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ASCO 2023: Updates from Major Breast Cancer Clinical Trials

By BCRF | June 28, 2023

This year’s meeting featured several trials involving CDK4/6 inhibitors and antibody-drug conjugates

The American Society for Clinical Oncology (ASCO) hosts the largest annual clinical meeting in cancer research—bringing together tens of thousands of scientists from every branch of oncology. BCRF investigators and others use this opportunity to share recent progress with their colleagues and preview the newest updates in their field. Although this meeting covers a wide range of cancers, the clinical trial updates in breast cancer were plentiful.

RELATED: Two BCRF Investigators Receive Special Awards at ASCO 2023

Here, we highlight reports that tested new treatments and treatment combinations, provided follow-up data for ongoing trials, and revealed some practice-changing results.

Jump ahead to read about different categories of trials: CDK4/6 inhibitors, antibody-drug conjugates, and other notables.

CDK4/6 inhibitors take center stage

CDK4/6 inhibitors block cancer cells’ ability to proceed through their growth cell cycle, thereby preventing cancer progression. They were developed as a treatment option in the event breast cancer cells become resistant to endocrine therapy. In 2015, palbociclib (Ibrance®) was the first CDK4/6 inhibitor to get FDA approval specifically for treating advanced hormone receptor (HR)–positive/HER2-negative breast cancer; other CDK4/6 inhibitors ribociclib (Kisqali®) and abemaciclib (Verzenio®) were approved shortly thereafter in 2017.

Researchers presented several clinical trials that may potentially change treatment strategies for both early- and advanced HR-positive/HER2-negative breast cancer—the most common type—in women of all ages.

NATALEE: Ribociclib benefits in early-stage breast cancer

One of the most exciting sets of results presented at this year’s ASCO meeting were those from the phase 3 NATALEE trial, which involved more than 5,000 patients with early-stage (2 or 3) HR-positive/HER2-negative breast cancer following surgery. Ribociclib (Kisqali®), which is not yet approved for early-stage breast cancer, was tested in combination with an aromatase inhibitor in this trial.

Trial results showed that ribociclib reduced recurrence risk by an additional 25 percent compared to treatment with an aromatase inhibitor alone. Further, the dose of ribociclib used in the study was found to be safe and well-tolerated by participants. These results support the use of ribociclib in this patient population and may soon give doctors an added option in addition to abemaciclib, which is currently being used in early-stage breast cancer. Ongoing studies are assessing the therapy’s overall survival benefit long-term.

monarchE: Looking at abemaciclib’s benefits by age

Almost half of breast cancer diagnoses occur in women older than 65, who often have a higher incidence of comorbidities and an increased risk for toxicities from treatments. Dr. Erika P. Hamilton of the Sarah Cannon Research Institute reported the efficacy and safety of abemaciclib (Verzenio®) plus hormonal therapy after surgery for early-stage HR-positive/HER2-negative breast cancer broken down by patient age.

The phase 3 monarchE trial showed that abemaciclib added to hormonal therapy reduced the risk of recurrence more than hormonal therapy alone across all ages. In addition, benefit was maintained beyond two years following treatment. But there was one notable difference: Older patients—especially those over 75—had more adverse side effects and tended to discontinue treatment. As Dr. Hamilton reported, results from monarchE can help guide care for older patients, and they suggest that early treatment and frequent surveillance may be key.

SONIA: Evaluating CDK4/6 inhibitors as first-line treatment

The use of CDK4/6 inhibitors for prolonged periods increases side effects and is costly for patients. Professor Gabe Sonke of the Netherlands Cancer Institute presented SONIA, a phase 3, randomized trial involving 1,050 patients with advanced HR-positive/HER2-negative breast cancer from across the Netherlands. This trial tested the efficacy, safety, and cost effectiveness of adding CDK4/6 inhibitors to endocrine therapy as an initial (first-line) or second-line strategy for patients with HR-positive/HER2-negative advanced breast cancer who had not yet received another therapy.

