First targeted therapy for cholangiocarcinoma shows clinical benefit in phase III trial

Barcelona, Spain, 30 September 2019 – New data have shown for the first time that targeted therapy can improve the outcome of patients diagnosed with advanced cholangiocarcinoma.

Cholangiocarcinoma is a subtype of bile duct cancer with aggressive behaviour and poor prognosis. (1) Despite the low incidence, most patients die from the disease and therefore new effective therapies are urgently needed.

The data reported at the ESMO Congress 2019 are the first to show clinical benefit with targeted therapy in cholangiocarcinoma. (2) Results of the ClarIDHy phase III trial have shown that ivosidenib, an oral drug targeting the isocitrate dehydrogenase 1 (IDH1) mutation, expected in around 15% of advanced cholagiocarcinoma patients, significantly improved progression-free survival with a trend to improved overall survival compared to placebo. (3)

“The ClarIDHy study demonstrates for the first time the feasibility and clinical benefit of targeting a molecularly defined subgroup in cholangiocarcinoma. It shows that targeting mutated IDH1 with ivosidenib significantly improves progression-free survival and gives a favourable trend in overall survival in patients with advanced IDH1-mutated cholangiocarcinoma,” said study author Dr Ghassan Abou-Alfa, Memorial Sloan-Kettering Cancer Center, New York, USA.

“The findings mean all patients with cholangiocarcinoma should be tested for IDH-1 mutation. Tumour mutation profiling should be a new standard for the care for patients with this heterogeneous tumour type,” he said. He considered that future studies should investigate ivosidenib as first-line treatment for IDH1-mutated cholangiocarcinoma in addition to its use in combination therapy and as adjuvant therapy.

Commenting on the relevance of the new data, Dr Chris Verslype, University Hospital Leuven, Belgium, said, “What we see in this study is really unprecedented. We previously had no options for patients with cholangiocarcinoma who failed systemic therapy, and they had very limited survival. These are important data. There is a gain in progression free survival with ivosidenib that is clinically relevant for this patient population,” he said.

Dr Angela Lamarca, Christie NHS Foundation Trust, Manchester, UK, representing the ESMO Press & Media Affairs Committee, agreed, “The reported median progression-free survival may seem short and some people may question whether this is clinically meaningful. However, for researchers working in cholangiocarcinoma it is a breakthrough. A treatment that increases the chance of being free from progression by 30% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families.”

Verslype noted, “It’s the first time in cholangiocarcinoma that a phase III study tests a drug targeted to a specific anomaly, and it seems to work. Importantly, you identify suitable patients by selecting them for IDH1 mutation. It’s precision medicine brought to the clinic. And it’s very likely to change clinical practice. It will, for sure, drive the further development of targeted therapy for this disease.”

Verslype considered there were few limitations. Patients selected for the study had to have good performance status after previous chemotherapy, so may not be representative of patients whose disease progresses rapidly on chemotherapy. “But it is still a strong study because of the randomisation to placebo. It showed a real effect.” The study had a high crossover rate from placebo to ivosidenib, making the overall survival endpoint difficult to assess, but he pointed out that allowing patients to crossover was important from an ethical perspective. “Additional analysis suggested a benefit in overall survival if there had been no crossover.”

Study results

The global phase 3 ClarIDHy study investigated the first in a new class of targeted drugs, ivosidenib, to target a mutant IDH-1 protein. Around one in six patients with cholangiocarcinoma have IDH1 mutations. These result in the production of a metabolite (D-2-hydroxyglutarate) that promotes oncogenesis.

The study randomised 185 patients with advanced cholangiocarcinoma and IDH1 mutations to ivosidenib or matched placebo. Patients could crossover from placebo to ivosidenib when their disease progressed.

