Addition of pembrolizumab promising in early-stage high-risk ER+/HER2- breast cancer

The addition of pembrolizumab to neoadjuvant chemotherapy in participants with early-stage, high-risk ER+/HER2- breast cancer leads to a statistically significant increase in pathological complete response (pCR) regardless of PD-L1 status, the first results of the KEYNOTE-756 trial showed.

Although patients with early-stage ER+/HER2- breast cancer generally have a better prognosis than those with other breast cancer subtypes, there is a high-risk subpopulation that benefits from neoadjuvant chemotherapy. For this subpopulation, the pCR rates after neoadjuvant chemotherapy range from 0 to 18% [1]. In triple-negative breast cancer (TNBC), the addition of pembrolizumab to neoadjuvant chemotherapy and continued as adjuvant therapy increased pCR and improved event-free survival (EFS) [2]. The current phase 3 KEYNOTE-756 trial (NCT03725059) explores the efficacy and safety of adding pembrolizumab to neoadjuvant chemotherapy and subsequent adjuvant pembrolizumab in participants with early-stage high-risk ER+/HER2- breast cancer. The final pCR results were presented by Dr Fatima Cardoso (Champalimaud Clinical Centre, Portugal) [3].

In KEYNOTE-756, 1278 participants (grade 3 ER+/HER2-, T1c-2 N1–2 or T3–4 N0–2) were randomised 1:1 to receiving neoadjuvant chemotherapy with pembrolizumab or placebo, followed by surgery and adjuvant pembrolizumab or placebo. The primary endpoints of the study are pCR and EFS. Results for EFS are not yet mature.

Progression (and discontinuation) during the neoadjuvant treatment was rare in both arms (2.2% in the pembrolizumab arm and 2.0% in the placebo arm). The addition of pembrolizumab to neoadjuvant chemotherapy significantly improved the pCR rate: 24.3% versus 15.6% in the placebo arm (P=0.00005, see Figure). A pCR benefit from pembrolizumab was observed in all predefined subgroups, including PD-L1 status. In particular, in participants with ER-low (<10%) tumours, the benefit of pembrolizumab was increased compared with neoadjuvant chemotherapy alone. “This particular finding fits in with the idea that ER-low tumours behave more like TNBCs,” said Dr Cardoso.

Figure: Pathological complete response (pCR) achieved by neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo with endocrine therapy at the first interim analysis [3]



^a Estimated treatment differences based on the Miettinen & Nurminen method stratified by the analysis randomisation stratification factors. Data cutoff date: May 25, 2023.Δ, difference; CI, confidence interval; IA1, interim analysis 1; pCR, pathological complete response.

Overall, the supplementation of pembrolizumab to neoadjuvant chemotherapy did not significantly increase adverse event rates (52.5% vs 46.4% grade 3–5 for pembrolizumab vs placebo arm). Immune-mediated adverse events were observed in 32.8% of pembrolizumab-treated participants (7.1% grade 3–5) with hypo- and hyperthyroidism being most prominent.

“The addition of pembrolizumab to neoadjuvant chemotherapy in participants with early-stage, high-risk ER+/HER2- breast cancer leads to a statistically significant increase in pCR regardless of PD-L1 status,” concluded Dr Cardoso.

1. 
   
   1. Torrisi R, et al. Crit Rev Oncol Hematol. 2021;160:103280.
   2. Schmid P, et al. N Engl J Med. 2022;387:217–226.
   3. Cardoso F, et al. KEYNOTE-756: Phase III study of neoadjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo), followed by adjuvant pembro or pbo + endocrine therapy (ET) for early-stage high-risk ER+/HER2– breast cancer. Abstract LBA21, ESMO 2023, 20–24 October, Madrid, Spain.

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Posted on 18 December, 202319 December, 2023