ESMO 2024 – degraders disappoint again

Degraders promised to be a big topic of this year’s ESMO meeting, but so far they haven’t lived up to expectations. Lacklustre data on Friday from Prelude’s selective SMARCA2 degrader PRT3789 and C4’s BRAF V600X degrader CFT1946 do little to support the theory that this approach could be more effective than straightforward inhibition.

The ESMO discussant, Professor Christophe Le Tourneau of the Institut Curie in Paris, dubbed antitumour activity with both agents “limited”, but noted that protein degradation wasn’t complete – perhaps leaving some hope for this modality. But the way forward, for PRT3789 at least, looks likely to be as part of a combination, he concluded.

SMARC bar

Prelude is one of the few companies with a SMARCA2 project in the clinic; the other major player is Foghorn, which got an endorsement from Lilly earlier this year for FHD-909, its selective SMARCA2 inhibitor.

Foghorn also has a SMARCA2/4 inhibitor further ahead in development, FHD-286, but that has so far disappointed, with only one partial response seen among 72 patients in a uveal melanoma trial. Development here was discontinued, but is ongoing in AML.

It’s hoped that hitting SMARCA2 selectively could improve performance, but on the evidence presented at ESMO it’s unclear whether this will be the case. The results came from a phase 1 dose-escalation trial of PRT3789, which is given intravenously, in various heavily pretreated solid tumours with SMARCA4 mutations.

A total of 46 patients were efficacy evaluable, but when presenting the data Dr Robin Guo of Memorial Sloan Kettering Cancer Center focused on 26 with NSCLC or oesophageal cancer; among this population there were three confirmed partial responses. Guo noted no tumour shrinkage in the 20 patients with other tumour types.

One avenue for improving efficacy could be homing in on those with loss-of-function SMARCA4 mutations, ESMO heard. As for combinations, the trial is already testing PRT3789 plus docetaxel, with plans to combine it with Keytruda.

But investors aren’t hanging around to see how this pans out: Prelude’s stock sank 40% today. The group also has an oral SMARCA2 degrader, PRT7732, which recently went into the clinic.

BRAF gaffe?

C4 Therapeutics was a loser of Monday’s ESMO abstract drop, although at least things don’t seem to have got any worse for that company.

It’s developing CFT1946, a BRAF V600X degrader, for patients who relapse after, or do not respond to, approved BRAF inhibitors. C4 claims that this is the only such project in clinical trials.

Its phase 1/2 trial enrolled second-line or later solid tumour patients with various BRAF mutations (including V600E, V600K and V600R), who had previously received a BRAF inhibitor (unless not available as per standard of care). The company reckons that completely removing the abnormal BRAF protein could overcome the problem of resistance with current therapies.

At a cutoff date of 19 July 2024 its study saw two confirmed partial responses among 27 patients receiving CFT1946 monotherapy – one in melanoma and one in pancreatic ductal adenocarcinoma. This is a slight improvement on the abstract, which detailed one confirmed and one unconfirmed response.

Le Tourneau, the discussant, said proof of concept had been achieved, but added that the jury was still out on whether this BRAF degrader would be more efficacious than BRAF/MEK inhibitor combos, or pan-RAF inhibitors.

After disappointing abstract data with Astellas’s KRAS G12D degrader, the latest results show how much this approach still has to prove.