A second-line degrader battle beckons

In the oral SERD arena many players have moved on to first-line and earlier breast cancer, but two readouts are approaching in the original second-line setting, where Menarini’s Orserdu remains the only approved therapy in this class.

Data are due in the second half from phase 3 trials of Lilly’s imlunestrant and Pfizer/Arvinas’s vepdegestrant, from the Ember-3 and Veritac-2 trials respectively. These trials look fairly similar, and their chances of success might come down to the proportion of patients with ESR1 mutations that have been recruited.

Mutation status

That’s because SERDs have so far performed better in this genetic subtype than in wild-type patients; indeed, Orserdu is only indicated for ER-positive, HER2-negative patients with ESR1 mutations.

Lilly describes imlunestrant as a SERD, while Pfizer and Arvinas call vepdegestrant a Protac (heterobifunctional) molecule. Both companies claim activity against both the wild-type and mutant oestrogen receptor.

Still, vepdegestrant has shown stronger activity in ESR1 mutant versus wild-type patients in the late-line phase 1/2 Veritac trial. Lilly doesn’t appear to have broken out data from its phase 1 Ember trial by ESR1m status.

Both Ember-3 and Veritac-2 will test progression-free survival in all comers as well as ESR1 mutants, Lilly having changed to this dual primary endpoint in September 2022. However, it is unclear whether the trials set out to enrich for this population.

So far, Menarini is the only one to take this approach: in its successful pivotal Emerald trial 48% of patients had ESR1 mutations. Meanwhile, ESR1 mutants made up 39% of Roche’s Acelera trial, which failed to show an overall benefit. 

While the Serena-2 study of AstraZeneca’s camizestrant (37% ESR1m) did succeed, there has been no news of a filing in this setting. Furthermore, all the aforementioned studies showed a more pronounced benefit in the ESR1m subgroup.

Oral SERD studies in 2nd-line ER-positive HER2-negative breast cancer

Note: *also includes imlunestrant + Verzenio arm. Source: OncologyPipeline & clinicaltrials.gov.

As for differences between Ember-3 and Veritac-2, a big one is that Lilly’s trial includes cohorts testing imlunestrant monotherapy, as well as imlunestrant plus Lilly’s CDK4/6 inhibitor Verzenio – both versus physician’s choice of endocrine therapy. Lilly has said it hopes the trial will support approval of both monotherapy and the Verzenio combo.

Veritac-2, meanwhile, is evaluating vepdegestrant monotherapy, versus AstraZeneca’s injectable SERD Faslodex.

Pfizer and Arvinas have disclosed plans to combine vepdegestrant and Pfizer’s Ibrance, “and potentially other CDK4/6 inhibitors” in a phase 3 trial in second-line disease, slated to start next year.

Another difference between Ember-3 and Veritac-2 is prior therapy. Pfizer’s study requires patients to have previously received CDK4/6 inhibitors, while Lilly’s trial allows this, but doesn’t mandate it. Both trials have excluded patients with prior chemo for metastatic disease, and prior Faslodex.

Early lines

Lilly and Pfizer/Arvinas might be hoping for a result in wild-type as well as ESR1m, but if the upcoming results run to form their drugs could be limited to a niche – it’s estimated that around 40% of patients develop ESR1 mutations after receiving endocrine therapy.

Many SERD players, such as Roche and AstraZeneca, have shifted their focus to first-line and adjuvant settings, where the incidence of ESR1m is low and, Roche has noted, tumours are still ER dependent.

Pfizer and Arvinas hope to start the first-line Veritac-3 phase 3 trial, testing vepdegestrant plus Ibrance, in 2025. Meanwhile, a phase 2 study of neoadjuvant vepdegestrant, Tactive-N, is due to yield data this year.

Lilly doesn’t appear to have any first-line studies in the works, according to OncologyPipeline, but the adjuvant Ember-4 study is ongoing.