A phase 3, multicenter, open, randomized controlled clinical study of gemcitabine plus capecitabine versus gemcitabine plus carboplatin in the first-line treatment for advanced triple-negative breast cancer.
Authors: Liu Xiaodong , Zhao Weipeng , Jia Yongsheng , Shi Yehui , Wang Xu , Li Shufen , Wang Chen , Hao Chunfang , Tong Zhongsheng 
Published: June 2022

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Background: Gemcitabine plus capecitabine (GX) regimen is still lack of phase Ⅲ clinical trial evidence for the first-line treatment of advanced triple-negative breast cancer (TNBC). We designed this phase Ⅲ trial to compare the efficacy and safety of GX with gemcitabine plus carboplatin (GC) in patients with advanced TNBC. We also explored the correlation between tumor infiltrating lymphocytes (TILs) and the prognosis in TNBC treated with different chemotherapy regimen. Methods: Patients with advanced TNBC were randomly assigned to receive gemcitabine (1,000 mg/m2) on days 1 and 8 plus oral capecitabine (1,000 mg/m2 twice a day) on days 1 through14; or, to receive gemcitabine (1,000 mg/m2) on days 1 and 8 plus carboplatin (AUC = 2) on days 1 and 8. The primary end point was progression free survival (PFS), and secondary end points were objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and safety. Immunohistochemistry was performed with antibodies against CD3, CD4, CD8, and CD 19 antigens on tissue sections of 52 TNBC patients. The margin used to establish non-inferiority was 1.2. This study is registered on Clinical Trials.gov, number NCT02207335. Results: From Jan 2014, to Dec 2020, 187 patients underwent eligibility assessment and were randomly assigned (93 in GX and 94 in GC). The ORRs in GX arm and GC arm were 37.6%, and 39.4%, respectively ( P = 0.808). The CBRs in GX arm and GC arm were 78.5% and 79.8%, respectively ( P = 0.828). Median PFS was 6.1 months for GX arm compared with 6.3months for GC arm (log-rank P = 0.348; HR = 1.148, 95% CI: 0.856 to 1.539, P = 0.357). The median OS in GX arm and GC arm was 21.0 months and 21.5 months, respectively (log-rank P = 0.992; HR = 1.002, 95% CI: 0.717 to 1.400, P = 0.992). Hematologic adverse events (AEs) were commonly observed in both arms, especially in GC arm. Non-hematological AEs such as hand-foot syndrome, diarrhea, and peripheral sensory neuropathy were more common observed in GX arm, while alopecia, nausea, vomiting, fatigue, decreased appetite, infusion related reaction, and hyperglycemia were more common in GC arm. Patients with high CD8+ TILs had a significantly longer PFS (HR = 0.559; 95% CI: 0.314 to 0.993, P = 0.047) and OS (HR = 0.436; 95% CI: 0.226 to 0.843, P = 0.014) compared with patients with low CD8+ TILs. In the high CD8+ group，patients treated with GC had prolonged PFS (HR = 0.322; 95% CI: 0.127 to 0.816, P = 0.017) and OS (HR = 0.300; 95% CI: 0.094 to 0.957, P = 0.042) compared with GX. Conclusions: The trial did not meet the prespecified criteria for the primary end point of PFS in the ITT population. Compared with GC, GX demonstrated lower toxicity. Compared to patients with low CD8+ TILs, patients with high CD8+ TILs showed better outcomes, and in these patients, GC regimen could improve survival compared with GX regimen. Clinical trial information: NCT02207335.