FDA Sheds Light on New Drug Approvals in Breast Cancer

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The 2024 San Antonio Breast Cancer Symposium (SABCS) is known for highlighting new, high-impact data, along with offering opportunities for the audience to engage with experts in the field to get insights on their own complex patient cases. The FDA was heavily featured from day 1 of this year’s meeting, with experts from the organization discussing efforts to modernize its approach to drug development and optimization.

FDA on New Drug Approvals

In the FDA special session on new drug approvals, Jennifer Gao, MD, a medical oncologist and associate director for education at the FDA Oncology Center of Excellence (OCE), discussed the recent FDA approval of ribociclib (Kisqali, Novartis) for adjuvant use in patients with stage II to III hormone receptor–positive (HR+) breast cancer. The NATALEE trial (NCT03701334) randomly assigned patients to 3 years of ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) or an NSAI alone. Gao explained that the improvement in invasive disease–free survival (iDFS) was statistically significant at the time of the third planned interim analysis; however, only about 20% of patients had completed their 3-year treatment course, leading the FDA to request more time prior to approving this therapy. At the time of the final iDFS analysis, 43% of patients had completed the adjuvant ribociclib.

The results of the NATALEE trial were published in The New England Journal of Medicine, with the study authors reporting a significant improvement in 36-month iDFS; these results led to FDA approval on September 17, 2024. Grade 3 to 4 adverse events (AEs) were more common in the ribociclib arm (56% vs 7%) of the trial, and the duration of therapy was longer than that of adjuvant abemaciclib (Verzenio; Eli Lilly and Company) at 2 years, which was previously approved for a similar patient population. Notably, the approved adjuvant dose of ribociclib (400 mg) is lower than the previously approved dose in the metastatic setting (600 mg), in an effort to make the regimen more tolerable.¹

Patient Representation in Clinical Research

The NATALEE Trial

During her presentation, Gao shared that the FDA flagged a notable challenge in the data from the NATALEE trial: a lack of participant diversity. The manufacturer responded to this with a postmarketing commitment to enhance diversity in the clinical trials through “an integrated analysis that has a sufficient number of patients of racial and ethnic minorities [to reflect] the diversity of patients in the United States, especially those who are Black or African American.”¹

Following Gao’s presentation, a panel of experts including medical oncologists (Antonio C. Wolff, MD, of Johns Hopkins Medicine; and Eric S. Winer, MD, of Dana-Farber Cancer Institute), representatives from the FDA (Gao; Suparna B. Wedam, MD; and Laleh Amiri-Kordestani, MD), and a patient advocate (Victoria Goldberg) further discussed the underrepresentation of diverse populations in breast cancer clinical trials. However, the group noted this issue extends beyond racial and ethnic minority representation to elderly patient representation as well. To support the process of addressing these issues in clinical trials, the panelists highlighted the importance of the OCE Equity Program at the FDA, which is aimed at increasing enrollment of underrepresented populations in clinical research.

The INAVO120 Trial

Wedam, a medical officer and breast cancer scientific liaison at the FDA Center for Drug Evaluation and Research, presented an overview of the phase 2/3 INAVO120 trial (NCT04191499), which studied inavolisib (Itovebi; Genentech, Inc) vs placebo in combination with palbociclib (Ibrance; Pfizer Inc) and fulvestrant (Faslodex; AstraZeneca) for patients with endocrine-resistant metastatic HR+ breast cancer. This trial reported a significant improvement in progression-free survival (PFS); however, AEs were significant, including hyperglycemia, which led to over half the patients in the inavolisib arm requiring treatment with an oral antihyperglycemic or insulin. Additionally, Wedam noted that the FDA was aware of patient-reported symptoms of diarrhea and mucositis in the INAVO120 trial results.

Similar to ribociclib, the manufacturer of inavolisib is tasked with demonstrating the safety and efficacy of the drug in a more diverse population. Additionally, it was asked to perform postmarketing studies to evaluate alternative doses of inavolisib in an effort to reduce its toxicity.²

The panel discussed a number of important considerations when implementing inavolisib in real-world practice. At the time of this study, palbociclib was still a recommended cyclin-dependent kinase (CDK) 4/6 inhibitor in the first-line metastatic setting.

Furthermore, the panelists noted there are ongoing questions about altering the endocrine therapy or CDK4/6 inhibitor as well as the impact of adjuvant CDK4/6 inhibitors on the efficacy of this new regimen. However, the oncologists expressed confidence in using the regimen as it is currently approved, particularly in patients with high disease burden.

The panel also acknowledged that a 3-drug regimen carries more financial and physical toxicity. Additionally, they highlighted the need to optimize the dose of inavolisib, noting that they are hopeful that the ongoing postmarketing study will help to address the high rates of patient-reported toxicities.

Implementation in Clinical Practice

The panel also discussed the importance of patient selection when applying new data in the clinic. According to the panelists, clinicians must evaluate the totality of the data and discuss with patients whether the toxicities (both physical and financial) are warranted for their individual case, regardless of their alignment with the FDA-approved population. “The answer isn’t to treat everyone with toxic chemotherapy to avoid a 1% chance of something happening,” Winer said during the SABCS panel. “What we desperately need, particularly for these lower-risk patients…is better [biomarker] predictors.”

