No Ameera glory for Sanofi

Amcenestrant flunks the long-delayed Ameera-3 trial in ER-positive Her2-negative breast cancer, so how much blame can be put on poor study design?

It was abundantly clear that Ameera-3, the trial of Sanofi’s amcenestrant whose readout had been delayed three times, was not going well. And yet some investors apparently still expected it to succeed: the French firm's stock opened down 5% this morning on news of the failure. 

The effect on Sanofi is obvious, likely wiping out the $518m of 2026 sales amcenestrant was, according to Evaluate Pharma sellside consensus, expected to bring in, and putting more pressure on the group’s pipeline. But investors will also want to know how much blame can be put on poor trial design, an issue that will gain importance as pivotal readouts approach for rival oral Serds.

Ameera-3, along with all the other pivotal studies of oral Serds (selective oestrogen receptor degraders) in the setting of ER-positive Her2-negative breast cancer, was always going to face the problem of prior CDK4/6 inhibitor use. This relatively new standard, including Pfizer’s Ibrance, has changed the treatment landscape, and it is still unclear what the best follow-on therapy is.

Ameera-3’s design mandated that at least 80% of patients had to have failed a CDK4/6 inhibitor. Thus one risk was that patients would have derived a strong resulting benefit, and that the numerical difference in progression-free survival between subsequent amcenestrant and Faslodex/aromatase inhibitor control would be too small to hit statistical significance.

Sanofi has so far released no detail about the underlying data. Ameera-3’s sole primary endpoint concerned PFS in all-comers.

No enrichment

But a possibly bigger issue was that Sanofi’s trial did not enrich for patients with ESR1 mutation. ESR1 is thought to be a common resistance mechanism to aromatase inhibitors, the backbone of therapy, but has been associated with a benefit for new-generation Serds.

The most important comparator here is Radius/Menarini’s rival project elacestrant, which after Sanofi’s protracted delays beat the French group to the punch with a positive pivotal readout. Elacestrant’s Emerald trial was positive in all-comers and ESR1 mutation carriers alike, but full data left no doubts about the fact that it was the mutant group that drove the all-comers benefit, which amounted to less than one month of PFS.

The crucial difference between Emerald and Ameera-3 was that the former did enrich for patients with the ESR1 mutation, thus maximising its chances of success.

Amcenestrant’s two phase 3 studies continue without change, Sanofi said. These are Ameera-5, in combination with Ibrance as front-line therapy, and Ameera-6, in a modified adjuvant setting; but, as these will not read out until 2024 and 2026 respectively, even if they are positive amcenestrant will have lost what had once looked like an important first-mover advantage to elacestrant.

Oral Serds in late-stage development for ER+ve/Her2-ve breast cancer
  Elacestrant Amcenestrant Giredestrant Camizestrant Imlunestrant
Company Radius Health/Menarini Sanofi Roche Astrazeneca Lilly
Registrational study Emerald Ameera-3 Acelera Serena-2 Ember-3
Prior CDK4/6 use Mandatory Mandatory for 80% Not mandatory Not mandatory Not mandatory
Enrichment for ESR1 mutation? Yes No No Unclear Unclear
Primary endpoint(s) PFS in all-comers PFS in all-comers (PFS in ESR1 mutants is secondary) PFS in all-comers (PFS in ESR1 mutants is secondary) PFS in all-comers PFS in all-comers (PFS in ESR1 mutants is secondary)
PFS in ESR1 mutants
Data All comers: 0.9mth benefit, HR=0.70 Failed primary endpoint Data due mid-2022 Ends Sep 2022 (previously Mar 2022) Ends Jun 2023 (previously Mar 2023)
ESR1 mutants: 1.9mth benefit, HR=0.55
Source: Evaluate Pharma &

Attention now falls on other rivals, which could all yield positive pivotal data before Sanofi even has a shot at the earlier settings.

Next up is Roche’s giredestrant, whose second/third-line Acelera trial could read out in the next three months. Like the Serena-2 trial of Astrazeneca’s camizestrant and the Ember-3 study of Lilly’s imlunestrant, this does not mandate prior CDK4/6 inhibitor use, and measures as primary endpoint PFS in all-comers.

Biotech investors will also be paying close attention to Arvinas and Olema, two small companies developing the oral ER degraders ARV-471 and OP-1250 respectively, which were both down this morning on the Sanofi news. Neither company has yet begun pivotal development, so perhaps Ameera-3’s readout will give them important insight in terms of study design.

For Roche, Astra and Lilly it might already be too late, unless these companies decide at the last minute to modify primary endpoints.

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