ESMO 2025 – Sanofi takes aim at Lutathera

Alpha-emitting radiopharmaceuticals still have much to prove, but Sanofi will hope to have derisked its lead-212-based, SSTR-targeting radioconjugate, Alphamedix, following promising mid-stage data reported at ESMO.

However, there’s still much work to be done, and it’s unclear whether lead-based compounds will eventually replace similarly acting lutetium-177-based radioconjugates like Novartis’s Lutathera, or merely supplement them, the ESMO discussants noted.

Meanwhile, Perspective Therapeutics spooked investors with new data from the phase 1/2 trial of its lead-212-based project, 212Pb-VMT-α-NET, also presented at the conference.

Alphamedix 

ESMO saw two separate presentations on the uncontrolled phase 2 Alphamedix-02 trial, which tested Alphamedix in patients with SSTR-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs).

Cohort one, in radioligand-naive patients, produced a 57% centrally confirmed ORR; this is in line with results presented at ASCO 2024, and looks better than the 13% seen with Lutathera in its pivotal Netter-1 trial.

Brand new data came from cohort two, in patients who had previously received Lutathera. Here, Alphamedix led to a less impressive 19% centrally confirmed ORR, although this was still described as clinically meaningful.

The Alphamedix-02 trial of Alphamedix in SSTR+ve GEP-NETs

Note: data cutoff 14 Apr 2025. Source: ESMO 2025.

Discussing the data in radioligand-experienced patients, Dr Arthur Braat of University Medical Center Utrecht, concluded that Alphamedix was “safe and [it] works”.

However, he added that it could be difficult to interpret ORR results in NETs, noting that this endpoint wasn’t always well correlated with survival outcomes in these tumours.

Another reason to be cautious is a high incidence of dysphagia, or difficulty swallowing, seen at grade 3 in 3-15% of patients in Alphamedix-02. This chronic side effect was treated with botox injections to the lower oesophageal sphincter, and these didn’t always provide long-term relief.

Kidney events were also seen with Alphamedix, although on the plus side there were no cases of acute myeloid leukaemia or myelodysplastic syndromes.

Sanofi, which licensed the project from Orano Med and RadioMedix last year for €100m, will now need to show a benefit in phase 3; a pivotal trial in GEP-NETs is “actively being planned”, the company said.

New Perspective

Also at ESMO, Perspective Therapeutics presented updated results with its rival lead-212-based contender, 212Pb-VMT-α-NET, from a phase 1/2 trial in radioligand-naive NETs. The company's stock has languished since last year, when it reported just one response among nine patients receiving the project dosed at 2.5mCi and 5.0mCi.

Now, more data from the 5.0mCi cohort has yielded a 35% ORR among 23 patients – which, on the face of it, looks less impressive than the Alphamedix result. Perspective claimed a 44% ORR among a subgroup of 16 patients with SSTR2 expression in all tumours (rather than just one tumour), but investors seemed unimpressed by this attempt to datamine, sending the group’s share price down almost 30% on Monday. 

While a couple of lutetium-177-based radioconjugates are FDA-approved, alpha emitters like lead-212 are thought to be more potent and precise. Still, lead-212 isn’t directly an alpha emitter; rather, it emits a beta particle to become bismuth-212, some of which then decays with the emission of an alpha particle.