下午四点的两个LBA，GEMSTONE-302和ORIENT-32，同时截图如下
LBA4 - GEMSTONE-302: A phase III study of platinum-based chemotherapy (chemo) with placebo or CS1001, an anti-PDL1 antibody, for first-line (1L) advanced non-small cell lung cancer (NSCLC) (ID 415)
CS1001, a full-length, fully human PD-L1 targeted IgG4 (s228p) mAb, was well tolerated and had demonstrated promising anti-tumor activities across a range of cancers including NSCLC in phase Ia/Ib study. GEMSTONE-302 is a randomized, double-blind, phase III study to compare the efficacy and safety of chemo with or without CS1001 as 1L treatment for advanced NSCLC.首个PD-L1单抗联合化疗治疗sq及nsqNSCLC的随机双盲临床3期俺就
Eligible pts with untreated advanced NSCLC were stratified by histology (sq vs nsq), PD-L1 expression (≥1% vs <1%), and ECOG PS (0 vs 1) and randomized 2:1 to receive CS1001 (1200 mg, Q3W, IV)/placebo + chemo up to 4 cycles, followed by CS1001 or placebo maintenance up to 2 yrs. In nsq pts, pemetrexed was also given as maintenance therapy. The primary endpoint is investigator-assessed PFS (RECISIT v1.1).未接受化疗的Stage IV NSCLC按照2:1随机分配到Sugemalimab+化疗组及安慰剂+化疗组（nsq化疗方案为卡铂+培美曲塞，sq化疗方案为卡铂+紫杉醇），Q3W 4个疗程后进入维持治疗阶段至多35个疗程：其中nsq分别接受Sugemalimab+培美曲塞或安慰剂+培美曲塞，而sq接受Sugemalimab或安慰剂，安慰剂组如果进展可以交叉接受Sugemalimab至35个疗程主要终点 研究者评估的PFS，分层因素包括组织分型、PD-L1表达、EGOG PS评分
·
Results
A total of 479 pts (320 in CS1001+chemo, 159 in placebo+chemo) were enrolled in the study. Baseline characteristics were balanced between 2 arms.
As of 8 Jun 2020, at the pre-planned PFS interim analysis (median follow-up 8.67 vs 8.34 mo), the mPFS was significantly prolonged in the CS1001+chemo arm (stratified HR 0.50 [0.39-0.64], p<.0001; mPFS 7.8 vs 4.9 mo).
主要终点研究者评估的PFS 7.82 vs 4.90 mo HR 0.50 ，Sugemalimab降低了50%的进展或死亡风险
BIRC评估的PFSL8.90 vs 4.93mo，Sugemalimab降低了46%的进展或死亡风险
不管PD-L1表达，Sugemalimab都能降低进展或死亡风险，延长PFS
PD-L1 TPS≥1%，PFS 8.90 vs 4.90 mo HR 0.42PD-L1 TPS＜1%，PFS 6.97 vs 4.93 mo HR 0.66
不管组织分型，Sugemalimab都能降低进展或死亡风险，延长PFS
鳞癌中 PFS 7.16 vs 4.70 mo HR 0.33非鳞癌 PFS 8.57 vs 5.16 mo HR 0.66
OS data was immature, but a clinical benefit trend was observed, (stratified HR 0.66 [0.44-0.97]; mOS NR vs 14.75 mo). OS数据尚未成熟，但是已经可以观察到临床获益的趋势
Subgroup analyses demonstrated clinical benefits across histology and PD-L1 expression levels. PFS亚组分析显示，几乎所有亚组都能从Sugemalimab中获益
ORR was 61.4% and 39.2% in CS1001+chemo and placebo+chemo arms, respectively.
ORR 61.4% vs 39.2%，DoR 9.69 vs 3.68mo
不管PD-L1表达还是组织分型，Sugemalimab都能带来ORR的提升PD-L1 TPS＜1% 50.0% vs 39.1%；PD-L1 TPS 1-49% 66.7% vs 35.4%；PD-L1 TPS≥50%，ORR 70.6% vs 43.5%
Grade ≥3 TEAEs were reported in 61.9% and 61.6% of pts in CS1001+chemo and placebo+chemo arms, respectively. The 2 arms had similar safety profile, with the exception of mostly Grade 1 and 2 immune-related AEs in CS1001+chemo arm. No new unexpected safety signals were found.
