Targeted therapy shows benefit in advanced cholangiocarcinoma
BARCELONA, Spain — Ivosidenib improved outcomes among patients with isocitrate dehydrogenase-mutated advanced cholangiocarcinoma, according to the results of the randomized phase 3 ClarIDHy study presented at European Society for Medical Oncology Congress.
The agent appeared associated with a doubling of PFS compared with placebo — although the median in the experimental arm remained less than 3 months. Researchers also observed a favorable trend in OS, particularly when crossover from placebo to the study drug was taken into account.
“Sadly, cholangiocarcinoma remains an aggressive disease with a median OS measured below 1 year,” Ghassan K. Abou-Alfa, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “We know that isocitrate dehydrogenase (IDH1) mutation itself does not carry a very favorable prognosis, so an increase in PFS or survival is a valid endpoint and something to move forward with.”
Cholangiocarcinoma — a rare but aggressive subtype of bile duct cancer — has a poor prognosis. Most patients die of the disease, and there is an urgent need for more effective therapies, according to study background.
IDH1 mutations occur in approximately 15% of cholangiocarcinoma cases. Ivosidenib (Tibsovo, Agios) is an oral small molecule inhibitor of the mutant IDH1 protein.
The ClarIDHy study included 185 patients (median age, 62 years; 117 women) with unresectable (8%) or metastatic (92%) IDH1-mutant cholangiocarcinoma.
Researchers randomly assigned 124 patients to ivosidenib (Tibsovo, Agios) dosed at 500 mg once daily. The other 61 patients received placebo. Investigators stratified randomization by the number of prior systemic therapies (one or two).
Study protocol allowed patients assigned placebo to cross over to ivosidenib treatment upon radiographic progressive disease.
PFS by central review served as the primary endpoint. PFS, safety, objective response rate and OS served as secondary endpoints.
Median PFS by central review was 2.7 months in the ivosidenib group and 1.4 months in the placebo group (HR = 0.37; 95% CI, 0.25-0.54). Ivosidenib-treated patients were more likely to be progression free at 6 months (32% vs. 22%) and 12 months (21.9% vs. 0%).
Three patients (2.4%) assigned ivosidenib achieved partial response compared with none in the placebo group. Rates of stable disease were 50.8% with ivosidenib and 27.9% with placebo.
By intention-to-treat analysis, median OS was 10.8 months with ivosidenib and 9.7 months with placebo (HR = 0.69; 95% CI, 0.44-1.1).
However, 57% of patients assigned placebo crossed over to ivosidenib. A rank-preserving structural failure time-adjusted analysis that accounted for crossover showed a statistically significant OS advantage with ivosidenib (median, 10.8 months vs. 6 months; HR = 0.46; 95% CI, 0.28-0.75).
Common adverse events in the ivosidenib 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%) and vomiting (16%).
No patients died due to treatment.
“PFS was statistically significant, but I think the most important thing to look at is the curve beyond the median,” Abou-Alfa told HemOnc Today. “We saw the separation as it moved forward. The curve did not really begin to separate until 6 weeks and continued to grow as it went on.” – by John DeRosier
Abou-Alfa GK, et al. Abstract LBA10. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
Disclosures: Abou-Alfa reports consultant roles with 3DMedicare, Agios, Amgen, Antengene, Aptus, Array, Aslan, Astellas, Bayer, Beigene, Bioline, Bristol-Myers Squibb, Boston Scientific, Bridgebio, Carsgen, Celgene, Cipla, CytomX, Debio, Delcath, Eisai, Eli Lilly, Exelixis, Genoscience, Halozyme, Hengrui, Incyte, Inovio, Ipsen, Jazz Pharmaceuticals, Janssen, Kyowa Kirin, Loxo Oncology, Merck, Mina, Novartis, Novella, OncoQuest, Onxeo, PCI Biotech, Pfizer, Roche, Sanofi, Servier, Silenseed, Sillajen, Sobi, Targovax, Tekmira, Twoxar, Vicus, Yakult and Yiviva. Please see the study for all other authors’ relevant financial disclosures.