BARCELONA—“Molecular profiling has to become a new standard of care in patients with cholangiocarcinoma—not only for IDH1 (isocitrate dehydrogenase 1) mutations, but also for FGFR2 (fibroblast growth factor receptor 2) mutations.” So said Angela Lamarca, MD, PhD, a medical oncologist at the Christie NHS Foundation Trust in Manchester, U.K., commenting on findings from a study investigating a molecularly directed treatment for an otherwise rapidly lethal tumor. Results were reported at the ESMO 2019 Congress (Abstract LBA10_PR).
A clear clinical step forward seems to be an offer in the light of findings from the phase III, randomized, placebo-controlled, double-blind ClarIDHy study of patients with cholangiocarcinoma (CC) who had mutated IDH1 and were treated with the molecularly targeted agent ivosidenib in comparison with placebo.
“The primary endpoint—progression-free survival—showed separation of the curves starting at the first CT scan, with a median of 2.4 months versus 1.7 months [that was] statistically and clinically significant, with continued separation,” said lead author Ghassan K. Abou-Alfa, MD, MBA, medical oncologist with the Gastrointestinal Oncology service at Memorial Sloan Kettering Cancer Center in New York.
No patient in the control arm remained free from disease progression at 6 months. But among those treated with ivosidenib, the progression-free survival (PFS) rate was 32 percent at 6 months and 22 percent after 12 months, noted Abou-Alfa.
He said cholangiocarcinoma was an aggressive disease with limited choices of therapy, but a better understanding had been emerging because about 20 percent of patients had mutated IDH1 that caused reduction of alpha-ketoglutarate to 2-hydroxyglutarate, a metabolite that caused oncogenic changes.
“Based on a phase I study, we [had] seen that, in a cohort of about 73 patients with cholangiocarcinoma, patients had an improvement in progression-free survival [and] in overall survival—enough that it was suggested we should carry on with a phase III trial, ClarIDHy, that randomized patients to [the oral, small-molecule inhibitor of mutant IDH1 protein] ivosidenib versus placebo,” he said.
The ClarIDHy study recruited patients who had histologic confirmation of CC and clear evidence of mutated IDH1 (assessed by next-generation sequencing), good performance status, at least one line of prior therapy (and a maximum of two lines—one of which had to be 5-fluorouracil or gemcitabine), and measurable disease, said Abou-Alfa.
A total of 185 patients, median age 62 years, was randomized “two-to-one” to the study drug or placebo (124 to ivosidenib, 61 to placebo). All patients had unresectable or metastatic disease. Crossover from placebo to ivosidenib was permitted for patients whose disease progressed. The primary endpoint of the study was PFS, and secondary endpoints included objective response rates (ORR), safety, and overall survival (OS).
The primary endpoint of PFS was met. The hazard ratio was 0.37 with a “p value” of less than 0.001. The median PFS duration was 2.7 months in patients treated with the study drug and 1.4 months in the control arm. PFS rates at 6 and 12 months were 32.0 percent and 21.9 percent in patients taking the molecular therapy—and zero at both of these time points among patients taking the placebo.
The ORR was 2.4 percent with ivosidenib treatment (there were three partial responses), and 50.8 percent of patients in the experimental arm had stable disease. There were no responses to placebo in the control arm and the rate of stable disease was 27.9 percent. Median OS duration was 10.8 months on the active treatment and 9.7 months with placebo.
The experimental treatment was associated with nausea in 32 percent of patients, diarrhea in 29 percent, fatigue in nearly a quarter, and cough in a fifth of them. Adverse events of at least grade 3 were reported by nearly half of the patients taking ivosidenib and more than a third of those on placebo. There were no treatment-related deaths.
The study concluded there had been a significant improvement in PFS and a “favorable OS trend” in patients taking ivosidenib compared to those on placebo.
“This is a new advance for patients with advanced cholangiocarcinoma—a population that really is in bad need for new therapies. And now we are able to move the field into genetic mutation-based therapy. This not only provides an opportunity for ivosidenib for patients with mutated IDH1, but is also opening the door for other therapies targeting genetic mutations in cholangiocarcinoma,” said Abou-Alfa.
“From my point of view, this trial is practice-changing because [of] the benefit in progression-free survival and improved PFS rate at 6 months and at 12 months,” said Lamarca.
She was hopeful that precision medicine would prove clinically useful targeting not only mutant IDH1, but she also noted another molecular feature, the FGFR2 pathway, that looked promising as a therapeutic target in many cancers and specifically in cholangiocarcinoma.
Peter M. Goodwin is a contributing writer.