【预告】ASCO GI 19 -1

• 1 KEYNOTE-181：Pembrolizumab对比化疗二线治疗晚期食管癌

• 2 Pembrolizumab+trastuzumab联合化疗一线治疗HER+的转移型食管腺癌的2期

• 3 REFLECT研究中接受Lenvatinib治疗患者的OS与ORR分析

• 4 Lonsurf (Trifluridine/Tipiracil)治疗w/o先前胃切除手术的mGC的3期研究 (TAGS)

• 5 【Failed】andecaliximab 对比安慰剂联合mFOLFOX6一线治疗胃癌及胃食管交界处腺癌的GAMMA-1研究

• 6 anlotinib治疗化疗难治的ESCC的随机双盲多中心2期研究

1 KEYNOTE-181: Pembrolizumab对比化疗二线治疗晚期食管癌

https://meetinglibrary.asco.org/record/169377/abstract

背景：晚期食管癌患者在一线化疗后预后交叉，后续治疗选择少。这里展示Pembrolizumab对比研究者选择的化疗作为二线治疗进展或转移型食管鳞癌(SCC)、腺癌及Siewert I型食管胃交界部腺癌的3期KN-181研究。

方法：入组患者按1：1随机分配到Pembrolizumab 200mg Q3W组和研究者选择的化疗组，包括紫杉醇、多西他赛或伊立替康，随机分组按照组织学和地区进行分层。主要临床终点：SCC、PD-L1 CPS≥10%及ITT群体的OS。

结果：628名患者包括401名SCC及222名CPS≥10%进行随机分组。截止至18年10月25日，中位随访时间7.1 mo vs 6.9mo。

在CPS≥10%群体中，Pembrolizumab治疗组的OS显著优于化疗组：9.3 vs 6.7 mo (HR 0.69; 95% CI 0.52-0.93; P=0.0074)。该群体12个月OS率 43% vs 20%。

在SCC群体中，尽管Pembrolizumab组OS有临床意义的提升：8.2 mo vs 7.1 mo (HR 0.78; 95% CI 0.63-0.96; P=0.0095)，但是对预设边界值来说没有统计学意义。

ITT群体中，尽管有OS获益的趋势，但是两组的OS值没有统计学差异：7.1mo vs 7.1 mo (HR 0.89; 95% CI 0.75-1.05; P=0.0560)。

Pembrolizumab组的整体药物相关不良事件（64% vs86%）及3-5级药物相关不良事件（18% vs 41%）均少于化疗组。

结论：Pembrolizumab二线治疗显著改善PD-L1 CPS≥10%的晚期食管癌患者的OS且有着更好的安全性，这些数据支持Pembrolizumab作为新的治疗PD-L1 CPS≥10%的食管癌患者的二线疗法。Pembrolizumab联合化疗一线治疗晚期食管癌的KEYNOTE-590研究正在进行中(NCT03189719)。

2 Pembrolizumab+trastuzumab联合化疗一线治疗HER+的转移型食管腺癌的2期

First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA).

https://meetinglibrary.asco.org/record/169420/abstract

Background:

Trastuzumab stimulates HER2-specific T cellresponses and increasestumor PD-L1 expression（？？）, andanti-PD-1 antibody can help enhance T cell-specific immunity of trastuzumab.Oxaliplatin can further enhance T-cells by activating dendritic cells. Weconducted a phase II trial of pembrolizumab with chemotherapy/trastuzumab.

Methods:

Patients with previously untreated HER2 IHC 3+ or FISH+ tumorsirrespective of PD-L1status received intravenous P 200 mg flat dose, T 6 mg/kg (after 8 mg/kgload), O 130 mg/m2 every 3 weeks and oral C 850 mg/m2 2 weeks on/1 week off (or5-FU continuous infusion). Theprimary endpoint was 6-months PFS; with target accrual of 37 patients.Secondary endpoints included safety, OS, ORR, exploratory biomarker analysisand 89Zr-trastuzumab PET.

