背景：Camrelizumab（抗 PD-1 抗體）和 nab-paclitaxel（nab-P）在免疫調節（IM）亞型轉移性三陰性乳腺癌（TNBC）患者中顯示出良好的抗腫瘤活性，在我們之前的傘式試驗（FUTURE）中，在接受過大量治療的患者中觀察到 52.6%的 ORR。由於已知抗血管生成藥物可增強對免疫檢查點抑製劑的反應，我們評估了 famitinib（靶向 VEGFR-2、PDGFR 和 c-kit 的酪氨酸激酶抑製劑）、camrelizumab 和 nab-paclitaxel 的新型三聯療法在 IM 亞型晚期 TNBC 患者中的有效性和安全性。

Background: Camrelizumab (anti-PD-1 antibody) and nab-paclitaxel (nab-P) have demonstrated promising anti-tumour activity in patients with immunomodulatory (IM) subtype metastatic triple negative breast cancer (TNBC), with 52.6% of ORR observed in heavily pretreated patients in our previous umbrella trial (FUTURE). As antiangiogenic agents were known to enhance the response to immune checkpoint inhibitors, we assessed the efficacy and safety of novel triplet combination of famitinib (tyrosine kinase inhibitor targeting VEGFR-2, PDGFR and c-kit), camrelizumab and nab-paclitaxel in patients with IM subtype advanced TNBC.

方法：在這項前瞻性、單臂、2 期研究中，符合條件的患者年齡為 18-70 歲，接受治療的 IM 亞型不能切除的局部晚期或轉移性 TNBC。免疫組化鑒定 IM 亞型為 CD8+。符合條件的患者接受camrelizumab（200mg iv，d1，15，q4w），nab-P（100mg/m2 iv，d1，8，15，q4w）和 famitinib（20mg po qd，d1-28，q4w）。治療一直持續到疾病進展、患者退出或出現不可接受的毒性反應。在沒有不可耐受毒性的情況下，給予 nab-P 至少 6 個周期。主要終點是根據 RECIST v1.1 判斷的的客觀有效率。我們用 484 個基因的靶向測序來探索預測性生物標誌物。

Methods: In this prospective, single-arm, phase 2 study, eligible patients were 18-70 years and had treatment-naive IM subtype unresectable locally advanced or metastatic TNBC. IM subtype was defined as CD8+ by immunohistochemistry. Eligible patients received camrelizumab (200 mg iv, d1, 15, q4w) with nab-P (100 mg/m2 iv, d1, 8, 15, q4w) and famitinib (20 mg po qd, d1-28, q4w). Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. In the absence of intolerable toxicity, nab-P was to be administered for a minimum of 6 cycles. Primary endpoint was objective response rate according to RECIST v1.1. We explored the predictive biomarkers using targeted sequencing with a 484-gene panel.

結果：從 2019 年 10 月到 2020 年 10 月，共有 48 名患者入選。意向治療人群 48 例中有 39 例（81.3%;95% CI 70.2%-92.3%）獲得了確認的客觀反應；依方案治療人群 46 例患者中有 39 例（84.8%;95%CI 74.4%-95.2%）獲得了確認的客觀反應。中位出現緩解的時間為 1.8 個月 （95% CI 1.8-2.0 個月）。中位隨訪時間為 9.0 個月，無進展生存率（PFS）和反應持續時間數據尚不成熟。30 名患者（62.5%）仍在接受研究治療。9 個月 PFS 率為 60.2%（95%CI，43.2%～77.3%）。3 級或 4級不良事件為中性粒細胞減少（33.3%）、貧血（10.4%）、發熱性中性粒細胞減少（10.4%）、血小板減少（8.3%）、高血壓（4.2%）、甲狀腺功能減退（4.2%）、蛋白尿（2.1%）、敗血症（2.1%）和免疫相關心肌炎（2.1%）。導致停藥的不良事件發生率為 6.3%。兩名患者出現與治療相關的嚴重不良事件。無治療相關死亡報告。生物標誌物分析表明，GSK3A 的體細胞突變可能具有預測免疫治療反應的潛力。

Results: From Oct 2019 to Oct 2020, 48 patients were enrolled. Confirmed objective responses were achieved in 39 (81.3%; 95% CI 70.2%-92.3%) of 48 patients in the intention-to-treat population and in 39 (84.8%; 95% CI 74.4%-95.2%) of 46 patients in the per-protocol population. Median time to response was 1.8 months (95% CI 1.8-2.0 months). With a median follow-up of 9.0 months, progression-free survival (PFS) and duration of response data were not mature. Thirty patients (62.5%) are still on the study treatment. The 9-month PFS rate was 60.2% (95% CI, 43.2% to 77.3%). Grade 3 or 4 adverse events were neutropenia (33.3%), anaemia (10.4%), febrile neutropenia (10.4%), thrombocytopenia (8.3%), hypertension (4.2%), hypothyroidism (4.2%), proteinuria (2.1%), septicemia (2.1%) and immune related myocarditis (2.1%). Adverse events that led to the discontinuation of any agent occurred in 6.3% of the patients. Two patients had treatment-related serious adverse events. No treatment-related deaths were reported. Biomarker analysis showed that somatic mutations of GSK3A may have the potential to predict immunotherapy response.

結論：famitinib 聯合 camriezumab 和 nab-paclitaxel 作為 IM 亞型晚期 TNBC 患者的一線治療具有良好的抗腫瘤活性，且毒性可控。正在進行的隨機對照試驗 FUTURE-SUPER（nct04395989）的結果令人期待。

Conclusions: Addition of famitinib to camrelizumab and nab-paclitaxel showed promising antitumour activity as first-line therapy with manageable toxicity profile for IM subtype advanced TNBC patients. Results from ongoing randomized controlled trial FUTURE-SUPER (NCT 04395989) are eagerly awaited.