He reported that there was no statistical difference in overall survival when comparing CDK4/6 inhibitors as the first- and second-line treatment. These results challenge the need for first-line treatment with CDK4/6 inhibitors, particularly as it extends toxicity, cost, and patients’ time on the drugs. Professor Sonke stressed the importance of evaluating patient-specific characteristics before deciding to proceed with CDK4/6 inhibitors as a first-line treatment.

PALMIRA: Inconclusive results still yield new data

The phase 2 PALMIRA trial results were eagerly anticipated going into ASCO, as trial investigators sought to clarify whether the efficacy of palbociclib (Ibrance®) could be extended by switching its endocrine therapy partner (letrozole or fulvestrant) if a patient stopped responding and their breast cancer continued to grow. This is a particularly critical question since 75 percent of women with breast cancer who are HR-positive/HER2-negative relapse on CDK4/6 inhibitors and 25 percent of this group develops metastatic disease.

Dr. Antonio Llombart-Cussac of the Hospital Arnau de Vilanova presented on PALMIRA, a trial that attempted to clarify conflicting findings from the previous MAINTAIN and PACE studies. Unfortunately, PALMIRA did not provide definitive answers. But researchers can still learn from trials with inconclusive results. As Dr. Llombart-Cussac detailed in his presentation, there was a small subgroup of patients that did benefit from this switch, which warrants further study to develop biomarkers to identify who will benefit from this approach and to test alternative second-line partners such as antibody-drug conjugates.

Antibody-drug conjugates continue to shine

Antibody-drug conjugates (ADCs) have received a lot of recent attention in breast cancer research, partly due to the practice-changing results of the DESTINY-Breast04 trial first presented at ASCO’s annual meeting last year. ADCs are an attractive treatment option because they leverage an antibody’s specificity to precisely target cancer cells with potent anti-cancer drugs while sparing healthy cells.

BCRF investigator Dr. Sarat Chandarlapaty opened a discussion on the past, present, and future of ADCs at this year’s meeting, detailing ADCs’ evolution and development and noting that research is ongoing to improve each component of ADCs and identify new cancer-specific markers. Researchers continue to push the envelope to not only construct and test new ADCs but to maximize their efficacy and assess their longer-term use.

TROPiCS-02: SG continues to be safe and effective

The phase 3 TROPiCS-02 investigators, including BCRF investigator Dr. Hope Rugo, conducted an exploratory analysis to determine the overall survival of patients with metastatic HR-positive/HER2-negative breast cancer treated with an ADC called sacituzumab govitecan (SG; Trodelvy®).

Rugo’s colleague, Dr. Sara M. Tolaney of Dana-Farber Cancer Institute, presented the results of this long-term follow-up of more than 12 months. The final overall survival analysis showed that SG provides clinically meaningful benefit over standard-of-care chemotherapy. Thus, it is a safe and effective treatment for these patients, who currently have limited treatment options.

NCT04699630: A promising HER3 antibody-drug conjugate

A close relative of HER2, the HER3 protein is a newer target being investigated in breast cancer. Both are cell membrane proteins involved in cell signaling and, in fact, act in concert to promote HER2-driven breast tumor formation. Researchers have developed a HER3-targeting ADC by linking patritumab (which recognizes the HER3 protein) with the toxic drug deruxtecan (DXd) that’s already being used in breast cancer.

The resulting ADC, HER3-T-DXd, was tested in a phase 2 study (NCT04699630) and showed promise for patients with heavily-pretreated estrogen receptor (ER)–positive or triple-negative metastatic breast cancer. Overall, 35 percent of patients responded, and clinical benefit was observed in about 43 percent of participants.

Moreover, HER3-T-DXd had a manageable safety profile and patients responded regardless of their HER3 expression. The trial presented at ASCO is one of three, and investigators anticipate that these studies will support the introduction of HER3-T-DXd into the clinic for people with all types of metastatic breast cancer.

Studies start to look at sequential ADCs in treatment

As more ADCs are developed, approved, and made available, patients could be candidates for several ADCs, so it’s important to determine if there is any benefit to using ADCs in a certain order. A team including BCRF investigator Dr. Neelima Vidula conducted a retrospective study to start to crack this.

