Toxicity and Outcomes of the KEYNOTE-522 Chemo-immunotherapy Regimen in Non-Metastatic Triple-negative Breast Cancer," for consideration for publication in the

Abstract Introduction Real-world implementation of the KEYNOTE-522 regimen presents substantial challenges, including high treatment-modification burden and adherence barriers, particularly in community and non-trial settings. Methods We conducted a retrospective cohort analysis of stage II-III TNBC patients treated at the University of Nebraska Medical Center from 2018–2024. Patients receiving neoadjuvant pembrolizumab with chemotherapy (KEYNOTE-522 regimen) (N = 50) were compared with a historical control group receiving dose-dense anthracycline-cyclophosphamide-taxane (ddACT) chemotherapy alone (N = 28). The primary focus was evaluating treatment-related toxicities, adherence challenges, pathologic complete response (pCR), and implications for surgical decision-making and clinical practice. Results Among 78 patients, 50 received the KEYNOTE-522 regimen and 28 received ddACT. High treatment-modification burden was more frequent in the pembrolizumab group, as reflected by treatment modifications or discontinuations (50.0% vs. 17.9%, p = 0.0051). pCR rates were higher with pembrolizumab (42.0% vs. 28.6%, p = 0.2391), and all pCRs corresponded to RCB 0. Recurrence occurred exclusively in non-pCR patients. At 12 months, recurrence and mortality were lower in the pembrolizumab group (16.0% vs. 44.4%, p = 0.0367; 8.0% vs. 29.6%, p = 0.0777), despite shorter median follow-up (17.7 vs. 40.4 months). EFS did not differ significantly by treatment (p = 0.1240), but was strongly associated with RCB class (p = 0.0118) and prognostic stage (p < 0.0001). In ddACT patients, treatment modification predicted worse EFS (p = 0.0215). No demographic or clinical variables were independently associated with pCR. Conclusions In this real-world cohort, the KEYNOTE-522 regimen was associated with high treatment-modification burden and adherence challenges, particularly among medically and socially complex patients. These findings suggest that implementing pembrolizumab outside clinical trials may require biomarker-guided patient selection and equity-focused implementation strategies before routine adoption in under-resourced settings.