Trabectedin-olaparib combination or trabectedin in advanced soft tissue sarcomas after failure of anthracycline-based treatment (TOMAS2): a randomized phase II study from the Italian Sarcoma Group.

We previously reported the feasibility and preliminary activity of trabectedin-olaparib combination in patients with advanced STS progressing after anthracycline-based regimens.

我们之前报告了在使用蒽环类药物治疗后进展的晚期STS患者中，曲贝替定-奥拉帕利联合治疗的可行性和初步活性。

patients_and_methods

In this investigator-initiated, open-label, phase II randomized trial, adult patients with advanced STS progressing after one or more prior lines of therapy, including at least one anthracycline-based regimen, were randomly assigned 1 : 1 to trabectedin 1.1 mg/m2 every 21 days (q21d) intravenous (i.v.) plus olaparib tablets 150 mg twice a day, or trabectedin 1.5 mg/m2 q21d i.v.

在这项由研究者发起的、开放标签的、II期随机试验中，接受过一次或多次治疗后疾病进展的成人晚期软组织肉瘤（STS）患者，包括至少一种蒽环类药物方案，被随机分配为1:1，一组接受每21天（q21d）静脉注射（i.v.）1.1 mg/m2的曲贝替定加上每日两次口服150 mg的奥拉帕利片剂，另一组接受每21天（q21d）静脉注射（i.v.）1.5 mg/m2的曲贝替定。

Randomization stratified patients by histology (L-sarcoma, i.e. leiomyosarcoma and liposarcoma versus non-L-sarcoma) and number of prior therapies (one versus two or more).

随机分组根据组织学类型（L-肉瘤，即平滑肌肉瘤和脂肪肉瘤与非L-肉瘤）和既往治疗次数（一次与两次或更多）进行分层。

The primary endpoint was progression-free survival(PFS) rate at 6 months (PFS6m) per RECIST1.1.

主要终点是根据RECIST1.1标准评估的6个月无进展生存（PFS）率（PFS6m）

Secondary endpoints included PFS, overall survival(OS), RECIST1.1 overall response rate (ORR), and safety.

次要终点包括无进展生存（PFS）、总生存（OS）、RECIST1.1总体反应率（ORR）和安全性

Exploratory endpoints encompassed biomarker/molecular analyses.

探索性终点包括生物标志物/分子分析。

Results

Between 25 May 2020 and 2 November 2022, 130 patients were enrolled at 13 Italian Sarcoma Group centers (81 female; 67 L-sarcoma; 93 one prior line).

2020年5月25日至2022年11月2日之间，共有130名患者在13个意大利肉瘤组中心入组（81名女性；67名L型肉瘤；93名有一线治疗史）。

With a median follow-up of 37.4 months, PFS6m and median PFS were 32% [95% confidence interval(CI) 22% to 46%] and 3.9 months (95% CI 2.7-5.2 months) with trabectedin-olaparib versus 28% (95% CI 19% to 42%) and 2.9 months (95% CI 2.2-3.6 months) with trabectedin [hazard ratio(HR) 0.722, 95% CI 0.501-1.041, P = 0.081].

在中位随访37.4个月时，接受曲贝替定-奥拉帕利治疗的患者中，6个月无进展生存率（PFS6m）和中位无进展生存期（PFS）分别为32%（95%置信区间[CI] 22%至46%）和3.9个月（95% CI 2.7-5.2个月），而仅接受曲贝替定治疗的患者中，这两个指标分别为28%（95% CI 19%至42%）和2.9个月（95% CI 2.2-3.6个月）[风险比（HR）0.722，95% CI 0.501-1.041，P = 0.081]。

Among 126 assessable patients, ORR was 12.7% (95% CI 6.1% to 22.7%) versus 7.9% (95% CI 3.0% to 16.7%), respectively (odds ratio 1.60, 95% CI 0.50-5.16, P = 0.43).

在126名可评估患者中，曲贝替定-奥拉帕利治疗组的客观缓解率（ORR）为12.7%（95%置信区间[CI] 6.1%至22.7%），而曲贝替定治疗组的ORR为7.9%（95% CI 3.0%至16.7%）[比值比（odds ratio）1.60，95% CI 0.50-5.16，P = 0.43]。

In the uterine leiomyosarcoma subgroup, 12-month PFS was 42.9% with trabectedin-olaparib versus 0% with trabectedin.

在子宫平滑肌肉瘤亚组中，接受曲贝替定-奥拉帕利治疗的患者12个月无进展生存（PFS）率为42.9%，而仅接受曲贝替定治疗的患者为0%。

PARP1 expression significantly correlated with improved PFS with trabectedin-olaparib (PFS6m and median PFS were 41.5% and 4.3 months versus 27.8% and 2.5 months; HR 0.537, 95% CI 0.337-0.855, P = 0.009).

PARP1表达与曲贝替定-奥拉帕利治疗改善无进展生存（PFS）显著相关（6个月PFS和中位PFS分别为41.5%和4.3个月，与27.8%和2.5个月相比；风险比HR为0.537，95%置信区间为0.337-0.855，P值为0.009）。

Grade ≥3 hematological toxicities were significantly more frequent with trabectedin-olaparib.

使用曲贝替定-奥拉帕利的患者中，3级及以上的血液毒性显著更频繁。

Conclusions

Although trabectedin-olaparib combination reached the prespecified threshold for statistical significance for PFS (P < 0.10), the benefit was marginal in the all-comers STS population.

尽管曲贝替定-奥拉帕利联合治疗在无进展生存期（PFS）上达到了预设的统计显著性阈值（P < 0.10），但在所有软组织肉瘤（STS）患者中的获益是边际性的。

Nonetheless, patients affected by PARP1-expressing STS and uterine leiomyosarcoma derived substantial benefit from the combination, supporting further histology- and biomarker-driven investigation in these settings.

尽管如此，PARP1表达的软组织肉瘤（STS）和子宫平滑肌肉瘤患者从这种联合治疗中获得了显著的益处，这支持在这些情况下进行进一步的组织学和生物标志物驱动的调查。