Reviewers Brief ODAC on Camizestrant Concerns

In advance of a 4/30 meeting of the FDA Oncologic Drugs Advisory Committee (ODAC) to discuss AstraZeneca’s breast cancer drug camizestrant, agency medical reviewers are raising concerns and asking the committee to consider whether there is a favorable benefit-risk assessment. The agency briefing document says camizestrant is a next-generation oral selective estrogen receptor degrader and complete estrogen receptor antagonist, indicated in combination with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) to treat adult patients with HR+ HER2- locally advanced or metastatic breast cancer upon emergence of estrogen receptor alpha gene mutation (ESR1m) during first-line endocrine-based therapy. The AZ application is based on results from the SERENA-6 trial, the document says.

FDA says the treatment paradigm evaluated in SERENA-6 is new, and currently, no drugs have agency approval for switching treatment in patients based on detection of an ESR1m before radiographic progression. “It is unclear whether changing treatment at this earlier timepoint, before radiographic progression, results in long-term benefit for patients with an incurable disease,” the reviewers say.

The primary endpoint in SERENA-6 was progression-free survival (PFS), which the document says the trial met. Key secondary endpoints were progression-free survival 2 (PFS 2) and overall survival (OS). Although the trial met its PFS 2 endpoint, the briefing document says, FDA does not consider it to be a suitable endpoint for regulatory decision-making. It adds that the current OS data are immature.

The briefing asks committee members to consider these concerns:

       *  evidence is lacking to show that switching treatment at detection of ESRIm rather than at radiographic progression is beneficial to patients;
       *  the starting time for PFS, upon detection of an ESRIm, is new, and the clinical meaningfulness of the PFS improvement measured from ESRIm detection is uncertain;
* PFS 2 is inadequate to show evidence of clinical benefit;
* OS is immature, underpowered, and may not reach statistical significance; and
* camizestrant is associated with heart-lowering and QT-prolonging effects, and when combined with drugs that can prolong the QT interval (such as ribociclib), may predispose patients to cardiac arrhythmias.

“In summary,” the reviewers write, “FDA is uncertain that overall positive benefit-risk for camizestrant has been demonstrated based on results of the SERENA-6 trial. Whether changing treatment at ESR1m detection before radiographic progression provides long-term benefit to patients is unknown; the clinical meaningfulness of the PFS result is uncertain, and OS data are immature and may not reach statistical significance.”

Committee members were asked to discuss the uncertainties regarding the interpretation of the SERENA-6 results and vote on this question: Based on the results of SERENA-6, whether the benefit-risk assessment is favorable for camizestrant in combination with a CDK4/6 inhibitor in patients with HR+HER2- advanced breast cancer upon detection of an ESR1 mutation while receiving a CDK4/6 inhibitor plus aromatase inhibitor.