Two ESR1 Approvals in Two Weeks Set Two Different Testing Schedules. The Evidence Behind Each Is Not the Same.
The FDA approved camizestrant on Sept. 4 for ESR1 mutations found on circulating tumor DNA before progression, and imlunestrant with abemaciclib on Sept. 18 for ESR1-mutated disease after progression. The evidence differs, and so does when the test is ordered.
Idea in Brief
The Approvals
Camizestrant (Etcamah) with a CDK4/6 inhibitor received accelerated approval Sept. 4 for ESR1 mutations detected during aromatase inhibitor plus CDK4/6 inhibitor therapy. Imlunestrant (Inluriyo) with abemaciclib was approved Sept. 18 after progression on endocrine therapy.
The Evidence
SERENA-6 (n=315) showed median progression-free survival of 16 versus 9.2 months (HR 0.44). The EMBER-3 ESR1 result (n=159, 11.1 versus 5.5 months, HR 0.53) is an exploratory subgroup.
The Caveats
Overall survival is immature for both. SERENA-6 measured benefit from ctDNA detection, not progression, and EMBER-3 compared the combination with imlunestrant alone.
Two oral estrogen receptor antagonists were approved for ESR1-mutated, ER-positive, HER2-negative breast cancer in September, and the two labels do not call for testing at the same moment. Camizestrant is tied to a circulating tumor DNA result found while the patient is still progression-free on an aromatase inhibitor plus a CDK4/6 inhibitor. Imlunestrant with abemaciclib is tied to progression after endocrine therapy.
On Sept. 4, the Food and Drug Administration granted accelerated approval to camizestrant (Etcamah, AstraZeneca) with a CDK4/6 inhibitor. Two weeks later, on Sept. 18, the agency approved imlunestrant (Inluriyo, Eli Lilly) with abemaciclib (Verzenio). The FDA named the Guardant360 CDx assay as the companion diagnostic for both.
What the two labels cover
The camizestrant indication is adults with hormone receptor-positive, HER2-negative locally advanced or metastatic disease upon detection of an ESR1 mutation during aromatase inhibitor and CDK4/6 inhibitor therapy. The dose is 75 mg once daily, with abemaciclib, palbociclib or ribociclib continued at the dose the patient was taking when the mutation was detected, according to the FDA announcement.
The imlunestrant indication is adults with ESR1-mutated disease that has progressed after at least one line of endocrine therapy. The dose is 400 mg once daily with abemaciclib 150 mg twice daily, per the FDA announcement, which does not describe the approval as accelerated.
What SERENA-6 supports
SERENA-6 (NCT04964934) was randomized, double-blind and placebo-controlled. It enrolled 315 patients who had taken an aromatase inhibitor plus a CDK4/6 inhibitor as initial endocrine-based therapy for at least six months without progression and whose blood showed an ESR1 mutation. Median progression-free survival was 16 months (95 percent CI, 12.7 to 18.2) with camizestrant versus 9.2 months (95 percent CI, 7.2 to 9.5) with continued aromatase inhibitor, a hazard ratio of 0.44 (95 percent CI, 0.31 to 0.60). Overall survival data were not mature, the FDA reported.
The caveat is the starting line. Progression-free survival was measured from the point the mutation was detected, and the FDA said in its announcement that it is not yet confirmed whether intervening then, rather than at confirmed progression, gives clinically meaningful benefit. Angelo de Claro, M.D., director of the FDA Oncology Center of Excellence, said in the announcement that "additional evidence is needed to confirm clinical benefit." OncLive reported that the Oncologic Drugs Advisory Committee voted 6 to 3 in April that SERENA-6 had not established clinically meaningful benefit, and that the FDA told AstraZeneca time to second progression would not support approval. The agency has required confirmatory studies.
Clinical Pearls
- The camizestrant approval is the first FDA approval of a cancer therapy guided by detection of a resistance mutation in ctDNA before imaging shows progression, according to the FDA.
- In SERENA-6, median progression-free survival was 16 months with camizestrant versus 9.2 months with continued aromatase inhibitor (HR 0.44; 95 percent CI, 0.31 to 0.60), with overall survival immature.
