The 2023 San Antonio Breast Cancer Symposium® featured a special session focused on three new drug approvals in different patient populations in the metastatic breast cancer (mBC) setting. In Special Session 1: New Drug Approvals for Metastatic Breast Cancer, presenters from the U.S. Food and Drug Administration (FDA) Office of Oncologic Diseases reviewed data and regulatory considerations for three targeted therapies—trastuzumab deruxtecan (T-Dxd), elacestrant, and capivasertib—approved in 2023.

The session, presented on Tuesday, December 5, is available on demand for registered 2023 SABCS^® participants through March 31, 2024, on the meeting platform. 

These new approvals represent distinctive firsts in the mBC space. T-Dxd is the first approval in HER2-low breast cancers; elacestrant is the first approval based on data entirely in the post-CDK4/6 inhibitor (CDK4/6i) setting; and capivasertib is the first AKT serine/threonine kinase inhibitor to be approved in mBC.

The session was co-moderated by Laleh Amiri-Kordestani, MD, Director of Division of Oncology 1 at the FDA, and Martine J. Piccart, MD, PhD, Professor of Oncology at the Université Libre de Bruxelles in Belgium.

The panel included SABCS® Co-Director Virginia G. Kaklamani, MD, Professor of Medicine, Hematology/Oncology Division, UT Health San Antonio; FDA biostatistician Flora Mulkey, MS; Vassiliki Karantza, MD, PhD, Associate Vice President of Global Clinical Development at Merck; and Janice K. Cowden, AA, BA, a former nurse and current patient advocate.

The robust panel discussion and Q&A sessions highlighted the importance of evolving concepts that impinge on the regulatory landscape and optimal patient-centered care in breast cancer.

Optimizing drug dosing by ensuring inclusion of a range of doses and collection of not only safety and tolerability but also efficacy data across doses in earlier clinical trial phases emerged as an important clinical study goal. Mirat Shah, MD, of the Office of Oncologic Diseases at the  FDA, alluded to Project Optimus, an FDA initiative focused on reforming the current dosing paradigm by moving away from maximum tolerated dose-based schemes to more robust and patient-centered schemes incorporating both efficacy and toxicity measures.

Consideration of the patient’s quality of life (QoL) measures in clinical trial design and data capture, early and consistently, emerged as another important throughline of the session.

T-Dxd approved for HER2-low mBC

Preeti Narayan, MD, of the Office of Oncologic Diseases at the FDA, reviewed data from the pivotal phase 3 DESTINY-Breast04 study, comparing T-Dxd to physician’s choice of chemotherapy (TPC) in patients with HER2-low (immunohistochemistry [IHC] 1+/2+, without HER2 amplification per in situ hybridization [ISH]-negative) mBC.

“Prior to this approval, HER2-low breast cancer was treated similarly to HER2-negative breast cancer, where therapy was guided by hormone receptor [HR] status,” Dr. Narayan noted.

She added that, historically, HER2-targeted therapies have not been effective for HER2-low cancers. Moreover, HER2-low breast cancers are heterogeneous in terms of their HR status and include triple-negative breast cancer (TNBC) and 50%–60% of cancers previously thought to be HER2-negative. Dr. Narayan reviewed the statistically significant and clinically meaningful improvement in progression-free survival (PFS) with T-Dxd, over TPC. The trial met both the primary endpoint (PFS by blinded independent central review [BICR] in HR+ patients) and key secondary endpoints (PFS by BICR in all patients and overall survival [OS] in HR+ and all patients).

Exploratory subgroup analysis of patients with TNBC or rapid progression within six months of neoadjuvant chemotherapy showed clinical benefits, in terms of PFS and OS, consistent with the overall and HR+ population. Dr. Narayan noted, “Therefore, it was reasonable to include these populations in the indication [for T-Dxd].”

A companion diagnostic was concomitantly approved by the FDA to assist in patient selection.

T-Dxd is approved in a similar setting in the European Union, said Aarón Sosa Mejia, MD, Chief Medical Officer, Danish Medicines Agency.

