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Phase II Multicenter, Open‐Label Study of Oral ENMD‐2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma

Phase II Multicenter, Open‐Label Study of Oral ENMD‐2076 for the Treatment of Patients with... Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 Clinical Trial Results Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma a,h b c b d a,h GHASSAN K. ABOU-ALFA, ROBERT MAYER, ALAN P. VENOOK, ALLISON F. O’NEILL, MUHAMMAD S. BEG, MICHAEL LAQUAGLIA, a,h a,h a,h a,h d a,h e PETER T. KINGHAM, RACHEL KOBOS, OLCA BASTURK, CAMERON BRENNAN, ADAM YOPP, JAMES J. HARDING, STEPHEN LEONG, f f g h h h i i JOHN CROWN, EMIR HOTI, GREGORY LEONARD, MICHELE LY, MIKAELA BRADLEY, EMILY VALENTINO, DAVID MARKOWITZ, ALEXANDER ZUKIWSKI, i c KEN REN, JOHN D. GORDAN a b Weill Medical College at Cornell University, New York, New York, USA; Dana-Farber Cancer Institute, Harvard University, Boston, c d Massachusetts, USA; University of California San Francisco, San Francisco, California, USA; UT Southwestern Medical Center, Dallas, e f g Texas, USA; University of Colorado Cancer Center, Aurora, Colorado, USA; St Vincent’s Private Hospital, Dublin, Ireland; Galway h i University Hospital, Galway, Ireland; Memorial Sloan Kettering Cancer Center, New York, New York, USA; CASI Pharmaceuticals, Inc., Rockville, Maryland, USA TRIAL INFORMATION � ClinicalTrials.gov Identifier: NCT02234986 � Principal Investigator: Ghassan K. Abou-Alfa � Sponsor: CASI Pharmaceuticals � IRB Approved: Yes LESSONS LEARNED � The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. � ENMD-2076 showed a favorable toxicity profile. � The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support fur- ther evaluation of ENMD-2076 as single agent. � Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components. ABSTRACT Background. Fibrolamellar carcinoma (FLC) represents approx- Results. Of 35 patients who enrolled and received treatment, imately 0.85% of liver cancers. The associated DNAJB1-PRKACA 1 (3%) had a partial response (PR) and 20 (57%) had stable gene fusion transcript RNA codes for the catalytic domain of disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 protein kinase A and overexpression of Aurora kinase A months, respectively. The most frequently reported drug- (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor. related serious adverse event was hypertension in three Methods. Patients aged >12 years with pathologically con- patients. Three deaths were reported on-study—two due to firmed incurable FLC, with measurable disease, Eastern Coop- disease progression and one due to pulmonary embolism erative Oncology Group performance status 0–2orLansky not related to ENMD-2076. 70–100, and adequate organ function were eligible. Patients Conclusion. The study provided no rationale for further were prescribed ENMD-2076 based on body surface area. studying ENMD-2076 as a single agent in FLC. The Oncologist The primary endpoint was overall objective response rate by 2020;25:e1837–e1845 RECIST v1.1, with a null hypothesis of true response rate of DISCUSSION 2% versus one-sided alternative of 15%. Secondary end- points included 6-month progression-free survival (PFS) Fibrolamellar hepatocellular carcinoma is a very rare liver cancer of adolescents and young adults [1]. It appears rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the that the cancer is driven by a fusion gene, DNAJB1- PRKACA, comprising the first exon of DNAJB1, the heat- study. Correspondence: Ghassan K. Abou-Alfa, M.D., Memorial Sloan Kettering Cancer Center, 300 East 66th St., New York, New York 10065, USA. Telephone: 646-888-4184; e-mail: abou-alg@mskcc.org Received December 21, 2020; accepted for publication February 3, 2020; published Online First on March 10, 2020. © AlphaMed Press; the data published online to support this summary is the property of the authors. http://dx.doi. org/10.1634/theoncologist.2020-0093 No part of this article may be reproduced, stored, or transmitted in any form or for any means without the prior permission in writing from the copyright holder. For information on purchasing reprints contact Commercialreprints@wiley.com. For permission information contact permissions@wiley.com. The Oncologist 2020;25:e1837–e1845 www.TheOncologist.com © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 e1838 Phase II of ENMD-2076 in FLC multiple prior treatments [4]. Although the DNAJB1- PRKACA is neither specific nor sensitive to FLC [5–7], its transcriptome characterization [3] provides critical clues that suggest potential therapeutic targets, including AURKA. How- ever, the present study provides no rationale to further study ENMD-2076 as a single agent in FLC. The transcriptional effects of DNAJB1-PRKACA have nominated other targets as well [8, 9]. The study of everolimus, leuprolide, and letrozole unfortunately did not show any promise [10], despite the attempt to block the cross-communication between the estrogen receptor and PI3K/Akt/mTOR pathway [11]. Simi- larly, the increased expression of the breast cancer oncogene v-erb-b2 avian erythroblastic leukemia viral oncogene homo- log 2 (ErbB2) [5] observed in FLC [3] led to the study of Figure 1. Kaplan-Meier plot of progression-free survival. neratinib as monotherapy in patients with FLC (ClinicalTrials. gov: NCT01953926). Despite the link between expression of the DNAJB1- PRKACA gene fusion and downstream changes of gene expres- sion and signaling, it is not yet possible to determine whether shock protein 40 fused with PRKACA exons 2 through 10 the latter changes are the result of increased expression [2]. This results in an overexpressed chimeric protein that of PRKACA as a consequence of the DNAJB1 promoter or has intact Aurora kinase A enzymatic activity. No specific whether there are changes in the activity of PRKACA [4]. It agents have been developed yet to target PRKACA or the remains unclear if the chimera is sufficient for transformation gene fusion. Unfortunately, this study evaluating the or which of the changes in reported 3500 gene expression Aurora kinase inhibitor ENMD-2076 in patients with FLC maybedriving thetransformation[4].One maywonderif did not meet its primary efficacy endpoint. This is despite a simultaneous targeting approach of the presumed preclinical in vivo animal model studies demonstrating the primary genetic driver for FLC, the chimera of DNAJB1- association of AURKA with FLC [3], ENMD-2076 anti- PRKACA, and the critical downstream components may be angiogenic activity, and a clinical benefit with a partial needed [12]. response in one patient with FLC who relapsed after TRIAL INFORMATION Disease Fibrolamellar carcinoma Stage of Disease/Treatment Metastatic/advanced Prior Therapy No designated number of regimens Type of Study Phase II, single arm Primary Endpoint Overall response rate Secondary Endpoint 6-month progression-free survival Secondary Endpoint Progression-free survival Secondary Endpoint Time to progression Secondary Endpoint Overall survival Secondary Endpoint Toxicity Secondary Endpoint Correlative endpoint Investigator’s Analysis Inactive because results did not meet primary endpoint DRUG INFORMATION Generic/Working Name ENMD-2076 Company Name CASI Pharmaceuticals Drug Type Biological Drug Class Aurora kinase A (ARUKA) Dose 150 mg/day, 200 mg/day, or 250 mg/day based on body surface area (mg per flat dose) Route p.o. © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 Abou-Alfa, Mayer, Venook et al. e1839 Schedule of Administration Body surface area, m Daily dose, mg <1.00 150 1.00 to <1.40 200 ≥1.40 250 PATIENT CHARACTERISTICS Number of Patients, Male 16 Number of Patients, Female 19 Age Median (range): 25 (12–52) Number of Prior Systemic Therapies Median (range): Median (Q3–Q1) is 4 (8–3) Performance Status ECOG status at baseline n (%) 0 12 (36.4) 1 19 (57.6) 2 2 (6.1) Lansky status at baseline n (%) = 100 1 (50.0) = 90 1 (50.0) The percentage for ECOG status at baseline is calculated using the number of patients aged 16 and older as the denominator. The percentage for Lansky status at baseline is based on the number of patients younger than 16 as the denominator. Abbreviation: ECOG, Eastern Cooperative Oncology Group. PRIMARY ASSESSMENT METHOD:OVERALL SURVIVAL Number of Patients Screened 43 Number of Patients Enrolled 35 Number of Patients Evaluable for Toxicity 35 Number of Patients Evaluated for Efficacy 35 (Median) Duration Assessments OS 18.6, CI: 12.9–29.8 KAPLAN-MEIER TIME UNITS,MONTHS No. at next Time of scheduled assessment No. progressed No. Percent at start of Kaplan- evaluation/No. and/or time of event (or deaths) censored evaluation period Meier % at risk 0 0 0 100.00 100.00 35 2 2 0 100.00 94.29 33 4 0 0 94.29 94.29 33 6 6 0 94.29 77.14 27 8 2 0 77.14 71.43 25 10 6 0 71.43 54.29 19 12 1 0 54.29 51.43 18 14 4 0 51.43 40.00 14 16 2 0 40.00 34.29 12 18 1 0 34.29 31.43 11 20 3 0 31.43 22.86 8 22 3 0 22.86 14.29 5 24 2 0 14.29 8.57 3 26 1 0 8.57 5.71 2 28 1 0 5.71 2.86 1 30 1 0 2.86 0.00 0 www.TheOncologist.com © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 e1840 Phase II of ENMD-2076 in FLC Kaplan-Meier Plot of Overall Survival (Efficacy Analysis Population) PRIMARY ASSESSMENT METHOD:PROGRESSION-FREE SURVIVAL Number of Patients Screened 43 Number of Patients Enrolled 35 Number of Patients Evaluable for Toxicity 35 Number of Patients Evaluated for Efficacy 35 Evaluation Method RECIST 1.1 Response Assessment CR n = 0 (0%) Response Assessment PR n = 1 (3%) Response Assessment SD n = 20 (57%) Response Assessment PD n = 10 (34.3%) Response Assessment OTHER n = 2 (5.7%) (Median) Duration Assessments PFS 3.9 months, CI: 2.3–5.5 (Median) Duration Assessments TTP 5 months, CI: 0.7–5.7 (Median) Duration Assessments Response Duration 14.69 months KAPLAN-MEIER TIME UNITS,MONTHS No. at next Time of scheduled assessment No. progressed No. Percent at start of Kaplan- evaluation/No. and/or time of event (or deaths) censored evaluation period Meier % at risk 0 0 1 100.00 100.00 34 1 3 0 100.00 91.18 31 2 8 0 91.18 67.65 23 3 3 0 67.65 58.82 20 4 3 0 58.82 50.00 17 5 2 0 50.00 44.12 15 6 6 1 44.12 25.21 8 7 3 0 25.21 15.76 5 8 0 0 15.76 15.76 5 9 0 0 15.76 15.76 5 10 1 0 15.76 12.61 4 11 0 0 12.61 12.61 4 © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 Abou-Alfa, Mayer, Venook et al. e1841 12 1 0 12.61 9.45 3 13 1 0 9.45 6.30 2 14 0 0 6.30 6.30 2 15 0 0 6.30 6.30 2 16 0 0 6.30 6.30 2 17 1 0 6.30 3.15 1 18 0 0 3.15 3.15 1 19 1 0 3.15 0.00 0 Kaplan-Meier Plot of Progression-Free Survival (Efficacy Analysis Population) ADVERSE EVENTS (ALL CYCLES) Name NC/NA 1 2 3 4 5 All grades Fatigue 23% 66% 11% 0% 0% 0% 77% Fever 91% 9% 0% 0% 0% 0% 9% Chills 94% 6% 0% 0% 0% 0% 6% Nausea 43% 46% 11% 0% 0% 0% 57% Vomiting 74% 20% 6% 0% 0% 0% 26% Diarrhea 35% 37% 11% 17% 0% 0% 65% Constipation 77% 17% 6% 0% 0% 0% 23% Anemia 74% 17% 6% 3% 0% 0% 26% Neutrophil count decreased 94% 6% 0% 0% 0% 0% 6% Platelet count decreased 86% 14% 0% 0% 0% 0% 14% Blood and lymphatic system disorders—increased hemoglobin 89% 11% 0% 0% 0% 0% 11% INR increased 91% 6% 3% 0% 0% 0% 9% Activated partial thromboplastin time prolonged 83% 11% 0% 6% 0% 0% 17% Cough 74% 20% 6% 0% 0% 0% 26% Pharyngolaryngeal pain 91% 9% 0% 0% 0% 0% 9% Sinus disorder 94% 6% 0% 0% 0% 0% 6% Dyspnea 71% 14% 9% 6% 0% 0% 29% Weight loss 80% 14% 3% 3% 0% 0% 20% Gastrointestinal disorders—decreased appetite 72% 17% 11% 0% 0% 0% 28% www.TheOncologist.com © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 e1842 Phase II of ENMD-2076 in FLC Dry mouth 94% 6% 0% 0% 0% 0% 6% Abdominal distension 94% 6% 0% 0% 0% 0% 6% Hypercalcemia 91% 6% 3% 0% 0% 0% 9% Hypomagnesemia 71% 23% 6% 0% 0% 0% 29% Hypertension 58% 11% 20% 11% 