ESMO 2024 preview – Astellas unveils its KRAS degrader

Targeted degradation, as opposed to just inhibiting the target, has gained traction as a modality, spreading beyond so-called SERDs into BTK and other proteins. In this space ESMO will feature one of the most intriguing projects, namely the Astellas molecule ASP3082, which is said to degrade KRAS G12D.

Very little is known about ASP3082, though Astellas noted its advancement into the clinic in 2022, at a time when more typical inhibition of KRAS G12D was already becoming a competitive area. Other degraders that will be of interest to investors at ESMO include projects from C4 Therapeutics, Bristol Myers Squibb and Prelude Therapeutics.

These all feature among the presentation titles that recently went live in the ESMO programme. Notably, however, ESMO hasn’t revealed the abstracts’ texts, or said anything about late-breakers or presentations selected for presidential symposia. Indeed, the deadline for submitting late-breakers doesn’t fall until 7 August.

As far as ASP3082 goes, Astellas has said that this molecule binds to G12D-mutated KRAS and E3 ligase, bringing these proteins together and catalysing degradation via the ubiquitin-proteasome system. So far only preclinical data have been revealed, and the company also claims to have a pan-KRAS degrader in its preclinical pipeline.

OncologyPipeline reveals other KRAS G12D degrader projects at Arvinas, Risen Pharmaceuticals and Seed Therapeutics, but none has yet entered human trials.

Degradation alone not enough?

In the SERD (selective oestrogen receptor degrader) space Olema has started calling its lead asset, palazestrant, an antagonist as well as a degrader, and Bristol appears to be following suit with the Celgene-originated BMS-986365, which targets the androgen receptor.

The title of BMS-986365's ESMO mini oral on castration-resistant prostate cancer calls the project an AR degrader and antagonist. Novartis’s recent pipeline update included the entry into phase 1 of the AR degrader JSB462, which is presumably the Swiss company’s own code for ARV-766, the project it licensed from Arvinas in April.

Meanwhile, C4’s CFT1946 is said to degrade BRAF V600E, while Prelude’s PRT3789 targets SMARCA2. The latter will be of interest to followers of Foghorn Therapeutics, which has a similar degrader in preclinical development, though the subject of that group’s deal with Lilly is the straight SMARCA2 inhibitor FHD-909.

Selected ESMO 2024 oral presentations on small-molecule approaches

Source: ESMO.

Away from degraders, there will of course be plenty of inhibitor therapeutics on show at ESMO too, according to the initial presentation titles released.

For instance, Nuvalent, a young biotech whose highly targeted small molecules have already earned it a $5bn valuation, will present further data on the ALK inhibitor NVL-655, which caused a stir at last year’s Triple meeting. Nuvalent’s lead asset, zidesamtinib, which hits the related kinase ROS1 and has generated preliminary ORR of 48% among 21 heavily pretreated NSCLC patients, has also secured an ESMO mini oral presentation.

And the emerging CDK2 inhibitor space will see monotherapy data on Incyte’s INCB123667, which has yet to yield anything beyond anecdotal case reports. Pfizer’s rival anti-CDK2 asset PF-07104091, meanwhile, will have data on 15 September from a HER2-negative breast cancer trial in which it is being combined with atirmociclib, a CDK4 inhibitor that’s already in phase 3.

ESMO will take place in Barcelona, Spain, on 13-17 September 2024.