Detrimental Impact of Chemotherapy Dose Reduction or Discontinuation in Early Stage Triple-Negative Breast Cancer Treated With Pembrolizumab and Neoadjuvant Chemotherapy: A Multicenter Experience

• Published in: Clinical breast cancer
• Main Authors: Krishnan, Jayasree, Patel, Archit, Roy, Arya Mariam, Alharbi, Malak, Kapoor, Ankita, Yao, Song, Khoury, Thaer, Hong, Chi-Chen, Held, Nicole, Chakraborty, Anumita, Kaliniski, Pawel, Salman, Ahmed, Catalfamo, Kayla, Attwood, Kristopher, Kirtani, Vatsala, Shaikh, Saba S., Chaudhary, Lubna N., Gandhi, Shipra
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 06.08.2024
• Subjects: Chemotherapy dose reduction; Immune related adverse events; Keynote-522 regimen; Pathologic complete response; Triple negative breast cancer; PR; OR; CI; ER; KN-522; RCB; NAC; Keynote-522 regimen; Chemotherapy dose reduction; RDI; TIL; HIPAA; Pathologic complete response; Immune related adverse events; irAEs; HER2; TNBC; Triple negative breast cancer; pCR; BMI
• ISSN: 1526-8209; 1938-0666; 1938-0666
• DOI: 10.1016/j.clbc.2024.08.005

Pembrolizumab combined with neoadjuvant chemotherapy (NAC) is the current standard of care in early stage triple-negative breast cancer (TNBC) based on higher event-free survival and pathological complete response (pCR) in Keynote-522 (KN-522) clinical trial. However, this aggressive five-drug regimen is associated with increased risks for immune-related adverse events (irAEs). We investigated real-world clinical outcomes and toxicity of this regimen as well as factors predictive of pCR and irAEs. We identified and abstracted data from 153 early-stage TNBC patients treated with the KN-522 regimen between July 1, 2021, and December 31, 2023, at 4 academic institutions in the U.S. Descriptive analysis was conducted, univariate and multivariate analyses were performed to identify factors associated with pCR and irAEs. The median age was 52 years (interquartile range, 42-60years), with 66% White and 24% Black patients with stage I/II (67%), node-negative disease (58%), grade 3 (86%) tumors, and ≥1 comorbidities (68%). Approximately 21% discontinued pembrolizumab, because of toxicity; ∼50% received a lower relative dose intensity (RDI) of chemotherapy (dose reduction or discontinuation). Of the 153 patients, 99 (64.7%) achieved pCR and 83 (54%) experienced an irAE, with 18 (12%) having ≥ grade 3 irAE. The majority (90%) of the irAEs were observed during neoadjuvant phase. Stage I/II versus stage III disease (OR 1.55, CI 1.04-2.33, P = .03), age (OR 0.96, CI 0.93-0.99, P = .01) and full versus reduced RDI of NAC (OR 1.53, CI 1.04-2.26, P = .03) were associated with higher pCR rates on multivariate analyses. Fewer cycles of pembrolizumab were associated with a higher likelihood of irAEs (OR 1.52, CI 1.07-2.16, P = .02), likely explained by the early discontinuation and receipt of less than 8 cycles of pembrolizumab in patients who experienced irAEs. Our study validates the clinical efficacy of KN-522 regimen; however, we observed a higher incidence of irAEs (54%) in this real-world population. Lower stage and younger age were associated with higher likelihood of achieving pCR. Toxicity-related chemotherapy dose reduction or discontinuation was observed to adversely impact the likelihood of achieving pCR. Neoadjuvant chemotherapy (NAC) with pembrolizumab is the current standard of care in early stage triple-negative breast cancer based on Keynote-522 (KN-522) clinical trial. We conducted a retrospective, multicenter study of 153 patients to investigate the real world clinical outcomes and toxicity of this regimen. The pathologic complete response (pCR) rate in our study population (64.7%) was comparable to that noted in KN- 522 trial, validating the effectiveness of this regimen. However, we observed a higher incidence of immune related adverse events (54%) than noted in the trial. Younger age, lower stage (I//II) and receipt of full dose of NAC were associated with increased likelihood of pCR. Our study highlights the toxicity of this intense regimen and underscores the need for optimal chemotherapy dosing to achieve pCR in patients treated with keynote-522 regimen.