Median progression-free survival was 2.7 months for patients treated with ivosidenib compared to 1.4 months with placebo (hazard ratio [HR] 0.37; 95% confidence interval [CI]: 0.25, 0.54, p

Results showed a favourable trend in overall survival with ivosidenib. Median overall survival was 10.8 months for ivosidenib and 9.7 months for placebo (HR 0.69, one-sided p=0.06). Adjusting the overall survival results to take account of 57% of placebo patients crossing over to ivosidenib gave an adjusted overall survival of 6 months for placebo, which was significantly shorter than with ivosidenib (HR 0.46, p=0.0008).

Ivosidenib was generally well tolerated, with Grade 3 or higher adverse events reported in 46% of patients on the targeted agent and 36% of those on placebo. There were no treatment-related deaths.

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Notes to Editors

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References

1 Patients are usually diagnosed in advanced stages when the cancer cannot be cured and when the aim is only to “control” the growth of the cancer. Treatment is based on chemotherapy and previous studies with targeted therapies failed to show any benefit to patients.

2 https://www.esmo.org/Conferences/ESMO-Congress-2019?hit=ehp

3 LBA10_PR ‘ClarIDHy: a global, phase 3, randomized, double-blind study of ivosidenib (ivo) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation’ will be presented by Ghassan Abou-Alfa during the Presidential Symposium III on Monday 30 September 2019, 16:30-18:15 CEST in Barcelona Auditorium (Hall 2). Annals of Oncology 30, Supplement 5, 2019.

About the European Society for Medical Oncology (ESMO)

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LBA10_PR – ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation

G.K. Abou-Alfa¹, T. Macarulla Mercade², M. Javle³, R.K. Kelley⁴, S. Lubner⁵, J. Adeva⁶, J.M. Cleary⁷, D.V. Catenacci⁸, M.J. Borad⁹, J.A. Bridgewater¹⁰, W.P. Harris¹¹, A.G. Murphy¹², D.-Y. Oh¹³, J. Whisenant¹⁴, B. Wu¹⁵, L. Jiang¹⁶, C. Gliser¹⁷, S.S. Pandya¹⁷, J.W. Valle¹⁸, A.X. Zhu¹⁹

1Memorial Sloan-Kettering Cancer Center, New York, United States of America, 2Medical Oncology Dept., Vall d’Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain, 3Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, United States of America, 4Medicine, University of California San Francisco, San Francisco, United States of America, 5Department Of Medicine, University of Wisconsin Carbone Cancer Center, Madison, United States of America, 6Department Of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain, 7Medicine, Dana-Faber Cancer Institute, Boston, United States of America, 8Gastrointestinal Oncology Program, University of Chicago, Chicago, United States of America, 9Department Of Internal Medicine, Mayo Clinic Cancer Center, Scottsdale, United States of America, 10Medical Oncology, UCL Cancer Institute/Paul O’Gorman Building, London, United Kingdom, 11Department Of Medicine, University of Washington School of Medicine, Seattle, United States of America, 12Department Of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America, 13Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea, 14Medical Oncology/haematology, Utah Cancer Specialists, Salt Lake City, United States of America, 15Translational/biomarker, Agios Pharmaceuticals, Inc., Boston, United States of America, 16Biostatistics – Clinical Development, Agios Pharmaceuticals, Inc., Boston, United States of America, 17Clinical Development, Agios Pharmaceuticals, Inc., Boston, United States of America, 18Department Of Medical Oncology, University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom, 19Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical Center, Boston, United States of America

Background: CC is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in up to ~15% of CC, resulting in production of the oncometabolite, D-2-hydroxyglutarate (2-HG), which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein.

Methods: Patients (pts) with mIDH1 CC were randomized 2:1 to IVO (500 mg once daily) or matched PBO and stratified by number of prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic mIDH1 CC based on central testing; ECOG PS 0-1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic PD. Primary endpoint: progression-free survival (PFS) by central review. Secondary endpoints included safety, ORR, PFS (local investigator review), and overall survival (OS; by ITT). Crossover-adjusted OS was derived using rank preserved structural failure time (RPSFT).

