Laying the Foundation for an Improved HR+/ HER2- Breast Cancer Treatment Paradigm

Aditya Bardia, MD, MPH

The continuous evolution of therapies for hormone receptor–positive/HER2- negative breast cancer has fueled investigators to evaluate HER2 expression further and data presented at the 2023 San Antonio Breast Cancer Symposium (SABCS) further ignited discussions surrounding CDK4/6 inhibitor use and the possibility of a new treatment for PIK3CA-mutant disease in this patient population.

Updated data from clinical trials are shedding light on the role of agents such as ribociclib (Kisqali) and datopotamab deruxtecan (Dato-DXd; DS-1062a). The final invasive disease-free survival (iDFS) analysis of the phase 3 multicenter, open label NATALEE trial (NCT03701334), which enrolled patients with hormone receptor-positive/HER2-negative early breast cancer, revealed that ribociclib plus a nonsteroidal aromatase inhibitor continued to a produce a statistically significant improvement in iDFS vs a nonsteroidal aromatase inhibitor alone in key subgroups. Investigators noted that 78.3% of patients of patients (n = 1996/2549) had stopped therapy with ribociclib by the final iDFS analysis. However, overall survival (OS) data are not mature at this time.¹

“We need additional follow-up to look at the full impact of 3 years of ribociclib because even at the time of study presentation, a number of patients were still within the 3 years of ribociclib [treatment]. But it’s very reassuring to see the updated results, which continued to show that the curves continue to separate and that ribociclib plus endocrine therapy is superior to endocrine therapy alone,” Aditya Bardia, MD, MPH, an attending physician and director of the Breast Cancer Research Program at Massachusetts General Hospital, and associate professor of medicine at Harvard Medical School, both in Boston, said in an interview with OncologyLive.

Diving into updates in the hormone receptor–positive/ HER2-negative breast cancer space during interviews with OncologyLive, investigators detailed how updates presented at SABCS are informing practice.

Trial Showcases Findings Extending PFS Outcomes

Meeting its dual primary progression-free survival (PFS) end point, findings from the phase 3, global, open-label, phase 3 TROPION-Breast01 trial (NCT05104866) revealed that Dato-DXd yielded a statistically significant and clinically meaningful improvement in PFS compared with investigator’s choice of chemotherapy in patients with previously treated unresectable or metastatic hormone receptor–positive/HER2-negative breast cancer. Patients who received Dato-DXd (n = 365) achieved a median PFS of 6.9 months vs 4.9 months in the chemotherapy arm (n = 367) by blinded independent central review (HR, 0.63; 95% CI, 0.52-0.76; P < .0001). The investigator- assessed 12-month PFS rates were 21.7% vs 9.9%, respectively.²

The Trop-2 directed antibody- drug conjugate (ADC) also showcased a favorable safety profile vs chemotherapy. “Patients who received Dato-DXd had a lower incidence of grade 3 or higher adverse effects [AEs] compared with standard chemotherapy,” Bardia said. “[With] Dato-DXd, the most common AE [was] mucositis.”

Bardia noted that the “unique” properties of Dato-DXd may contribute to this safety profile because the agent “has an optimized drug-to-antibody ratio and a stable linker that reduces off-target toxicity [that] is cleavable inside the tumor…. [Additionally], the payload is membrane permeable so it can address tumor heterogeneity.”

Additionally, those who received Dato-DXd experienced a confirmed median time to deterioration (TTD) in terms of physical functioning of 12.5 months vs 6.2 months for patients in the chemotherapy arm (HR, 0.77; 95% CI, 0.59-1.01). The confirmed median TTD in terms of pain was 9.0 months vs 5.5 months, respectively (HR, 0.72; 95% CI, 0.55-0.94). The confirmed median TTD in terms of global health status/QOL was 9.0 months in the Dato-DXd arm compared with 4.8 months in the chemotherapy arm (HR, 0.76; 95% CI, 0.58-0.98).²

“Dato-DXd is being evaluated in [first-line] metastatic triple-negative breast cancer in the phase 3 TROPION-Breast02 study [NCT05374512],” Bardia said, detailing next steps for the agent. “It’s also being evaluated in patients who have residual disease despite standard neoadjuvant therapy in [the phase 3] TROPION-Breast03 study [NCT05629585]. There’s a planned study in the neoadjuvant setting, [the phase 3] TROPIONBreast04 trial [NCT06112379], where patients will receive Dato- DXd as first therapy after diagnosis of localized triple-negative breast cancer,” he said.

Parasifal-Long Study Sheds Light on CDK4/6 Inhibitor Use

“There are now ample data to suggest that the [median] OS after treatment with palbociclib [Ibrance] approaches 5 and a half years. The OS of abemaciclib [Verzenio], even though it was not statistically significant from the phase 3 MONARCH 3 trial [NCT02246621], approached 5 and a half years, and the OS from ribociclib is 5 and a half years. It’s even more than that now that we have other agents like ADCs,” Adam M. Brufsky, MD, PhD, said in an interview with OncologyLive. Brufsky is a professor of medicine at the University of Pittsburgh School of Medicine and associate director of Clinical Investigation, associate chief of the Division of Hematology/ Oncology, and codirector of the Comprehensive Breast Cancer Center at the University of Pittsburgh Cancer Institute in Pennsylvania.

Data from PARSIFAL-LONG, the 5-year extended follow-up of the phase 2 PARSIFAL trial (NCT02491983), demonstrated that patients with hormone receptor–positive/HER2-negative advanced breast cancer who received fulvestrant and palbociclib (n = 197) experienced a median OS of 68.5 months (95% CI, 54.3-81.6) compared with 61.9 months (95% CI, 55.7-71.3) for those treated with letrozole and palbociclib (n = 192; HR, 0.94; 95% CI, 0.72-1.23; P = .635).³

“There was no difference [in OS] between the arms, but it was important to note in a trial designed for OS with endocrine-sensitive patients, the median OS was 65.4 months [in both cohorts combined], which is the same as ribociclib and the same as abemaciclib. To me, that says that all of the CDK4/6 inhibitors in the metastatic setting behave the same. The choice of CDK4/6 inhibitor in the first-line setting should be determined by the patient and the potential toxicities of the drug. Physicians can be comfortable giving any of those 3 [agents] in the first line,” Brufsky said.

Brufsky noted that efforts are now centered on addressing the unmet need of determining why some patients do very well on CDK4/6 inhibitors in the first line, but others become endocrine resistant and progress within 12 months.

New Data May Inform Treatment of PIK3CA-Mutant Disease

Further, according to findings from the phase 3 INAVO120 study (NCT04191499), patients with PIK3CA-mutant hormone receptor–positive/ HER2-negative advanced breast cancer who experienced recurrence on or within 12 months of adjuvant endocrine therapy, inavolisib plus palbociclib and fulvestrant yielded a statistically significant and clinically meaningful improvement in PFS vs palbociclib and fulvestrant alone.⁴

“These are very interesting data, and we have to wait a bit to see some updates,” Brufsky said. “This may also be a potential treatment up front with a PI3K inhibitor to treat the hard-to-treat, primarily endocrine-resistant [disease group]. That’s an unmet need.”

The median PFS in the triplet arm (n = 161) was 15.0 months (95% CI, 11.3-20.5) vs 7.3 months (95% CI, 5.6-9.3) in the doublet arm (n = 164; HR, 0.43; 95% CI, 0.32-0.59; P < .0001) at a median follow-up of 21.3 months. The median OS was not estimable (NE; 95% CI, 27.3-NE) compared with 31.1 (95% CI, 22.3-NE), respectively (HR, 0.64; 95% CI, 0.43-0.97; P = .0338). Additionally, patients experienced a median duration of response of 18.4 months (95% CI, 10.4-22.2) in the inavolisib, palbociclib, and fulvestrant arm compared with 9.6 months (95% CI, 7.4-16.6) in the palbociclib and fulvestrant arm (HR, 0.57; 95% CI, 0.33-0.99).⁴

“[The trial showed a doubling of PFS [and a] trend toward improvement in OS as well. The triplet combination was more efficacious [and] also has more toxicity, but there are AEs that we expect from PI3K inhibitors [such as] mucositis, hyperglycemia, [and] rash, [and] with palbociclib, neutropenia,” Bardia said. “It was good to see results of this triplet regimen in this setting, and if it is approved this would be the first approval for inavolisib.”

