Memorial Sloan Kettering Cancer Center, New York, New York.
University of Milan-Bicocca and Istituto Europeo di Oncologia, IRCCS, Milan, Italy.
JAMA Oncol. 2023 Jan 1;9(1):29-39. doi: 10.1001/jamaoncol.2022.5218.
Nonclinical studies suggest that the combination of poly(ADP-ribose) polymerase and programmed cell death 1/programmed cell death-ligand 1 inhibitors has enhanced antitumor activity; however, the patient populations that may benefit from this combination have not been identified.
To evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type.
DESIGN, SETTING, AND PARTICIPANTS: In this pan-cancer tumor-agnostic phase 2b nonrandomized controlled trial, patients with advanced BRCA1/2-altered or ATM-altered solid tumors were enrolled into 2 respective parallel cohorts. The study was conducted from July 2, 2018, to April 12, 2020, at 42 institutions in 9 countries.
Patients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily.
The primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review.
A total of 200 patients (median [range] age, 59.0 [26.0-89.0] years; 132 [66.0%] women; 15 [7.5%] Asian, 11 [5.5%] African American, and 154 [77.0%] White participants) were enrolled: 159 (79.5%) in the BRCA1/2 cohort and 41 (20.5%) in the ATM cohort. The confirmed OR rate was 26.4% (42 patients, including 9 complete responses [5.7%]) in the BRCA1/2 cohort and 4.9% (2 patients) in the ATM cohort. In the BRCA1/2 cohort, responses were more frequent (OR rate, 30.3%; 95% CI, 22.2%-39.3%, including 8 complete responses [6.7%]) and more durable (median duration of response: 10.9 months [95% CI, 6.2 months to not estimable]) in tumor types associated with increased heritable cancer risk (ie, BRCA1/2-associated cancer types, such as ovarian, breast, prostate, and pancreatic cancers) and in uterine leiomyosarcoma (objective response in 3 of 3 patients and with ongoing responses greater than 24 months) compared with non-BRCA-associated cancer types. Responses in the BRCA1/2 cohort were numerically higher for patients with tumor mutational burden of 10 or more mutations per megabase (mut/Mb) vs less than 10 mut/Mb. The combination was well tolerated, with no new safety signals identified.
In this phase 2b nonrandomized controlled trial, neither the BRCA1/2 nor ATM cohort met the prespecified OR rate of 40%. Antitumor activity for the combination of avelumab and talazoparib in patients with BRCA1/2 alterations was observed in some patients with BRCA1/2-associated tumor types and uterine leiomyosarcoma; benefit was minimal in non-BRCA-associated cancer types.
ClinicalTrials.gov Identifier: NCT03565991.
非临床研究表明，聚（ADP-核糖）聚合酶和程序性细胞死亡 1/程序性细胞死亡配体 1 抑制剂的联合具有增强的抗肿瘤活性；然而，尚未确定可能从这种联合治疗中获益的患者人群。
评估avelumab 和 talazoparib 联合治疗致病性 BRCA1/2 或 ATM 改变的患者是否有效，无论肿瘤类型如何。
设计、地点和参与者：在这项泛癌种肿瘤不可知的 2b 期非随机对照试验中，招募了患有晚期 BRCA1/2 改变或 ATM 改变的实体瘤患者，分别进入 2 个平行队列。该研究于 2018 年 7 月 2 日至 2020 年 4 月 12 日在 9 个国家的 42 个机构进行。
患者每 2 周接受 800mg 的 avelumab 和每天 1mg 的 talazoparib。
主要终点是通过盲法独立中心审查确认的按 RECIST 1.1 标准的客观缓解（OR）。
共有 200 名患者（中位[范围]年龄，59.0[26.0-89.0]岁；132[66.0%]为女性；15[7.5%]为亚洲人，11[5.5%]为非裔美国人，154[77.0%]为白人参与者）入组：159 名（79.5%）在 BRCA1/2 队列和 41 名（20.5%）在 ATM 队列。BRCA1/2 队列的确认 OR 率为 26.4%（42 名患者，包括 9 名完全缓解[5.7%]），而 ATM 队列为 4.9%（2 名患者）。在 BRCA1/2 队列中，在与遗传性癌症风险增加相关的肿瘤类型（即 BRCA1/2 相关的癌症类型，如卵巢癌、乳腺癌、前列腺癌和胰腺癌）和子宫平滑肌肉瘤中，反应更频繁（OR 率为 30.3%[95%CI，22.2%-39.3%]，包括 8 名完全缓解[6.7%]）且更持久（中位缓解持续时间：10.9 个月[95%CI，6.2 个月至无法评估]），而在非 BRCA 相关的癌症类型中则不然。在肿瘤突变负担为 10 个或更多突变/兆碱基（mut/Mb）的患者中，BRCA1/2 队列的反应率高于肿瘤突变负担小于 10 mut/Mb 的患者。该联合治疗耐受性良好，未发现新的安全信号。
在这项 2b 期非随机对照试验中，BRCA1/2 队列和 ATM 队列均未达到预设的 40%的 OR 率。在 BRCA1/2 改变的患者中，avelumab 和 talazoparib 的联合治疗观察到一些 BRCA1/2 相关肿瘤类型和子宫平滑肌肉瘤的抗肿瘤活性；在非 BRCA 相关癌症类型中获益极小。
ClinicalTrials.gov 标识符：NCT03565991。
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