0% 0% 42% Renal and urinary disorders—hypernatremia 91% 9% 0% 0% 0% 0% 9% Aspartate aminotransferase increased 31% 43% 17% 9% 0% 0% 69% Abdominal pain 34% 31% 29% 6% 0% 0% 66% Alanine aminotransferase increased 26% 37% 14% 20% 3% 0% 74% Alkaline phosphatase increased 57% 26% 14% 3% 0% 0% 43% Hypoalbuminemia 71% 23% 3% 3% 0% 0% 29% Hypoglycemia 91% 9% 0% 0% 0% 0% 9% Hyperglycemia 54% 37% 6% 3% 0% 0% 46% Hyponatremia 74% 26% 0% 0% 0% 0% 26% Hyperkalemia 83% 14% 3% 0% 0% 0% 17% Mucositis oral 88% 9% 3% 0% 0% 0% 12% Dizziness 91% 9% 0% 0% 0% 0% 9% Palpitations 94% 6% 0% 0% 0% 0% 6% Dry skin 94% 6% 0% 0% 0% 0% 6% Rash acneiform 86% 14% 0% 0% 0% 0% 14% Hypocalcemia 85% 9% 3% 3% 0% 0% 15% Headache 66% 23% 11% 0% 0% 0% 34% Insomnia 85% 9% 6% 0% 0% 0% 15% Myalgia 89% 11% 0% 0% 0% 0% 11% Palmar-plantar erythrodysesthesia syndrome 88% 6% 6% 0% 0% 0% 12% Proteinuria 80% 6% 11% 3% 0% 0% 20% Blurred vision 94% 6% 0% 0% 0% 0% 6% White blood cell decreased 94% 6% 0% 0% 0% 0% 6% Rash acneiform 94% 6% 0% 0% 0% 0% 6% Alopecia 97% 3% 0% 0% 0% 0% 3% Encephalopathy 94% 3% 0% 3% 0% 0% 6% Fecal incontinence 97% 3% 0% 0% 0% 0% 3% Back pain 88% 3% 6% 3% 0% 0% 12% Blood bilirubin increased 82% 3% 6% 9% 0% 0% 18% Creatinine increased 97% 3% 0% 0% 0% 0% 3% Noncardiac chest pain 94% 6% 0% 0% 0% 0% 6% Chest pain—cardiac 97% 3% 0% 0% 0% 0% 3% Colitis 97% 3% 0% 0% 0% 0% 3% Bruising 97% 3% 0% 0% 0% 0% 3% Depression 97% 3% 0% 0% 0% 0% 3% Dyspepsia 94% 3% 3% 0% 0% 0% 6% Dysphasia 97% 3% 0% 0% 0% 0% 3% Left ventricular systolic dysfunction 91% 3% 6% 0% 0% 0% 9% Electrocardiogram QT corrected interval prolonged 97% 3% 0% 0% 0% 0% 3% Infections and infestations—enteritis 94% 3% 0% 3% 0% 0% 6% Epistaxis 97% 3% 0% 0% 0% 0% 3% Flatulence 97% 3% 0% 0% 0% 0% 3% Eye disorders—pain 97% 3% 0% 0% 0% 0% 3% Gastrointestinal disorders—reflux 97% 3% 0% 0% 0% 0% 3% Gastrointestinal disorders—hyperchlorhydria 97% 3% 0% 0% 0% 0% 3% Hyperuricemia 97% 3% 0% 0% 0% 0% 3% © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 Abou-Alfa, Mayer, Venook et al. e1843 Hearing impaired 97% 3% 0% 0% 0% 0% 3% Renal and urinary disorders—hypochloremia 97% 3% 0% 0% 0% 0% 3% Hypokalemia 97% 3% 0% 0% 0% 0% 3% Hypophosphatemia 86% 3% 11% 0% 0% 0% 14% Chest wall pain 97% 3% 0% 0% 0% 0% 3% Generalized muscle weakness 97% 3% 0% 0% 0% 0% 3% Pain 94% 6% 0% 0% 0% 0% 6% Edema limbs 97% 3% 0% 0% 0% 0% 3% Neck pain 97% 3% 0% 0% 0% 0% 3% Infections and infestations—candidiasis 97% 3% 0% 0% 0% 0% 3% Peripheral sensory neuropathy 97% 3% 0% 0% 0% 0% 3% Pelvic pain 94% 3% 3% 0% 0% 0% 6% Gastrointestinal disorders—polydipsia 97% 3% 0% 0% 0% 0% 3% Blood and lymphatic system disorders—polycythemia 97% 3% 0% 0% 0% 0% 3% Rash acneiform 83% 17% 0% 0% 0% 0% 17% Respiratory, thoracic, and mediastinal disorders—rhinorrhea 97% 3% 0% 0% 0% 0% 3% Insomnia 97% 3% 0% 0% 0% 0% 3% Tinnitus 97% 3% 0% 0% 0% 0% 3% Reproductive system and breast disorders—wheezing 97% 3% 0% 0% 0% 0% 3% Infections and infestations—bacteremia 97% 0% 0% 0% 3% 0% 3% Amnesia 97% 0% 3% 0% 0% 0% 3% Respiratory failure 97% 0% 0% 0% 3% 0% 3% Colitis 91% 0% 0% 9% 0% 0% 9% Infections and infestations—Clostridium difficile 97% 0% 3% 0% 0% 0% 3% Blood and lymphatic system disorders—deep vein thrombosis 97% 0% 3% 0% 0% 0% 3% Dehydration 94% 0% 3% 3% 0% 0% 6% Thromboembolic event 94% 0% 0% 6% 0% 0% 6% Cardiac disorders—diastolic hypertension 97% 0% 3% 0% 0% 0% 3% Gastrointestinal disorders—hematemesis 97% 0% 3% 0% 0% 0% 3% Hypotension 97% 0% 0% 3% 0% 0% 3% Hypothyroidism 94% 0% 6% 0% 0% 0% 6% Hypoxia 97% 0% 0% 0% 3% 0% 3% Infections and infestations—skin 97% 0% 0% 3% 0% 0% 3% Irritability 97% 0% 3% 0% 0% 0% 3% Lymphocyte count decreased 94% 0% 0% 6% 0% 0% 6% Confusion 97% 0% 3% 0% 0% 0% 3% Bone pain 97% 0% 3% 0% 0% 0% 3% Photophobia 97% 0% 3% 0% 0% 0% 3% General disorders and administration site conditions—night 97% 0% 3% 0% 0% 0% 3% sweats Pleural effusion 97% 0% 3% 0% 0% 0% 3% Pleuritic pain 97% 0% 3% 0% 0% 0% 3% Fracture 97% 0% 3% 0% 0% 0% 3% Seizure 97% 0% 0% 3% 0% 0% 3% Upper respiratory infection 97% 0% 3% 0% 0% 0% 3% Sepsis 97% 0% 0% 0% 3% 0% 3% Sinus tachycardia 91% 0% 9% 0% 0% 0% 9% Rhinitis infective 97% 0% 3% 0% 0% 0% 3% Urinary tract infection 97% 0% 3% 0% 0% 0% 3% Abbreviation: NC/NA, no change from baseline/no adverse event. www.TheOncologist.com © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 e1844 Phase II of ENMD-2076 in FLC SERIOUS ADVERSE EVENTS Name Grade Attribution Sepsis 4 Unlikely Liver failure 4 Possible Respiratory failure 4 Unlikely Seizure 3 Possible ASSESSMENT,ANALYSIS, AND DISCUSSION Completion Study completed Investigator’s Assessment Inactive because results did not meet primary endpoint Fibrolamellar carcinoma (FLC) was first described by critical clues that suggest potential therapeutic targets, Edmondson in 1956 [13]. It is a distinctly uncommon primary including AURKA. However, the present study provides no liver neoplasm and very rare cancer of adolescents and young rationale to further study ENMD-2076 as a single agent in adults [2]. It represents 0.6%–8.6% of all hepatocellular carci- FLC, but it does seem to suggest a combination multitargeted nomas based on the 1986–1999 Surveillance, Epidemiology, therapeutic approach rather than a single-agent approach. and End Results data and various international series [14]. The transcriptional effects of DNAJB1-PRKACA have nominated FLC is characterized pathologically with large polygonal cells other targets as well. We started our efforts based on the pos- with abundant eosinophilic cytoplasm and large nucleoli. The tulation that FLC has a neuroendocrine origin [8, 9]. Unfortu- term fibrolamellar is related to the presence of thick fibrous nately, the study of everolimus, leuprolide, and letrozole collagen bands surrounding the cancer cells. Cytoplasmic pale did not show any promise [10], despite the attempt to bodies and copper