Breast cancer has launched a new revolution in precision therapy.

On September 4, the FDA overruled the negative votes from its expert advisory committee and greenlighted AstraZeneca's oral SERD camizestrant, granting it accelerated approval.

This reversal directly turned an originally tug-of-war regulatory dispute into a landmark event in precision oncology treatment.

The approval of camizestrant covers its use in combination with CDK4/6 inhibitors for the treatment of patients with HR+/HER2- metastatic breast cancer. However, there is a critical precondition for medication: patients must have been detected with ESR1 gene mutations during first-line treatment with Aromatase Inhibitor (AI) combined with CDK4/6 inhibitors.

It is precisely this limitation that subverts the underlying logic of oncology clinical practice, shifting treatment decisions toward early intervention based on molecular markers: before the tumor mass is detected to be enlarged by CT or MRI, ctDNA provides early warning and directly switches the treatment regimen. This means that the intervention node for breast cancer has been significantly advanced.

However, only one week after the accelerated approval, the phase III SERENA-4 study, which aimed to expand camizestrant to a broader patient population, failed to meet its primary endpoint. This is already the third failure of oral SERDs in the first-line all-comer population in recent years. The successive setbacks of the same class of drugs in the same population indicate that the problem most likely lies in the matching of mechanism and patient population, rather than the defect of a single molecule.

To a certain extent, this further highlights the value of precise stratification and "early intervention". In any case, a revolution in oncology intervention driven by "molecular warning" has quietly torn open a gap.

/ 01 / Switching Treatment Before the Tumor Progresses

The underlying logic of traditional oncology treatment is usually "tackle problems as they arise": only when CT or MRI imaging confirms that the tumor has enlarged will clinicians make the decision to switch the treatment regimen, at which point the cancer cells have often already metastasized.

The accelerated approval of camizestrant breaks this default path. For patients with HR-positive, HER2-negative metastatic breast cancer who are receiving first-line treatment with AI combined with CDK4/6 inhibitors, even if there is no radiological progression, as long as a new ESR1 mutation is detected via ctDNA, the regimen can be switched to camizestrant combined with CDK4/6 inhibitor, instead of waiting for radiological progression of the tumor.

The reason why ctDNA can indicate risks earlier than imaging stems from the biological characteristics of ESR1 mutations. Most ESR1 mutations are acquired during first-line AI treatment, which frees the estrogen receptor from ligand dependence and enables continuous self-activation, making it the main mechanism of endocrine therapy resistance.

More critically, such mutation signals will preferentially enter the peripheral blood, and the time point when ctDNA captures them is usually earlier than the time when the tumor grows to a visible size on imaging. This is the biological basis for ctDNA-guided early intervention.

The phase III results of the Serena-6 clinical trial verified the clinical benefit of "early intervention". This clinical trial enrolled patients with HR+/HER2- breast cancer. These patients had not yet developed disease progression on traditional radiological scans (such as CT/MRI), but new ESR1 mutations were detected via ctDNA testing in their blood.

The results showed that compared with patients who continued the original regimen, patients who switched to the camizestrant + CDK4/6 inhibitor regimen in advance had a 56% reduction in the risk of disease progression or death, with a median progression-free survival (mPFS) of 16 months, compared with only 9.2 months in the control group. In addition, the new regimen reduced the risk of tumor progression before patients switched to the next line of treatment by 23%. The overall survival data is not yet mature, but shows a favorable trend.

At the expert advisory committee meeting in April this year, experts raised questions about the design of Serena-6: the trial did not conduct a head-to-head comparison with the traditional standard of "waiting for radiological progression before switching treatment", and the cross-medication rate in the control group was relatively low; they also worried that approval based on this would set a precedent with unassessable risks for "using liquid biopsy to replace imaging to drive clinical decisions", and the committee finally voted 6 against and 3 in favor.

The turning point came from a key ctDNA analysis data that AstraZeneca submitted as supplementary information at the FDA's request:

At week 8 of treatment, the total ctDNA level in the camizestrant group decreased by 99%, while that in the control group increased by 64%;

An exploratory analysis showed that ctDNA clearance was strongly correlated with a 61% improvement in overall survival.

It should be noted that this 61% improvement in overall survival is still an exploratory conclusion. But it is precisely this clinical evidence at the ctDNA level that led the FDA to change its position after extending the review and grant accelerated approval to camizestrant.

As a result, camizestrant has become the world's first oral SERD to launch the paradigm of "ctDNA molecular monitoring for early intervention", breaking the traditional late-line endocrine salvage framework and locking in an earlier first-line treatment window.

This is not only an important moment in the field of breast cancer treatment, but also means that the FDA has recognized this novel treatment strategy that intervenes based on liquid biopsy markers before conventional tumor progression.

Of course, accelerated approval means that AstraZeneca still needs to supplement verification data with confirmatory trials, but the shift in regulatory attitude itself is already a key signal.

/ 02 / First-line Challenge Against AI Hits a Setback

Just one week after camizestrant received accelerated approval, the news came that the SERENA-4 study had failed.