Conclusions
This is the first phase III trial conducted in China on an anti-PD-L1 mAb plus chemo that enrolls advanced, treatment-naive sq and nsq NSCLC pts. CS1001 combined with chemo shows statistically significant and clinically meaningful benefit in PFS with a well-tolerated safety profile against chemo across histology and PD-L1 expression levels. It will potentially become a new SOC for 1L treatment of advanced NSCLC once receiving regulatory approval.
Clinical trial identification NCT03789604.
后面的DISCUSSION
整体上看下来，趋势上就是非鳞不如189(HR 0.66 vs HR 0.49)但鳞癌好于407(HR 0.33 vs HR 0.57)，中国的鳞癌太amazing了
LBA2 - Sintilimab plus bevacizumab biosimilar vs sorafenib as first-line treatment for advanced hepatocellular carcinoma (ORIENT-32)2 (ID 523)
Background
ORIENT-32 is a randomized, open-label, multi-center phase II/III study to evaluate the efficacy and safety of sintilimab (anti-PD-1 antibody) plus a bevacizumab biosimilar (anti-VEGF antibody), versus sorafenib as first-line treatment for advanced hepatocellular carcinoma (HCC). The phase II part has demonstrated an acceptable safety of this combination. Here we report the result of phase III part (NCT03794440).
Atezolizumab联合Bevacizumab相比索拉非尼已经在uHCC中证明带来显著的OS获益，ORIENT-32旨在评估Sintilimab联合Bevacizumab对比索拉非尼治疗不可手术的或转移未接受过系统治疗的HCC的疗效及安全性，之前Phase 2 run-in部分已经证明了初步疗效。
Methods
Patients (pts) with unresectable or metastatic, systemic treatment naive HCC were enrolled and randomized (2:1) to receive sintilimab (200 mg IV Q3W) plus bevacizumab biosimilar (15 mg/kg IV Q3W) (SinBev arm) or sorafenib (400 mg orally, BID) (Sor arm). Stratification factors were macrovascular invasion and/or extrahepatic metastasis (presence vs absence), baseline alpha fetoprotein level (< 400 vs ≥400 ng/mL) and ECOG PS (0 vs 1). The primary endpoints were OS and PFS by independent radiographic review committee (IRRC) per RECIST 1.1.不可手术或者转移且未接受过系统治疗的HCC患者按照2:1随机分配到Sintilimab+Bevacizumab和索拉非尼组治疗直至PD或不可耐受的毒性主要终点OS和独立影像委员会即iRRC基于RECIST v1.1标准评估的PFS，次要终点包括基于RECIST v1.1标准评估的PFS、iRRC基于RECIST v1.1及HCC mRECIST标准评估的ORR分层因素包括：有无大血管侵犯 and/or 肝外转移、基线AFP水平及ECOG PS评分
统计上双侧检验α=0.05，主要终点PFS最终分析α=0.002、OS 第一次期中分析α=0.0035
Results
As data cutoff date (Aug 15, 2020), 571 pts were enrolled to SinBev arm (n=380) and Sor arm (n=191). The baseline characteristics were well balanced between two arms, with most pts had hepatitis B infection (94.2%) and 4.2% of pts with Child-Pugh B. With a median follow-up of 10.0 m, median OS was significantly longer in SinBev arm than that in Sor arm (NE vs. 10.4 m, HR 0.57, 95%CI: 0.43-0.75, P<0.0001). Median PFS was significantly improved in SinBev arm as compared with Sor arm (4.5 m vs. 2.8 m, HR 0.57, 95%CI: 