ASCO 2023 Meeting Report — Breast Cancer

The 2023 American Society of Clinical Oncology (ASCO) annual meeting, held June 2 to 6 in Chicago, highlighted important advances in treatment across a broad spectrum of malignancies. Here, Editor-in-Chief Dr. William Gradishar reviews key trials in breast cancer.

Researchers presented long-awaited disease-free survival results from a planned interim analysis of the NATALEE trial, which evaluated adjuvant therapy with the CDK4/6 inhibitor ribociclib in patients with high-risk ER+/HER2− early-stage breast cancer (abstract LBA500). This large, industry-funded, phase 3 trial randomized a broader population of patients than either the PALLAS (palbociclib) or monarchE (abemaciclib) adjuvant trials; in addition to patients with anatomical stage IIB and III disease, NATALEE also included those with stage IIA disease (node negative with grade 2 and evidence of high-risk features such as Ki-67 ≥20% or high genomic risk based on a molecular assay or with grade 3).

In the trial, 5101 patients were randomized to receive a nonsteroidal aromatase inhibitor (AI) for 5 years with or without ribociclib (400 mg/day; 3 weeks on/1 week off) for 3 years; male and premenopausal patients also received goserelin. In trials of ribociclib in metastatic breast cancer, 600 mg/day is the standard dose, but efficacy was found to be similar with 400 mg and tolerability was improved.

The treatment groups were well balanced with respect to menopausal status and exposure to prior adjuvant endocrine therapy and chemotherapy. At the time of the report, 57% of patients had completed ≥2 years of ribociclib therapy and 20% had completed 3 years. The absolute 3-year invasive disease-free survival (iDFS) benefit with ribociclib plus AI compared with AI alone was 3.3% (90.4% vs. 87.1%; P=.0014), representing a 25% relative risk reduction. All subgroups seemed to benefit. The absolute 3-year distant DFS benefit with ribociclib was 2.2% (90.8% vs. 88.6%; P=0017). Overall survival was immature. No new safety signals were identified, and the incidence of QT prolongation was lower than reported with the higher dose of ribociclib in other trials.

Comment: Although most patients had not yet completed all therapy or even all 3 years of ribociclib at the time of this analysis, there is clearly a reduction in recurrence risk with adjuvant ribociclib. Longer follow-up will be needed to identify which subgroups benefit from the addition of ribociclib.

Since researchers first reported the benefit of combining endocrine therapy with a CDK4/6 inhibitor in the first- or second-line setting in patients with endocrine-sensitive, metastatic breast cancer, no patient group has been identified for which the addition of a CDK4/6 inhibitor does not improve progression-free survival (PFS) compared with endocrine therapy alone. To address this, the Dutch phase 3 SONIA trial randomized 1050 patients with ER+/HER2− metastatic breast cancer to receive a nonsteroidal aromatase inhibitor (AI) with or without a CDK4/6 inhibitor (abstract LAB1000). At the time of disease progression, patients who received a CDK4/6 inhibitor started fulvestrant, while those who received a nonsteroidal AI alone started fulvestrant and a CDK4/6 inhibitor. Patients were ineligible for the trial if they had received prior therapy for metastatic disease, although neoadjuvant or adjuvant therapy was permitted.

Progression-free survival (PFS) on first-line therapy was superior in patients who had received a CDK4/6 inhibitor compared with those who had received an AI alone (median 24.7 vs. 16.1 months; hazard ratio, 0.59; P=0.0001). However, PFS on second-line therapy — the primary outcome — did not differ between patients who received a CDK4/6 inhibitor in the first line and those who received a CDK4/6 inhibitor in the second line (31.0 and 26.8 months; HR, 0.87; P=0.10). There was no difference in overall survival (OS) or quality of life between the two treatment arms. Median duration on the CDK4/6 inhibitor was 24.6 months in the first-line group compared with 8.1 months in the second-line group. Grade 3/4 toxicity was more common with first-line than second-line therapy.

Comment: Delaying use of a CDK4/6 inhibitor to the second-line setting did not affect OS, PFS, or quality of life; however, patients who received a CDK4/6 inhibitor in the first-line setting were able to stay on first-line therapy for 16.5 months longer. Most patients in the trial received palbociclib, and this choice raises the possibility that a more effective CDK4/6 inhibitor could have generated different results. There is always some attrition between first-line and second-line therapy, so most U.S. oncologists will likely continue to use CDK4/6 inhibitors in the first line. Being able to stay on a given therapy longer is also encouraging for patients psychologically, although it is associated with increased drug costs and toxicity.

Much attention has been focused on de-escalating therapy in both the early- and late-stage setting in an effort to more precisely craft treatment for individual patients and avoid unnecessary toxicity. The industry-sponsored, phase 2 PHERGain trial assessed the opportunity of chemotherapy de-escalation with a response-adapted strategy in patients with HER2+ stage I–IIIa breast cancer who were eligible for neoadjuvant therapy (abstract LBA506).