They looked at patients with metastatic HER2-negative breast cancer who—with the recent approvals of SG/Trodelvy for HR-positive/HER2-negative and triple-negative breast cancer along with T-DXd/Enhertu® for HER2-low breast cancers—are eligible for either ADC. They examined how patients responded to one ADC after another, particularly what sequence yielded better responses and minimized the chances of resistance. Initial findings showed that resistance was less prevalent if the ADCs used had different antibody targets i.e., if SG that targets the Trop2 protein was used in sequence with T-DXd that targets HER2.

These findings are being validated in further studies to guide and optimize the best order for ADC-based treatment options.

Other takeaways and developments from breast cancer trials

Outside of trials focused on CDK4/6 inhibitors and ADCs, this year’s ASCO annual meeting featured several other notable studies in breast cancer—including a practice-changing new strategy for oral chemotherapy and positive updates on a treatment that is expected to receive FDA approval soon.

PHERGAIN: Some patients can forgo chemotherapy

The standard of care for HER2-positive early breast cancer is HER2-targeted therapy plus chemotherapy, while patients at a high risk of recurrence instead receive dual HER2 blockade plus chemotherapy. Recent studies suggest that dual anti-HER2 therapy alone, without chemotherapy, is also associated with improved survival. At ASCO, Dr. Javier Cortés of the Ramón y Cajal University Hospital presented the PHERGAIN trial, a randomized, phase 2 study that tested a strategy to spare some patients chemotherapy.

The team, including Dr. Justin Balko of Vanderbilt University Medical Center, designed an innovative study that used PET scans early in treatment to identify patients that were responding to HER2-targeted therapies. This information could then inform treatment decisions—giving clinicians information to change plans if needed. Using this adaptive-response design, clinicians could identify patients who could forego chemotherapy or, for those not responding to HER2-targeted therapy, revert to standard care with added chemotherapy.

Researchers reported that one-third of the PET-determined responders could be essentially cured without chemotherapy. The results from PHERGain support the use of the unique adaptive-response design, paving the way for similar trials in other settings.

X-7/7 study: Practice-changing strategy for oral chemotherapy

Researchers are seeking new approaches to make the oral chemotherapy agent capecitabine (Xeloda®) more tolerable for patients with breast cancer. Once in the body, capecitabine is broken down into substances that interfere with the production of DNA, RNA, and proteins. While this hinders cancer cells’ growth and is effective for treating breast cancer, patients experience several side effects that impact their quality of life.

The FDA-approved dosing schedule for capecitabine is 14 days on and 7 days off, giving patients little time to recover. The X-7/7 clinical trial challenged this paradigm and tested a novel dosing schedule with seven days on and seven days off capecitabine. Drs. Qamar J. Khan and BCRF investigator Priyanka Sharma showed that this strategy was effective; it yielded a significant reduction in side effects while achieving similar overall and progression-free survival rates.

These findings are practice-changing and define a new strategy to ensure that patients receive the benefits of capecitabine therapy without compromising their quality-of-life post-treatment.

CAPItello-291: More promising updates

BCRF investigators Drs. Hope Rugo, Mafalda Oliveira, and their colleagues reported updates on CAPItello-291, a phase 3 trial that tested capivasertib (an AKT inhibitor) in combination with fulvestrant (a selective estrogen degrader) in patients with advanced HR-positive/HER2-negative breast cancer. Prior results from this trial provided support for the FDA to fast-track the therapy’s approval in January 2023 and grant a priority review in June 2023. (As of this story’s publication, capivasertib had not yet received approval but is expected to.)  

At this year’s ASCO meeting, the study investigators reported a detailed analysis of side effects patients experienced in this study. They concluded that the most common ones associated with this regiment (capivasertib combined with fulvestrant) occur early in treatment and are generally low-grade and manageable.

Taken together, these results and previous findings from CAPItello-291 provide support for capivasertib’s approval as the first AKT inhibitor for treating breast cancer—an approval that will be especially important for metastatic breast cancer patients.