It’s not typical for audiences at major cancer research conferences to break into rapturous applause. But at this year’s American Society for Clinical Oncology (ASCO) meeting, one presentation on a treatment for metastatic breast cancer (MBC) got just that.
Dr. Shanu Modi of Memorial Sloan Kettering Cancer Center shared practice-changing results from the DESTINY-Breast04 clinical trial. In this phase 3 trial, patients with MBC whose tumors had low levels of the HER2 protein were given trastuzumab deruxtecan (T-DXd/Enhertu®), a HER2-specific antibody-drug conjugate. The drug significantly lengthened progression-free and overall survival compared to standard chemotherapy—and is poised to become a new standard of care.
Since the mid-1990s, pathologists have measured levels of HER2 in breast and other tumors. Initially, these levels were used to predict prognosis, but thanks to research, today they are used to classify tumors as either HER2-positive or HER2-negative to match patients to HER2-directed therapies such as trastuzumab (Herceptin®). Approximately 80 percent of breast cancers have been termed HER2-negative, but researchers now recognize that 55 percent of all breast cancers may actually contain low levels of HER2—levels that are still targetable by HER2-directed therapies such as T-DXd.
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DESTINY-Breast04’s results provide ample evidence that this is the case. The results showed that T-DXd treatment stopped tumors from growing for 10 months compared to five months with chemotherapy alone. This translated to a survival of 23.9 months with T-DXd treatment versus 16.8 months with chemotherapy. The investigators noted that T-DXd not only targeted HER2 on tumor cells but also seeped through the tumor cell walls, killing surrounding cancer cells as well (a process known as the bystander effect)—all of which no doubt contributed to T-DXd’s efficacy.
The patients in this study had received prior treatments that did not work, or their tumors became therapy resistant. T-DXd proved to be effective regardless of subtype: Hormone receptor (HR)–positive and –negative patients were included in this study, and one third had triple-negative breast cancer, which lacks treatment targets and is otherwise difficult to treat.
DESTINY-Breast04’s stunning results garnered a standing ovation from the thousands of oncologists and researchers in the audience, who hailed it as the biggest breakthrough in breast cancer treatment since Herceptin® was approved in 1998. Investigators are now looking at T-DXd efficacy as a first-line therapy.
In HER2-positive MBC research, several researchers reported progress expanding treatment options and targets including Dr. Javier Cortes of the Vall d’Hebron Institute of Oncology, who discussed innovative treatment combinations that had not been tested before.
For example, one novel strategy being investigated: treating patients with trastuzamab (Herceptin®) and pertuzamab (Perjeta®) in the first and/or second line followed by T-DM1 (Kadcyla®) or tucatinib (Tukysa®) in the third line. He stressed that determining the sequence and combination of treatments is heavily dependent on the drugs’ safety profiles and further studies are underway to determine this now.
BCRF investigators Drs. Nancy Lin and Priscilla Brastianos presented recent findings and clinical trials for treating HER2-positive breast cancer with brain metastases, which remains a challenge. For these patients, systemic therapies can reach the brain but only a subset of patients respond.
Dr. Brastianos discussed recent research regarding the molecular drivers of brain metastases and their implications for treatment. She noted that it’s important to understand and decipher the changes that occur when primary tumors become metastases. Laboratory studies have identified candidate gene alterations that are enriched in brain metastases compared to the primary tumor, but whether they are specific drivers of brain metastases and where in the process they occur remain open questions that are currently being studied.
Dr. Lin, who spearheaded the HER2CLIMB trial that led to FDA approval of tucatinib for treating breast cancer brain metastases, gave an overview of multiple agents being tested in clinic trials. This includes tyrosine kinase inhibitors (TKIs) such as tucatinib, monoclonal antibodies, and antibody-drug conjugates such as T-DM1 and the aforementioned T-DXd. She noted that ongoing trials (HER2CLIMB02, TBCRC-022, and HER2CLIMB04) are exploring different combinations of these agents and that several new antibody-drug conjugates are in development.
