FDA Panel Gives Thumbs Down to Novel Strategy for Switching Breast Cancer Therapy

A novel strategy for switching breast cancer therapy intrigued members of an FDA advisory committee but failed to sway the panel to recommend approval of the strategy.

By a 6-3 vote, the Oncologic Drugs Advisory Committee (ODAC) agreed with an FDA staff assessment that a randomized trial of the oral selective estrogen receptor degrader camizestrant plus a CDK4/6 inhibitor did not clearly establish a clinically meaningful benefit for patients who switched to the combination on the basis of a molecular marker (ESR1 mutation). In a briefing document prepared for ODAC, FDA staff argued that accepting the strategy would represent a paradigm shift from reliance on clinical/radiographic evidence to define disease progression to use of a biomarker.

“I think it’s a huge change in clinic and practice for a lot of women that have no chance of benefiting from it, given the large number of women that have to be tested [for ESR1 mutation],” said ODAC panelist Sarah Colonna, MD, of the University of Utah Huntsman Cancer Institute in Salt Lake City. “I don’t think we know that detection of a mutation should serve as our gold-standard marker for progression at this point. I hope that this is the future, but my hopes aren’t enough to make me vote for it.”

The concept of using molecular testing to determine how to treat patients “fascinated” Michael Kelley, MD, of Duke University Medical Center in Durham, North Carolina, but like Colonna, he remained unconvinced that “the implementation of this particular drug in this particular setting improves the clinical outcome for patients.”

“I’m concerned about the design of this study,” said Kelley. “I don’t think we need a perfectly designed study, but I do think we need one that answers the question. One part of that could be offering the experimental drug as an option to be used at a future point.”

Mixed Feelings

Even panelists who voted to recommend approval of the combination admitted to conflicted feelings.

“I voted yes, although quite frankly, I was about as much on the fence as you could get,” said William Gradishar, MD, of Northwestern University in Chicago. “I don’t think it’s a perfect study. I don’t think there will be a perfect study. If I were seeing a patient today and they were to ask me what am I going to do about second-line therapy, I have no idea. It’s not just the patient circumstance 6 months, 12 months, or 2 years from now. The field is changing so fast, the landscape is sand under our feet.”

“The sentiment of keeping a patient on a particular kind of therapy for an extended period of time with metastatic disease is ultimately the goal we have for all of our patients with metastatic breast cancer, particularly those with ER [estrogen receptor]-positive disease before we pivot to something more toxic,” he added. “I thought it was a worthwhile effort to try and improve outcome.”

Principal support for the new drug application came from the SERENA-6 trial involving patients with newly diagnosed advanced hormone receptor-positive/HER2-negative breast cancer. All patients started treatment on an aromatase inhibitor plus a CDK4/6 inhibitor. Patients who responded to treatment had follow-up that included assessment of circulating tumor (ct)DNA to detect ESR1 mutation. At that point, patients were randomized to switch to the camizestrant combination or continue treatment with the aromatase inhibitor and CDK4/6 inhibitor until radiographic progression.

The primary analysis showed a 7-month improvement in progression-free survival (PFS), a 56% reduction in the hazard ratio, in patients who switched to the camizestrant combination. Data on overall survival (OS) remained immature but suggested no detrimental effect with the switch (HR 0.91, 95% CI 0.48-1.73). Moreover, the switch was associated with a fourfold improvement in time to deterioration in quality of life.

Nonetheless, FDA staff found the study failed to prove that switching at the first sign of ESR1 mutation is better than waiting until radiographic progression.

“To our knowledge, no prior trial or other body of evidence has established that the SERENA-6 approach improves long-term outcomes compared to the standard approach,” said Mirat Shah, MD, of the FDA’s Center for Drug Evaluation and Research, during the ODAC meeting. “The SERENA-6 trial also does not answer this question, as there is no evaluation of changing therapy at an earlier time point compared to changing therapy at a standard time point built into the trial design.”

Looking Ahead

Acting ODAC Chair Neil Vasan, MD, PhD, of NYU Langone Health in New York City, voted to recommend approval but agreed with the FDA staff that the SERENA-6 approach represents a paradigm shift that “may warrant a higher evidentiary bar.”

“The issue is what that bar should be,” said Vasan. “I felt that the large benefit in PFS and PFS2 [time to second progression or death], with an OS that was directionally favorable, was clinically meaningful. The FDA is correct that this trial does not define an optimal sequence, but the field itself has not defined one in ER-positive metastatic breast cancer. Second-line therapy is not a single standard. It’s a plurality of options shaped by biomarkers, toxicities, access, timing.”

“A perfect trial, defined in retrospect, would likely have required mandating therapies that were either unavailable at the time or are now outdated,” he continued. “A design that maximizes interpretability might sacrifice relevance. Any attempt to fully specify therapy in advance would create a trial that is internally consistent but externally constrained, locking patients into predetermined pathways and risking obsolescence before it reads out.”

When discussing treatment with a patient who has newly diagnosed metastatic ER-positive breast cancer, second-line therapy “is not preordained,” said Vasan. “As a field, we have to think about trial designs that might lock patients into yesterday’s treatments.”

Acknowledging the growing impact of ctDNA assessment in clinical trial design, Vasan said clinicians “need clearer guidance on how to act on molecular progression in metastatic cancer because the field has already begun to move.”