Primary analysis of the KEYNOTE-522 trial shows a statistically significant and clinically meaningful improvement in the event-free survival (EFS) of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant chemotherapy versus neoadjuvant chemotherapy alone in patients with early triple-negative breast cancer (TNBC). Prespecified sensitivity and subgroup analyses for EFS show the benefit is consistent across a broad selection of patient subgroups.

Pembrolizumab has shown antitumor activity and manageable safety in metastatic TNBC [1,2]. In addition, results from the phase 1b KEYNOTE-173 trial showed that pembrolizumab plus neoadjuvant chemotherapy had promising antitumor activity and manageable toxicity in patients with early-stage TNBC [3]. The phase 3 KEYNOTE-522 trial (NCT03036488) evaluates the efficacy and safety of pembrolizumab plus chemotherapy versus placebo plus chemotherapy as neoadjuvant therapy and pembrolizumab versus placebo as adjuvant therapy in patients with early-stage TNBC. In KEYNOTE-522, 1,174 patients with previously untreated, non-metastatic, centrally confirmed TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC) were randomized (2:1) to pembrolizumab (200 mg every 3 weeks) or placebo, both given with 4 cycles of paclitaxel/carboplatin, then with 4 cycles of doxorubicin or epirubicin/cyclophosphamide (neoadjuvant phase). After definitive surgery, patients received pembrolizumab or placebo for 9 cycles or until recurrence or unacceptable toxicity (adjuvant phase). Dual primary endpoints are pathological complete response (pCR) rate and EFS. The primary analysis showed a statistically significant and clinically meaningful improvement in EFS with pembrolizumab plus chemotherapy followed by pembrolizumab [4]. To assess the robustness and consistency of the primary EFS result, prespecified sensitivity and subgroup analyses for EFS were performed, including 2 that assessed the impact of different censoring rules and 3 that assessed the impact of different event definitions. Treatment effects on EFS were examined in prespecified patient subgroups defined by nodal involvement (positive or negative), disease stage (II or III), menopausal status (pre-menopausal or post-menopausal), HER2 status (2+ by IHC but FISH- or 0-1+ by IHC), and LDH (>ULN or ≤ULN). Dr. Peter Schmid (Barts Cancer Institute, UK) presented the results of these analyses [5]. After a median follow-up of 39.1 months, the benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab versus neoadjuvant chemotherapy alone was generally consistent with the primary EFS results for all 5 sensitivity analyses and in each evaluated subgroup. HR for the sensitivity analyses ranged from 0.63 to 0.65 (vs 0.63 in the primary analysis); HR for the subgroup analyses was also in line with the primary analysis (range from 0.58 to 0.73). “These results show a robust treatment benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab for previously untreated non-metastatic TNBC. The EFS benefit was generally consistent across a broad selection of patient subgroups. These results further support neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab as a new standard of care for patients with early TNBC,” concluded Dr. Schmid.

  1. Adams S, et al. Ann Oncol 2019;30:397-404.
  2. Adams S, et al. Ann Oncol 2019;30:405-412.
  3. Schmid P, et al. Ann Oncol 2020;31:569-581.
  4. Schmid P, et al. N Eng J Med 2020;382:810-821.
  5. Schmid P, et al. KEYNOTE-522 study of neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy, followed by adjuvant pembrolizumab vs placebo for early-stage TNBC: Event-free survival sensitivity and subgroup analyses. SABCS 2021 Virtual Meeting, abstract GS1-01.

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