A Randomized Phase II Study of Combination Atezolizumab and Varlilumab (CDX-1127) with or without Cobimetinib in Previously Treated Unresectable Biliary Tract Cancer.

Although MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy.

尽管MEK抑制剂可能增加肿瘤细胞的免疫原性，但它们可能会损害T细胞的启动/效应功能，限制了联合治疗的效果。

We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance antitumor immunity in this combination.

我们假设添加CD27激动剂可以恢复T细胞功能，并增强这种组合中的抗肿瘤免疫。

patients_and_methods

We conducted a randomized, phase II trial evaluating atezolizumab (840 mg, intravenously, days 1 and 15) in combination with the CD27 costimulatory monoclonal antibody [CDX-1127/varlilumab (3 mg/kg, intravenously, days 1 and 15)], with/without the addition of an MEK inhibitor [cobimetinib (60 mg, orally, daily, days 1-21, off days 22-28)] in unresectable biliary tract cancer following at least one metastatic therapy.

我们进行了一项随机、II期试验，评估了在至少接受过一种转移治疗后的不可切除胆道癌患者中，使用阿替利珠单抗（840毫克，静脉注射，第1天和第15天）联合CD27共刺激单克隆抗体[CDX-1127/瓦利鲁单抗（3毫克/公斤，静脉注射，第1天和第15天）]，有无MEK抑制剂[科比特尼布（60毫克，口服，每日，第1-21天，停药日22-28天）]的疗效。

Overall response rate (ORR) and PFS were coprimary endpoints.

总体反应率(ORR)和无进展生存期(PFS)是共同的主要终点。

Treatment-related changes in CD8+ tumor-infiltrating lymphocytes (TIL) were the primary correlative outcomes.

治疗相关的CD8+肿瘤浸润淋巴细胞(TIL)变化是主要的相关结果。

Results

The trial was closed early following interim preplanned ORR analysis.

在中期预先计划的ORR分析后，试验提前关闭。

At closure, 57 patients had been enrolled [n = 29 in the cobimetinib + atezolizumab + varlilumab (CAV) arm; n = 28 in the atezolizumab + varlilumab (AV) arm].

在试验结束时，共有57名患者入组[n=29在科比特尼布+阿替利珠单抗+瓦利鲁单抗(CAV)组；n=28在阿替利珠单抗+瓦利鲁单抗(AV)组]。

A majority (67%) had intrahepatic cholangiocarcinoma, and 32% were immunotherapy experienced.

大多数患者（67%）患有肝内胆管癌，32%的患者有免疫治疗经验。

Both regimens were well tolerated without new safety signals.

两种治疗方案都耐受性良好，没有出现新的安全信号。

Objective responses were rare [0% (CAV); 3.8% (AV)].

客观反应很少见[0%（CAV）；3.8%（AV）]。

The median PFS (mPFS) was 2.40 (CAV) and 1.84 (AV) months [hazard ratio(HR), 0.67; 95% confidence interval(CI), 0.38-1.18].

中位无进展生存期（mPFS）为2.40个月（CAV）和1.84个月（AV）[风险比（HR），0.67；95%置信区间（CI），0.38-1.18]。

Among immunotherapy-experienced patients, the mPFS was 3.62 (CAV) and 1.84 (AV) months (HR, 0.54; 95% CI, 0.18-1.62).

在有免疫治疗经验的患者中，mPFS为3.62个月（CAV）和1.84个月（AV）（HR，0.54；95% CI，0.18-1.62）。

Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV.

与AV治疗相比，CAV治疗增加了肿瘤内CD8+ T细胞密度。

Conclusions

The combinations of atezolizumab and varlilumab with/without cobimetinib were safe, but neither meaningfully improved outcomes in biliary tract cancer treated in the later lines.

阿替利珠单抗和瓦利鲁单抗与/不联合科布美替尼的组合是安全的，但对晚期胆道癌的治疗结果没有实质性改善。

Correlative tissue studies validated preclinical work that MEKi increases CD8+ TILs.

相关组织研究验证了MEKi增加CD8+ TILs的临床前工作。