deposits may be present. On immunohis- block the cross-communication between the estrogen recep- tochemistry, the presumed correlated to liver and/or neuro- tor and PI3K/Akt/mTOR pathway [11]. Similarly, the increased endocrine primary, α-fetoprotein, synaptophysin, and expression of the breast cancer oncogene v-erb-b2 avian chromogranin, are typically absent. In contrast, immunoreac- erythroblastic leukemia viral oncogene homolog 2 (ErbB2)[5] tivity for HepPar-1, polyclonal carcinoembryonic antigen observed in FLC [3] led to the study of neratinib as (pCEA), cytokeratin 7, and epithelial membrane antigen is monotherapy in patients with FLC (ClinicalTrials.gov: present in nearly all FLC tumors, suggesting that this disease NCT01953926). The present work using an Aurora kinase A entity may be a hepatobiliary hybrid [15]. Data suggest a inhibitor also derived from study of the transcriptional effects slight female preponderance [14]. The relatively high preva- of DNAJB1-PRKACA. lence of this disease among whites is noteworthy and may This effort was also based on nonreported preclinical represent referral bias, with a possible socioeconomic under- study of three different human hepatocellular carcinoma cell current. Reports of long-term survival with resection and/or lines (SMMC-7721, QGY-7703, and HepG 2) with tumor xeno- transplantation helped promote a perception of FLC as being graft models in nude mice. These cell lines were subject to an indolent disease. In the referenced cohort of 95 patients ENMD-2076 treatment alone or in combination with chemo- with FLC collected from three institutions (Memorial Sloan therapy agents, including doxorubicin or fluorouracil. The fol- Kettering Cancer Center, the University of California San Fran- lowing clinical studies were encouraging with a clinical cisco, and Johns Hopkins Hospital) from 1986 to 2011, benefit observed with one unconfirmed partial response in a median overall survival for the entire cohort was 6.7 years, patient with FLC as mentioned above. The patient relapsed with a median follow-up time for living patients of 3.4 years, after multiple treatments including transarterial chemo showing high recurrence rates after surgery [14]. Factors sig- embolization (TACE)/doxorubicin, TACE/cisplatin, liver trans- nificantly associated with poor survival were female sex, plantation, and sorafenib. The patient was on ENMD-2076 advanced stage, lymph node metastases, macrovascular inva- for eighteen 4-week cycles while maintaining stable disease sion, and unresectable disease. for 17 months [4]. It appears that the cancer is driven by a fusion gene, Despite the link between expression of the gene fusion DNAJB1-PRKACA, comprising the first exon of DNAJB1, the and changes of gene expression and signaling, it is, as yet, heat-shock protein 40 fused with PRKACA exons 2 through not possible to determine whether the changes are the 10 [2]. No specific agents have been developed yet to target result of increased expression of the PRKACA as a conse- PRKACA or the gene fusion. quence of the DNAJB1 promoter, or changes of activity of Unfortunately, this study evaluating the Aurora kinase A PRKACA [4]. More than 3,500 genetic expression changes (AURKA) inhibitor ENMD-2076 in patients with FLC did not have been noted in FLC [4]. It remains unclear if these wide- meet its primary efficacy endpoint. This is despite preclinical spread gene expression changes could be accounted for by in vivo animal model studies demonstrating the association AURKA effects on transcription factors, and if the chimera is of AURKA with FLC [3], ENMD-2076 antiangiogenic activity, sufficient for transformation or which of the changes in and a clinical benefit with a partial response in one patient gene expression are driving the transformation. Thus, a with FLC who relapsed after multiple prior treatments [4]. simultaneous targeting approach of the presumed primary Although the DNAJB1-PRKACA is neither specific nor sensitive genetic driver for FLC, the chimera of DNAJB1-PRKACA, and to FLC [5–7], its transcriptome characterization [3] provides the critical downstream components may be needed [12]. © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 Abou-Alfa, Mayer, Venook et al. e1845 Janssen Pharmaceuticals (E); James J. Harding: Bristol-Meyers DISCLOSURES Squibb, Eisai, Exelexis, Imvax, Cytomx (C/A); Alexander Ghassan K. Abou-Alfa: Casi Pharmaceuticals (C/A), Casi Zukiwski: CASI Pharmaceuticals (E, OI); John D. Gordan: CASI Pharmaceuticals, Puma (RF); Alan P. Venook: Genentech, Pharmaceuticals (RF). The other authors indicated no financial Roche (C/A), Amgen (RF); Muhammad S. Beg: Ipsen (C/A), relationships. Celgene, Bristol-Myers Squibb, AstraZeneca/MedImmune, (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert Merck Serono, Agios, Five Prime Therapeutics, MedImmune, testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ ArQule, Genentech, Sillajen, CASI Pharmaceuticals, inventor/patent holder; (SAB) Scientific advisory board Immunesensor, Tolero Pharmaceuticals (RF); Rachel Kobos: REFERENCES 1. El-Serag HB, Davila JA. Is fibrolamellar carci- fibrolamellar hepatocellular carcinoma. Mod Pathol 11. Prat A, Baselga J. The role of hormonal ther- noma different from hepatocellular carcinoma? https://doi.org/10.1038/s41379-019-0398-2. apy in the management of hormonal-receptor- A US population-based study. Hepatology 2004; positive breast cancer with co-expression of 6. Graham RP, Lackner C, Terracciano L et al. 39:798–803. HER2. Nat Clin Pract Oncol 2008;5:531–542. Fibrolamellar carcinoma in the Carney complex: 2. 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Phase II Multicenter, Open‐Label Study of Oral ENMD‐2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma

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Oxford University Press
