Immunotherapy Benefits Demonstrated for the First Time in Hormone-Positive Early Breast Cancer

Treatments known as immune checkpoint inhibitors, or immunotherapies, have demonstrated efficacy and received approval in approximately 20 different types of cancer to date. However, positive results have been less common in cancers closely associated with hormones, such as breast and prostate cancer. In breast cancer, these drugs are approved only for the triple-negative subtype . However, some of the most notable studies presented on the first day of the ESMO Congress 2023, which began on October 20 in Madrid, Spain, showed for the first time that immunotherapies may also be effective in hormone-positive breast cancer.

Presentations at this year's congress provided findings in hormone receptor (HR)-positive early breast cancer on the benefits of adding neoadjuvant (preoperative tumor-shrinking) immunotherapy to chemotherapy, drawing on data from two separate phase-III studies :

• KEYNOTE-756 evaluated pembrolizumab and
• CheckMate 7FL evaluated nivolulab

Updated findings in triple-negative breast cancer (TNBC) were also shared.

KEYNOTE-756 Study:

Methodology:

• This study included 1,278 patients and compared pathological complete response (pCR) rates with pembrolizumab plus chemotherapy versus placebo plus chemotherapy.
• The patients had been diagnosed with invasive ductal ER-positive/HER2-negative breast cancer. They received neoadjuvant pembrolizumab or placebo with chemotherapy, followed by surgery. After surgery, patients received pembrolizumab plus hormone-suppression therapy or placebo plus hormone therapy.

Findings:

• Among patients who received pembrolizumab with chemotherapy as neoadjuvant treatment, the pCR rate was 24.3% , compared with 15.6% in the placebo arm. The treatment difference was 8.5%, with a 95% confidence interval (CI) of 4.2–12.8; p=0.00005.
• During the neoadjuvant phase, grade ≥3 treatment-related adverse-event rates were 52.5% with pembrolizumab and 46.4% with placebo.

CheckMate 7FL Study:

Methodology:

• The study included patients with high-risk, early-stage ER+ HER2- breast cancer.
• Nivolumab + Neoadjuvant Chemotherapy (NACT) Group (Arm A): Patients in this group received the immunotherapy drug nivolumab together with neoadjuvant chemotherapy (NACT). After completing neoadjuvant chemotherapy, they underwent surgery and then continued nivolumab together with adjuvant endocrine therapy (ET). There were 257 patients in this arm.
• Placebo + Neoadjuvant Chemotherapy (NALT) Group (Arm B): Patients in this group received a placebo together with neoadjuvant chemotherapy (NACT). After completing neoadjuvant chemotherapy, they continued placebo together with adjuvant endocrine therapy (ET). There were 253 patients in this arm.
• The primary outcome measure was the pathological complete response (pCR) rate in each group. Secondary outcome measures included pCR rates in PD-L1-positive patients, residual cancer burden 0-1 rates in all patients and in PD-L1+ patients, and adverse-event and mortality data.

Findings:

• The pCR rate in Arm A (NIVO + NACT / NIVO + ET) was 24.5% , significantly higher than in Arm B (PBO + NACT / ET), where it was 13.8%(P = 0.0021).
• NIVO had a greater benefit for pCR in PD-L1+ patients, with rates of 44.3% in Arm A and 20.2% in Arm B.
• Residual cancer burden 0-1 rates also improved overall, with an even greater improvement in PD-L1+ patients.
• During the neoadjuvant phase, the frequency of grade 3/4 treatment-related adverse events was similar in both arms (35% versus 32%).
• Two deaths related to the study drug (pneumonitis and hepatitis) were reported in Arm A, and immune-mediated adverse events were more frequent in Arm A than in Arm B.

These details show that both studies evaluated the potential benefits and safety of immunotherapy in HR-positive early breast cancer and that pembrolizumab and nivolumab may improve pCR rates in selected patients.

The chart shows how pembrolizumab and nivolumab affected pCR rates compared with placebo in the "KEYNOTE-756" and "CheckMate 7FL" studies.

Latest Findings in Triple-Negative Breast Cancer

Pembrolizumab Efficacy in Patients with TNBC

In the treatment of triple-negative breast cancer (TNBC), pembrolizumab previously showed positive results in KEYNOTE-522, leading to its approval for neoadjuvant treatment. Updated findings from KEYNOTE-522 were presented at the ESMO Congress 2023.

After 63.1 months of follow-up, among 1,174 patients with early TNBC, those who received pembrolizumab combined with chemotherapy had a better disease-free survival rate (EFS) than those who received chemotherapy alone (81.3% versus 72.3%; hazard ratio [HR] 0.63, 95% confidence interval 0.49–0.81). Pembrolizumab's positive effect on disease-free survival was consistent across different subgroups, such as those defined by PD-L1 expression and lymph node status. However, overall survival data are not yet available.

Negative Results with Atezolizumab

Atezolizumab is a PD-L1 inhibitor and was tested in TNBC in the NeoTRIP study. After 54 months of follow-up, disease-free survival rates were slightly lower among patients who received atezolizumab combined with chemotherapy than among those who received chemotherapy alone (70.6% versus 74.9%; HR 1.076; 95% confidence interval 0.670–1.731). Unlike pembrolizumab and nivolumab, atezolizumab directly targets PD-L1 on tumor cells, which may explain these negative results.

Commentary

These studies indicate that immunotherapy may play an important role in different types of breast cancer and that some agents may yield more favorable results by targeting PD-1 rather than PD-L1. The findings in HR-positive breast cancer could lead to important changes in treatment practice. Further studies aim to identify the patients who benefit most and determine whether postoperative immunotherapy is necessary when a pathological complete response (pCR) is achieved.

In conclusion, the positive results from randomized controlled studies of two different neoadjuvant immunotherapies for HR-positive breast cancer are certainly noteworthy. However, without overall survival data, it is difficult to regard these results as fully positive. Pathological complete response (pCR) may be an important treatment goal in HR-positive breast cancer, but overall survival will be more decisive in determining whether these expensive treatments can change clinical practice.