FDA on Dose Optimization

Following the FDA special session on new drug approvals, a panel of experts convened to lead a clinical workshop on dose optimization, which expanded on several of the concepts discussed in the prior panel. In this FDA special session, panel participants included experts from the FDA (Mallorie Fiero, PhD; Mirat Shah, MD, MHS; and Stacy Shord, PharmD), medical oncologists (Patricia LoRusso, DO, of Yale Medicine; and Michail Ignatiadis, MD, PhD, of Institut Jules Bordet), and a patient advocate (Julia Maués).

During the panel discussion, panelists discussed the tendency of conventional studies on cytotoxic therapies to focus on identifying the maximum tolerated dose (MTD). Compared with cytotoxics, modern small molecules have wider therapeutic indices, are continued for longer durations, and often do not include breaks in treatment to allow for toxicity resolution. The MTD of novel targeted therapies may not be reached in studies or be necessary to achieve the intended therapeutic effect; however, it is still used in clinical trials.

In phase 3 trials evaluating small molecules, 45% of patients required dose modifications due to toxicity, according to LoRusso. Conversely, in studies where the phase 2 dose utilized is below the MTD, there are significantly fewer dose modifications needed in subsequent phase 3 studies, and efficacy is retained.³

Project Optimus

Another FDA OCE initiative, Project Optimus, is intended to reform the dosing paradigm in oncology drug development, according to LoRusso. Project Optimus is amazing because it focuses on the totality of data,” LoRusso said. “It brings the science into the clinical trial of the drug for improved dose decision-making…minimizing toxicity, enhancing efficacy, and improving outcomes for patients.”³

One alternative strategy that is now recommended by the FDA is to study multiple doses of a drug up front in clinical trials to assess activity, safety, and tolerability. A randomized, parallel dose-response trial can be used in the registration trial to evaluate multiple doses at once, or sequential stand-alone trials evaluating different doses can be conducted. Inavolisib was approved following the INAVO120 trial in October 2024 at a dose of 9 mg; however, this is not considered to be the optimized dose given high rates of AEs and dose modifications. Clinical data are limited at lower dosages, though, because only 1 dose was studied. Similar to ribociclib, the FDA is also requiring the manufacturer to conduct a postmarketing study for inavolisib, but in this case the study will evaluate a lower dose of the drug.

While this postmarketing approach should help to identify a more tolerable dose, Shord acknowledged that it can be very challenging to conduct dosage optimization post approval. She shared that about 15% of newly approved drugs require postmarketing studies to evaluate dosage optimization, which takes an average of 6.5 years to complete. During this time, many patients may be under- or overtreated, so Shord noted that the FDA is recommending that manufacturers optimize the dose prior to submitting for approval.⁴

Regimen Optimization

Beyond drug dose optimization, the panel highlighted the need to address optimization of regimens (eg, treatment duration and multiphase regimens) to ensure that patients are receiving effective therapy without unnecessary toxicities. The KEYNOTE-522 regimen, which consists of a neoadjuvant phase with chemotherapy and pembrolizumab (Keytruda; Merck) followed by an adjuvant phase with pembrolizumab, was studied and approved as an entire yearlong regimen for patients with stage II to III triple-negative breast cancer.

However, the benefit of each treatment phase for the KEYNOTE-522 regimen has not been establish ed. The pathologic complete response (pCR) end point demonstrates the benefit of the neoadjuvant portion of this regimen, but the significant PFS and overall survival results are based on the entire regimen. Currently, it is unclear whether the additional cost and toxicities associated with the adjuvant portion of the KEYNOTE-522 regimen are balanced with added efficacy, according to the panelists.

During the discussion, Shah noted 3 alternative study designs to better optimize regimens like the KEYNOTE-522 regimen, as follows:

1. Conduct sequential trials where the first trial includes a neoadjuvant regimen. If results are positive, proceed with a second trial that compares a neoadjuvant-only regimen with one with both a neoadjuvant and adjuvant arm.
2. Design a 3-arm study in which arm 1 contains the investigational drug in the neoadjuvant phase only, arm 2 contains the drug in both the neoadjuvant and adjuvant phases, and arm 3 contains no study drug.
3. Conduct a neoadjuvant study, then again randomly assign patients based on their pCR results.

Although the FDA does not directly require companies to adopt specific study designs, it is making efforts to support achieving regimen and dose optimization, according to Shah.⁵

Pharmacists are trained to critically evaluate literature prior to incorporating new drugs or regimens into clinical practice. Understanding ongoing efforts by the FDA to improve clinical trials will help to inform the quality of data we see in the future.

REFERENCES

1. Gao J. Ribociclib: in combination with an aromatase inhibitor for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. Presented at: San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX.

2. Wedam S. New drug approvals for breast cancer: inavolisib. Presented at: San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX.

3. LoRusso P. Why now? the need for dosage optimization in oncology. Presented at: San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX.

4. Shord S. The nuts and bolts of dosage optimization. Presented at: San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX.

5. Shah M. Regimen optimization in breast cancer clinical trials. Presented at: San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX.