Standard first-line treatment consists of HER2-targeted therapy plus chemotherapy. Although effective, chemotherapy can cause short- and long-term toxicities that may diminish quality of life and sometimes affect patients’ willingness to continue treatment.
“Because most chemotherapies are administered intravenously, patients are required to come into the clinic at least every 3 weeks,” Patel said. “Utilizing a treatment combination that does not involve chemotherapy — and instead uses mostly pills — is very convenient for patients and allows them more time at home. The hope is that they will be able to tolerate these medications for a longer time and maintain a good quality of life.”
In the ASPIRE trial, Patel and colleagues evaluated a four-drug combination for front-line treatment of hormone receptor-positive, HER2-positive metastatic breast cancer.
The regimen — which combined endocrine therapy with drugs that target two pathways that drive tumor growth — consisted of therapies that can be delivered orally or subcutaneously.
All patients received 1 mg anastrozole daily plus two HER2-targeted therapies — trastuzumab, administered at an 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks, and pertuzumab (Perjeta, Genentech), administered at an 840 mg loading dose followed by 420 mg every 3 weeks.
Patients also received palbociclib (Ibrance, Pfizer) — a cyclin-dependent kinase 4/6 inhibitor — on a 21-days-on, 7-days-off schedule.
Treatment continued until disease progression or unacceptable toxicity.
Clinical benefit rate — defined as the percentage of patients who achieved complete response, partial response or stable disease for at least 6 months — served as the primary endpoint. Secondary endpoints included OS, PFS and safety.
Durable disease control
The analysis included 29 response-evaluable patients (median age, 58 years; range, 37-82; 66% white). Twenty-eight (96.5%) were women. More than half had recurrent disease and visceral metastases (59% each).
Researchers reported a clinical benefit rate of 97% (95% CI, 82%-99%), with median duration of clinical benefit reaching 19.6 months (95% CI, 13.8-51.8).
Five patients (17%) achieved complete responses and 16 (55%) achieved partial responses. Median duration of response reached 37.8 months (95% CI, 14-not estimable).
“Many patients had durable responses. They were able to be on the same treatment combination for a long period, which is great for their quality of life and speaks to the regimen’s ability to provide disease control for a long period,” Patel said.
Median follow-up for survival reached 39.4 months, at which time 27 patients (93%) remained alive. Median OS had not been reached.
Median PFS reached 24.9 months (95% CI, 17.2-44.8). No patients had progressive disease within the first 6 months of treatment.
The most common treatment-related adverse events included neutropenia (86.2%), leukopenia (79.3%), diarrhea (62.1%), anemia (58.6%) and hot flashes (31%). About one-quarter of patients developed thrombocytopenia, arthralgias, infusion reactions or mucositis (27.6% each).
More than half (62%) of patients experienced grade 3/grade 4 treatment-related adverse events, the most common of which included neutropenia (51.7%), leukopenia (20.6%), anemia (10.3%) and lymphopenia (10.3%). No treatment-related deaths occurred.
Median treatment duration reached 20.2 months (range, 17.7-34). Three patients (10.3%) remained on treatment at data cutoff, with one patient having been on the regimen for more than 6 years.
One patient (3.4%) discontinued due to adverse events. Other reasons for discontinuation included disease progression (58.6%), subject’s withdrawal (10.3%) and physician decision (6.9%).
“The side effects we observed were consistent with the known side effects of the drugs used in the study,” Patel said, noting decreased blood counts — a known toxicity with palbociclib — could be managed with dose reductions. “Only one patient discontinued treatment due to adverse events and many patients were on the regimen for a few years, speaking to its tolerability.”
‘De-escalate treatment’
Researchers acknowledged study limitations, noting the small sample size and lack of comparison to standard-of-care therapy may limit generalizability of the findings.
When Patel and colleagues designed ASPIRE, standard first-line treatment consisted of HER2-targeted therapies plus chemotherapy.
The FDA has since approved fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi-Sankyo, AstraZeneca), an antibody-drug conjugate that combines a targeted HER2 monoclonal antibody with a chemotherapy drug, for use in the frontline setting.
“Part of the challenge of conducting clinical trials in breast cancer is that the treatment landscape is rapidly evolving. There are limitations when comparing trials that are designed differently and have different patient populations,” Patel said. “However, it is important to keep in mind that our study offers patients a regimen that is less toxic and offers significantly better quality of life than what we see with chemotherapy, while providing disease control and efficacy that is at least comparable.”
A larger study to validate the ASPIRE findings and compare the four-therapy combination with standard-of-care treatment is in the discussion phase, Patel said.
The rationale for the combination also aligns with a philosophical shift in breast cancer toward treatment de-escalation.
“In oncology, we have traditionally focused on ‘doing more’ — adding therapies or intensifying treatments,” Patel said. “As our therapeutic options have become increasingly targeted and effective, studies like ours are challenging that paradigm. Perhaps we don’t always need to do more. Instead, we can de-escalate treatment and achieve comparable, or even better, efficacy while reducing toxicity and improving patients’ quality of life.”
