Neoadjuvant pembrolizumab plus chemotherapy benefits event-free survival in TNBC

Primary analysis of the KEYNOTE-522 trial showed a statistically significant and clinically meaningful improvement in the event-free survival (EFS) of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab versus neoadjuvant chemotherapy alone, in patients with early triple-negative breast cancer (TNBC).

Pembrolizumab showed anti-tumour activity and manageable safety in metastatic TNBC [1,2].

In addition, results from the phase 1b KEYNOTE-173 trial (NCT02622074) showed that pembrolizumab plus neoadjuvant chemotherapy had promising anti-tumour activity and manageable toxicity in patients with early-stage TNBC [3].

The phase 3 KEYNOTE-522 trial (NCT03036488) evaluated 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. A total of 1,174 patients with previously untreated, non-metastatic, centrally confirmed TNBC were randomised 2:1 to pembrolizumab or placebo, both given with 4 cycles of paclitaxel plus carboplatin, then with 4 cycles of doxorubicin or epirubicin plus 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 were pathological complete response 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, pre-specified 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 pre-specified patient subgroups defined by nodal involvement (positive or negative), disease stage (1 or 3), menopausal status (premenopausal or postmenopausal), HER2 status (2+ by IHC but FISH- or 0–1+ by IHC), and LDH (>ULN or ≤ULN). Prof. 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 subgroup evaluated. Hazard ratio (HR) for the sensitivity analyses varied from 0.63–0.65 (versus 0.63 in the primary analysis). Also, HR for the subgroup analyses was in line with the primary analysis: 0.58–0.73 (see Table).

Table: Hazard Ratio of subgroup analyses [5].



 

 

 

 

 

 

IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; LDH, lactate dehydrogenase; ULN, upper limit of normal; HR, hazard ratio.

“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,” concluded Prof. 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. GS1-01, SABCS 2021 Virtual Meeting, 7–10 December.

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Posted on 31 January, 202225 March, 2024