ASCO-GI 2021: Agios will file for a new Tibsovo label in 2L cholangiocarcinoma despite an OS advantage setback

GlobalData Healthcare 20th January 2021 (Last Updated January 20th, 2021 13:43)

ASCO-GI 2021: Agios will file for a new Tibsovo label in 2L cholangiocarcinoma despite an OS advantage setback
Cholangiocarcinoma is a rare cancer with few marketed therapies available, and gemcitabine-based chemotherapy is most commonly used for newly diagnosed patients. Credit: Papa Annur/Shutterstock.

Agios Pharmaceuticals presented mature data from its pivotal Phase III study ClarIDHy in cholangiocarcinoma for its IDH1 inhibitor Tibsovo (ivosidenib) during a presentation at the virtual American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO-GI) on 15–17 January. Tibsovo had previously achieved its primary endpoint of an improvement in progression-free survival (PFS), but in the final analysis for the secondary endpoint of overall survival (OS), failed to demonstrate a statistically significant difference versus placebo. Given reasons to question the significance of an OS readout, in this case, Agios will continue as planned with its supplemental new drug application (sNDA) to the FDA in Q1 2021.

In ClarIDHy, patients with advanced, IDH1-mutant cholangiocarcinoma who progressed on previous systemic therapy were randomised to receive Tibsovo (n = 126) or placebo (n = 61). As of data cut-off, May 2020, the median OS in the Tibsovo arm was 10.3 months compared with 7.5 months in the placebo arm (HR = 0.79). Treatment-related adverse events (AEs) leading to treatment discontinuation were more common with placebo than with Tibsovo (8.5% versus 6.6%). Grade 3 or higher treatment-related AEs occurred in 53% of patients treated with Tibsovo and 37.3% of patients treated with placebo. The lack of an OS advantage with Tibsovo is not conclusive, as patients treated with placebo were allowed to cross over to Tibsovo upon disease progression, and a high 70.5% of patients did. This possibility had been taken into account during trial design and a pre-specified analysis for crossover was allowed. After adjustment, the OS for the placebo arm was shown to be 5.1 months (HR = 0.49). Targeted therapies are well known to be held to a different standard for evaluations and most frequently improvement in PFS or ORR is enough to prompt a regulatory approval, particularly in cancers of high unmet need. Previously, Tibsovo led to a median PFS (mPFS) of 2.7 months versus 1.4 months for the placebo (HR = 0.37). GlobalData expects this, in addition to adjusted OS data, to be enough for Agios to convince the regulators for marketing authorisation in this setting.

Cholangiocarcinoma is a rare cancer with few marketed therapies available, and gemcitabine-based chemotherapy is most commonly used for newly diagnosed patients. In April 2020, the FDA also approved the FGFR inhibitor, Incyte’s Pemazyre (pemigatinib), for FGFR2-mutant patients who progressed on chemotherapy. IDH1 mutations present in about 10% of cases, making Tibsovo an attractive option for all lines of therapy. The excellent tolerability of Tibsovo makes it an ideal partner in combinational regimens. In acute myeloid leukaemia (AML), the main benefit of IDH1 / 2 inhibitors is expected to come about with rational combinations in the first line of treatment since Tibsovo monotherapy, while useful, has not impressed physicians. The lack of combinational therapies for cholangiocarcinoma in Tibsovo’s clinical trials portfolio is thus surprising and poses questions about the future direction of its clinical program.

Tibsovo has ongoing trials in various oncology indications such as AML, chondroma, glioma, and myelodysplastic syndromes. Interestingly, Agios’ oncology portfolio was announced to be acquired by Servier in December 2020, in a deal worth up to $2B plus royalties. While Tibsovo’s 2020 sales of $160–170M (company expectation) certainly contributed to Servier’s motivation for the deal, it is more likely that Servier’s lifecycle management aspirations include a gradual expansion to other IDH-affected indications to achieve notably higher sales. As part of the deal, Servier will also acquire the US co-marketing rights (collaboration with Bristol-Myers Squibb) for the IDH2 inhibitor Idhifa (enasidenib), receive full rights to the pipeline agent dual IDH1 / 2 inhibitor vorasidenib, and wholly acquire all earlier-stage clinical and pre-clinical oncology assets from Agios. The opportunity to commercialise the next-generation inhibitor vorasidenib uniquely positions Servier for a market-leading position in the field of IDH1 / 2 inhibitors.