First oral SERD offers a more convenient option for patients with mutations in ESR1

Elacestrant is the first oral selective estrogen receptor (ER) degrader (SERD), approved by the FDA for treatment of patients with ER+ HER2-negative ESR1-mutated mBC, based on the significant PFS benefit seen in the phase 3 EMERALD study. Elacestrant is also approved in the EU.

ESR1 mutations are a common mechanism of acquired resistance to endocrine therapies, Dr. Shah noted. Although the trial was not formally powered to assess PFS differences in patients without ESR1 mutations, exploratory analyses indicated that the PFS improvements seen in the overall population were predominantly driven by improved PFS in the ESR1-mutated subgroup and that elacestrant showed no PFS benefit in patients lacking ESR1 mutations. Dr. Shah noted that the FDA’s decision was based on the uncertainty in PFS benefit in this subset, short PFS in the control arm, and emerging data for activity of other SERDs in ESR1-mutated mBC.

Patient advocates expressed optimism for the first oral SERD as an option to fulvestrant, administered via intramuscular injection and requiring a clinic visit. However, they also noted being disappointed that an oral SERD is not yet available for patients without ESR1 mutations.

Late-breaking approval of capivasertib for PI3KC/AKT/PTEN-altered mBC

Capivasertib, an inhibitor of all three AKT isoforms, was approved in combination with fulvestrant for the treatment of patients with HR+ HER2-negative mBC with ≥1 alteration in PI3KC/AKT/PTEN, based on data from the phase 3 CAPItello-291 study. Christy Osgood, MD, of the Office of Oncologic Diseases at the FDA, reviewed the results, which showed improvements with capivasertib in both co-primary endpoints of PFS in the overall population and in the biomarker-positive subgroup. Exploratory analysis of the biomarker-negative subgroup indicated a statistically significant, but not clinically meaningful, improvement in outcomes for patients with biomarker-negative or unknown status, for example, median PFS difference with the addition of capivasertib was around five days in the biomarker-negative subgroup. Although prior CDK4/6i therapy was not a requirement for trial enrollment, most (~70%) patients had received prior treatment with a CDK4/6i.

As with the other new approvals, a companion diagnostic—a next-generation sequencing-based assay for assessing relevant biomarker alterations—was FDA-approved concomitantly.

Dr. Sosa noted that capivasertib is currently under review with the European Medicines Agency for treatment of biomarker-positive patients, with a likely approval over the next few months.

New approvals also underscore challenges and queries for further investigation

The availability of new targeted therapies, while welcome and important, also underscores challenges.

Assessment of HER2-low status remains challenging due to the heterogeneity in HER2 status across metastatic sites, Dr. Piccart noted. She said that access limitations, due to cost or lack of insurance coverage, is a critical issue, as is treatment sequencing. Sequencing and/or selecting from between capivasertib and alpelisib, for examples, remains an open question.

Dr. Kaklamani noted that including biomarker-negative patients, such as patients lacking PI3KC/AKT/PTENalterations, in studies of AKT pathway inhibitors may be prudent, as these therapies may be of benefit to patients with AKT/PIK3C overexpression without genomic changes.

A look behind the curtain: The FDA’s approach to approval of targeted therapies

Throughout their review of the new approvals, the FDA staff alluded to several key considerations that inform regulatory approval of biomarker-guided targeted therapies. These include the biological rationale for the drug, precision with which the biomarker can be detected, biomarker prevalence, efficacy in biomarker-negative patients, difference in efficacy between biomarker-positive vs. -negative populations, OS benefit, safety profile, and the totality of evidence from trial/trial-external data.

When new drugs are added to existing options, the improvement in outcomes is often accompanied by additional toxicity from the newly added drugs. Therefore, the evaluation of the risk-benefit profile, based on not just the efficacy of the drug, but on the outcome improvements weighed against the added toxicity from the added drugs is also a key regulatory consideration for approvals.