European Commission Approves Pembrolizumab Plus Chemotherapy for High-Risk Early-Stage TNBC

The European Commission has approved pembrolizumab (Keytruda) for use in combination with chemotherapy as neoadjuvant therapy, and then continued as monotherapy as adjuvant treatment after surgery for adults with locally advanced or early-stage triple-negative breast cancer (TNBC) at high risk of recurrence.¹

The approval is based on data from the pivotal phase 3 KEYNOTE-522 trial (NCT03036488), which showed a significant improvement in event-free survival (EFS) when pembrolizumab was given with chemotherapy consisting of carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide prior to surgery and continued as monotherapy following surgery, vs neoadjuvant chemotherapy alone in patients with untreated stage II or stage III TNBC (HR, 0.63; 95% CI, 0.48-0.82; P = .001[CR1] ). The median follow-up was 39.1 months (range, 30.0-48.0).²

“TNBC has a high risk of recurrence within the first five years, so it’s meaningful for patients to have access to new therapies that can reduce the risk of disease progression,” Peter Schmid, MD, PhD, lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute in London, England, stated in a press release. “The approval of this [pembrolizumab] regimen marks a turning point for patients with high-risk early-stage TNBC, as they now have an immunotherapy option in early stages of the disease that has demonstrated significant improvements in pathological complete response and event-free survival compared to neoadjuvant chemotherapy.”

In July 2021, the FDA approved the combination for use in the same indication. Both approvals were based on findings from the randomized, double-blind, phase 3 KEYNOTE-522 trial. The primary end points were pathological complete response (pCR) rate, defined as pathological stage ypT0/Tis ypN0 at the time of definitive surgery, and EFS, defined as the time from randomization to the time of first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause.

A key secondary end point was overall survival (OS). The study enrolled 1,174 patients who were randomized 2:1 to receive pembrolizumab plus paclitaxel and carboplatin, followed by pembrolizumab plus cyclophosphamide and doxorubicin or epirubicin as neoadjuvant therapy, followed by pembrolizumab alone as adjuvant therapy after surgery (n = 784); or placebo plus paclitaxel and carboplatin, followed by placebo plus cyclophosphamide and doxorubicin or epirubicin as neoadjuvant therapy, followed by placebo alone as adjuvant therapy after surgery (n = 390).

Prior data presented during the 2019 ESMO Congress demonstrated that patients who received pembrolizumab experienced a pCR rate of 64.8% vs 51.2% with placebo (P = .00055).³

Findings from the study’s fourth interim analysis demonstrated that the estimated 36-month EFS rate was 84.5% (95% CI, 81.7%-86.9%) in the chemoimmunotherapy arm vs 76.8% (95% CI, 72.2%-80.7%) in the placebo arm.²

Additionally, the analysis of distant progression-free or distant recurrence-free survival showed an HR of 0.61 for distant progression, distant recurrence, or death with pembrolizumab vs placebo (95% CI, 0.46-0.82).

OS data were immature at the time of this analysis. However, the estimated 36-month OS rate was 89.7% (95% CI, 87.3%-91.7%) in the chemoimmunotherapy arm vs 86.9% (95% CI, 83.0%-89.9%) in the placebo arm (HR, 0.72; 95% CI, 0.51-1.02).

Regarding safety, any-grade treatment-related adverse effects (TRAEs) in the neoadjuvant and adjuvant phases were reported in 98.9% of those in the chemoimmunotherapy arm vs 99.7% of those in the placebo arm; 77.1% and 73.3% of these effects, respectively, were grade 3 or greater in severity.

The most common AEs with the chemoimmunotherapy regimen vs the placebo regimen included nausea (63.2% vs 63.0%, respectively), alopecia (60.2% vs 56.6%), anemia (54.8% vs 55.3%), neutropenia (46.9% vs 47.6%), fatigue (42.1% vs 38.8%), and diarrhea (30.4% vs 25.2%), among others.

Any-grade immune-mediated AEs occurred in 33.5% and 11.3% of patients in the pembrolizumab and placebo arms, respectively; 12.9% vs 1.0% of these effects, respectively, were grade 3 or greater.

The toxicity profile of the regimen at the updated analysis was consistent with previously reported findings for each regimen. No new safety signals were reported.

“[Pembrolizumab] was first approved in Europe to address an unmet need in certain patients with metastatic TNBC, and today’s approval extends the use of [pembrolizumab] to more patients facing this difficult-to-treat cancer – this time in earlier stages of TNBC,” Gursel Aktan, MD, PhD, vice president, global clinical development, Merck Research Laboratories, stated in a press release. “We are very proud that today’s approval marks the fifth indication for [pembrolizumab] in Europe for patients with breast or a gynecological cancer, an important area where patients need continued research and innovation.”

References

1. European Commission approves KEYTRUDA® (pembrolizumab) plus chemotherapy as neoadjuvant treatment, then continued as adjuvant monotherapy after surgery for locally advanced or early-stage triple-negative breast cancer at high risk of recurrence. News release. Merck. May 24, 2022. Accessed May 24, 2022. https://bit.ly/38e1J1Z
2. Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. doi:10.1056/NEJMoa2112651
3. Schmid P, Cortés J, Dent R, et al. KEYNOTE-522: phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC). Ann Oncol. 2019;30(suppl 5):V853-V854. doi:10.1093/annonc/mdz394.003