Arvinas seeks to outdo Astellas

Arvinas only took its KRAS G12D degrader ARV-806 into the clinic in the middle of last year, but it’s already approaching its first readout. Indeed, the project has overtaken the group’s BCL6 degrader ARV-393, which started human trials in 2024.

The phase 1 study of ARV-393 is set to yield data in the second half; results on ARV-806 will likely come sooner, said Arvinas’s new chief executive, Randy Teel, during an interview with ApexOnco – although he wouldn’t reveal the exact timing. A key competitor will be Astellas’s rival G12D degrader setidegrasib, which has reported early data and recently went into phase 3.

KRAS G12D inhibitors are also in the mix, including Revolution Medicines’ zoldonrasib, with pivotal trials set to start soon. But the development of resistance has been a problem with KRAS inhibitors, something that Teel reckons the degraders could address.

“One of the resistance mechanism we see with inhibitors is amplification of KRAS. And a degrader just takes care of that, it removes the selective pressure for KRAS amplification, which we think could translate into more durability.”

More potent?

Teel believes that ARV-806 could have other advantages over setidegrasib, by virtue of the Arvinas project being a Protac degrader, while setidegrasib uses an E3 ligase to achieve target degradation.

He claims that, based on preclinical data, ARV-806 is 25 to 40-fold more potent than the KRAS G12D inhibitors and setidegrasib. “We’d hope that potency will allow us to use doses that don’t result in some of the toxicity issues that others have seen, like transaminitis,” he added.

The first data on setidegrasib were marked by lacklustre efficacy and dose-limiting toxicities, including liver enzyme elevations. Although efficacy has since improved, a just-published NEJM paper cites a 3% rate of grade 3 or higher treatment-related ALT increases with setidegrasib.

Pancreatic focus

Arvinas will soon have a chance to back up its claims. The phase 1 study is evaluating ARV-806 monotherapy in G12D-mutated relapsed solid tumours, but this is likely to be dominated by pancreatic cancer, where around 40% of patients have G12D mutations.

Setigrasib has set the bar here, with a 24% overall response rate among 21 second and third-line pancreatic patients.

However, Astellas is now focused on a front-line chemo combo, the regimen that will be tested in phase 3. In phase 1 setigrasib plus chemo produced a 42% ORR among 12 pancreatic patients; however, serious adverse events and drug-related discontinuations were seen in 23% of patients.

The other big focus for Astellas so far has been relapsed NSCLC, where setigrasib has produced an ORR of 33% among 45 patients, plus another unconfirmed response. Astellas has said it’s planning registrational studies in NSCLC, but hasn’t yet given any details.

Teel took the helm at Arvinas in February, replacing John Houston, who announced his retirement not long after the company’s oestrogen degrader vepdegestrant produced data that looked similar to other oral SERDs.

The new chief exec, meanwhile, emphasised the importance of “creating programmes that are strongly differentiated versus their competition”. Arvinas will soon have a chance to show whether it can do this.

Setting the bar: phase 1 data with Astellas’s setidegrasib

Notes: all efficacy data with 600mg setidegrasib dose; *also 1 unconfirmed PR. Source: NEJM (data cutoff 10 Nov 2025).