- The FDA's Oncologic Drugs Advisory Committee voted 6 to 3 in April that SERENA-6 had not established clinically meaningful benefit, as OncLive reported, and the FDA has required confirmatory studies.
- In EMBER-3, the ESR1-mutated subgroup (n=159) had median progression-free survival of 11.1 months with imlunestrant plus abemaciclib versus 5.5 months with imlunestrant alone, and the FDA calls the analysis exploratory.
- Imlunestrant alone did not improve progression-free survival over investigator's choice of endocrine therapy in the overall population or in patients without a detected ESR1 mutation.
- Both labels require an FDA-authorized test, and the Guardant360 CDx assay is the named companion diagnostic for each; camizestrant carries a boxed warning for QTc prolongation.
What EMBER-3 supports
EMBER-3 (NCT04975308) was randomized and open-label. It enrolled 874 adults and assigned them 1:1:1 to imlunestrant, investigator's choice of fulvestrant or exemestane, or imlunestrant plus abemaciclib. The major efficacy measure for the combination was investigator-assessed progression-free survival in the overall population against imlunestrant alone, per the FDA. In the New England Journal of Medicine report, the 426 patients in that comparison had median progression-free survival of 9.4 months versus 5.5 months (hazard ratio 0.57; 95 percent CI, 0.44 to 0.73).
The ESR1 result is a subgroup. The FDA calls the analysis in 159 patients with ESR1-mutated tumors exploratory. Median progression-free survival was 11.1 months (95 percent CI, 7.4 to 13.7) with the combination and 5.5 months (95 percent CI, 3.8 to 7.2) with imlunestrant alone (hazard ratio 0.53; 95 percent CI, 0.35 to 0.80). Response rates were 35 percent versus 15 percent. Overall survival was immature at the interim analysis, with deaths in 35 percent of this subgroup.
Two further limits apply. The comparator was imlunestrant alone, not standard endocrine therapy with or without a CDK4/6 inhibitor. And imlunestrant alone did not improve progression-free survival over investigator's choice of endocrine therapy in the overall population or in patients without a detected ESR1 mutation; the FDA says benefit was observed only in the ESR1-mutated group.
Both approvals rest on progression-free survival, and neither has shown an overall survival benefit. One is measured from a blood test before progression; the other comes from an exploratory subgroup of 159 patients.
Safety and the labels
The camizestrant label carries a boxed warning for arrhythmia from QTc prolongation, particularly when it is taken with other QTc-prolonging drugs, plus warnings for bradycardia and embryo-fetal toxicity, the FDA said. The imlunestrant label warns of embryo-fetal toxicity. The abemaciclib label adds diarrhea, neutropenia, interstitial lung disease or pneumonitis, hepatotoxicity and venous thromboembolism, according to the FDA.
Among 208 safety-evaluable patients on the EMBER-3 combination, the most common grade 3 or 4 adverse effects were diarrhea (9 percent), infections (7 percent) and fatigue (5 percent), OncLive reported.
What practices should do now
Decide whether your practice will test before progression. The camizestrant label applies only if a mutation is found during aromatase inhibitor plus CDK4/6 inhibitor therapy, which means plasma testing has to happen while the patient is doing well on imaging. The imlunestrant combination needs a test at or after progression. Neither FDA announcement sets a testing interval, so the schedule is a practice decision.
Confirm the order pathway for Guardant360 CDx and who owns it, since both labels require an FDA-authorized test. In EMBER-3 the assay was limited to specific ESR1 mutations in the ligand-binding domain, per the FDA. Ask your billing office how payers are handling prior authorization and coverage for repeat plasma testing before the first request arrives.
Check the CDK4/6 inhibitor too. The imlunestrant combination is labeled only with abemaciclib, while camizestrant is labeled with any of the three. Review concomitant QTc-prolonging drugs before camizestrant. For the other recent change in metastatic breast cancer, see our report on tucatinib as first-line maintenance. Then write down which testing schedule your practice is using and why, so that the next ESR1 result has a plan waiting for it.
Reported, fact-checked and edited by The Script Pad's editorial staff.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
