ESMO 2023: New Advances in Breast Cancer Treatment

Breast cancer treatment is on the brink of major innovations. New research presented at the ESMO 2023 Congress is expanding treatment options. Here is a detailed look at some of these developments:

TROPION-Breast01 findings suggested a potential new standard treatment for previously treated patients with inoperable or metastatic, hormone receptor (HR)-positive, HER2-negative breast cancer: datopotamab deruxtecan (Dato-DXd).

Checkmate 7FL and KEYNOTE-756 both suggested that, in patients with early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer, neoadjuvant chemotherapy combined with an immunotherapy could increase pathologic complete response (pCR) rates. For the first time, this provided such strong evidence of immunotherapy's benefits in hormone-positive breast cancer.

And the FALCON trial's final overall survival (OS) results showed no significant OS difference between fulvestrant and anastrozole in postmenopausal patients with endocrine (hormone suppression) therapy–naive, HR-positive, HER2-negative advanced breast cancer.

TROPION-Breast01: Longer PFS With Dato-DXd

In the phase 3 TROPION-Breast01 trial, Dato-DXd prolonged progression-free survival (PFS) compared with investigator's choice of chemotherapy in patients with HR-positive, HER2-negative, inoperable or metastatic breast cancer previously treated with 1 to 2 lines of chemotherapy.

The trial enrolled 732 patients randomized to Dato-DXd (365 patients) or investigator's choice of chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine; 367 patients). Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

• Median PFS was 6.9 months in the Dato-DXd arm and 4.9 months in the chemotherapy arm (hazard ratio, 0.63; 95% CI, 0.52-0.76; P <0.0001).
• Twelve-month PFS rates were 25.5% and 14.6%, respectively.
• Although median overall survival data were immature, the results showed a trend toward improvement with Dato-DXd (hazard ratio, 0.84; 95% CI, 0.62-1.14).

Treatment-related adverse effects occurred in 94% of patients in the Dato-DXd arm and 86% in the chemotherapy arm. Grade 3 or higher treatment-related adverse effects were reported in 21% and 45%, respectively.

In conclusion, these data suggest that Dato-DXd could become a new standard treatment option for patients with previously treated, metastatic, HR-positive breast cancer. If approved by the FDA (US Food and Drug Administration), it would be a potential option alongside sacituzumab govitecan and trastuzumab deruxtecan in this setting.

Checkmate 7FL: Nivolumab Improves pCR Rates

In the phase 3 CheckMate 7FL trial, adding nivolumab to neoadjuvant chemotherapy improved pCR rates in patients with newly diagnosed, early-stage, high-risk, ER-positive, HER2-negative breast cancer.

A total of 510 patients were randomized to neoadjuvant chemotherapy (an anthracycline and cyclophosphamide) plus either nivolumab (257 patients) or placebo (253 patients). After surgery, they received nivolumab or placebo, respectively, along with investigator's choice of endocrine therapy.

• The pCR rate was significantly higher in the nivolumab arm than in the placebo arm: 24.5% versus 13.8%.
• Among PD-L1-positive patients, pCR rates were 44.3% and 20.2%, respectively.

During the neoadjuvant phase, grade 3-4 treatment-related adverse effects occurred in 35% with nivolumab plus chemotherapy and 32% with chemotherapy alone. There were 2 treatment-related deaths in the nivolumab arm (pneumonia and hepatitis), while none were reported in the chemotherapy arm.

Although these findings do not directly change our current clinical practice, they show the need for further research into how increased pCR translates into long-term clinical outcomes. Nevertheless, they are promising, providing strong indications that immunotherapy may benefit hormone receptor-positive cancers, the most common breast cancer subtype. The research also makes an important contribution to studies showing that immunotherapy's benefits in early-stage breast cancer are not limited to triple-negative disease.

KEYNOTE-756: Pembrolizumab Improves pCR Rates

Like Checkmate 7FL, KEYNOTE-756 showed that adding immunotherapy to chemotherapy before surgery increases pathologic complete response (pCR) rates. This is particularly exciting because we previously had no evidence of immunotherapy's benefit in hormone receptor-positive (HR-positive) breast cancer.

Long-term follow-up data from KEYNOTE-756 are needed to determine whether combining neoadjuvant (preoperative) pembrolizumab with chemotherapy effectively prevents disease recurrence. These long-term data are critical before adopting the combination as standard treatment.

FALCON: No Overall Survival Difference Between Fulvestrant and Anastrozole

The phase 3 FALCON trial studied postmenopausal patients with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer who had not received endocrine therapy but had received one line of chemotherapy.

They were randomized to fulvestrant or anastrozole. In total, 462 patients were enrolled: 230 received fulvestrant and 232 received anastrozole.

For the prespecified primary endpoint of disease-free survival (PFS), the fulvestrant group showed a significant improvement compared with the anastrozole group.

• Median PFS was 16.6 months with fulvestrant versus 13.8 months with anastrozole (hazard ratio, 0.80; 95% confidence interval, 0.64-1.00; P = 0.049).

Fulvestrant's favorable PFS effect was particularly evident in patients whose disease had not spread to organs such as the liver or lungs (hazard ratio, 0.59; 95% confidence interval, 0.42-0.84). No significant difference was seen in those with disease that had spread to organs (hazard ratio, 0.99; 95% confidence interval, 0.74-1.33).

In the final OS analysis, mean overall survival was 44.8 months with fulvestrant and 42.7 months with anastrozole, with no statistically significant difference (hazard ratio, 0.97; 95% confidence interval, 0.77-1.21; P = 0.76).

In the phase 3 FALCON trial, among patients without visceral spread, median overall survival was 65.2 months with fulvestrant and 47.8 months with anastrozole (hazard ratio, 0.85; 95% confidence interval, 0.60-1.20). In contrast, among patients with visceral disease, mean OS was 37.2 months with fulvestrant and 40.7 months with anastrozole (hazard ratio, 1.06; 95% confidence interval, 0.80-1.42). These data suggest that fulvestrant as initial treatment may offer a meaningful long-term OS advantage in patients without visceral spread. The findings were described as supporting fulvestrant's potential to provide an important long-term OS benefit in patients without visceral metastases.

The study's focus on people with metastatic disease who were generally endocrine therapy–naive may pose a problem. This may be particularly relevant to newly diagnosed patients with metastatic disease, but it should be recognized that previously treated patients generally receive endocrine therapy as their initial treatment.

Despite these results, current clinical practice generally favors CDK4/6 inhibitors plus endocrine therapy as first-line treatment. Treatment choices are usually based on the duration of a patient's previous endocrine therapy exposure.

Studies are also ongoing to determine whether combining a fulvestrant-class drug with a CDK4/6 inhibitor is more effective than combining an aromatase inhibitor with a CDK4/6 inhibitor. Their results are needed to fully understand endocrine therapy selection and its potential synergy with CDK4/6 inhibitors.

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