Results: As of 31Jan2019, 185 pts were randomized to IVO (n=124) or PBO (n=61). Median age 62 y, M/F 68/117, 91% intrahepatic CC, 92% metastatic disease, 43% had 2 prior therapies. Primary endpoint (PFS by central review) was met: HR=0.37 (95% CI 0.25, 0.54; p15%) in IVO arm: nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), vomiting (16.0%). Grade greater than equal to 3 adverse events reported in 46% IVO vs. 36% PBO. There were no treatment-related deaths.

Conclusions: IVO resulted in significant improvement in PFS and favorable OS trend vs. PBO. This is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in pts with advanced mIDH1 CC.

Clinical trial identification: NCT02989857

Editorial acknowledgement: Yvonna Fisher-Jeffes of Agios Pharmaceuticals, Inc and Helen Varley of Envision Pharma Group

Legal entity responsible for the study: Agios Pharmaceuticals, Inc.

Funding: Agios Pharmaceuticals, Inc.

Disclosure: G.K. Abou-Alfa: Advisory / Consultancy, Research grant / Funding (institution): 3DMedcare; Advisory / Consultancy: ActaBiologica; Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy: Alignmed; Advisory / Consultancy: Amgen; Advisory / Consultancy: Antengene; Advisory / Consultancy: Aptus; Research grant / Funding (institution): Array; Advisory / Consultancy: Aslan; Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Astra Zeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy: Bioline; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Boston Scientifc; Advisory / Consultancy: Bridgebio; Advisory / Consultancy: Carsgen; Advisory / Consultancy, Research grant / Funding (institution): Casi; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Cipla; Advisory / Consultancy: CytomX; Advisory / Consultancy: Daiichi; Advisory / Consultancy: Debio; Advisory / Consultancy: Delcath; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Genentech; Advisory / Consultancy: Genoscience; Advisory / Consultancy, Research grant / Funding (institution): Halozyme; Advisory / Consultancy: Hengrui; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Inovio; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Jazz; Advisory / Consultancy: Jansen; Advisory / Consultancy: Kyowa Kirin; Advisory / Consultancy: LAM; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Loxo; Research grant / Funding (institution): Mabvax; Advisory / Consultancy: Merck; Advisory / Consultancy: Mina; Research grant / Funding (institution): Novartis; Advisory / Consultancy: Novella; Research grant / Funding (institution): OncoQuest; Advisory / Consultancy: Onxeo; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pieris; Research grant / Funding (institution): Polaris; Research grant / Funding (institution): Puma; Advisory / Consultancy, Research grant / Funding (institution): QED; Advisory / Consultancy: Redhill; Research grant / Funding (institution): Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Silenseed; Advisory / Consultancy: Sillajen; Advisory / Consultancy: Sobi; Advisory / Consultancy: Targovax; Advisory / Consultancy: Tekmira; Advisory / Consultancy: Twoxar; Advisory / Consultancy: Vicus; Advisory / Consultancy: Yakult; Advisory / Consultancy: Yiviva.

T. Macarulla Mercade: Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self): Sanofi; Honoraria (self): Tesaro; Honoraria (self), Advisory / Consultancy: Shire; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Advisory / Consultancy: QDE; Advisory / Consultancy, Travel / Accommodation / Expenses: H3B; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi/Aventis; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Baxalta; Honoraria (self): Genzyme; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Aslan; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (institution): Genentech; Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution): Hallozyme; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merrimarck; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Novocure; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics.

M. Javle: Research grant / Funding (self): QED; Research grant / Funding (self): Novartis; Honoraria (self): Taiho; Research grant / Funding (self): Meclun; Honoraria (self): Seattle Genetics; Research grant / Funding (institution): Arqule; Honoraria (self): Merck; Research grant / Funding (institution): Lilly; Advisory / Consultancy: Origimed; Advisory / Consultancy: More Health; Advisory / Consultancy: EDO.

R.K. Kelley: Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy, Research grant / Funding (institution): Astra Zeneca; Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): QED; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy: Target Pharma Solutions; Advisory / Consultancy: Genentech/Roche.

