Treatment-emergent thyroid disorders and outcomes of first-line pembrolizumab plus chemotherapy in metastatic triple-negative breast cancer: A real-world study.

Abstract

e13125 Background: Pembrolizumab+chemotherapy (P+C) is a standard first-line treatment for PD-L1 positive metastatic triple-negative breast cancer (mTNBC). Thyroid dysfunction is a common immune-related adverse event (irAE) of PD-1 blockade and has been associated with improved outcomes in other malignancies, particularly non–small cell lung cancer and melanoma. We evaluated the association between treatment-emergent thyroid dysfunction and real-world effectiveness of first-line P+C in mTNBC. Methods: CEBCC-101 was a retrospective, multicenter real-world study including 178 patients treated with first-line P+C for mTNBC across 20 centers in Poland, the Czech Republic and Slovakia. Treatment-emergent thyroid dysfunction was the primary exposure of interest. Endpoints included progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Survival was estimated using Kaplan–Meier methods and compared with the log-rank test; categorical outcomes were compared using chi-squared or Fisher’s exact tests. A p value < 0.05 was considered statistically significant. Results: Treatment-related thyroid dysfunction occurred in 34 patients (19.1%), including hypothyroidism in 28 (15.7%) and hyperthyroidism in 6 (3.4%). The median onset was cycle 4 (range 1-10). All events were grade 1 (n = 7, 21%) or grade 2 (n = 27, 79%). Median OS was 20.4 months in patients without thyroid dysfunction versus 19.5 months in those with any thyroid dysfunction (log rank p = 0.863), and median PFS was 8.4 versus 9.0 months, respectively (p = 0.567). ORR did not differ between groups (53.47% vs 58.82%, p = 0.61). Exploratory analyses by thyroid dysfunction type, grade and time of onset showed no statistically significant differences in survival or response outcomes. Conclusions: The real-world frequency of thyroid dysfunction in this study closely aligned with data from KEYNOTE-355 trial. Although thyroid irAEs have been linked to improved outcomes in several malignancies, evidence in advanced breast cancer is limited. Prior data suggest a positive association between pembrolizumab-related thyrotoxicosis and pathologic complete response in early-stage TNBC treated with neoadjuvant P+C. In contrast, in this real-world cohort of mTNBC, treatment-emergent thyroid dysfunction was not associated with better outcomes. These findings indicate that, in first-line P+C for mTNBC, thyroid dysfunction should be interpreted with caution and should not serve as a robust on-treatment surrogate of benefit. Since irAEs are time-dependent exposures, future confirmatory analyses should address the potential impact of event timing on outcome estimates.