0.46-0.70, P<0.0001). The superior OS and PFS benefits with SinVev over Sor were generally consistent across all relevant subgroups. Among pts with evaluable tumor assessment at baseline, the confirmed ORR by IRRC per RECIST 1.1 was 20.3% (74/364, 95%CI: 16.3%-24.8%) in SinBev arm and 4.1% (7/172, 95%CI: 1.7%-8.2%) in Sor arm. Of pts receiving at least one drug dose, the incidences of treatment related adverse events were 88.7% in SinBev arm (n=380) and 93.5% in Sor arm (n=185). Grade 3-4 TRAEs occurred in 33.7% and 35.7% of pts, respectively.中位年龄-53，基线AFP≥400ng/mL占-43%，ECOG PS 1分的过半 -51%，BCLC分期C占-85%，Child-Pugh B的~4%，MVI and/or EHS的占-79%，HBV 感染的~94%，先前接受过TACE治疗的！66%
主要终点OS：Sin+Bev降低了43%的死亡风险，显著延长OS NE vs 10.4mo p＜0.0001 HR 0.569，1年OS 62.4% vs 48.5%
共同主要终点IRRC-PFS：Sin+Bev降低了43.5%的死亡或进展风险，显著延长PFS 4.6 vs 2.8mo p＜0.0001 HR 0.565，6mo/9mo PFS 43.6%/32.7% vs 19.5%/11.6%
OS亚组分析显示几乎所有亚组都能从Sin+Bev中获益
OS亚组分析显示也是几乎所有亚组都能从Sin+Bev中获益
安全性方面持续治疗时间 6.6-7mo vs 3.5mo，治疗疗程中位值 8 vs 3Gr3-4的TRAE 33.7% vs 35.7%，治疗相关的SAE 17.1% vs 10.3%，因TRAE引起的死亡1.6%vs1.1%，因TRAE引起的治疗终止 13.7% vs 5.9%
具体的常见AE基本都是1-2级，Sin+Bev组≥Gr3 AE占比＞10%的只有高血压，其余主要≥Gr3 AE：血小板降低、蛋白尿、胆红素升高、甲减及AST升高、腹泻
在可评估ADA的患者中，只有3.3%的患者TEADA阳性
另外新冠疫情也会临床有所影响，Sin+Bev组受影响更高一些36.8% vs 19.5%，其中给药推迟26.1% vs 8.6%，影像学评估 23.4% vs 15.1%
Conclusions
Sintilimab plus bevacizumab biosimilar as first-line treatment was associated with significantly improved clinical benefits than sorafenib in pts with advanced HCC.
Clinical trial identification NCT03794440.和IMBrave150的Global及中国患者部分比较下
OS NR vs 13.2mo HR 0.58
PFS 6.8 vs 4.3mo HR 0.59
OS NR vs 11.4mo HR 0.44
Among Chinese patients, Tecentriq in combination with Avastin reduced the risk of death (OS) by 56% (hazard ratio [HR]=0.44; 95% CI: 0.25–0.76) and reduced the risk of disease worsening or death (PFS) by 40% (HR=0.60; 95% CI: 0.40–0.90), compared with sorafenib. Tecentriq and Avastin were generally well-tolerated with manageable toxicities, and the safety profile was consistent with the known safety profiles of the individual medicines and with the underlying disease.
尽管global两组间还算平衡，但是中国患者两组间在一些基线特征上还是有5-10%的偏差
Global随访8.6mo OS NR vs 13.2mo HR 0.58中国患者随访6.8mo OS NR vs 11.4mo HR 0.44
Global随访8.6mo PFS 6.8 vs 4.3mo HR 0.59中国患者随访6.8mo PFS 5.7 vs 3.2mo HR=0.60
Global ORR per RECIST 1.1 27% vs 12%，DoR NE vs 6.3mo中国患者 ORR per RECIST 1.1 25% vs 7%Global ORR per IRF HCC mRECIST 33% vs 13%，DoR NE vs 6.3mo中国患者 ORR per IRF HCC mRECIST 30% vs 8%
所以考虑基线、COVID-19等因素，Sin+Bev和Atezo+Bev在中国患者没有太本质的差别，都已经将各自和Bev发挥到了极致，接下来就是箪食壶浆 翘首盼王师
中午卫星会
Optimising the immune response: exploring high-dose priming with
anti-CTLA-4 therapy in unresectable HCC
Recent advances in the treatment of unresectable HCC
