A Phase II Feasibility Study Combining Pembrolizumab and Metformin in Patients with Metastatic Head and Neck Cancer.

Metformin increases tumor-infiltrating CD8+ T and natural killer (NK) cells, which harbor PD-1.

二甲双胍可以增加肿瘤浸润的CD8+ T细胞和自然杀伤（NK）细胞，这些细胞携带有PD-1。

In this phase II clinical trial (NCT04414540), we combined metformin and pembrolizumab to evaluate the overall response rate (ORR) in R/M HNSCC and assess NK-cell activity.

在这项II期临床试验（NCT04414540）中，我们将二甲双胍和派姆单抗联合使用，以评估R/M HNSCC的总体反应率（ORR）并评估NK细胞的活性。

patients_and_methods

Eligible patients were randomized 1:1 into two arms: (i) metformin extended-release (ER) dose escalation to 2,000 mg over 14 days followed by combination with pembrolizumab 200 mg every 3 weeks or (ii) pembrolizumab 200 mg every 3 weeks followed by combination with metformin ER 2,000 mg daily.

符合条件的患者被随机分为两组：(i) 二甲双胍缓释（ER）剂量逐渐增加至2000 mg，持续14天，然后与每3周一次的派姆单抗200 mg联合使用，或(ii) 每3周一次的派姆单抗200 mg，然后与每天2000 mg的二甲双胍ER联合使用。

The primary endpoint was ORR per RECIST 1.1.

主要终点是根据RECIST 1.1评估的ORR。

Nineteen evaluable patients were planned to estimate the proportion of approximately 32% ORR.

计划对19名可评估患者进行评估，以估计大约32%的ORR比例。

Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0.

安全性是根据不良事件通用术语标准v5.0进行评估的。

The distribution, activation, and cytotoxic function of NK cells were analyzed via flow cytometry.

通过流式细胞术分析NK细胞的分布、激活和细胞毒性功能。

Results

Twenty-one patients were enrolled; 76% were male, 52% were smokers, and the median age was 64 years.

共有21名患者入组；76%为男性，52%为吸烟者，中位年龄为64岁。

Ten patients had oropharyngeal tumors, of which nine were p16+.

10名患者患有口咽部肿瘤，其中9名为p16阳性。

Eighteen patients were evaluable for response, including four complete and five partial responses for an ORR of 50% [95% confidence interval(29-71)].

18名患者可评估疗效，包括4例完全缓解和5例部分缓解，总体缓解率为50% [95%置信区间(29-71)]。

Combination therapy was well tolerated with no unexpected adverse events (AE).

联合治疗耐受性良好，没有出现意外的不良事件(AE)。

Five grade 3 AEs occurred: nausea, diarrhea, fatigue, and weight loss.

发生了5例3级不良事件：恶心、腹泻、疲劳和体重减轻。

Metformin led to increased peripheral NK-cell maturation and cytotoxic ability.

二甲双胍导致外周自然杀伤(NK)细胞成熟度和细胞毒性能力增加。

Conclusions

The combination of metformin and pembrolizumab was well tolerated with mild gastrointestinal AEs and promising activity, warranting further investigation in a randomized trial.

二甲双胍和派姆单抗的联合使用耐受性良好，轻度的胃肠道不良事件和有希望的活性，值得在随机试验中进一步研究。