RLY-2608

Videos

Sarah Sammons, MD, highlights ReDiscover trial findings, showcasing the durable efficacy, potent mutant-selective targeting, and favorable safety profile of RLY-2608 combined with fulvestrant in patients with PIK3CA-mutant HR+/HER2− advanced breast cancer, validating its potential as the first allosteric, pan-mutant PI3Kα inhibitor.

Efficacy of RLY-2608, a mutant-selective PI3Kα inhibitor, in patients with PIK3CA-mutant HR+HER2- advanced breast cancer: ReDiscover trial

Sarah Sammons, MD, discusses the rationale for examining brain metastases in HER2-positive breast cancer, highlighting the implications of recent data.

Dr Sammons on the Investigation of Brain Metastases in HER2+ Breast Cancer

Sarah Sammons, MD, associate director, Metastatic Breast Cancer Program, Dana-Farber Cancer Institute, discusses the background of examining brain metastases in HER2-positive breast cancer, highlighting the implications of these data.

 delved into an examination of data sourced from the United States Flatiron Health de-identified database, encompassing a cohort of 18,075 patients. Within this dataset, 3062 patients exhibited hormone receptor (HR)–positive, HER2-positive disease, and 902 patients displayed HR-negative, HER2-positive disease. The findings elucidated that the incidence of brain metastases notably varied across different tumor subtypes and treatment lines among all breast cancer cases.

Brain metastases pose a treatment challenge in HER2-positive breast cancer, Sammons begins, adding that retrospective clinical trials indicate that approximately 30% of patients with HER2-positive breast cancer will develop brain metastases during their disease trajectory. The rate of brain metastases occurrence varies depending on HR status, and patients with HR-positive/HER2-positive metastatic breast cancer face an approximate 23% risk of developing brain metastases. However, this risk tends to be slightly higher in patients with solely HER2-driven disease, Sammons explains. Deferring local therapy, particularly in patients with HER2-positive brain metastases, remains an evolving aspect of disease management, according to Sammons.

ASCO issued guidelines in 2021 outlining disease scenarios suitable for considering the deferral of local therapy in patients with HER2-positive brain metastases, she continues. This decision requires a multidisciplinary approach involving input from a radiation oncologist and potentially a neurosurgeon, along with the patient's involvement, Sammons says. Deferral may be considered in cases with a favorable prognosis, Sammons adds. Criteria for deferral include the presence of asymptomatic brain metastases measuring less than 2 cm, the absence of symptomatic mass effect, and the availability of systemic therapy with a high intracranial response rate, she elucidates.

Agents such as tucatinib (Tukysa), capecitabine (Xeloda), trastuzumab (Herceptin), or fam-trastuzumab deruxtecan-nxki (Enhertu), known for their intracranial efficacy, are pivotal treatment considerations, Sammons expands. The feasibility of deferring local therapy in patients with HER2-positive brain metastases is still under evaluation, with certain situations warranting a delay in interventions such as whole-brain radiation or high-volume repeat stereotactic radiation therapy, Sammons explains. The presence of highly effective systemic therapies with demonstrated intracranial response rates prompts further consideration of deferral in appropriate cases, she concludes.

Sarah Sammons, MD, discusses the rationale for examining brain metastases in HER2-positive breast cancer, highlighting the implications of recent data. 

Dr Sammons on the Real-World Incidence of Brain Metastases in HER2+ Breast Cancer 

Sarah Sammons, MD, associate director, Metastatic Breast Cancer Program, Dana-Farber Cancer Institute, discusses the real-world incidence of brain metastases in HER2-positive breast cancer per line of treatment as well as cumulatively.

Brain metastases are a significant concern in HER2-positive breast cancer, with approximately 30% of patients developing them at some point during their disease course. The timing of these metastases relative to the line of therapy has not been well characterized, prompting investigators to delve into this unmet need by utilizing real-world data, Sammons begins.

A study presented at the 2023 SABCS Conference analyzed data from the US Flatiron Health de-identified database, comprising 18,075 patients, Sammons details. Of these, 3,062 had with hormone receptor–positive, HER2-positive disease and 902 had hormone receptor–negative, HER2-positive disease. 

