Investigators presented several potentially practice-changing treatment advances for these patients
At the annual meeting of the American Society of Clinical Oncology (ASCO), there was a keen focus on metastatic breast cancer (MBC). Thanks to research, more patients are living with MBC than ever before—but it remains incurable. Investigators are expanding our understanding of MBC and continually looking for new strategies and treatments to give patients more time—and with better quality of life.
This year’s ASCO meeting underscored this progress and gave researchers the opportunity to present the latest updates across the spectrum of MBC research. Several BCRF investigators and others shared potentially practice-changing treatment strategies and more.
Here are six developments you need to know.
Pairing ctDNA monitoring and a next-gen SERD to get ahead of resistance
Some ER-positive breast cancers treated with hormone therapy can develop mutations that allow them to become resistant to certain therapies. Estrogen receptor mutations (ESR1 mutations) commonly cause resistance to aromatase inhibitors plus CDK4/6 inhibitors.
BCRF investigator Dr. Nicholas Turner presented the results from the paradigm-changing SERENA6, which showed that ctDNA analysis can be leveraged to predict resistance in real-time, before disease progression occurs and can be detectable by scans. SERENA6 is the first global phase 3 trial assessing a ctDNA-guided approach to detect the emergence of ESR1 mutations during first-line treatment using aromatase inhibitors plus a CDK4/6 inhibitor in patients with hormone receptor (HR)–positive/HER2-negative advanced breast cancer. Since increasing ESR1 mutations can predict resistance, the earlier they can be detected, the earlier a patient can switch therapies to stop resistance before it occurs.
Dr. Turner’s team analyzed circulating tumor DNA (ctDNA) in patient blood samples. Results demonstrated that this novel approach can indeed detect the emergence of ESR1 mutations during first-line treatment. In this study, when these mutations were detected, the team switched to camizestrant, a next-generation selective estrogen receptor degrader (SERD) that has shown efficacy in ER-positive breast cancers with and without ESR1 mutations.
When camizestrant was given with CDK4/6 inhibitors after ESR1 mutations were detected during the first-line treatment, patients experienced a statistically significant and clinically meaningful improvement in progression-free survival (PFS; a measure of how long a patient lives without the disease getting worse). PFS benefit was consistent across the three CDK4/6 inhibitors. The rate of treatment discontinuation—a factor used to indicate if a drug is well-tolerated by patients—remained low, though neutropenia (low levels of white blood cells called neutrophils) was slightly increased.
The prestigious New England Journal of Medicine published the SERENA6 results in parallel with Dr. Turner’s talk, and the FDA has since given this strategy breakthrough approval for further testing.
A first-in-class PROTAC may have wide impact
Dr. Erika Hamilton of the Sarah Cannon Research Institutepresented potentially practice-changing results of the phase 3 VERITAC-2 trial that evaluated the first drug (vepdegestrant) in a new class of treatments called PROTACs (PROteolysis TArgeting Chimeras) in ER-positive/HER2-negative advanced breast cancer with ESR1 mutations. The trial included 624 patients at 213 sites across 25 countries and showed that vepdegestrant significantly improved PFS compared to another anti-estrogen drug called fulvestrant (Faslodex®) in this population: five months with vepdegestrant versus 2.1 months with fulvestrant. Preliminary data after six months showed that patients with ESR1 mutations had double the progression-free survival with vegdegestrant compared to fulvestrant.
Investigators found that vepdegestrant was well tolerated, with patients reporting mostly mild side effects such as fatigue. About 43 percent of patients with ER-positive/HER2-negative breast cancer have ESR1 mutations, so this trial may have wide impact. The New England Journal of Medicine also published these results simultaneously—a nod to their importance.
Inavolisib helps patients delay chemotherapy
Dr. Turner presented the final overall survival (OS) analysis and updated efficacy and safety results ofINAVO120, a phase 3 trial that enrolled patients with PIK3CA-mutated, HR-positive/HER2-negative advanced breast cancers that were endocrine resistant. The team demonstrated that adding inavolisib (Itovebi™)—a recently approved, first-in-class P13K inhibitor—to a CDK4/6 inhibitor (palbociclib/ Ibrance®) and fulvestrant improved overall survival by 34 months compared to 27 months without inavolisib.
When patients were on inavolisib for longer treatment, researchers reported that patients could delay chemotherapy by about two years. As Dr. Turner explained, inavolisib-based therapy not only helped patients live longer but more than doubled the time before their cancer progressed or worsened and they needed subsequent chemotherapy.