After undergoing baseline ¹⁸F-FDG PET/CT imaging, patients were randomized to receive two cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP; group A) or trastuzumab and pertuzumab alone (group B). After the two cycles, PET/CT was repeated. In group A, treatment was continued for another 4 to 6 cycles, followed by surgery. In group B, patients judged by PET/CT to have a metabolic response continued treatment for another 4 to 6 cycles, followed by surgery, whereas those who did not achieve a metabolic response were switched to TCHP for 4 to 6 cycles, followed by surgery. The primary endpoints were pathologic complete response (pCR) in group B patients with a PET/CT response and 3-year invasive disease-free survival (iDFS) in group B patients who underwent surgery.

Of the 285 patients in group B, 79.6% had a PET/CT response, and of those, 37.9% had a pCR. The 3-year iDFS was 95.4% overall and 98.8% among patients who had both a PET/CT response and a pCR.

Comment: Although longer follow-up is required, these results suggest that a metabolic biomarker (¹⁸F-FDG PET/CT) may identify a group of HER2+ patients who can avoid chemotherapy and still have an exceptionally good prognosis.

HER3-DXd is an antibody-drug conjugate made up of patritumab, a human anti-HER3 IgG1 monoclonal antibody, linked covalently to deruxtecan, a topoisomerase inhibitor. A prior phase 1/2 study demonstrated HER3-DXd activity in patients with heavily pretreated metastatic breast cancer, regardless of breast cancer subtype and HER2 expression (J Clin Oncol; 40:16 suppl 1002).

Now, in an industry-funded phase 2 trial, researchers evaluated HER3-DXd in patients with HER2− locally advanced or metastatic breast cancer who had hormone receptor-positive (HR+) disease and had received endocrine therapy, a CDK4/6 inhibitor, and 2 or fewer lines of chemotherapy, or had HR− disease and had received 1 to 3 lines of chemotherapy (abstract 1004). Patients were treated with HER3-DXd every 3 weeks (5.6 mg/kg IV). The primary endpoint was objective response rate (ORR) and progression-free survival (PFS) at 6 months.

Of the 61 patients, median age was 59, 77% were white, 90% had received chemotherapy in the metastatic setting, and 8% had received sacituzumab govitecan. Approximately 50% of tumors were ER+/PR+, and baseline HER3 expression was >75% in 64% of tumors. The ORR was 35% and was not higher in high- versus low-HER3-expressing tumors. The duration of response was at least 6 months in 48% of patients who responded. Most adverse events were grade 1 and 2, most commonly nausea, fatigue, and diarrhea.

Comment: Patritumab deruxtecan appeared to have activity across breast cancer subtypes regardless of HER3 expression, although there were few patients with HER3 expression <25% in the trial. Assessing whether this agent will work in HER3 low-expressing tumors as seen with trastuzumab deruxtecan will help us to understand if target expression is important.

Capecitabine is one of the most widely used chemotherapy drugs for treatment of advanced breast cancer. It is also one of the few oral chemotherapy drugs available with a reasonable toxicity profile, yet many patients experience debilitating or prohibitive side effects, such as hand-foot syndrome and diarrhea. Long ago, the FDA-approved standard dose of 1250 mg/m² twice daily, 2 weeks on/1 week off, was modified for routine use to 1000 mg/m² twice daily, 2 weeks on/1 week off. Many physicians also adopted a 1 week on/1 week off schedule for patients not tolerating the standard schedule. The efficacy and tolerability of these two schedules had not previously been directly compared.

The phase 2 X-7/7 trial randomized patients with metastatic breast cancer to fixed-dose capecitabine (1500 mg twice daily, 1 week on/1 week off) or to the FDA-approved or standard dose capecitabine (1250 mg/m² twice daily, 2 weeks on/1 week off; (abstract 1007). The trial was pragmatic, as it allowed any number of prior endocrine or chemotherapy treatments in the metastatic disease setting. Of 153 patients enrolled, 78% had ER+ disease, and only a few had HER2+ disease (requiring concurrent trastuzumab).

Progression-free survival was the same in both treatment arms at 3 months (the primary outcome) and at 12, 24, and 36 months. Overall survival also did not differ between arms. Grade 2 to 4 adverse events, including diarrhea, oral mucositis, and hand-foot syndrome, were significantly less frequent with the fixed-dose regimen (49% vs. 23%).

Comment: Although this study did not report a novel therapy, the findings are critically important for clinicians in day-to-day practice. A fixed-dose schedule of capecitabine in patients with metastatic breast cancer achieves the same therapeutic effect as the FDA-approved dose and schedule, but with far less toxicity. This is a win for patients.