Ivosidenib confers clinical benefit in advanced cholangiocarcinoma subset
Click Here to Manage Email Alerts
Ivosidenib modestly extended OS among patients with previously treated isocitrate dehydrogenase 1-mutated advanced cholangiocarcinoma, according to final results of the phase 3 ClarIDHy trial presented at Gastrointestinal Cancers Symposium.
The agent also appeared well-tolerated compared with placebo.
“Cholangiocarcinoma is a rare, aggressive malignancy with limited effective treatment options,” Andrew X. Zhu, MD, PhD, director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, said during his presentation. “Isocitrate dehydrogenase 1 [IDH1] mutations occur in up to 20% of intrahepatic cholangiocarcinoma and lead to a burden production of D-2-hydroxyglutarate, which promotes oncogenesis. Ivosidenib [Tibsovo, Agios] is a first-in-class oral inhibitor that targets the mutant IDH1 protein.”
The ClarIDHy trial included 187 patients (median age, 62 years; 119 women) with previously treated IDH1-mutant cholangiocarcinoma. A majority of patients (91%) had intrahepatic cholangiocarcinoma, 93% had metastatic disease and 47% received two prior therapies.
Researchers randomly assigned patients 2:1 to 500 mg once-daily oral ivosidenib (n = 126) or placebo (n = 61).
Most patients (70%) assigned placebo crossed over to ivosidenib treatment upon disease progression, as permitted by study protocol. At the time of data cutoff, 13 patients remained on treatment with ivosidenib.
Healio previously reported on the primary endpoint of the trial, PFS by independent radiology center review, which showed median PFS of 2.7 months with ivosidenib vs. 1.4 months with placebo (HR = 0.37; 95% CI, 0.25-0.54). In addition, ivosidenib-treated patients were more likely to be progression free at 6 months (32% vs. 22%) and 12 months (21.9% vs. 0%). The disease control rate was 53% with ivosidenib and 28% with placebo.
During the symposium, Zhu reported on the secondary endpoint of OS. There were 150 OS events documented, including among 79.4% of those assigned ivosidenib group and among 82% of those assigned placebo. Median OS was 10.3 months with ivosidenib vs. 7.5 months with placebo (HR = 0.79; 95% CI, 0.56-1.12).
To adjust for the 70% crossover rate, investigators used the rank-preserving structural failure time model, which showed median OS of 5.1 months with placebo (HR = 0.49; 95% CI, 0.34-0.7).
Grade 3 or greater treatment-emergent adverse events were more common with ivosidenib vs. placebo (53% vs. 37.3%). Common adverse events with ivosidenib included nausea (41.5%), diarrhea (35%), fatigue (30.9%), cough (25.2%), abdominal pain (24.4%), decreased appetite (24.4%), ascites (22.8%), vomiting (22.8%), anemia (17.9%) and constipation (15%).
Adverse events led to treatment discontinuation among 6.6% of patients assigned ivosidenib vs. 8.5% of patients assigned placebo. No treatment-related deaths were reported.
Results of health-related quality of life assessed by EORTC QLQ-C30 and BR21 questionnaires showed ivosidenib preserved physical functioning with no worsening of pain symptoms compared with significant declines in physical functioning and pain subscales with placebo for cycle two, day 1 of treatment. However, neither ivosidenib nor placebo differed on appetite loss or eating subscales.
“The ClarIDHy study represents the first phase 3 study of a targeted oral therapeutic with a noncytotoxic mechanism of action in advanced IDH1-mutant cholangiocarcinoma,” Zhu said. “Ivosidenib significantly improved PFS compared with placebo. Despite a high rate of crossover of approximately 70%, ivosidenib was associated with a numerical improvement in OS, which is further supported by the rank-preserving structural failure time adjustment for crossover. Along with the tolerable safety profile and supportive quality-of-life data, these final efficacy results demonstrate the clinical benefit of ivosidenib in this patient population, for which there is an urgent need for new therapies.”
Although first-line chemotherapy for metastatic cholangiocarcinoma with gemcitabine plus cisplatin achieves modest rates of response and survival, second-line therapy with FOLFOX has marginal benefit, and treatment for these patients represents an unmet need. Molecular profiling has indicated that intrahepatic, extrahepatic and gallbladder cancers have unique molecular signatures, with intrahepatic cholangiocarcinoma having commonly occurring and targetable molecular alterations. The FGFR-targeted tyrosine kinase inhibitor pemigatinib (Pemazyre, Incyte) received regulatory approval last year for patients with cholangiocarcinoma harboring FGFR gene fusions or rearrangements. Intrahepatic cholangiocarcinoma has activating IDH1 mutations in 20% of cases.
Perspective
Back to Top
Although first-line chemotherapy for metastatic cholangiocarcinoma with gemcitabine plus cisplatin achieves modest rates of response and survival, second-line therapy with FOLFOX has marginal benefit, and treatment for these patients represents an unmet need. Molecular profiling has indicated that intrahepatic, extrahepatic and gallbladder cancers have unique molecular signatures, with intrahepatic cholangiocarcinoma having commonly occurring and targetable molecular alterations. The FGFR-targeted tyrosine kinase inhibitor pemigatinib (Pemazyre, Incyte) received regulatory approval last year for patients with cholangiocarcinoma harboring FGFR gene fusions or rearrangements. Intrahepatic cholangiocarcinoma has activating IDH1 mutations in 20% of cases.
During this year’s Gastrointestinal Cancers Symposium, investigators reported updated results of the previously reported ClarIDHy trial, an industry-sponsored, double-blind, placebo-controlled trial of the IDH1 TKI ivosidenib in patients with previously treated cholangiocarcinoma harboring an activating IDH1 mutation.
The positive results of ClarIDHy indicate that IDH1 is targetable in metastatic cholangiocarcinoma and may represent a new option for later-line therapy. Results of this and other trials in cholangiocarcinoma indicate the need for routine molecular profiling of these cancers, given these emerging therapy options and the potential to offer patients genomically directed novel targeted therapies.
Reference:
Abou-Alfa GK, et al. Lancet Oncol. 2020;doi:10.1016/S1470-2045(20)30157-1.
Memorial Sloan Kettering Cancer Center
Collapse
Zhu AX, et al. Abstract 266. Presented at: Gastrointestinal Cancers Symposium (virtual meeting); Jan. 15-17, 2021.
Click Here to Manage Email Alerts