Mar Nataliya, Zakharia Yousef, Falcon Alejandro, Morales-Barrera Rafael, Mellado Begona, Duran Ignacio, Oh Do-Youn, Williamson Stephen K, Gajate Pablo, Arkenau Hendrik-Tobias, Jones Robert J, Teo Min Yuen, Turan Tolga, McLaughlin Robert T, Peltier Hillary M, Chong Elizabeth, Atluri Harisha, Dean James P, Castellano Daniel
Division of Hematology/Oncology, University of California Irvine, Orange, CA 92868, USA.
Division of Hematology/Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.
Cancers (Basel). 2023 May 30;15(11):2978. doi: 10.3390/cancers15112978.
Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0-37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC.
依鲁替尼是首个获批用于治疗多种B细胞恶性肿瘤和慢性移植物抗宿主病的布鲁顿酪氨酸激酶抑制剂。我们评估了依鲁替尼单药或联合标准治疗方案，用于晚期尿路上皮癌（UC）成人患者的安全性和疗效。依鲁替尼每日一次口服给药，剂量为840mg（单药或联合紫杉醇）或560mg（联合帕博利珠单抗）。1b期确定了依鲁替尼的推荐2期剂量（RP2D），2期评估无进展生存期（PFS）、总缓解率（ORR）和安全性。分别有35例、18例和59例患者接受了RP2D剂量的依鲁替尼、依鲁替尼联合帕博利珠单抗以及依鲁替尼联合紫杉醇治疗。安全性特征与各单药一致。单药依鲁替尼的最佳确认ORR为7%（2例部分缓解），依鲁替尼联合帕博利珠单抗的最佳确认ORR为36%（5例部分缓解）。依鲁替尼联合紫杉醇的中位PFS为4.1个月（范围1.0 - 37.4+）。最佳确认ORR为26%（2例完全缓解）。在既往接受过治疗的UC患者中，依鲁替尼联合帕博利珠单抗的ORR高于单药治疗（意向性治疗人群的历史数据）。依鲁替尼联合紫杉醇的ORR高于单药紫杉醇或依鲁替尼的历史值。这些数据表明有必要进一步评估依鲁替尼联合方案用于UC的疗效。
