ESMO 2023 – Jiangsu Hengrui sets a low bar in KRAS G12D inhibition

In the KRAS world G12D is shaping up to be the next big target after G12C. However, the first human data with a G12D inhibitor do not exactly look earth shattering. The inhibitor in question is Jiangsu Hengrui’s HRS-4642, and a late-breaking ESMO abstract shows just one partial response among 13 evaluable patients in a phase 1 trial across various late-line solid tumours. True, patient numbers are small, and the ideal dose has yet to be nailed down; the study is testing HRS-4642 at 15-300mg per week, and the response was seen in a subject receiving 200mg. But the fact that one patient experienced serious liver enzyme elevations raises questions about the therapeutic window; G12C inhibitors have also been linked with liver toxicity. And grade 3 or greater hypercholesterolaemia was seen in 17% of HRS-4642-treated patients. The G12D pipeline has been expanding of late, with Revolution Medicines recently taking RMC-9805 into the clinic. The next projects to yield data will be Astellas’s ASP3082 and MRTX1133 from Mirati (soon to be part of Bristol Myers Squibb), with results on both due in the early part of next year.