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Copyright © 2022 Oxford University Press
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1083-7159
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1549-490X
DOI
10.1634/theoncologist.2020-0093
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Abstract

Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 Clinical Trial Results Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma a,h b c b d a,h GHASSAN K. ABOU-ALFA, ROBERT MAYER, ALAN P. VENOOK, ALLISON F. O’NEILL, MUHAMMAD S. BEG, MICHAEL LAQUAGLIA, a,h a,h a,h a,h d a,h e PETER T. KINGHAM, RACHEL KOBOS, OLCA BASTURK, CAMERON BRENNAN, ADAM YOPP, JAMES J. HARDING, STEPHEN LEONG, f f g h h h i i JOHN CROWN, EMIR HOTI, GREGORY LEONARD, MICHELE LY, MIKAELA BRADLEY, EMILY VALENTINO, DAVID MARKOWITZ, ALEXANDER ZUKIWSKI, i c KEN REN, JOHN D. GORDAN a b Weill Medical College at Cornell University, New York, New York, USA; Dana-Farber Cancer Institute, Harvard University, Boston, c d Massachusetts, USA; University of California San Francisco, San Francisco, California, USA; UT Southwestern Medical Center, Dallas, e f g Texas, USA; University of Colorado Cancer Center, Aurora, Colorado, USA; St Vincent’s Private Hospital, Dublin, Ireland; Galway h i University Hospital, Galway, Ireland; Memorial Sloan Kettering Cancer Center, New York, New York, USA; CASI Pharmaceuticals, Inc., Rockville, Maryland, USA TRIAL INFORMATION � ClinicalTrials.gov Identifier: NCT02234986 � Principal Investigator: Ghassan K. Abou-Alfa � Sponsor: CASI Pharmaceuticals � IRB Approved: Yes LESSONS LEARNED � The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. � ENMD-2076 showed a favorable toxicity profile. � The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support fur- ther evaluation of ENMD-2076 as single agent. � Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components. ABSTRACT Background. Fibrolamellar carcinoma (FLC) represents approx- Results. Of 35 patients who enrolled and received treatment, imately 0.85% of liver cancers. The associated DNAJB1-PRKACA 1 (3%) had a partial response (PR) and 20 (57%) had stable gene fusion transcript RNA codes for the catalytic domain of disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 protein kinase A and overexpression of Aurora kinase A months, respectively. The most frequently reported drug- (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor. related serious adverse event was hypertension in three Methods. Patients aged >12 years with pathologically con- patients. Three deaths were reported on-study—two due to firmed incurable FLC, with measurable disease, Eastern Coop- disease progression and one due to pulmonary embolism erative Oncology Group performance status 0–2orLansky not related to ENMD-2076. 70–100, and adequate organ function were eligible. Patients Conclusion. The study provided no rationale for further were prescribed ENMD-2076 based on body surface area. studying ENMD-2076 as a single agent in FLC. The Oncologist The primary endpoint was overall objective response rate by 2020;25:e1837–e1845 RECIST v1.1, with a null hypothesis of true response rate of DISCUSSION 2% versus one-sided alternative of 15%. Secondary end- points included 6-month progression-free survival (PFS) Fibrolamellar hepatocellular carcinoma is a very rare liver cancer of adolescents and young adults [1]. It appears rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the that the cancer is driven by a fusion gene, DNAJB1- PRKACA, comprising the first exon of DNAJB1, the heat- study. Correspondence: Ghassan K. Abou-Alfa, M.D., Memorial Sloan Kettering Cancer Center, 300 East 66th St., New York, New York 10065, USA. Telephone: 646-888-4184; e-mail: abou-alg@mskcc.org Received December 21, 2020; accepted for publication February 3, 2020; published Online First on March 10, 2020. © AlphaMed Press; the data published online to support this summary is the property of the authors. http://dx.doi. org/10.1634/theoncologist.2020-0093 No part of this article may be reproduced, stored, or transmitted in any form or for any means without the prior permission in writing from the copyright holder. For information on purchasing reprints contact Commercialreprints@wiley.com. For permission information contact permissions@wiley.com. The Oncologist 2020;25:e1837–e1845 www.TheOncologist.com © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 e1838 Phase II of ENMD-2076 in FLC multiple prior treatments [4]. Although the DNAJB1- PRKACA is neither specific nor sensitive to FLC [5–7], its transcriptome characterization [3] provides critical clues that suggest potential therapeutic targets, including AURKA. How- ever, the present study provides no rationale to further study ENMD-2076 as a single agent in FLC. The transcriptional effects of DNAJB1-PRKACA have nominated other targets as well [8, 9]. The study of everolimus, leuprolide, and letrozole unfortunately did not show any promise [10], despite the attempt to block the cross-communication between the estrogen receptor and PI3K/Akt/mTOR pathway [11]. Simi- larly, the increased expression of the breast cancer oncogene v-erb-b2 avian erythroblastic leukemia viral oncogene homo- log 2 (ErbB2) [5] observed in FLC [3] led to the study of Figure 1. Kaplan-Meier plot of progression-free survival. neratinib as monotherapy in patients with FLC (ClinicalTrials. gov: NCT01953926). Despite the link between expression of the DNAJB1- PRKACA gene fusion and downstream changes of gene expres- sion and signaling, it is not yet possible to determine whether shock protein 40 fused with PRKACA exons 2 through 10 the latter changes are the result of increased expression [2]. This results in an overexpressed chimeric protein that of PRKACA as a consequence of the DNAJB1 promoter or has intact Aurora kinase A enzymatic activity. No specific whether