Dr Ma on Interim Efficacy and Safety Data With RLY-2608 in PI3Kα-Mutant HR+/HER2– Breast Cancer

Cynthia X. Ma, MD, PhD, professor, Division of Oncology, Section of Medical Oncology, Washington University School of Medicine in St. Louis, discusses positive interim data from the first-in-human, phase 1 ReDiscover trial (NCT05216432) evaluating RLY-2608 in combination with fulvestrant (Faslodex) in heavily pretreated patients with 

-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer.

As of the August 12, 2024, interim data cutoff, 118 patients were enrolled in the dose-escalation and -expansion portions of the trial, with 64 receiving the recommended phase 2 dose (RP2D) of RLY-2608 at 600 mg twice daily plus fulvestrant, Ma begins. The patient population was heavily pretreated, with all patients having received at least 1prior CDK4/6 inhibitor and at least 1 prior line of endocrine therapy, she details. Among those treated at the RP2D, 45% had undergone at least 2 prior lines of therapy, 52% had received a prior selective estrogen receptor degrader, and 25% had been previously treated with chemotherapy or an antibody-drug conjugate.

On September 9, 2024, a press release announced that 

clinically meaningful progression-free survival

 (PFS) outcomes and a favorable safety profile in this patient population, Ma reports. At a median follow-up of 7.5 months, patients without 

 co-mutations who received the RP2D (n = 52) achieved a median PFS of 9.2 months, and the clinical benefit rate was 57% among 35 evaluable patients in the overall population. In patients with measurable disease at the RP2D (n = 30), the overall response rate (ORR) was 33% regardless of kinase mutation status, and tumor reductions were observed in 73% of patients. In those with measurable disease and kinase mutations (n = 15), the ORR reached 53%.

RLY-2608 plus fulvestrant was generally well tolerated, with most adverse effects being low grade, treatment-related, and manageable, Ma continues. Hyperglycemia, a common concern with PI3K inhibitors, was rare and primarily low grade, she notes. Rates of diarrhea and rash were also much lower compared with historical data from other PI3K inhibitors, such as alpelisib (Piqray) and capivasertib (Truqap), Ma adds. These safety and efficacy data indicate that RLY-2608 could be a meaningful new treatment option for this patient population pending further validation in randomized trials, she concludes.

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Cynthia X. Ma, MD, PhD, discusses positive interim data from the phase 1 ReDiscover trial in PI3Kα-mutated HR-positive, HER2-negative breast cancer.

Dr Ma on Mechanisms of Resistance to CDK4/6 Inhibitors in HR+ Breast Cancer

Cynthia X. Ma, MD, PhD, professor of medicine, Division of Oncology, Section of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri, discusses the mechanisms of resistance and current unmet needs associated with the use of CDK4/6 inhibitors in the treatment of patients with hormone receptor–positive breast cancer.

Ma emphasizes that understanding the mechanisms of resistance to CDK4/6 inhibitors is vital, especially for patients who experienced early disease progression on these agents. Identifying appropriate treatment strategies following progression on CDK4/6 inhibitors is a significant unmet need. She notes that the mechanisms of resistance to CDK4/6 inhibitors is likely heterogenous, and these mechanisms can help influence subsequent treatment decisions. Using the mechanisms to inform personalized treatment decisions should be addressed in future research, Ma says.

For example, patients who experience early disease progression, treatment options currently include chemotherapy, antibody-drug conjugates (ADCs), immunotherapy, and other targeted therapies, Ma says, adding that more needs to be learned about this specific subgroup of patients.

Moreover, Ma underscores the importance of exploring targeted therapies following disease progression on CDK4/6 inhibitors in patients who do not harbor mutations in the AKT pathway or 

capivasertib (Truqap) plus fulvestrant (Faslodex) is approved by the FDA

 for the treatment of adult patients with HR–positive, HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more 

alterations after progression on at least 1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. Additionally, 

the regulatory agency previously approved elacestrant (Orserdu)

 for the treatment of postmenopausal women or adult men with estrogen receptor–positive, HER2-negative, 

-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy. However, an unmet need remains for patients without these alterations, Ma says.