J.M. Cleary: Honoraria (self), Travel / Accommodation / Expenses: Agios; Honoraria (self), Travel / Accommodation / Expenses: BMS; Research grant / Funding (self): Merck; Research grant / Funding (self): Tesaro; Travel / Accommodation / Expenses: Roche.

D.V. Catenacci: Honoraria (self): Astellas; Honoraria (self): Five Prime; Honoraria (self): BMS; Honoraria (self): Merck; Honoraria (self): Lilly; Honoraria (self): Taiho; Honoraria (self): Daichii Sankyo; Honoraria (self): Genentech/Roche; Honoraria (self): Foundation Medicine; Honoraria (self): Tempus; Honoraria (self): Guardant Health.

M.J. Borad: Research grant / Funding (institution): Senhwa Pharmaceuticals; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Agios Pharmaceuticals; Research grant / Funding (institution): Halozyme Pharmaceuticals; Research grant / Funding (institution): Celgene Pharmaceuticals; Research grant / Funding (institution): EMD Merck Serono; Research grant / Funding (institution): Toray; Research grant / Funding (institution): Dicerna; Research grant / Funding (institution): Taiho Pharmaceuticals; Research grant / Funding (institution): Sun Biopharma; Research grant / Funding (institution): Isis Pharmaceuticals; Research grant / Funding (institution): Redhill Pharmaceuticals; Research grant / Funding (institution): Boston Biomed; Research grant / Funding (institution): Basilea; Research grant / Funding (institution): Incyte Pharmaceuticals; Research grant / Funding (institution): Mirna Pharmaceuticals; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Bioline; Research grant / Funding (institution): Sillajen; Research grant / Funding (institution): ARIAD; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): Novartis Pharmaceuticals; Research grant / Funding (institution): QED Pharmaceuticals; Research grant / Funding (institution): Pieris; Honoraria (self): Exelixis; Honoraria (self): G1 Therapeutics; Honoraria (self): Immunovative Therapies; Shareholder / Stockholder / Stock options: OncBioMune Pharmaceuticals; Honoraria (self): Western Oncolytics; Honoraria (self): Lynx Group; Travel / Accommodation / Expenses: Astra Zeneca; Honoraria (self): Inspyr Therapeutics; Honoraria (self): ADC Therapeuctics; Shareholder / Stockholder / Stock options: Intercept; Shareholder / Stockholder / Stock options: AVEO.

J.A. Bridgewater: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Incyte; Advisory / Consultancy: Basilea; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen; Travel / Accommodation / Expenses: MDS Oncology; Travel / Accommodation / Expenses: Bristol-Myers Squibb/Medarex; Travel / Accommodation / Expenses: Bristol-Myers Squibb.

W.P. Harris: Advisory / Consultancy: NeoTherma; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Bristo-Myers Squibb; Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Halozyme; Research grant / Funding (institution): BTG; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Merck.

A.G. Murphy: Research grant / Funding (self): Bristol Myers Squibb.

D. Oh: Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme; Research grant / Funding (institution): Array; Research grant / Funding (institution): Eli Lilly.

B. Wu: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Agios.

L. Jiang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Agios.

C. Gliser: Shareholder / Stockholder / Stock options, Full / Part-time employment: Agios.

S.S. Pandya: Shareholder / Stockholder / Stock options, Full / Part-time employment: Agios.

J.W. Valle: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: NuCana; Advisory / Consultancy, Speaker Bureau / Expert testimony: Abbott; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Sirtex; Advisory / Consultancy: Agios; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Baxalta; Advisory / Consultancy: Bioven; Advisory / Consultancy: Delcath; Advisory / Consultancy: Genoscience Pharma; Advisory / Consultancy: Incyte; Advisory / Consultancy: Keocyt; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Midatech; Advisory / Consultancy: Mundipharma; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Pieris Pharmaceuticals; Advisory / Consultancy: QED Pharmaceuticals.

A.X. Zhu: Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Lilly; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Roche/Genentech.