Targeting isocitrate dehydrogenase 1 mutations in cholangiocarcinoma is a promising strategy
The phase III trial confirms that targeting isocitrate dehydrogenase 1 mutations in cholangiocarcinoma is a promising strategy, but debate is open on whether results are clinically meaningful. In view of encouraging results in the treatment of cholangiocarcinoma covered in the Daily Reporter on Saturday, further progress towards the delivery of precision medicine came yesterday from the Late-Breaking Abstract presentation of the phase III ClarIDHy trial at Presidential Symposium III (Abstract LBA10_PR).
In up to 15% of cholangiocarcinomas, mutated isocitrate dehydrogenase-1 (mIDH1) leads to elevated levels of the potent oncometabolite, D-2-hydroxyglutarate. ClarIDHy investigators studied whether ivosidenib, a small-molecule mIDH1 inhibitor, could improve currently poor survival rates. Previously treated patients with advanced mIDH1 cholangiocarcinoma and progression after 1–2 systemic therapies were randomised 2:1 to ivosidenib 500 mg once daily (n=124) or placebo (n=61), with ivosidenib crossover permitted at the time of documented progression. Ivosidenib led to significant improvements in progression-free survival (PFS) versus placebo (median 2.7 months versus 1.4 months; hazard ratio [HR] 0.37; 95% confidence interval 0.25–0.54; p<0.001). There was a trend towards improved median overall survival with ivosidenib (10.8 months versus 9.7 months for placebo; HR 0.69; one-sided p=0.06), with 57% of placebo-treated patients crossing over to ivosidenib (crossover-adjusted median overall survival was 6 months for placebo; HR 0.46; p=0.0008). The safety profile of ivosidenib was similar to previous phase I findings. Respective PFS rates at 6 and 12 months were 32.0% and 21.9% in the ivosidenib arm; no patients randomised to the placebo arm were progression-free after 6 months.
Already approved in Europe and the USA for the treatment of acute myeloid leukaemia harbouring mIDH1, these data indicate a place for ivosidenib in the treatment of selected patients with advanced cholangiocarcinoma, explains Dr Angela Lamarca from The Christie NHS Foundation Trust, Manchester, UK. "The reported median PFS may seem short and it may be questioned whether this is clinically meaningful. However, the effect of ivosidenib is clinically relevant when analysing other parameters. Not only did the ClarIDHy investigators report a clinically meaningful increase in the PFS rate at 6 and 12 months from treatment initiation, but there was also a trend toward prolonged overall survival after adjusting for crossover,” she clarifies. "Other attempts at using targeted therapies in biliary tract carcinomas have failed, mainly due to lack of adequate patient selection; this is real precision medicine.” Lamarca concludes by highlighting the importance of changing the mindset of clinicians treating patients with biliary tract carcinomas, for whom tumour profiling is likely to become a new standard, not only testing for isocitrate dehydrogenase-1 (IDH1) mutations but also to identify patients with fibroblast growth factor receptor-2 fusions (FGFR2).
ESMO Congress 2019 abstract:
LBA10_PR - ClarIDHy: A global, phase III, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation