Chemotherapy-Free Four-Drug Regimen Yields 97% Clinical Benefit in HER2-Positive, HR-Positive Metastatic Breast Cancer
核心洞察
The phase 1/2 ASPIRE trial combined anastrozole, palbociclib, trastuzumab and pertuzumab as first-line therapy for treatment-naive hormone receptor-positive, HER2 (搜索)-positive metastatic breast cancer (搜索).
The single-arm study reported a 97% clinical benefit rate (95% CI, 82%-99%) with median progression-free survival of 24.9 months and 93% of patients alive at 39.4 months.
Investigators reported no unexpected safety signals, with neutropenia, leukopenia, diarrhea and anemia the most common adverse events and only one patient discontinuing treatment.
A four-drug, chemotherapy-free regimen produced durable disease control in patients with treatment-naive hormone receptor (HR)-positive, HER2 (搜索)-positive metastatic breast cancer (搜索), according to results of the phase 1/phase 2 ASPIRE trial presented by investigators at the Icahn School of Medicine at Mount Sinai.
The single-arm study combined endocrine therapy with agents targeting two pathways that drive tumor growth, all of which can be delivered orally or subcutaneously. Patients received 1 mg anastrozole daily plus two HER2 (搜索)-targeted therapies — trastuzumab at an 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks, and pertuzumab (Perjeta, Genentech) at an 840 mg loading dose followed by 420 mg every 3 weeks. They also received palbociclib (Ibrance, Pfizer), a cyclin-dependent kinase 4/6 (搜索) inhibitor, on a 21-days-on, 7-days-off schedule. Treatment continued until disease progression or unacceptable toxicity.
Durable Disease Control in a Difficult Subtype
About 10% of breast cancers are both HR-positive and HER2 (搜索)-positive. 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.
The analysis included 29 response-evaluable patients (median age, 58 years; range, 37-82; 66% white), 28 of whom (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%), defined as the percentage of patients achieving complete response, partial response or stable disease for at least 6 months, which served as the primary endpoint. Median duration of clinical benefit reached 19.6 months (95% CI, 13.8-51.8). Five patients (17%) achieved complete responses and 16 (55%) achieved partial responses, with median duration of response of 37.8 months (95% CI, 14-not estimable).
At a median follow-up for survival of 39.4 months, 27 patients (93%) remained alive and median overall survival had not been reached. Median progression-free survival reached 24.9 months (95% CI, 17.2-44.8), and no patients had progressive disease within the first 6 months of treatment. Median treatment duration reached 20.2 months (range, 17.7-34), with three patients (10.3%) remaining on treatment at data cutoff — including one who had been on the regimen for more than 6 years.
"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," first author Rima Patel, MD, assistant professor of medicine at Icahn School of Medicine at Mount Sinai, told Healio.
Safety Profile Consistent With Known Drug Effects
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%) experienced grade 3 or grade 4 treatment-related adverse events, most commonly neutropenia (51.7%), leukopenia (20.6%), anemia (10.3%) and lymphopenia (10.3%). No treatment-related deaths occurred.
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 that 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."
Convenience and the De-Escalation Paradigm
Patel framed the regimen's practical advantages in terms of administration burden. "Because most chemotherapies are administered intravenously, patients are required to come into the clinic at least every 3 weeks," she 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."
Amy Tiersten, MD, told Newsweek that the study is "part of an overall effort within breast medical oncology to de-escalate therapy by delivering less toxic therapy with the same or better efficacy," and described the possibility of achieving "an incredibly high clinical benefit rate that is durable."
Patel said the challenge in treating this specific breast cancer subtype amounts to "balancing effectiveness with quality of life," adding that "many patients, particularly older adults or those with other medical conditions, may not be ideal candidates for chemotherapy." A targeted regimen given primarily through oral medication and subcutaneous injection "could offer a more convenient option while reducing some of chemotherapy's burden," she said.
The rationale aligns with a broader philosophical shift in breast cancer care. "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."
Evolving Landscape and Next Steps
Researchers acknowledged study limitations, noting the small sample size and lack of comparison to standard-of-care therapy may limit generalizability of the findings. "These results should be viewed as hypothesis-generating but, in our opinion, they are quite provocative," Patel said. "They warrant further study — ideally larger randomized trials that compare this regimen to other standard therapies."
The treatment landscape has also shifted since ASPIRE was designed. When Patel and colleagues designed the trial, standard first-line treatment consisted of HER2 (搜索)-targeted therapies plus chemotherapy. The FDA has since approved fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi-Sankyo (搜索), 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.
Breast cancer remains the most common cancer in women in the United States after skin cancer, accounting for around 1 in 3 new cancers in women each year, according to the American Cancer Society.