A subsequent presentation by Dr. Janice Lu of University of Southern California presented a trial to test one of these new antibody-drug conjugates, ARX788. This novel, HER2-targeted drug is being tested in patients with HER2-positive MBC whose disease is resistant to either T-DM1, T-DXd, or tucatinib–containing regimens or combinations of these agents.
Taken together, these ongoing studies are advancing our understanding of HER2-positive breast cancer and give added hope to people with HER2-positive MBC, including those with brain metastases, that new and effective therapies are on the horizon.
The phase 3 TROPiCS-02 trial compared the antibody-drug conjugate sacituzumab govitecan-hziy (SG/Trodelvy®) with standard chemotherapy for treating HR-positive/HER2-negative advanced breast cancer. BCRF investigator Dr. Hope Rugo reported progression-free survival results at six, nine, and 12 months that showed clinically meaningful improvement in the patients receiving SG versus chemotherapy. They had been heavily pretreated for metastatic disease.
In fact, 21 percent of patients treated with SG had no disease progression and were alive at 12 months, compared to only seven percent treated with chemotherapy.
Dr. Virginia Kaklamani of MD Anderson Cancer Center presented updates from the EMERALD trial, which compared a novel oral selective estrogen receptor (ER) degrader called elacestrant to standard-of-care endocrine therapy (fulvestrant/Faslodex® or aromatase inhibitor) in ER-positive/HER2-negative MBC. This study showed that elacestrant significantly reduced the risk of disease progression or death by 30 percent. At one year, approximately one out of four patients receiving elacestrant had no disease progression and were alive, compared to approximately one out of 10 patients receiving standard endocrine therapy.
Among patients with ER-positive/HER2-negative MBC who had not received prior chemotherapy, elacestrant significantly prolonged progression-free survival compared to standard endocrine therapy. Six-month progression free survival rates were 38 percent with elacestrant and 23 percent with standard of care; 12-month progression-free survival rates were 27 percent with elacestrant and 12 percent with standard of care.
Dr. Lowell Hart of Sarah Cannon Research Institute presented a summary of the MONALEESA2 trial, which had previously demonstrated a significant benefit of adding the CDK4/6 inhibitor ribociclib (Kisqali®) to letrozole as first line therapy in patients with HR-positive/HER2-negative MBC.
The new analysis examined the effect of dose reduction of ribociclib on overall survival and confirmed the benefit of ribociclib plus endocrine therapy even in patients who required dose reductions due to adverse side effects or other reasons—further demonstrating the efficacy of this first-line combination for MBC.
MBC clinical trials are hugely important. Their findings gleaned from trials inform future treatments and standards of care. Black patients, however, only represent approximately three percent of clinical trial participants; as a consequence, the advances that result from trials may not necessarily be relevant to them. That’s why clinical trials need diverse patient populations.
The Black Experience of Clinical Trials and Opportunities for Meaningful Engagement (BECOME) survey, a project of the MBC Alliance (Alliance), specifically examined the barriers that preclude Black women from joining a clinical trial.
Stephanie Walker, an Alliance patient advocate member living with MBC presented the BECOME survey results at ASCO. Ms. Walker and the Alliance team found that while 80 percent of Black patients with MBC said they would consider joining a clinical trial, only 40 percent were offered the chance to participate. This disconnect is multi-factorial and partly due to institutional biases or preconceptions about Black patients. BECOME highlighted the factors that lead to this disconnect (read more here).
By presenting these findings at ASCO—one of the field’s biggest conferences—Walker was able to shed light on this issue in hopes that trialists and other health care professionals can take steps to decrease this disparity for Black cancer patients.
“What you can do as a group of oncologists is get to know your patients, talk to your patients,” she said. “Instead of putting the burden on the patient to come to you to ask you about those clinical trials, I think you need to know who your patient is.”
This year’s ASCO meeting was an exciting one for MBC research, as the practice-changing DESTINY-Breast04 trial and these other highlights show. New treatments and breakthroughs are still desperately needed to end deaths from MBC, but as this year’s ASCO presentations show, progress in this area is significantly accelerating and we are continually discovering and improving therapies for MBC—all thanks to research.
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