New first-in-class drug for the treatment of ER+ MBC

On Apr 30th, the FDA approved a new first-in-class drug for the treatment of ER+ metastatic breast cancer (MBC). The new drug Vepdegestrant was approved only for patients with tumors that harbor ESR1 mutations, based on results from trials including the VERITAC-2 phase 3 trial which compared this oral drug with the established second-line endocrine therapy Fulvestrant for patients who have received a CDK4/6 inhibitor with aromatase inhibitor.  Vepdegestrant (brand name Veppanu) is the first FDA approved PROTAC, a type of drug that selectively degrades a target protein, in this case the Estrogen Receptor.  Breast cancers that express the ER often rely on estrogen for their growth and survival through ER, hence it’s logical that removing ER from the tumor cells would be a logical approach to block this pathway.   In addition, patients who receive aromatase inhibitors for prolonged periods of time, sometimes develop resistance mutations in ER (ie “ESR1”) that change the protein conformation and reduce drug binding of Fulvestrant, making this agent relatively ineffective.

This drug was created to address 2 limitations of the current treatment Fulvestrant which is an intramuscular shot given on Day 1 of a 28-day cycle (with an additional dose on day 15 of cycle 1 only). Fulvestrant shots are not completely absorbed (poorly bioavailable) and therefore ER degradation is only partial, leaving some opportunity for estrogen to bind to the remaining ER protein like normal.  ESR1 mutation also reduces the ability for Fulvestrant to effectively degrade it.   Newer oral SERD drugs such as Elacestrant and Vepdegestrant may be given continually (daily) and therefore overcome both of these problems.

Unfortunately IBC patients were explicitly excluded from the registrational trial so we do not know.   In addition, prior chemo for metastatic disease was not allowed, and patients with visceral crisis, meaning substantial organ involvement such as liver, lung or large volume pleural effusions were not candidates for the study which is a scenario we see often in recurrent ER+ IBC.  Data from MD Anderson’s IBC registry has shown that the efficacy of Fulvestrant alone in a similar treatment line in IBC is pretty dismal – the average progression-free survival (PFS) time is 1.9 months.  Assuming an equal margin of efficacy based on the trial, we might expect to see an additional 2-3 months of benefit in the IBC population – definitely not a cure or major breakthrough!

Now that Vepdegestrant will be on market very shortly, there may be small subsets of IBC patients that may be deemed suitable candidates upon progression on Kisqali or Verzenio + AI.  For example patients who have had prolonged responses to CDKi, with bone-only disease or limited nodal burden with known ESR1 mutations and no PIK3CA mutation. Such patients may have liquid biopsies performed to assess for the presence of ESR1 mutations that may guide therapy with Vepdegestrant or Elacestrant, prior to moving onto more toxic but effective therapies such as ADCs (Enhertu/Trodelvy/Datroway). On the other hand, IBC patients with significant visceral progression after 2-3 months on their first line metastatic regimen are less likely to be driven by ESR1 mutation pathways and may be better candidates for other treatments or clinical trials.

Of note, to date there is not an FDA approval for any oral SERD combination with PI3K-pathway agents (such as Capivasertib or Alpelisib). PI3K pathway is another major resistance pathway to endocrine therapy, so patients with tumors expressing PIK3CA or AKT mutations will likely be offered combinations of traditional endocrine therapy and targeted agents against this pathway in the near future until such data is generated showing safety and efficacy of upfront combination therapy. We know in general in breast cancer, if there is a known actionable mutation, the earlier it can be targeted, the better the outcome will be, and this is an important rationale why next-gen tumor sequencing along with liquid biopsies during endocrine-based treatment lines is crucial in MBC and IBC.

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