Based on a convincing benefit in event-free survival, KEYNOTE-522 established the combination of neoadjuvant chemotherapy with pembrolizumab (pembro) followed by surgery and adjuvant pembro as a new standard of care for patients with early-stage triple negative breast cancer. During ESMO 2024, it became clear that this EFS benefit also translates into a significant overall survival benefit for patients.
KEYNOTE-522 is a prospective randomised placebo-controlled phase III trial evaluating pembro in the neoadjuvant and adjuvant treatment of patients with high-risk, early-stage TNBC. Previously, the study convincingly met its dual primary endpoints by showing a superior rate of pathological complete response (pCR, p< 0.001) and a significantly longer event-free survival (EFS, HR: 0.63; P<0.001) for patients treated with the pembro-containing regimen. Based on these findings, regulatory authorities worldwide have approved pembro in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery for high-risk, early-stage TNBC. During the presidential session at ESMO 2024, results for the key secondary endpoint of overall survival (OS) were presented after a median follow-up of 75.1 months.
KEYNOTE-522 randomly assigned (in a 2:1 ratio) 1,174 patients with previously untreated stage II or stage III TNBC to receive neoadjuvant therapy with four cycles of pembro (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin or placebo plus paclitaxel and carboplatin. Patients in both groups subsequently received an additional four cycles of pembro or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembro or placebo every 3 weeks for up to nine cycles. The primary endpoints of the study consisted of the pCR rate at the time of definitive surgery and the EFS in the intention-to-treat (ITT) population.
After a median follow-up 75.1 months, it was clear that the significant benefit in EFS translated into a significantly better OS for patients treated with pembrolizumab (HR[95%CI]:0.66[0.50-0.87], p= 0.0015). At the 5-year landmark, 86.6% of patients in the pembrolizumab arm were still alive, which is 4.9% more than in the control arm. Importantly, this OS benefit was observed in all the investigated subgroups, irrespective of nodal status, tumour size, carboplatin schedule, PD-L1 status and age. Furthermore, the benefit in OS was also seen irrespective of whether the patient obtained a pCR at the end of the neoadjuvant therapy or not (HR for OS 0.69 and 0.76 for patients with and without a pCR). In addition to this, the long-term data of KEYNOTE-522 solidified the previously reported findings on EFS. After 5 years, 81.2% of patients in the pembrolizumab arm were event-free as compared to 72.2% in the control arm (HR[95%CI]: 0.65[0.51-0.83]).
With respect to safety, the updated analysis did not reveal any new findings. Any-grade immune-mediated adverse events (AEs) were reported in 35% of patients in the pembro arm as compared to 13.1% in the control arm. Corresponding rates of grade ≥3 immune-mediated AEs were 13.0% and 1.5%, respectively. Immune mediated AEs led to treatment discontinuation in 7.7% of patients in the pembro arm as compared to 1.0% in the control arm.
Neoadjuvant pembro plus chemotherapy followed by adjuvant pembro results in a statistically significant and clinically meaningful improvement in OS compared with neoadjuvant chemo alone in patients with previously untreated, high-risk, early-stage TNBC. Furthermore, after more than 6 years of median follow-up, this regimen continued to show a clinically meaningful improvement in EFS. As such, these results provide further support for neoadjuvant pembro + platinum-containing chemotherapy followed by adjuvant pembro after surgery as the standard-of-care for patients with high-risk, early-stage TNBC.
Reference
Schmid P, et al. Neoadjuvant Pembrolizumab or Placebo + Chemotherapy Followed by Adjuvant Pembrolizumab or Placebo for High-Risk Early Stage Triple Negative Breast Cancer: Overall Survival Results from the Phase 3 KEYNOTE 522 Study. Presented at ESMO 2024, Abstract LBA4.
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