BARCELONA – Ivosidenib, a first-in-class, oral, small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) protein, significantly improved progression-free survival, compared with placebo, for the treatment of advanced cholangiocarcinoma in the global, randomized, phase 3 ClarIDHy trial.
A trend toward favorable overall survival was also seen in the pivotal double-blind trial, Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported at the European Society for Medical Oncology Congress.
Median progression-free survival (PFS) in 124 patients randomized to receive 500 mg of ivosidenib (IVO) once daily was 2.7 months, compared with 1.4 months in 61 patients who received placebo (hazard ratio, 0.37).
The primary study endpoint – PFS by central review – was reached, Dr. Abou-Alfa said, noting that the PFS rates at 6 and 12 months were 32% and 22% in the IVO arm, whereas none of the patients in the placebo arm were progression-free for 6 or more months.
Although the 1.3-month difference in PFS between the treatment and placebo arms “may seem short and some people may question whether this is clinically meaningful,” this outcome actually represents an important breakthrough for patients with a disease that has few treatment options, Angela Lamarca, MD, PhD, of the Christie NHS Foundation Trust, Manchester, England, explained in a press release about the study.
“A treatment that increases the chance of being free from progression by 32% 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,” said Dr. Lamarca, representing the ESMO Press & Media Affairs Committee.
Indeed, the overall response rate in the IVO arm was 2.4%, representing three partial responses, and the stable disease rate was 50.8%. The overall response rate and stable disease rates in the placebo arm were 0% and 28%, Dr. Abou-Alfa said.
Median overall survival in the intent-to-treat population, including the 57% of placebo arm patients who crossed over to the treatment arm at the time of radiographic progression as allowed by study protocol, was 10.8 months, compared with 9.7 months in the placebo arm, respectively (HR, 0.69), Dr. Abou-Alfa said.
Crossover-adjusted overall survival was 6 months for the placebo arm (HR, 0.46) as assessed using rank-preserving structural failure time analysis, which suggested that the overall survival benefit would have been statistically significant had there been no crossover.
Study subjects had unresectable or metastatic mIDH1 cholangiocarcinoma, good performance status, and measurable disease. They had a median age of 62 years, and 68 were men. Most had intrahepatic disease (91%) and metastatic disease (92%), and 43% had two prior therapies, he noted.
They were randomized 2:1 to the treatment and placebo arms, respectively.
Since IVO targets mIDH1, which occurs in about 20% of patients with cholangiocarcinoma and results in production of the oncogenesis-promoting oncometabolite D-2-hydroxyglutarate, and since the IVO has shown encouraging activity in smaller prior studies, ClarIDHy was designed to evaluate it in the advanced mIDH1 cholangiocarcinoma setting because patients with this aggressive disease have generally poor prognosis and few treatment options beyond chemotherapy, he explained.
In addition to providing significant, clinically meaningful survival benefit, the treatment also was generally well tolerated, he noted.
Treatment-emergent adverse events occurring in more than 15% of patients in the IVO arm included 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%), and vomiting (16.0%). Grade 3 or higher adverse events were reported in 46% and 36% of the IVO and placebo patients, respectively.
The findings are notable, in part because of the unmet need and also because this is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma, he said, concluding that “these pivotal data demonstrate the clinical relevance and benefit of ivosidenib in mIDH1 cholangiocarcinoma ... [and] establish the role for genomic testing in this rare cancer with a high unmet need.”
He also said studies should investigate IVO in the first-line setting for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.
In the ESMO press release, Chris Verslype, MD, of University Hospital Leuven (Belgium) called the findings of this study unprecedented given the lack of treatment options in those who fail systemic therapy, which has led to very limited survival.
The findings are “very likely to change clinical practice” and “will, for sure, drive the further development of targeted therapy for the disease,” he said.
Despite being limited by the requirement that patients have good performance status after prior chemotherapy (which means the findings may not be representative of all patients), ClarIDHy is “still a strong study because of the randomization to placebo.”
“It showed a real effect,” he said.
ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa reported both personal and institutional relationships with industry. These include advisory /consulting roles and research grants/funding from numerous pharmaceutical companies.
SOURCE: Abou-Alfa GK et al. ESMO 2019, Abstract LBA10-PR.