图解ASCO19 day5 / 开普饭

最后半天的内容，主要是MGAH22、Neratinib和Pyrotinib的内容，一年一度的ASCO大会结束了，这是一次团结的大会，这是一次胜利的大会，这是一次继往开来的大会。

昨天合作方的供稿再发一遍，因为他们说格式不对，真是白瞎了我的好图（多图版 checkmate-040 update，因为本人一贯奉行无图言D），欢迎阅读，另外也没说给qian，大家出个主意该怎么要。

从明天开始停更，这几天累的跟牲口一样，最后端午节即将来临，给大家拜个晚年，月饼一定要吃吃小龙虾馅儿的！节后正常。

本次ASCO系列报道

首先放下CARsgen的CLDN18.2 CAR-T

苦于没有CLDN18.2 CAR-T的更多数据，该团队先前研究可以点击去年的推送：科济生物展示CAR-Claudin18.2-T数据及最新文献

Tips:

1) GC中CLDN18.2 阳性的比例

A total of 298 GC/GEJ tissue samples (North America, n = 100; Asia, n = 100; Europe, n = 98) were assessed; 148 (50%) were histologically classified as intestinal, 123 (41%) diffuse, 18 (6%) mixed, and 9 (3%) other. In American samples, intestinal histology was the most prevalent; diffuse and intestinal were similar within Asian and European samples. Of the 286 evaluable samples, 30% (n = 86/286) were CLDN18.2^high (moderate-to-strong CLDN18.2 membrane staining in ≥75% of tumor cells). CLDN18.2^highprevalence ranged from 24% (n = 22/92) in Asian samples to 34% (n = 33/97) in American samples. CLDN18.2^high prevalence was 30% (n = 35/115) in diffuse and 28% (n = 40/145) in intestinal subtypes. HER2+ and PD-L1+ (≥1% membrane-stained tumor cells) occurred in 10% (n = 29/291) and 37% (n = 107/289) of the evaluable samples, respectively. Of CLDN 18.2^high samples with evaluable status for HER2, CLDN18.2 overlapped with HER2 in 12% (n = 10/83) of cases.

2) NCT01197885 ：anti-CLDN18.2 mAb IMAB362后线治疗GC/GEJC的单臂二期

54 patients were included in this study: 4 patients received 300 mg/m2 and 50 patients 600 mg/m2. The median age was 62 (range 45–66) years in the 300 mg/m2 and 60 (range 35–77) years in the 600 mg/m2 dose group. More than 50% of patients had received chemotherapy in the 6 months preceding this study. The full analysis set comprised 40 patients (all in 600 mg/m2 group) including 9 patients who continued to receive IMAB362 following the study period. The response rate was 10% and the disease control rate was 30% (best observed response: PR, n = 4 and SD, n = 8). Median PFS was 102 days (95% CI, 70–146 days). All observed adverse events were of grade 1–3, adverse events of grade 4/5 did not occur. Nausea and vomiting were the most common study drug-related adverse events in 31 (n = 8 with grade 3 nausea) and 27 (n = 13 with grade 3 vomiting) of 54 patients, respectively. PK supports 3-weekly IV dosing.

3) NCT01630083：anti-CLDN18.2 mAb IMAB362+化疗对比化疗一线治疗GC/GEJC的二期，目前三期正在进行中

686 pts were assessed for CLDN18.2, 334 tumors (48%) were positive per protocol criteria, most with homogenous expression. 161 pts (44% diffuse, 33% intestinal) were randomized into arms 1 and 2, 116 pts had 2+/3+ CLDN18.2 staining in ≥ 70% of tumor cells.

IMAB362 plus EOX consistently improved PFS (median 4.8 v 7.9 mon; HR 0.47; 95% CI 0.31–0.70, p = 0.0001), OS (8.4 v 13.2 mon; HR 0.51, 95% CI 0.36–0.73, p = 0.0001) and ORR (28% vs 43%) compared to EOX.

IMAB362-related adverse events included vomiting, neutropenia, and anemia, mostly of NCI-CTC grade 1 or 2. Grade 3/4 events were not significantly increased by IMAB362.

