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Jump to Key Points The FDA has approved the selective estrogen receptor degrader (SERD) imlunestrant (Inluriyo, Eli Lilly) in combination with CDK4/6 inhibitor abemaciclib (Verzenio, Eli Lilly) for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy.
The agency also approved Guardant360 Liquid CDx, a circulating tumor DNA (ctDNA) assay, to detect the mutation.
The greenlight came just 2 weeks after the FDA gave accelerated approval to a rival combination for a similar indication: the SERD camizestrant (Etcamah, AstraZeneca) plus any of three CDK4/6 blockers — abemaciclib, palbociclib, or ribociclib.
About 50% of patients develop ESR1 mutations during upfront aromatase inhibitor (AI) therapy, which causes resistance to the AI. Both regimens swap it out for an oral SERD. The main difference between the two options is that while the switch to imlunestrant/abemaciclib comes after disease progression, the switch to the camizestrant regimen comes after the ESR1 mutation is detected while patients are still on an AI.
- FDA approved imlunestrant + abemaciclib for ER+/HER2−, ESR1-mutated advanced/metastatic breast cancer.
- Indication: disease progression after ≥1 line endocrine therapy; FDA-authorized test required.
- Guardant360 Liquid CDx approved to detect ESR1 ctDNA mutation.
- EMBER-3 subgroup: PFS 11.1 mo vs 5.5 mo with imlunestrant alone.
- Grade 3/4 AEs: diarrhea 9%, neutropenia 21%, ALT 5%, AST 2.5%; ILD 3%, VTE <5%.
The camizestrant approval was the first time the FDA OK'd a change in cancer treatment based on ctDNA testing instead of disease progression.
In announcing the approval, AstraZeneca said it would allow clinicians to make a therapeutic switch early, before the cancer "becomes harder to treat, and patient outcomes and quality of life worsen."
But that argument didn't pass muster with the FDA's Oncologic Drugs Advisory Committee in April. It voted 6-3 against approval after some panelists said there's no evidence that clinical outcomes improve if an AI is switched to a SERD before disease progression. The FDA acknowledged the concern and required additional studies to confirm benefit.
Meanwhile, Lilly made the case for its imlunestrant/abemaciclib strategy when it announced the approval, stating that "all available evidence suggests that switching endocrine therapy and CDK4/6 inhibitor at clinical progression improves patient outcomes more than switching therapy earlier."
Lilly's approval was based on a subgroup analysis of 159 patients with ESR1-mutated disease in the EMBER-3 trial; 92 received imlunestrant alone and 67 received the combination, both after progression on an AI with or without a CDK4/6 blocker.
Median progression-free survival was 11.1 months with the combination vs 5.5 months with imlunestrant alone.
Grade 3 or 4 toxicity with the combination included diarrhea (9%), neutropenia (21%), alanine aminotransferase elevation (5%), and aspartate aminotransferase elevation (2.5%). About 3% of patients developed interstitial lung disease (ILD)/pneumonitis, while just under 5% had venous thromboembolic events.
Abemaciclib 's label includes warnings and precautions for diarrhea, neutropenia, ILD, hepatotoxicity, venous thromboembolism, and embryo-fetal toxicity. Imlunestrant carries warnings and precautions for embryo-fetal toxicity.
Imlunestrant is taken orally at a once-daily dose of 400 mg; the recommended dosage for abemaciclib is 150 mg orally twice a day.
M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net
