The 2024 San Antonio Breast Cancer Symposium® highlighted the regulatory decision-making process for two recent U.S. Food and Drug Administration (FDA) drug approvals, as well as the importance of monitoring ovarian toxicity in breast cancer clinical trials, during a special session on Tuesday, December 10.

A recording of the session, FDA Special Session: New Drug Approvals, is available on demand for registered 2024 SABCS® participants until March 31, 2025.

Participants in the session provided insights on how FDA teams weigh evidence during the drug approval process. Some of the recurring themes were the need to incorporate dose optimization pre-approval, including in early-phase studies, improving adequate representation of diverse populations in cancer clinical studies, and post-marketing commitments that augment available information and confirm favorable benefit-risk profiles of approved drugs.

Laleh Amiri-Kordestani, MD, Director of FDA Division of Oncology 1 in the Center for Drug Evaluation and Research (CDER) Office of Oncologic Diseases, and Eric Winer, MD, Alfred Gilman Professor of Medicine and Pharmacology and Deputy Dean of Cancer Research at Yale School of Medicine, moderated the session.

Jennifer Gao, MD, Associate Director for Education at the FDA Oncology Center of Excellence (OCE); Suparna Wedam, MD, Medical Oncologist at the FDA Office of Oncologic Diseases; and Antonio C. Wolff, MD, Interim Director of the Breast and Gynecologic Malignancies Group at Johns Hopkins Medicine, presented during the session. Victoria Goldberg, a patient advocate from New York City; Tiffany Ricks, PhD, Pharmacology/Toxicology Supervisor at the FDA Office of Oncologic Diseases; and Mallorie Fiero, PhD, Supervisory Mathematical Statistician in the FDA Office of Biostatistics, joined the moderators and speakers in a panel discussion.

Adjuvant ribociclib approval

Dr. Gao provided a brief historical overview of ribociclib approvals in metastatic breast cancer, before reviewing the September 2024 FDA approval of ribociclib with an aromatase inhibitor in the adjuvant early-stage setting, based on the phase III NATALEE study.

Underrepresentation of patients from racial/ethnic minority populations in cancer clinical trials is a key gap, which the FDA has sought to address through the OCEs’ Equity Program, Dr. Gao said.

“Of note, the NATALEE trial did enroll few racial and ethnic minority patients, and this was a post-marketing commitment,” she said, noting that the drug developer also committed to continued overall survival (OS) analyses.

Moreover, a lower dose of ribociclib (400 mg) was used in NATALEE, compared to the approved dose in the metastatic setting (600 mg).

The robust discussion and Q&A following the presentation underscored the importance of dose optimization prior to approval in cancer clinical trials. Dr. Wolff noted that dose adaptation, with a lower starting dose or a dose reduction after initiation of therapy, is not uncommon in routine clinical practice. Goldberg agreed, noting that even in the metastatic setting, patients report being on a reduced dose of ribociclib.

Dr. Amiri-Kordestani called attention to a subsequent SABCS® session, Clinical Workshop: Dose Optimization in Breast Medical Oncology, focused on optimizing dose and duration of therapy.

Inavolisib-based triplet approval

Dr. Wedam spoke about the FDA’s review process and October 2024 approval of inavolisib in combination with palbociclib and fulvestrant for treating adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer.

In addition to looking at the investigator-assessed progression-free survival (PFS) efficacy endpoint, the FDA also reviewed, and included in the labeling information, data for Patient-Reported Outcomes (PROs) on treatment tolerability.

“The increased toxicity seen with this triplet combination really does present an opportunity for future dose optimization,” Dr. Wedam said.

The PRO tolerability data were consistent with the clinically observed adverse events (AEs) and the expected safety profile based on the add-on design for a PIK3 inhibitor. Hyperglycemia is the most common AE associated with PI3K inhibitors and is included under Warnings and Precautions in the inavolisib labeling information, along with diarrhea and stomatitis.

Concurrent with the approval of the inavolisib triplet, the FDA approved a companion diagnostic device for identifying patients with PIK3CA mutations.

Sponsors of the INAVO120 study of the inavolisib triplet also made post-marketing commitments, including: A randomized clinical trial comparing the approved dose of inavolisib to lower doses; continued follow-up for final OS analysis; and integrated analysis to further characterize the pharmacokinetics/pharmacodynamics, safety, and efficacy of inavolisib in a more diverse population.

Following the presentation, the panel discussed the utility of using inavolisib in other triplet combinations, such as with different CDK4/6 inhibitors or aromatase inhibitors, as an area warranting further clinical investigation. In addition, panelists also addressed the role of PFS as a primary endpoint for registrational trials and discussed the patient population most likely to benefit from this novel triplet.

Monitoring ovarian toxicity

Ovarian toxicity in breast cancer clinical trials is an important issue to be mindful of, since a majority of patients with a new diagnosis of early-stage breast cancer will survive, Dr. Wolff explained.

“They will have, in some cases, to live with the consequences of our good intentions,” he said.

Ovarian toxicity is a hidden toxicity for many patients and may not be as apparent as alopecia or diarrhea, Dr. Wolff said. Chemotherapy has broad effects on ovarian function, impacting not only menstrual cycles during or soon after therapy but also long-term health and fertility. Other classes of drugs used to treat patients with breast cancer can also affect ovarian function and fertility.

Clinicians do not have all the information they need to discuss the issue with patients, Dr. Wolff said, although labeling information for many drugs includes recommendations for discussing potential fertility impacts with a healthcare provider. He also called attention to gonadal toxicity in men diagnosed with cancer, for which data is also lacking.

Dr. Wolff noted that tools are available to facilitate prospective data collection on ovarian toxicity in cancer clinical trials. The American Society of Clinical Oncology has also published a research statement and convened a task force focused on this issue.

In November 2024, the FDA published a draft guidance for industry on assessment of ovarian toxicity in premenopausal adults in cancer clinical studies. Dr. Wolff encouraged inclusion of stronger recommendations in the draft guidance, calling for a mandate or set of minimum standards for ovarian function/toxicity assessments.