Episode 13: The KEYNOTE-522 update
Presented by Dr Kevin Punie (GZA Hospitals) and Prof Evandro De Azambuja (Institut Jules Bordet)
KEYNOTE-522, a widely recognized phase 3 trial, has led to a paradigm shift in the management of high-risk early-stage TNBC. The trial incorporates pembrolizumab within the neoadjuvant platinum-based chemotherapy regimen. Following definitive surgery, patients underwent adjuvant pembrolizumab or placebo administration for 9 cycles or until recurrence or intolerable toxicity.
The initial interim analysis showcased a statistically noteworthy enhancement in pCR, demonstrating a 13.6 percentage point improvement. The fourth interim analysis at 3 years, validated a statistical significant enhancement in EFS, elucidating a HR of 0.63 favouring the pembrolizumab-treated cohort.
An update presented by Peter Schmid included EFS endpoint data and subgroup analysis after a median follow-up of 63 months. Distant recurrence is the prevalent first EFS event, which underscores the critical role of a therapeutic intervention augmenting EFS in the early phase. The durability of EFS benefits over an extended follow-up period was evidenced by a consistent HR at 60 months for the pembrolizumab-treated cohort. The clinically relevant and statistically significant 9% EFS improvement primarily stems from a reduction in distant recurrence.
Subgroup analyses elucidated a uniform relative benefit across stages 2 and 3, with even the lowest-risk group manifesting a 10% absolute benefit in relapse risk reduction at 5 years. These comprehensive findings affirm the prevailing standard of care and underscore the sustained impact on EFS. The translation of EFS benefits into OS advantages is awaited, with detailed analysis expected in the coming year.
Pertinent questions include the post-surgery efficacy of pembrolizumab. Patients who did not achieve a complete pCR derive advantages from continued treatment. Notably, non-randomized exploratory analyses reveal an intriguing 4% absolute EFS benefit for patients achieving pCR over those attaining pCR through chemotherapy alone. This effect becomes more obvious over time, escalating from a 1.8% difference at the initial analysis to 4% at the 5-year follow-up.
Despite the optimistic outcomes associated with pembrolizumab in facilitating pCR, its administration does not guarantee freedom from recurrence, particularly in this high-risk population. Novel treatments remain necessary, especially for patients with residual disease and an inherently bad prognosis.
The eagerly awaited biomarker data in 2024 holds promise in tailoring treatments according to individual patient profiles.
References:
Schmid P et al. (2023) Pembrolizumab or placebo plus chemotherapy followed by pembrolizumab or placebo for early-stage TNBC: Updated EFS results from the phase III KEYNOTE-522 study. Annals of Oncology 34 (suppl_2): S1254-S1335. 24.