Determining whether patients without these mutation would benefit more from alternative targeted therapies or a switch to systemic chemotherapy remains a critical question, Ma continues. Future studies should aim to refine patient selection criteria for these therapeutic approaches to optimize outcomes, she concludes.

Cynthia X. Ma, MD, PhD, discusses current unmet needs associated with the use of CDK4/6 inhibitors in the treatment of breast cancer.

Questions Regarding Treatment Sequencing in CDK4/6 Inhibitor–Resistant Breast Cancer

Dr Ma on Questions Regarding Treatment Sequencing in CDK4/6 Inhibitor–Resistant Breast CancerDr Ma on the Use of AKT Inhibitors vs PI3K Inhibitors in Breast Cancer

Cynthia Ma, MD, PhD, medical oncologist, Siteman Cancer Center, Washington University Medical Campus, discusses unanswered questions and remaining unmet needs regarding the optimization and sequencing of therapy for patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer who develop resistance to CDK4/6 inhibitors.

The mechanism of resistance to CDK4/6 inhibitors in breast cancer is likely to be heterogeneous, Ma begins. Accordingly, this necessitates a nuanced approach to treatment decision-making in patients who experience disease progression following treatment with a CDK4/6 inhibitor, she says.

Research into individualized therapy based on specific resistance mechanisms is critical for advancing patient care, Ma says, adding that understanding the best subsequent treatment options for patients experiencing early progression or those who rapidly progress on prior CDK4/6 inhibitors is particularly essential. Potential treatment strategies for this patient population include chemotherapy, antibody-drug conjugates, immunotherapy, and other emerging therapies, Ma details.

mutations, research is also needed to identify alternative pathways to target, Ma continues. Several targeted therapies, such as CDK2 inhibitors and CDK7 inhibitors, are currently in development to potentially address this need, she reports. Determining the most appropriate settings and patient subsets for these agents is another important area of ongoing research, Ma reiterates.

For patients who progress on therapies targeted against the 

pathway, identifying the most effective agents before switching to chemotherapy is vital, Ma emphasizes. Future studies should focus on these areas to provide more precise and personalized treatment options for patients who develop resistance to initial targeted therapies, she adds.

Overall, developing comprehensive resistance profiles and integrating them into clinical decision-making will enhance the ability to select the most appropriate subsequent therapies for patients with HR-positive, HER2-negative breast cancer, ultimately leading to better patient outcomes in the post-CDK4/6 inhibition setting.

Cynthia Ma, MD, PhD, discusses unanswered questions regarding treatment sequencing for patients who develop CDK4/6 inhibitor–resistant breast cancer.

Dr Ma on Questions Regarding Treatment Sequencing in CDK4/6 Inhibitor–Resistant Breast Cancer

The Use of AKT Inhibitors vs PI3K Inhibitors in Breast Cancer

Dr Ma on the Use of AKT Inhibitors vs PI3K Inhibitors in Breast Cancer

Cynthia Ma, MD, PhD, medical oncologist, Siteman Cancer Center, Washington University Medical Campus, discusses the use of AKT inhibitors vs PI3K inhibitors in breast cancer.

At the 2023 Bridging the Gaps in Breast Cancer meeting, Ma delved into an in-depth exploration of the pivotal role played by the PI3K pathway in breast cancer tumorigenesis, shedding light on this pathway’s involvement in mediating resistance to both endocrine therapy and CDK4/6 inhibitors. Focusing specifically on estrogen receptor-positive breast cancer, the discussion encompassed various genetic alterations, including mutations in 

, as well as loss-of-function mutations of 

. Furthermore, the phenomenon of hyperactivation resulting from pathway rewiring subsequent to the administration of CDK4/6 inhibitors and endocrine therapy was examined.

In response to these insights, a multitude of agents are currently in development that target the PI3K pathway. Alpelisib (Vijoice), a selective PI3K inhibitor, 

 for patients with hormone receptor (HR)–positive, HER2-negative, 

-mutated advanced or metastatic breast cancer based on data from the phase 3 SOLAR-1 trial (NCT02437318) and the subsequent phase 2 BYLieve study(NCT03056755). In these trials, alpelisib generated progression-free survival advantages, even in patients who had previously received CDK4/6 inhibitors, Ma explains.

FDA approval of capivasertib (Truqap) plus fulvestrant (Faslodex)

for patients with advanced HR-positive HER2-negative breast cancer with 

 alterations was backed by findings from the phase 3 CAPItello-291 study (NCT04305496). This regulatory decision marks a noteworthy development in this treatment paradigm, Ma expands. Additionally, the consideration of mTOR inhibitors in breast cancer adds another layer of complexity to the therapeutic arena, she says.

The complexity of potential mechanisms of resistance to alpelisib or capivasertib was examined throughout the discission at the meeting, with an understanding that certain alterations may signify resistance and indicate a potential sensitivity to an AKT inhibitor, she states. This nuanced perspective invites contemplation on the replacement potential of AKT inhibitors, particularly considering their safety profile, which is more tolerable than that of other agents, Ma notes.

Cynthia Ma, MD, PhD, discusses the use of AKT inhibitors vs PI3K inhibitors in breast cancer.


Cynthia Ma, MD, PhD, associate professor of Medicine, Medical Oncology at the Washington University School of Medicine in St. Louis, discusses the role of immunotherapy in triple-negative breast cancer (TNBC).

There are several trials investigating immunotherapy in TNBC, says Ma. Washington University School of Medicine is participating in a phase I/II study of pembrolizumab (Keytruda) in combination with eribulin (Halaven) which is ongoing. There are also combination therapy trials of pembrolizumab with other immunotherapy agents in TNBC. In addition to pembrolizumab, there are PD-L1 antibodies in development, many of which are being investigated in combination with chemotherapy in this space.  

TNBC has a high mutational load which may make it more immunogenic. This is particularly true when compared to ER-positive patients. In neoadjuvant studies, immune-cell infiltrates have been shown to correlate with responses and long-term outcomes, so there is some evidence that TNBC may be more immunogenic, says Ma.

Dr. Cynthia Ma on Immunotherapy in TNBC

Cynthia Ma, MD, PhD, associate professor of Medicine, Washington University School of Medicine, discusses the METRIC trial in triple-negative breast cancer (TNBC).

The METRIC trial is a randomized study comparing glembatumumab vedotin (CDX-011), a gpNMB-targeted antibody-drug conjugate, with capecitabine in patients with metastatic TNBC.

Patients are being randomized in a 2:1 ratio to receive glembatumumab vedotin or capecitabine. The study is selecting patients who are positive for gpNMB, which is present in about 40% of TNBC cases. Initial preliminary data have shown that patients with TNBC may have longer progression-free survival when they have increased gpNMB expression.

Cynthia Ma, MD, PhD, associate professor of Medicine, Washington University School of Medicine, discusses the METRIC trial in triple-negative breast cancer.

Cynthia Ma, MD, PhD

Articles

Dr Ma on Interim Efficacy and Safety Data With RLY-2608 in PI3Kα-Mutant HR+/HER2– Breast Cancer

Dr Ma on Mechanisms of Resistance to CDK4/6 Inhibitors in HR+ Breast Cancer

Dr Ma on Questions Regarding Treatment Sequencing in CDK4/6 Inhibitor–Resistant Breast Cancer

Dr Ma on the Use of AKT Inhibitors vs PI3K Inhibitors in Breast Cancer

Dr. Cynthia Ma on Immunotherapy in TNBC

Dr. Ma on the METRIC Trial in Triple-Negative Breast Cancer