Regarding safety, 88.3% of patients in the triplet arm and 82.1% of patients in the doublet arm experienced grade 3 to 4 AEs, and serious AEs occurred in 24.1% and 10.5% of patients, respectively. AEs led to discontinuation of treatment (6.8% vs 0.6%) and dose modification or interruption of treatment (82.7% vs 74.7%) in patients in the triplet vs doublet arms, respectively. Six patients in the investigative arm died due to AEs and 2 patients in the control arm died due to AEs.⁴

The most common any-grade AEs were neutropenia (88.9% vs 90.7%), thrombocytopenia (48.1% vs 45.1%), stomatitis/mucosal inflammation (51.2% vs 26.5%), anemia (37.0% vs 36.4%), hyperglycemia (58.6% vs 8.6%), diarrhea (48.1% vs 16.0%), and nausea (27.8% vs 16.7%).⁴

Evaluating HER2 Expression in Advanced Disease

The retrospective, real-world RELIEVE study collected data from patients with metastatic breast cancer of any HER2 or hormone receptor status who received fam-trastuzumab deruxtecan- nxki (Enhertu) at Dana-Farber Cancer Institute in Boston, Massachusetts, or Duke Cancer Institute in Durham, North Carolina. A total of 191 patients with HER2-positive disease (n = 126; 66%), HER2-low (n = 44; 23%), or HER2-0 (n = 21; 11%) were included. Most had hormone receptor–positive (57%) disease, and patients had received a median of 2 (range, 0-9) prior lines of chemotherapy.⁵

The median time to next treatment (TTNT) was 10.4 months, 7.6 months, and 3.7 months in the HER2-positive, HER2-low, and HER2-0 groups, respectively. Additionally, the novel ctDNA test DNADX predicted the real-world activity of trastuzumab deruxtecan. Fifty-one patients with any HER2 status and a tumor fraction value of greater than 1% were evaluated. The DNADX HER2 signature results showed the median TTNT for patients with HER2 signature-high disease was 10 months, HER2 signature-medium disease was 7 months, and HER2 signature-low was 5 months.⁵

Sara M. Tolaney, MD, MPH, explained in an interview with OncologyLive that HER2-low disease is dynamic. “For example, you can start out with a tumor that’s HER2-0 that becomes HER2-low and then you go on [to give a patient] trastuzumab deruxtecan or [vice versa],” Tolaney said. “Does it matter what the dynamics [are] with relationship to efficacy? We found that if a patient was consistently HER2-low, whether that was HER2-low on primary [diagnosis] and HER2- low in the metastatic setting, for example, PFS was better than if you went from being HER2- low to HER2-0 or [vice versa]. It makes sense that if [patients] are stably HER2-low, [their] disease control will be better.”

Tolaney is chief of the Division of Breast Oncology, associate director at Susan F. Smith Center for Women’s Cancers, and a senior physician at Dana-Farber Cancer Institute, as well as an associate professor of Medicine at Harvard Medical School.

The median TTNT was 9.4 months for those with stable HER2-low disease (n = 21) who received trastuzumab deruxtecan, 5.6 months for those with HER2-0 disease at primary diagnosis and HER2-low disease at metastasis (n = 21), and 3 months for those with HER2-low disease at primary diagnosis and HER2-0 disease at metastasis (n = 10).⁵

“We see HER2-low status switching and being quite dynamic, and understanding how that impacts efficacy is useful,” Tolaney said. “As we learn more about trastuzumab deruxtecan, hopefully we’ll be able to figure out who’s going to benefit so that we can tailor therapy more. This is going to get more important as we see more ADCs get into this space. We’re going to need to figure out what is the optimal ADC to use first, and maybe better understanding these biomarker predictors will help us get there.”