Results showed demonstrated that the prevalence of brain metastases generally differed by tumor subtype and by line of therapy across all breast cancers, Sammons reports. Notably, patients with hormone receptor (HR)–positive or –negative disease tended to develop brain metastases early, often by the third-line of therapy, she notes. The cumulative incidence of brain metastases was highest in the HR-negative, HER2-positive, and triple-negative breast cancer (TNBC) subgroups, with the HR-positive, HER2-negative subgroup experiencing the lowest incidence, Sammons details. However, due to the larger number of cases in the hormone receptor–positive, HER2-negative group, they represented the largest proportion of brain metastasis events.

These findings underscore the importance of identifying clinical and biological predictors of brain metastases and implementing strategies to prevent their onset, she concludes. Additionally, the data shed light on the impact of brain metastasis inclusion and exclusion criteria in clinical trials for patients with metastatic breast cancer, emphasizing the need for tailored approaches in trial design and patient management.

Sarah Sammons, MD, discusses the real-world incidence of brain metastases in HER2-positive breast cancer per line of treatment as well as cumulatively.

Dr Sammons on Treating Patients With Breast Cancer Who Present With Brain Metastases

Sarah Sammons, MD, medical oncologist, clinical investigator, the Breast Oncology Center, associate director, Metastatic Breast Cancer Program, Dana-Farber Cancer Institute, discusses the goals of treating patients with breast cancer who present with active vs stable brain metastasis.

Clinical trials involving patients with brain metastases often categorize patients as having stable or active metastases, Sammons begins. Stable brain metastases have typically undergone local regional therapies, such as radiation, possibly combined with resection for solitary lesions, resulting in metastases stability on subsequent scans, she states. Conversely, active brain metastases are defined as those that are either untreated or are treated with local modalities, such as radiation, but continue to progress, Sammons explains.

The overarching goals for treating all brain metastases remain consistent: alleviating neurologic symptoms, preventing neurologic death, hindering the occurrence or progression of metastases, and enhancing overall survival and quality of life, she emphasizes. However, treatment approaches vary based on the stability of the brain metastases, Sammons expands. For stable brain metastases, local modalities, such as radiation, prove highly effective, she says. The treatment focus in these cases is on prolonging central nervous system (CNS) progression-free survival, aiming to delay the onset of another CNS event, whether it be the growth of a previously radiated metastasis or the emergence of new lesions, Sammons notes, adding that this is primarily achieved through systemic therapies.

Conversely, patients with active brain metastases may have multiple lesions, often exceeding 6 or 10 lesions, and may be deferring whole-brain radiation therapy. In such cases, the key treatment objective is intracranial control, Sammons continues, with an emphasis on identifying systemic therapies with well-established intracranial activity and a high response rate. This is crucial for rapidly shrinking lesions and effectively managing brain disease, especially when patients are delaying local therapy or facing progression after inadequate local treatment, Sammons states. A swift response in the brain is imperative in these situations, she concludes.

Sarah Sammons, MD, discusses the goals of treating patients with breast cancer who present with active vs stable brain metastasis.


Sarah Sammons, MD, associate director, Metastatic Breast Cancer Program, Dana-Farber Cancer Institute, discusses whether CDK4/6 inhibitors should be considered a standard first-line treatment within hormone receptor (HR)–positive, HER2-negative advanced breast cancer according to primary results from the phase 3 SONIA trial (NCT03425838).

The investigator-initiated, randomized study was designed to evaluate the efficacy, safety, and cost-effectiveness of first- or second-line CDK4/6 inhibition in this population. The trial challenged the current trend of moving effective treatments like CDK4/6 inhibitors to earlier lines for the general patient population, and aimed to better inform the optimal sequencing of these agents, specifically palbociclib (Ibrance), Sammons begins.

Patients were randomly assigned 1:1 to receive a nonsteroidal aromatase inhibitor (AI) plus a CDK4/6 inhibitor or a nonsteroidal AI alone, Sammons details. Individuals who progressed on the CDK4/6 regimen went on to receive fulvestrant (Faslodex). Conversely, those who progressed on an AI alone went on to receive both fulvestrant and a CDK4/6 inhibitor, she states. Patients in the experimental arm were treated with either palbociclib, abemaciclib (Verzenio), or ribociclib (Kisqali) according to physician's choice. The majority of patients were treated with palbociclib, Sammons notes.

