Asco 2023 – liver tox casts a pall over Servier’s Indigo readout

 Vorasidenib’s performance in the Indigo trial goes some way to justifying Servier’s $1.8bn acquisition of Agios Pharmaceuticals’ cancer portfolio – in terms of efficacy, at least. The IDH1/2 inhibitor, the lead asset from that transaction, could become the first targeted treatment for low-grade glioma, Asco data from the phase 3 Indigo trial suggest.

So far, so good. However, the impressive efficacy hit, reducing patients’ risk of progression or death by 61% versus placebo, has come with significant levels of liver toxicity. Most concerningly, two cases of liver enzyme elevation were severe enough to trigger Hy’s law, a rule of thumb that suggests patients are at risk of fatal drug-induced liver injury.

Researchers were keen to play down the finding, stressing that the liver enzyme elevations were transient. Dr Patrick Wen of the Dana-Farber Cancer Institute, a co-author of Indigo, said the hepatotoxicity was very manageable and reversible: “The dose can be reduced if it is severe, and relatively few patients stop the drug because of the hepatotoxicity.”

Servier’s oncology head, Susan Pandya, confirmed that the liver enzyme increases were “reversible and [could] be monitored through routine blood work as part of the clinical management of the patient”, and said the firm did “not foresee this as having an impact on the success of vorasidenib”.

IDH1/2

Indigo was conducted in patients with grade 2 glioma that was positive for IDH1/2, a mutation that occurs in most of these low-grade cancers, and had been surgically removed within the previous one to five years. It tested vorasidenib’s ability to delay the need for radiation or chemotherapy versus watchful waiting, the current standard.

On this primary endpoint the IDH1/2 inhibitor produced median PFS of 27.7 months versus with 11.1 months for placebo, producing an impressive and highly statistically significant hazard ratio of 0.39, today’s Asco late-breaker reveals.

This was achieved at the expense of elevations in alanine aminotransferase increases, seen in 39% of patients given vorasidenib. In 10% of patients receiving the project this adverse event was seen at grade 3 or above, an accompanying NEJM paper revealed. The two cases of Hy’s law were disclosed by Servier to Evaluate Vantage.

Source: NEJM.

Servier expects approvals in the second half of 2024, though clearly this will depend on the extent to which the FDA considers liver toxicity to be a stumbling block in this cancer setting.

A regulatory green light would also be a boon for Agios, which is eligible to receive a $200m milestone payment for vorasidenib on US approval, plus 15% royalties. Servier also now plans to expand vorasidenib development to other forms of glioma.

In addition to vorasidenib the French group’s acquisition of Agios’s cancer pipeline brought the IDH1 inhibitor Tibsovo, approved for IDH1-positive AML and cholangiocarcinoma. The industry pipeline includes several inhibitors of IDH1 and IDH2, but not many hit both mutations, something essential for activity in glioma. Among the latter group Hutchmed’s HMPL-306 is in phase 1.

This article was jointly authored by Scrip's Alex Shimmings. Scrip and Evaluate Vantage are part of the same parent company, Norstella.

https://www.evaluate.com/vantage/articles/events/conferences-trial-results/asco-2023-liver-tox-casts-pall-over-serviers