These results may widen the therapeutic window and enable other drug combinations. Indeed, studies are underway to assess other CDK4/6 inhibitors besides palbociclib. The significant improvements observed in both survival and quality of life can also give doctors confidence in this treatment as a new go-to option with this form of breast cancer.
A potential new first-line treatment for metastatic TNBC
BCRF investigator Dr. Sara Tolaney reported primary results from the phase 3 ASCENT-04/KEYNOTE-D19 study. This is the first study to evaluate the efficacy and safety of using sacituzumab govitecan (SG/Trodelvy®, an antibody-drug conjugate) plus pembrolizumab (Ketruda®, a checkpoint inhibitor) as a first-line treatment for patients with previously untreated advanced triple-negative breast cancer (TNBC) that is PD-L1–positive. The researchers compared this drug combination to standard-of-care chemotherapy plus pembrolizumab. This study’s encouraging results support SG plus pembrolizumab as a potential new standard of care for this form of breast cancer that lacks many targeted treatments.
After 12 months, the team found that SG plus pembrolizumab improved progression-free survival to 72 months (compared to 63 months for chemotherapy plus pembrolizumab). The objective response rate—a measure of how many participants have a partial response or complete response to the treatment within a certain period of time—stood at 60 percent for SG plus pembrolizumab compared to 53 percent for chemotherapy plus pembrolizumab. What’s more: No new adverse effects were observed with this combination.
A potential new first-line treatment for HER2-positive MBC
The standard first-line treatment for patients with HER2-positive MBC is what’s known as the THP regimen; patients get a combination of Taxol (Paclitaxel®), trastuzumab (Herceptin®), and pertuzumab (Perjeta®). Earlier trials have shown that the groundbreaking antibody-drug conjugate trastuzumab-deruxtecan (T-DXd/Enhertu®) benefitted these patients in later lines of treatment.
Could T-DXd replace taxol and trastuzumab as the standard first-line treatment for HER2-positive MBC? Dr. Tolaney and her team conducted the DESTINY-Breast09 study to find out—and reported exciting initial results at ASCO.
They showed that patients with HER2-positive MBC who received T-DXd and pertuzumab as a first-line treatment had a lower risk of progression or death compared to people who received the standard-of-care THP regimen. At two years, about 70 percent of cancers treated with T-DXd and pertuzumab hadn’t grown compared to 52 percent of those treated with THP. Further, about 85 percent of cancers treated with T-DXd and pertuzumab shrunk or disappeared compared to about 78 percent treated with THP.
This data is preliminary but indicates T-DXd and pertuzumab may improve overall survival. Serious side effects were similar for both treatment groups, but more people who received T-DXd and pertuzumab stayed on the treatment.
There has been no significant innovation in first-line treatments for HER2-positive MBC in over a decade. Ongoing studies will help determine if T-DXd and pertuzumab become the new standard-of-care first-line treatment for these patients.
An emerging oral SERD with fewer side effects
Imlunestrant is a next-generation oral SERD that continuously inhibits ER activity, even in cancers with ESR1 mutations. At ASCO, Dr. Giuseppe Curigliano of Istituto Europeo di Oncologia and the University of Milano discussed patient-reported outcomes and quality-of-life results from EMBER3 that confirm that imlunestrant alone is better than the current standard of care in patients with ESR1 mutations. Further, results support a combination of imlunestrant plus abemaciclib as a new standard of care in these patients—without significantly affecting quality of life.
Classified as an investigational drug, imlunestrant has not been FDA approved for general use but is being tested in clinical to determine its efficacy as well as determine how it might be used to treat a disease, how much is needed, and potential side effects and benefits.EMBER3 is a phase 3 trial that evaluated imlunestrant against standard endocrine therapy in patients with ER-positive/HER2-negative advanced breast cancer. Studies reported that both imlunestrant alone and imlunestrant plus a CDK4/6 inhibitor (abemaciclib) improved progression-free survival. Serious side effects were lowest for the imlunestrant alone and highest for the imlunestrant plus abemaciclib, as measured by incidence rates of grade 3 or higher adverse events.
The data on patient-reported outcomes confirm that quality of life did not significantly differ across all treatment regimens: imlunestrant, standard of care, and abemaciclib plus imlunestrant. Patients reported major issues regarding injection site reactions with the standard of care, and diarrhea was more frequent with imlunestrant plus abemaciclib versus imlunestrant alone.
The takeaway
These and other presentations at ASCO highlight a growing list of treatment options for MBC. More than a dozen drugs are currently in development for this form of breast cancer, and researchers continue to seek ways to give patients the best quality of life for as long as possible. Because of research and trials like these presented at ASCO, we’re improving outcomes for patients living with MBC.
