Immunotherapy eliminates tumor cells in early-stage triple-negative breast cancer (KEYNOTE-522 study)

31 Dec 2019

Triple-negative breast cancer (TNBC) is an aggressive form of the disease accounting for 10-20% of all breast carcinomas and characterized by the low expression of progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2.1  TNBC represents an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents, limiting treatment options to chemotherapy. According to the recent findings from KEYNOTE-522 trial presented at the ESMO Congress 2019 in Barcelona, Spain, the addition of immune therapy to chemotherapy improves the pathological complete response (pCR) in patients with early TNBC, giving the emergence of new therapeutic targets for patients with TNBC.2

TNBC is the most aggressive subtype of breast cancer and more often affects young women. Patients typically receive chemotherapy, followed by surgery to remove the tumor, allowing the best chance of pCR. Women with a pCR have a 85–90% likelihood of being cured, while those with residual viable tumor tissue have a 40–50% probability of recurrence, which often occurs within three years.3

KEYNOTE-522, a randomized, placebo-controlled, phase 3 trial of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with early-stage high-risk TNBC, tested whether adding immune therapy to chemotherapy prior to surgery could improve pCR and event-free survival.  A total of 1,174 patients were randomized at a 2:1 ratio to pembrolizumab or placebo, both added to preoperative chemotherapy with anthracyclines, taxanes and platinum, for five to six months. After surgery, patients continued their allocated treatment of pembrolizumab or placebo for nine cycles.2

By the time of data presentation at the ESMO Congress 2019, a median follow-up time consisted of 15.5 months. The pCR, assessed in the first 602 patients, significantly increased from 51.2% (95% CI: 44.1-58.3) in the placebo group to 64.8% (95% CI: 59.9-69.5) in the pembrolizumab group (p=0.00055). “We found a 13.6% difference which is a clinically meaningful benefit,” said study author Prof. Peter Schmid, Barts Cancer Institute, Queen Mary University of London, UK.

The interim analysis of event-free survival demonstrated a favorable trend for the pembrolizumab group with a HR of 0.63 (95% CI: 0.43–0.93). This preliminary data provides a strong sign that the addition of immune therapy to neoadjuvant chemotherapy prevents breast cancer recurrence, however, longer time of follow-up is required to confirm these findings.

Treatment-related side effects of grade 3 or higher occurred in 78.0% and 73.0% of the pembrolizumab and placebo groups, respectively. Many of the side effects were driven by the intensive chemotherapy regimen. Side effects with a potential link to immune therapy occurred in 42% of patients in the pembrolizumab group compared with 21% on placebo. “Immune therapy added some side effects to chemotherapy, but there were no new safety signals,” added Prof. Schmid.

While a large benefit in response rate was expected, the poor predictive value of PD-L1 was surprising. “This is probably because most early-stage TNBCs express some degree of PD-L1, sometimes below the predefined cut-off of positivity. The role of chemotherapy as a sensitizer for anti-PD-1 in PD-L1-low early-stage TNBC should also be explored,” commented Prof. Fabrice André, Institut Gustave Roussy, Villejuif, France.“ The next step will be to define which patients are resistant and prioritize which targets should be hit in this population. We also have to determine the impact of this new class of drug on survivorship issues.”

  1. Al-Mahmood S, Sapiezynski J, Garbuzenko OB, Minko T. Metastatic and triple-negative breast cancer: challenges and treatment options. Drug Deliv Transl Res. 2018;8(5):1483-1507.
  2. P. Schmid et al. KEYNOTE-522: Phase 3 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early triple-negative breast cancer. Annals of Oncology. Volume 30, Supplement 5, October 2019. Accessed November 4, 2019.
  3. Immune Therapy Eliminates Tumour Cells in Early Triple Negative Breast Cancer [ESMO 2019 Press Release]. Accessed November 4, 2019.
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