This study enrolled 1,371 ER-positive, HER2-negative breast cancer patients who had not received prior systemic treatment for advanced disease, comparing camizestrant combined with palbociclib versus anastrozole combined with palbociclib. The results showed that the treatment group had improved PFS, but did not reach statistical significance.

The setback of SERENA-4 targeted a larger commercial goal. Because it aimed to verify whether the new-generation oral SERD could replace Aromatase Inhibitors from the very beginning. If successful, the market space of camizestrant would expand from the ESR1 mutation population to all HR+ advanced patients.

Unfortunately, the PFS did not eventually show a statistically significant difference.

This is exactly the same as Roche's setback. In the phase III persevERA trial announced in March this year, giredestrant combined with palbociclib versus letrozole combined with palbociclib for first-line treatment of 992 patients also only yielded a numerical improvement in PFS (median PFS 33.1 months vs 28.2 months), failing to reach a statistically significant improvement.

Earlier, Sanofi's amcenestrant suffered a setback in the AMEERA-5 trial. This phase III trial of 1,068 patients also compared oral SERD combined with palbociclib versus letrozole combined with palbociclib, enrolling unselected first-line all-comer patients, and the results even failed to outperform the standard regimen.

Three oral SERDs from different companies have suffered successive failures in the same setting of "first-line challenge against AI in advanced breast cancer", indicating that this path is difficult to take in the short term.

The root cause may lie in the mutation base of the patient population. An analysis of the study entitled "Kinetics and Determinants of ESR1 Mutation Detection in Metastatic Breast Cancer" shows that blood ESR1 mutations are rare at baseline in ER+/HER2- metastatic breast cancer, with a detection rate of only 3.2%. Among patients who progressed after first-line AI treatment, this proportion rose to 41.7%.

The success of SERENA-6 precisely captures the time point when ESR1 mutations have been enriched under the pressure of AI treatment and the original regimen begins to fail; while the successive failed all-comer studies try to prove superiority in the all-comer population with an extremely low mutation rate where AI is still effective, the therapeutic effect is diluted by the majority of patients without mutations.

The "shattered dream" of the all-comer population further highlights the value of ESR1 mutations. As Susan Galbraith, Executive Vice President of Oncology R&D at AstraZeneca, said: "We are disappointed with the results of SERENA-4, but this makes us more focused on maximizing the benefit population defined by SERENA-6."

/ 03 / The Ongoing Paradigm Revolution

At present, about 37,000 patients with HR-positive metastatic breast cancer in the United States are receiving CDK4/6 combined endocrine therapy, of whom about 30% will develop ESR1 mutations during first-line treatment and before radiological progression. This is the current accessible patient population for camizestrant. Its recent commercial performance will depend more on whether regular ESR1 testing can be implemented, whether patients can be identified in time, and the acceptance of the "early switch" strategy by physicians.

For the underlying liquid biopsy/companion diagnostic industry, this also means a subversion of the underlying logic: ctDNA has thus been recognized by regulators as a marker that can trigger treatment decisions, rather than just a prognostic monitoring tool.

According to the clinical design of camizestrant, blood tests are required every 2 to 3 months during first-line treatment. This continuous and dynamic ctDNA monitoring is bound to bring incremental demand for clinical testing.

The greater commercial imagination lies in the unapproved early breast cancer indication: AstraZeneca is advancing two phase III studies, CAMBRIA-1 and CAMBRIA-2, which together cover about 10,000 patients with medium and high recurrence risk, to evaluate the effect of camizestrant in reducing recurrence risk in adjuvant therapy.

Previously, AstraZeneca set a peak sales of over 5 billion US dollars for camizestrant. Overseas analysts believe that the currently approved "first-line treatment switch" population is only a small part of its grand commercial landscape, and the main future performance growth will depend on further expansion in adjuvant therapy for early breast cancer.

This is not difficult to understand: more than 90% of breast cancer patients are diagnosed at an early stage, and the adjuvant therapy market is far larger than the advanced salvage market. It is worth noting that after the first-line setback of Roche's giredestrant, the company cut into the early breast cancer adjuvant therapy track through the lidERA study, which is currently under FDA priority review.

For the industry, the most far-reaching significance still lies in this treatment logic of "ctDNA detects problems before imaging, and intervenes before drug resistance worsens", which is not limited to oral SERDs, nor is it limited to breast cancer.

Theoretically, this is applicable to all cancer types that have detectable acquired drug resistance markers, and the markers appear earlier than radiological progression. For example, acquired driver gene mutations after targeted therapy in lung cancer, and drug resistance mutations related to the androgen receptor pathway in prostate cancer, may all become targets for ctDNA to trigger early intervention.

Once this pathway is verified in more cancer types, and clinical treatment decisions shift from relying on radiological progression to relying on molecular markers, the overall rhythm of oncology treatment may move forward, changing the long-term outcomes of countless patients.

As analysts from the investment bank Jefferies stated in the report, the approval of camizestrant is an important moment in the field of breast cancer treatment. Its core significance does not only lie in the drug itself, but in the fact that it has verified a brand new treatment paradigm.

This article is from the WeChat Official Account "Amino Observation" (ID: anjiguancha), author: Amino Jun, published with authorization from 36Kr.