line therapy (primarily gemcitabine combinations). Of the 23 tumors assessed, 17 were wild type (WT) on all loci tested and 6 had mutations (1 MET, 1 PIK3CA, 2 KRAS, 2 PTEN null). The most common treatment-related AEs were rash, nausea, vomiting, diarrhea, peripheral edema, fatigue and central serous-like retinopathy, and most were Grade (G) 1 or 2. G3/4 treatment-related AEs were anasarca, hypokalemia, hyponatremia, upper/lower gastrointestinal hemorrhage and mucositis (1 each). Thirteen pts were dose reduced for AEs, of which, G1/2 central serous-like retinopathy was the most frequently reported event (6). Three pts were discontinued for treatment-related AEs (G2 central serous-like retinopathy, G1 nausea, G4 anasarca). Of the 26 pts evaluable for response, 1 CR, 1 PR and 11 SD (≥ 6 weeks) were observed. Of note, both responders were WT on all loci tested and had extrahepatic CC. The PK in this population was equivalent to that observed in prior studies. A consistent mean reduction (40-60%) of circulating TNFα was observed. Conclusions: MEK162 has an acceptable safety profile and desirable PK properties at 60 mg BID and RECIST responses were observed in pts with BTC. Additional expansion cohorts are ongoing in pts with KRAS- or BRAF-mutant metastatic colorectal cancer.

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