给免疫治疗“增效”但不“减毒”的辅助药物（二）：普萘洛尔

《Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity》
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Purpose: Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma.
Patients and methods: A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months.
% \) R5 b. }) e8 tResults: Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders.
Conclusions: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.
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: I% M/ A& n9 Z, U& @3 h0 e+ D: A这是个一期临床试验，试验结果确定了二期普洛萘尔联合K药的剂量是 Propranolol 30 mg twice a day。
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6 k$ a5 g, w: p5 a# G8 V这个一期临床的ORR是78%，平均15.6个月的随访，尚未达到PFS和OS的中值。
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这篇论文说，按照 《Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study》这篇论文说，晚期黑色素瘤首用K药的ORR是46%,中位PFS为11.6个月。
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因此普萘洛尔+K药相比K药单药，ORR和PFS都是有显著改善的（OS中位期还未到无法比较）。
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当然也因为普萘洛尔+K药这个一期试验的人数比较少，只有9个患者；患者人数上去以后，ORR这些未必就能这么高了。
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