Abstract

Background

It has been shown that androgens are immunosuppressive. Androgen deprivation with GnRH agonists regenerates the thymus and its functions in adults, leading to increase in blood and lymphoid organ lymphocytes, in naive lymphocytes with expansion of TCR Vbeta repertoire, and in Tumour Infiltrating Lymphocytes (TILs) in prostate tumours. This phase I study evaluated the safety of triptorelin in combination with nivolumab, as well as its potential to reverse resistance to PD-1 inhibitors in male melanoma patients.

Methods

Treatment consisted of triptorelin 3.75 mg i.m. every 4 weeks and nivolumab 3 mg/kg i.v. every 2 weeks. Bicalutamide 50 mg p.o. QD was added for the first 28 days. Evaluation of response was performed after 3 months. Triptorelin PK was assessed and various PDy markers were measured in blood and tumour samples. Planned treatment duration was 48 weeks.

Results

Fourteen male patients were included, of whom 11 were white and 3 were black, with mean age 65 years (range 45-82). At screening 4 were locally advanced while 10 had distant metastases (2 with M1a, 1 with M1b, 6 with M1c and 1 with M1d). Ten patients had cutaneous melanoma, 2 patients had mucosal melanoma, and 2 had an unknown primary. Safety: No grade 4 AEs were reported. Five grade 3 AEs were reported in 4 patients, of which one (abdominal pain) was attributed to triptorelin and resolved after 39 days (causing no treatment interruption as it started on the day treatment was discontinued due to progression), and one (neutropenia) was considered related to nivolumab and resolved following treatment interruption for 14 days. Efficacy: BOR (RECIST 1.1) was assessed as 2 PR, 5 SD, and 7 PD. The two patients with PR showed reductions from baseline in Target Lesions of 76% (one pancreas metastasis) and32% (two inguinal lymph nodes), following an initial pseudoprogression.

Conclusion

The association of triptorelin to nivolumab was well tolerated and yielded partial response in two patients.

Legal entity responsible for the study

Debiopharm International S.A.

Funding

Debiopharm International S.A.

Disclosure

C. Robert: Advisory / Consultancy: Novartis, Bristol-Myers Squibb, MSD, Roche, Sanofi, Amgen, Pierre Fabre. F.J. Lejeune: Honoraria (self): Debiopharm International SA. C. Lebbé: Honoraria (self): Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen, Pierre Fabre, Pfizer, Incyte; Advisory / Consultancy: Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen; Travel / Accommodation / Expenses: Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: Roche, Bristol-Myers Squibb, Novartis ,Amgen; Advisory / Consultancy: Aventis. T. Lesimple: Research grant / Funding (self): Roche; Advisory / Consultancy: MSD, Novartis, Pierre Fabre. E. Lundström: Full / Part-time employment: Debiopharm International SA. V. Nicolas: Full / Part-time employment: Debiopharm International SA. B. Gavillet: Full / Part-time employment: Debiopharm International SA. V. Grégoire: Full / Part-time employment: Debiopharm International SA. P. Crompton: Full / Part-time employment: Debiopharm International SA.

中文翻译：

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雷公藤甲瑞林与尼古拉单抗联合120P治疗ICI耐药晚期黑色素瘤

抽象的

背景

已经表明，雄激素具有免疫抑制作用。用GnRH激动剂剥夺雄激素可在成年人中再生胸腺及其功能，从而导致血液和淋巴器官淋巴细胞，TCR Vbeta组成扩展的幼稚淋巴细胞以及前列腺肿瘤中的肿瘤浸润淋巴细胞（TILs）增多。这项I期研究评估了曲普瑞林与nivolumab联用的安全性，以及其逆转男性黑色素瘤患者对PD-1抑制剂耐药性的潜力。

方法

治疗包括每4周一次3.75 mg曲普瑞林和每2周一次3 mg / kg的nivolumab。在最初的28天中加入比卡鲁胺50 mg口服QD。3个月后进行反应评估。对曲普瑞林PK进行了评估，并在血液和肿瘤样本中测量了各种PDy标记。计划的治疗时间为48周。

结果

包括14名男性患者，其中11名是白人，3名是黑人，平均年龄为65岁（范围45-82）。筛查时有4例局部转移，而10例有远处转移（M1a 2例，M1b 1例，M1c 6例，M1d 1例）。皮肤黑素瘤10例，粘膜黑素瘤2例，原发性不明2例。安全性：未报告4级AE。在4例患者中报告了5例3级AE，其中1例（腹部疼痛）归因于曲普瑞林并在39天后消退（由于进展而中断治疗，因此从治疗开始当天就没有治疗中断），而1例（中性粒细胞减少症）被认为与nivolumab有关，并在中断治疗14天后得到解决。功效：BOR（RECIST 1.1）被评估为2 PR，5 SD和7 PD。

结论

曲普瑞林与nivolumab的关联被很好地耐受，并且在两名患者中产生了部分反应。

负责研究的法人实体

Debiopharm International SA

资金

Debiopharm International SA

揭露

罗伯特（C. Robert）：咨询/顾问：诺华，百时美施贵宝，MSD，罗氏，赛诺菲，安进，皮埃尔·法布尔。FJ Lejeune：Honoraria（个体）：Debiopharm International SA。C.Lebbé：Honoraria（自己）：Roche，Bristol-Myers Squibb，诺华，MSD，Amgen，Pierre Fabre，Pfizer，Incyte；咨询/顾问：罗氏（Roche），百时美施贵宝（Bristol-Myers Squibb），诺华（Novartis），医学博士，安进（Amgen）；旅行/住宿/费用：布里斯托尔-迈尔斯·斯奎布（MSD）；发言人办公室/专家证词：罗氏，百时美施贵宝，诺华，安进；咨询/顾问：Aventis。T. Lesimple：研究资助/资助（个体经营）：Roche；咨询/顾问：MSD，诺华，Pierre Fabre。E.Lundström：全职/兼职：Debiopharm International SA。V. Nicolas：全职/兼职：Debiopharm International SA。B. Gavillet：全职/兼职：Debiopharm International SA。V.格雷戈尔：全职/兼职：Debiopharm International SA。P. Crompton：全职/兼职：Debiopharm International SA。