Results showed that use of CDK4/6 inhibitor plus endocrine therapy in the first-line setting did not significantly prolong time to progression on second-line therapy (PFS2) or overall survival (OS) compared with the regimen's employment in the second-line, Sammons reports. However, a progression-free survival (PFS) advantage was observed with first-line administration of the combination, with median PFS increasing by 16.5 months, she says.

Notably, patients who received a first-line CDK4/6 inhibitor had a median OS of 45.9 months vs 53.7 months with second-line CDK4/6 inhibitor treatment, Sammons adds. This is substantially lower than the median OS produced by first-line ribociclib or abemaciclib, she states.

Although these results were not practice changing, they indicate that first-line palbociclib is not superior to second-line use, Sammons explains. Accordingly, patients with toxicity concerns may consider starting with an AI alone before proceeding to second-line CDK4/6 inhibitor treatment, Sammons concludes.

Disclosures: Dr Sammons reports research funding from AstraZeneca, AbbVie, Bristol Myers Squibb, Eli Lilly, Seagen, and Sermonix; and consulting roles with Foundation Medicine, AstraZeneca, Daiichi Sankyo, Eli Lilly, Incyclix Bio, Merck, Pfizer, Seagen, Sermonix, and Novartis.

Sarah Sammons, MD, discusses whether CDK4/6 inhibitors should be considered a standard first line treatment within hormone receptor–positive, HER2-negative advanced breast cancer according to primary results from the phase 3 SONIA trial.

Dr Sammons on the SONIA Trial of First-Line CDK4/6 Inhibitor Use in HR+/HER2– Breast Cancer

Sarah Sammons, MD, assistant professor of medicine, Department of Medicine, Duke University School of Medicine, member, Duke Cancer Institute, Duke Health, discusses findings from the phase 3 EMERALD trial (NCT03778931) in estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer.

EMERALD is the first randomized phase 3 trial evaluating an oral selective ER degrader to read out, Sammons says. The study enrolled 477 men and postmenopausal women with advanced or metastatic ER-positive, HER2-negative breast cancer who had progressed or relapsed on 1 or 2 lines of endocrine therapy, 1 of which was given with a CDK4/6 inhibitor in the metastatic setting. Patients were randomized 1:1 to 400 mg of elacestrant daily or investigator’s choice of standard-of-care endocrine therapy with fulvestrant (Faslodex), anastrozole, letrozole, or exemestane. The co-primary end points were progression-free survival (PFS) in the intention-to-treat (ITT) population and PFS in the 

The findings showed a statistically significant improvement in PFS in the ITT population; the median PFS was 2.79 months with elacestrant vs 1.91 months with standard endocrine therapy, resulting in a hazard ratio of 0.697. In the 

-mutant subgroup, the median PFS was 3.78 months with elacestrant vs 1.87 months with standard endocrine therapy, resulting in a hazard ratio of 0.546 and greater magnitude of benefit, Sammons concludes.

Sarah Sammons, MD, discusses findings from the phase 3 EMERALD trial in estrogen receptor–positive, HER2-negative advanced or metastatic breast cancer.

Sarah Sammons, MD

Articles

Efficacy of RLY-2608, a mutant-selective PI3Kα inhibitor, in patients with PIK3CA-mutant HR+HER2- advanced breast cancer: ReDiscover trial

Dr Sammons on the Investigation of Brain Metastases in HER2+ Breast Cancer

Dr Sammons on the Real-World Incidence of Brain Metastases in HER2+ Breast Cancer

Dr Sammons on Treating Patients With Breast Cancer Who Present With Brain Metastases

Dr Sammons on the SONIA Trial of First-Line CDK4/6 Inhibitor Use in HR+/HER2– Breast Cancer

Dr. Sammons on Findings From the EMERALD Trial in ER+ Advanced or Metastatic Breast Cancer