there are changes in the activity of PRKACA [4]. It agents have been developed yet to target PRKACA or the remains unclear if the chimera is sufficient for transformation gene fusion. Unfortunately, this study evaluating the or which of the changes in reported 3500 gene expression Aurora kinase inhibitor ENMD-2076 in patients with FLC maybedriving thetransformation[4].One maywonderif did not meet its primary efficacy endpoint. This is despite a simultaneous targeting approach of the presumed preclinical in vivo animal model studies demonstrating the primary genetic driver for FLC, the chimera of DNAJB1- association of AURKA with FLC [3], ENMD-2076 anti- PRKACA, and the critical downstream components may be angiogenic activity, and a clinical benefit with a partial needed [12]. response in one patient with FLC who relapsed after TRIAL INFORMATION Disease Fibrolamellar carcinoma Stage of Disease/Treatment Metastatic/advanced Prior Therapy No designated number of regimens Type of Study Phase II, single arm Primary Endpoint Overall response rate Secondary Endpoint 6-month progression-free survival Secondary Endpoint Progression-free survival Secondary Endpoint Time to progression Secondary Endpoint Overall survival Secondary Endpoint Toxicity Secondary Endpoint Correlative endpoint Investigator’s Analysis Inactive because results did not meet primary endpoint DRUG INFORMATION Generic/Working Name ENMD-2076 Company Name CASI Pharmaceuticals Drug Type Biological Drug Class Aurora kinase A (ARUKA) Dose 150 mg/day, 200 mg/day, or 250 mg/day based on body surface area (mg per flat dose) Route p.o. © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 Abou-Alfa, Mayer, Venook et al. e1839 Schedule of Administration Body surface area, m Daily dose, mg <1.00 150 1.00 to <1.40 200 ≥1.40 250 PATIENT CHARACTERISTICS Number of Patients, Male 16 Number of Patients, Female 19 Age Median (range): 25 (12–52) Number of Prior Systemic Therapies Median (range): Median (Q3–Q1) is 4 (8–3) Performance Status ECOG status at baseline n (%) 0 12 (36.4) 1 19 (57.6) 2 2 (6.1) Lansky status at baseline n (%) = 100 1 (50.0) = 90 1 (50.0) The percentage for ECOG status at baseline is calculated using the number of patients aged 16 and older as the denominator. The percentage for Lansky status at baseline is based on the number of patients younger than 16 as the denominator. Abbreviation: ECOG, Eastern Cooperative Oncology Group. PRIMARY ASSESSMENT METHOD:OVERALL SURVIVAL Number of Patients Screened 43 Number of Patients Enrolled 35 Number of Patients Evaluable for Toxicity 35 Number of Patients Evaluated for Efficacy 35 (Median) Duration Assessments OS 18.6, CI: 12.9–29.8 KAPLAN-MEIER TIME UNITS,MONTHS No. at next Time of scheduled assessment No. progressed No. Percent at start of Kaplan- evaluation/No. and/or time of event (or deaths) censored evaluation period Meier % at risk 0 0 0 100.00 100.00 35 2 2 0 100.00 94.29 33 4 0 0 94.29 94.29 33 6 6 0 94.29 77.14 27 8 2 0 77.14 71.43 25 10 6 0 71.43 54.29 19 12 1 0 54.29 51.43 18 14 4 0 51.43 40.00 14 16 2 0 40.00 34.29 12 18 1 0 34.29 31.43 11 20 3 0 31.43 22.86 8 22 3 0 22.86 14.29 5 24 2 0 14.29 8.57 3 26 1 0 8.57 5.71 2 28 1 0 5.71 2.86 1 30 1 0 2.86 0.00 0 www.TheOncologist.com © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 e1840 Phase II of ENMD-2076 in FLC Kaplan-Meier Plot of Overall Survival (Efficacy Analysis Population) PRIMARY ASSESSMENT METHOD:PROGRESSION-FREE SURVIVAL Number of Patients Screened 43 Number of Patients Enrolled 35 Number of Patients Evaluable for Toxicity 35 Number of Patients Evaluated for Efficacy 35 Evaluation Method RECIST 1.1 Response Assessment CR n = 0 (0%) Response Assessment PR n = 1 (3%) Response Assessment SD n = 20 (57%) Response Assessment PD n = 10 (34.3%) Response Assessment OTHER n = 2 (5.7%) (Median) Duration Assessments PFS 3.9 months, CI: 2.3–5.5 (Median) Duration Assessments TTP 5 months, CI: 0.7–5.7 (Median) Duration Assessments Response Duration 14.69 months KAPLAN-MEIER TIME UNITS,MONTHS No. at next Time of scheduled assessment No. progressed No. Percent at start of Kaplan- evaluation/No. and/or time of event (or deaths) censored evaluation period Meier % at risk 0 0 1 100.00 100.00 34 1 3 0 100.00 91.18 31 2 8 0 91.18 67.65 23 3 3 0 67.65 58.82 20 4 3 0 58.82 50.00 17 5 2 0 50.00 44.12 15 6 6 1 44.12 25.21 8 7 3 0 25.21 15.76 5 8 0 0 15.76 15.76 5 9 0 0 15.76 15.76 5 10 1 0 15.76 12.61 4 11 0 0 12.61 12.61 4 © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 Abou-Alfa, Mayer, Venook et al. e1841 12 1 0 12.61 9.45 3 13 1 0 9.45 6.30 2 14 0 0 6.30 6.30 2 15 0 0 6.30 6.30 2 16 0 0 6.30 6.30 2 17 1 0 6.30 3.15 1 18 0 0 3.15 3.15 1 19 1 0 3.15 0.00 0 Kaplan-Meier Plot of Progression-Free Survival (Efficacy Analysis Population) ADVERSE EVENTS (ALL CYCLES) Name NC/NA 1 2 3 4 5 All grades Fatigue 23% 66% 11% 0% 0% 0% 77% Fever 91% 9% 0% 0% 0% 0% 9% Chills 94% 6% 0% 0% 0% 0% 6% Nausea 43% 46% 11% 0% 0% 0% 57% Vomiting 74% 20% 6% 0% 0% 0% 26% Diarrhea 35% 37% 11% 17% 0% 0% 65% Constipation 77% 17% 6% 0% 0% 0% 23% Anemia 74% 17% 6% 3% 0% 0% 26% Neutrophil count decreased 94% 6% 0% 0% 0% 0% 6% Platelet count decreased 86% 14% 0% 0% 0% 0% 14% Blood and lymphatic system disorders—increased hemoglobin 89% 11% 0% 0% 0% 0% 11% INR increased 91% 6% 3% 0% 0% 0% 9% Activated partial thromboplastin time prolonged 83% 11% 0% 6% 0% 0% 17% Cough 74% 20% 6% 0% 0% 0% 26% Pharyngolaryngeal pain 91% 9% 0% 0% 0% 0% 9% Sinus disorder 94% 6% 0% 0% 0% 0% 6% Dyspnea 71% 14% 9% 6% 0% 0% 29% Weight loss 80% 14% 3% 3% 0% 0% 20% Gastrointestinal disorders—decreased appetite 72% 17% 11% 0% 0% 0% 28% www.TheOncologist.com © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 e1842 Phase II of ENMD-2076 in FLC Dry mouth 94% 6% 0% 0% 0% 0% 6% Abdominal distension 94% 6% 0% 0% 0% 0% 6% Hypercalcemia 91% 6% 3% 0% 0% 0% 9% Hypomagnesemia 71% 