A new targeted therapy can improve the outcome of patients diagnosed with advanced cholangiocarcinoma, a subtype of bile duct cancer with aggressive behavior and poor prognosis.
Cholangiocarcinom, also known as bile duct cancer, is an uncommon form of cancer that occurs mostly in people older than 50 years of age and is very difficult to treat. But despite a low incidence, most patients diagnosed with the disease die and therefore new effective therapies to meet the medical need of these patients are urgently needed.
Results of the ClarIDHy phase III trial (NCT02989857), a multicenter, randomized, double-blind, placebo-controlled study, presented during the European Society for Medical Oncology (ESMO) Congress 2019, being held in Barcelona, Spain, September 27 – October 1, 2019, demonstrated, for the first time, a clinical benefit with targeted therapy in cholangiocarcinoma.
The researcher investigated the first in a new class of targeted drugs. The results show that ivosidenib (Tibsovo®; Agios Pharmaceuticals), also known as AG-120, a first-in-class, oral, small-molecule inhibitor 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. 
The mutation result in the production of a metabolite D-2-hydroxyglutarate (2-HG) that promotes oncogenesis.
“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 Ghassan K. Abou-Alfa, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York, USA, specialized in gastrointestinal gncology, including pancreas, gall bladder, bile duct tumors and primary liver cancer.
“The findings mean all patients with cholangiocarcinoma should be tested for IDH-1 mutation. Tumor mutation profiling should be a new standard for the care for patients with this heterogeneous tumor type,” he said.
Abou-Alfa 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.
“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,” noted Prof Dr. Chris Verslype, MD, Ph.D, at the University Hospital Gasthuisberg, Leuven, in Belgium, commenting on the relevance of the study and the study results.
“This is important data. There is a gain in progression free survival with ivosidenib that is clinically relevant for this patient population,” Verslype said.
“The reported median progression-free survival may seem short and some people may question whether this is clinically meaningful,” agreed Angela Lamarca, MD, Ph.D, MSc, Christie NHS Foundation Trust, Manchester, UK.
“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,” she added.
“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 explained.
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 randomization to placebo. It showed a real effect,” he said.
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,” Verslype concluded.
The study randomized 185 patients with advanced cholangiocarcinoma and IDH1 mutations 2:1 to ivosidenib (500 mg once daily) or matched placebo. Patients were stratified by number of prior systemic therapies (1 or 2) and could crossover from placebo to ivosidenib when their disease progressed.
Patients with unresectable or metastatic mIDH1 CC based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1) were eligible for treatment.
The primary endpoint was 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).
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<0.001). The median progression-free survival rate at six months was 32.0% with ivosidenib, while no patients randomized to placebo were free from progression at this time-point.
Results showed a favorable 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).
The results of the trial show that 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.
This is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma.
The study was funded by Agios Pharmaceuticals.
Note: 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.
Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy) – NCT02989857
 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.
 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.