下面正式开始今天的推送，看几家HER2+ MBC的后线治疗

第一个是MGAH22的SOPHIA研究，slides下载链接：

http://ir.macrogenics.com/static-files/75942c0b-c6df-49ac-b502-19fed2993d2

之前的两次相关推送

研究背景：晚期HER2+ BC在包括trastuzumab+pertuzumab+化疗的一线和T-DM1的二线后的选择很少，一般是化疗+trastuzumab±lapatinib，也就是trastuzumab联合各类不同的化疗

MGAH22的差异化设计：通过Fc的改造提升对增强型FcγR的亲和力，降低对抑制型FcγR的亲和力

相关细节可以阅读 ASCO19 Abs 第二番

临床前的数据也证明改造后的MGAH22可以增强携带CD16A-158F等位基因的NK细胞的细胞毒作用

相关细节可以阅读 ASCO19 Abs 第二番

研究设计与基线情况：

SOPHIA研究入组了先前重度治疗的群体——至少2轮抗HER2治疗（基线显示全部患者之前接受过trastuzumab和pertuzumab，90%以上接受过T-DM1），随机分组分别接受MGAH22+化疗和Trastuzumab+化疗，主要终点是PFS和OS（统计假设略）。

先看主要终点CBR评估的ITT 群体PFS，MGAH22+化疗相比trastuzumab+化疗降低了24%的疾病进展风险，中位PFS 5.8 vs 4.9 mo，有不到1mo的延长，但是之前的统计学预设：PFS(by CBA; n=257; HR=0.67; α=0.05; power=90%)，这个结果我也很为难

次要终点：研究者评估的ITT群体的PFS 5.6 vs 4.2 mo，降低了30%的疾病进展风险。。。

PFS的亚组分析：绝大多数分组都能从MGAH22中获益

下面是探索性终点：基于不同FcγR基因型的PFS分析

首先是主要的激活型FcγR CD16A，只有携带158F才会从MGAH22中获益，而VV型更偏向trastuzumab
激活型的CD32A和抑制型的CD32B的所有类型均能从MGAH22中获益

18年10月份的内部分析显示，另一个主要终点ITT群体的OS曲线并没有区分开，而在CD16A-158F群体中，MGAH22也只是在~15个月的时候开始甩开trastuzumab，还需要等成熟后做最终的OS分析

不过我觉得基本没什么luan用了

ORR 22.1% vs 16.0% 在统计学上没有差异

CBR 36.6% vs 24.8% MGAH22组有优势

AE基本一致，毕竟两者差异并不大

具体的不良事件上的差异，应该更多是化疗的影响

总结：几个点前面基本都提到了，反正吧，多说也无益

第二个是Neratinib的NALA研究，对应的也是≥3线患者，slides下载链接如下：

http://www.pumabiotechnology.com/docs/June%204%202019%20ASCO%202019%20Puma%20NALA%20slides.pdf

根据摘要

患者1：1随机入组到Nera+Cape或者Lapa+Cape，共同主要终点中心检测的OS和PFS，次要终点研究者检测的PFS、ORR、DoR、CBR、至CNS转移症状时间、安全性事件等

入组621名患者，307和314名随机分配至N+C和L+C。相比L+C，N+C降低了24%的疾病进展和死亡风险(HR = 0.76; 95% CI 0.63–0.93; p = 0.006)，6mo和12mo PFS对比分别47.2% vs 37.8% 和28.8% vs 14.8% 。而6mo和12mo的OS分别 90.2% vs 87.5% and 72.5% vs 66.7% (HR = 0.88; 95% CI 0.72–1.07; p = 0.2086)。另外相比L+C，N+C的次要终点均有有提升，ORR 2.8% vs 26.7%(p = 0.1201)， CBR2.8% vs 26.7%(p = 0.1201)，DoR (HR = 0.50; 95% CI 0.33–0.74; p = 0.0004)。另外在至中枢神经转移症状出现时间上，N+C的发生率也低于L+C：22.8% vs 29.2%; p = 0.043，发生得到延迟。两组间TEAEs相似，但是N+C组≥3级腹泻更高24.4% vs 12.5%，另外因TEAEs引起的治疗终止也上N+C更低 10.9% vs 14.5%。