23% 6% 0% 0% 0% 29% Hypertension 58% 11% 20% 11% 0% 0% 42% Renal and urinary disorders—hypernatremia 91% 9% 0% 0% 0% 0% 9% Aspartate aminotransferase increased 31% 43% 17% 9% 0% 0% 69% Abdominal pain 34% 31% 29% 6% 0% 0% 66% Alanine aminotransferase increased 26% 37% 14% 20% 3% 0% 74% Alkaline phosphatase increased 57% 26% 14% 3% 0% 0% 43% Hypoalbuminemia 71% 23% 3% 3% 0% 0% 29% Hypoglycemia 91% 9% 0% 0% 0% 0% 9% Hyperglycemia 54% 37% 6% 3% 0% 0% 46% Hyponatremia 74% 26% 0% 0% 0% 0% 26% Hyperkalemia 83% 14% 3% 0% 0% 0% 17% Mucositis oral 88% 9% 3% 0% 0% 0% 12% Dizziness 91% 9% 0% 0% 0% 0% 9% Palpitations 94% 6% 0% 0% 0% 0% 6% Dry skin 94% 6% 0% 0% 0% 0% 6% Rash acneiform 86% 14% 0% 0% 0% 0% 14% Hypocalcemia 85% 9% 3% 3% 0% 0% 15% Headache 66% 23% 11% 0% 0% 0% 34% Insomnia 85% 9% 6% 0% 0% 0% 15% Myalgia 89% 11% 0% 0% 0% 0% 11% Palmar-plantar erythrodysesthesia syndrome 88% 6% 6% 0% 0% 0% 12% Proteinuria 80% 6% 11% 3% 0% 0% 20% Blurred vision 94% 6% 0% 0% 0% 0% 6% White blood cell decreased 94% 6% 0% 0% 0% 0% 6% Rash acneiform 94% 6% 0% 0% 0% 0% 6% Alopecia 97% 3% 0% 0% 0% 0% 3% Encephalopathy 94% 3% 0% 3% 0% 0% 6% Fecal incontinence 97% 3% 0% 0% 0% 0% 3% Back pain 88% 3% 6% 3% 0% 0% 12% Blood bilirubin increased 82% 3% 6% 9% 0% 0% 18% Creatinine increased 97% 3% 0% 0% 0% 0% 3% Noncardiac chest pain 94% 6% 0% 0% 0% 0% 6% Chest pain—cardiac 97% 3% 0% 0% 0% 0% 3% Colitis 97% 3% 0% 0% 0% 0% 3% Bruising 97% 3% 0% 0% 0% 0% 3% Depression 97% 3% 0% 0% 0% 0% 3% Dyspepsia 94% 3% 3% 0% 0% 0% 6% Dysphasia 97% 3% 0% 0% 0% 0% 3% Left ventricular systolic dysfunction 91% 3% 6% 0% 0% 0% 9% Electrocardiogram QT corrected interval prolonged 97% 3% 0% 0% 0% 0% 3% Infections and infestations—enteritis 94% 3% 0% 3% 0% 0% 6% Epistaxis 97% 3% 0% 0% 0% 0% 3% Flatulence 97% 3% 0% 0% 0% 0% 3% Eye disorders—pain 97% 3% 0% 0% 0% 0% 3% Gastrointestinal disorders—reflux 97% 3% 0% 0% 0% 0% 3% Gastrointestinal disorders—hyperchlorhydria 97% 3% 0% 0% 0% 0% 3% Hyperuricemia 97% 3% 0% 0% 0% 0% 3% © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 Abou-Alfa, Mayer, Venook et al. e1843 Hearing impaired 97% 3% 0% 0% 0% 0% 3% Renal and urinary disorders—hypochloremia 97% 3% 0% 0% 0% 0% 3% Hypokalemia 97% 3% 0% 0% 0% 0% 3% Hypophosphatemia 86% 3% 11% 0% 0% 0% 14% Chest wall pain 97% 3% 0% 0% 0% 0% 3% Generalized muscle weakness 97% 3% 0% 0% 0% 0% 3% Pain 94% 6% 0% 0% 0% 0% 6% Edema limbs 97% 3% 0% 0% 0% 0% 3% Neck pain 97% 3% 0% 0% 0% 0% 3% Infections and infestations—candidiasis 97% 3% 0% 0% 0% 0% 3% Peripheral sensory neuropathy 97% 3% 0% 0% 0% 0% 3% Pelvic pain 94% 3% 3% 0% 0% 0% 6% Gastrointestinal disorders—polydipsia 97% 3% 0% 0% 0% 0% 3% Blood and lymphatic system disorders—polycythemia 97% 3% 0% 0% 0% 0% 3% Rash acneiform 83% 17% 0% 0% 0% 0% 17% Respiratory, thoracic, and mediastinal disorders—rhinorrhea 97% 3% 0% 0% 0% 0% 3% Insomnia 97% 3% 0% 0% 0% 0% 3% Tinnitus 97% 3% 0% 0% 0% 0% 3% Reproductive system and breast disorders—wheezing 97% 3% 0% 0% 0% 0% 3% Infections and infestations—bacteremia 97% 0% 0% 0% 3% 0% 3% Amnesia 97% 0% 3% 0% 0% 0% 3% Respiratory failure 97% 0% 0% 0% 3% 0% 3% Colitis 91% 0% 0% 9% 0% 0% 9% Infections and infestations—Clostridium difficile 97% 0% 3% 0% 0% 0% 3% Blood and lymphatic system disorders—deep vein thrombosis 97% 0% 3% 0% 0% 0% 3% Dehydration 94% 0% 3% 3% 0% 0% 6% Thromboembolic event 94% 0% 0% 6% 0% 0% 6% Cardiac disorders—diastolic hypertension 97% 0% 3% 0% 0% 0% 3% Gastrointestinal disorders—hematemesis 97% 0% 3% 0% 0% 0% 3% Hypotension 97% 0% 0% 3% 0% 0% 3% Hypothyroidism 94% 0% 6% 0% 0% 0% 6% Hypoxia 97% 0% 0% 0% 3% 0% 3% Infections and infestations—skin 97% 0% 0% 3% 0% 0% 3% Irritability 97% 0% 3% 0% 0% 0% 3% Lymphocyte count decreased 94% 0% 0% 6% 0% 0% 6% Confusion 97% 0% 3% 0% 0% 0% 3% Bone pain 97% 0% 3% 0% 0% 0% 3% Photophobia 97% 0% 3% 0% 0% 0% 3% General disorders and administration site conditions—night 97% 0% 3% 0% 0% 0% 3% sweats Pleural effusion 97% 0% 3% 0% 0% 0% 3% Pleuritic pain 97% 0% 3% 0% 0% 0% 3% Fracture 97% 0% 3% 0% 0% 0% 3% Seizure 97% 0% 0% 3% 0% 0% 3% Upper respiratory infection 97% 0% 3% 0% 0% 0% 3% Sepsis 97% 0% 0% 0% 3% 0% 3% Sinus tachycardia 91% 0% 9% 0% 0% 0% 9% Rhinitis infective 97% 0% 3% 0% 0% 0% 3% Urinary tract infection 97% 0% 3% 0% 0% 0% 3% Abbreviation: NC/NA, no change from baseline/no adverse event. www.TheOncologist.com © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 e1844 Phase II of ENMD-2076 in FLC SERIOUS ADVERSE EVENTS Name Grade Attribution Sepsis 4 Unlikely Liver failure 4 Possible Respiratory failure 4 Unlikely Seizure 3 Possible ASSESSMENT,ANALYSIS, AND DISCUSSION Completion Study completed Investigator’s Assessment Inactive because results did not meet primary endpoint Fibrolamellar carcinoma (FLC) was first described by critical clues that suggest potential therapeutic targets, Edmondson in 1956 [13]. It is a distinctly uncommon primary including AURKA. However, the present study provides no liver neoplasm and very rare cancer of adolescents and young rationale to further study ENMD-2076 as a single agent in adults [2]. It represents 0.6%–8.6% of all hepatocellular carci- FLC, but it does seem to suggest a combination multitargeted nomas based on the 1986–1999 Surveillance, Epidemiology, therapeutic approach rather than a single-agent approach. and End Results data and various international series [14]. The transcriptional effects of DNAJB1-PRKACA have nominated FLC is characterized pathologically with large polygonal cells other targets as well. We started our efforts based on the pos- with abundant eosinophilic cytoplasm and large nucleoli. The tulation that FLC has a neuroendocrine origin [8, 9]. Unfortu- term fibrolamellar is related to the presence of thick fibrous nately, the study of everolimus, leuprolide, and letrozole collagen bands surrounding the cancer cells. Cytoplasmic pale did not show any promise [10], despite the attempt to bodies and copper deposits may be present. On immunohis- block the cross-communication between the estrogen recep- tochemistry, the presumed correlated to liver and/or neuro- tor and PI3K/Akt/mTOR pathway [11]. Similarly, the increased endocrine primary, α-fetoprotein, synaptophysin, and expression of the breast cancer oncogene v-erb-b2 avian chromogranin, are typically absent. In contrast, immunoreac- erythroblastic leukemia viral oncogene homolog 2 (ErbB2)[5] tivity for HepPar-1, polyclonal carcinoembryonic antigen observed in FLC [3] led to the study of neratinib as (pCEA), cytokeratin 7, and epithelial membrane antigen is monotherapy in patients with FLC (ClinicalTrials.gov: present in nearly all FLC tumors, suggesting that this disease NCT01953926). The present work using an Aurora kinase A entity may be a hepatobiliary hybrid [15]. Data suggest a inhibitor also derived from study of the transcriptional effects slight female preponderance [14]. The relatively high preva- of DNAJB1-PRKACA. lence of this disease among whites is noteworthy and may This effort was also based on nonreported preclinical represent referral bias, with a possible socioeconomic under- study of three different human hepatocellular carcinoma cell current. Reports of long-term survival with resection and/or lines (SMMC-7721, QGY-7703, and HepG 2) with tumor xeno- transplantation helped promote a perception of FLC as being graft models in nude mice. These cell lines were subject to an indolent disease. In the referenced cohort of 95 patients ENMD-2076 treatment alone or in combination with chemo- with FLC collected from three institutions (Memorial Sloan therapy agents, including doxorubicin or fluorouracil. The fol- Kettering Cancer Center, the University of California San Fran- lowing clinical studies were encouraging with a clinical cisco, and Johns Hopkins Hospital) from 1986 to 2011, benefit observed with one unconfirmed partial response in a median overall survival for the entire cohort was 6.7 years, patient with FLC as mentioned above. The patient relapsed with a median follow-up time for living patients of 3.4 years, after multiple treatments including transarterial chemo showing high recurrence rates after surgery [14]. Factors sig- embolization (TACE)/doxorubicin, TACE/cisplatin, liver trans- nificantly associated with poor survival were female sex, plantation, and sorafenib. The patient was on ENMD-2076 advanced stage, lymph node metastases, macrovascular inva- for eighteen 4-week cycles while maintaining stable disease sion, and unresectable disease. for 17 months [4]. It appears that the cancer is driven by a fusion gene, Despite the link between expression of the gene fusion DNAJB1-PRKACA, comprising the first exon of DNAJB1, the and changes of gene expression and signaling, it is, as yet, heat-shock protein 40 fused with PRKACA exons 2 through not possible to determine whether the changes are the 10 [2]. No specific agents have been developed yet to target result of increased expression of the PRKACA as a conse- PRKACA or the gene fusion. quence of the DNAJB1 promoter, or changes of activity of Unfortunately, this study evaluating the Aurora kinase A PRKACA [4]. More than 3,500 genetic expression changes (AURKA) inhibitor ENMD-2076 in patients with FLC did not have been noted in FLC [4]. It remains unclear if these wide- meet its primary efficacy endpoint. This is despite preclinical spread gene expression changes could be accounted for by in vivo animal model studies demonstrating the association AURKA effects on transcription factors, and if the chimera is of AURKA with FLC [3], ENMD-2076 antiangiogenic activity, sufficient for transformation or which of the changes in and a clinical benefit with a partial response in one patient gene expression are driving the transformation. Thus, a with FLC who relapsed after multiple prior treatments [4]. simultaneous targeting approach of the presumed primary Although the DNAJB1-PRKACA is neither specific nor sensitive genetic driver for FLC, the chimera of DNAJB1-PRKACA, and to FLC [5–7], its transcriptome characterization [3] provides the critical downstream components may be needed [12]. © AlphaMed Press 2020 Downloaded from https://academic.oup.com/oncolo/article/25/12/e1837/6443932 by DeepDyve user on 01 February 2022 Abou-Alfa, Mayer, Venook et al. e1845 Janssen Pharmaceuticals (E); James J. Harding: Bristol-Meyers DISCLOSURES Squibb, Eisai, Exelexis, Imvax, Cytomx (C/A); Alexander Ghassan K. Abou-Alfa: Casi Pharmaceuticals (C/A), Casi Zukiwski: CASI Pharmaceuticals (E, OI); John D. Gordan: CASI Pharmaceuticals, Puma (RF); Alan P. Venook: Genentech, Pharmaceuticals (RF). The other authors indicated no financial Roche (C/A), Amgen (RF); Muhammad S. Beg: Ipsen (C/A), relationships. Celgene, Bristol-Myers Squibb, AstraZeneca/MedImmune, (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert Merck Serono, Agios, Five Prime Therapeutics, MedImmune, testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ ArQule, Genentech, Sillajen, CASI Pharmaceuticals, inventor/patent holder; (SAB) Scientific advisory board Immunesensor, Tolero Pharmaceuticals (RF); Rachel Kobos: REFERENCES 1. El-Serag HB, Davila JA. Is fibrolamellar carci- fibrolamellar hepatocellular carcinoma. Mod Pathol 11. Prat A, Baselga J. The role of hormonal ther- noma different from hepatocellular carcinoma? https://doi.org/10.1038/s41379-019-0398-2. apy in the management of hormonal-receptor- A US population-based study. Hepatology 2004; positive breast cancer with co-expression of 6. Graham RP, Lackner C, Terracciano L et al. 39:798–803. HER2. Nat Clin Pract Oncol 2008;5:531–542. Fibrolamellar carcinoma in the Carney complex: 2. 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Published: Dec 1, 2020

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