Results:

有效性方面，24名可评估患者全部观察到肿瘤缩小，ORR 83.3%(3 CR+17 PR)，PFS 11.4 mo

100% of the 24 evaluable pts had tumorregression (ranging from -22% to -100%). The RECIST 1.1 ORR was 83% [95%CI: 63%-95%] (17 PR , 3CRs), median PFS11.4 [95%CI: 6-15] months.

安全性方面，31名可评估患者中常见的>10%以上的AE包括：2级疲劳 (35%)、2/3级呕吐(35%)、2级腹泻 (26%)、2级转氨酶升高 (16%)和3级中西里细胞减少 (16%)。免疫相关毒性以下各发现1例：2级肠炎、3级间质性肾炎、3级转氨酶升高，接受激素治疗后全部恢复。

In 31 pts evaluable for toxicity, common (> 10%) adverse events included Gr 2 fatigue (35%), Gr 2/3 nausea (35%), Gr 2diarrhea (26%), Gr2 AST/ALT elevation (16%), Gr2 neutropenia (16%). Immune related toxicities observedin 1 pt each: Gr 2 colitis, Gr 3 interstitial nephritis, Gr 3 AST/ALTelevation; and resolved with steroids.

21名可获得样本的患者中，1）29%（6/21）表达PD-L1，这6人中5例PR+1例CR

Of 21 patients with available material, 6 (29%) expressed PD-L1. Ofthese 6 patients, 5 had a PR while 1 had a CR.

25名患者的治疗前的肿瘤样本中经NGS检测56%患者发现ERBB2扩增，剩下的NGS检测阴性可能是肿瘤异质性或者样本量少

ERBB2 amplification was evident on NGS in56% of pre-treatment tumors from 25 tested patients, while the remaining wereERBB2- by NGS likely due to tumor heterogeneity or low tumor content.

68%和16%患者分别发现TP53和KRAS突变

Mutations in TP53 and alterations in KRASoccurred in 68% and 16%, respectively.

为了研究获得性耐药机制，进展后的患者样本活检，6例中发现2例在进展后ERBB2扩增缺失

To identify mechanisms of acquired resistance, patients are biopsied atprogression. In 6 paired sample analysis, we identified two patients with lossof ERBB2 amp at progression.

Conclusions:

Updated survival, correlative studies and89Zr-trastuzumab PET imaging will be presented. These promising preliminarysafety and efficacy results led to initiation of a definitive phase III Keynote811 trial.

HER2 in esophagogastric adenocarcinoma

Pembrolizumab in esophagogastric adenocarcinoma

3 REFLECT研究中接受Lenvatinib治疗患者的OS与ORR分析

https://meetinglibrary.asco.org/record/169342/abstract

In REFLECT, Lenvatinib (LEN)demonstrated treatment effect on overall survival (OS) by statisticalconfirmation of noninferiority to sorafenib (SOR). OR rates for LEN versus SORwere: 24% versus 9% by investigator review and 41% versus 12% by independentreview (Kudo et al 2018). Sincethe relationship between OR and OS in phase III HCC studies is unclear, weexplored the relationship between OR and OS in REFLECT.

Median OS was 22.4 months forresponders and 11.4 months for nonresponders. Hazard ratios (HR) oflandmark analyses at 2, 4, and 6 months were 0.75 (95% CI, 0.57–0.98), 0.72(95% CI, 0.56–0.92), and 0.73 (95% CI, 0.57–0.93). Independent predictors of OSbased on unstratified Cox regression are in the table.

In REFLECT, OR was an independent predictor of OS in pts with HCCregardless of treatment. The results indicate this correlation is worthfurther investigation.

4 Lonsurf (Trifluridine/Tipiracil)治疗w/o先前胃切除手术的mGC的3期研究 (TAGS)

https://meetinglibrary.asco.org/record/169361/abstract

Lonsurf：大冢的复方制剂，15年FDA批准治疗化疗及靶向失败的mCRC(≥3L)，Trifluridine：三氟尿苷，一种核苷类似物）；tipiracil：嘧啶二酮盐酸盐，一种胸苷磷酸化酶抑制剂。

≥ 3L mGC

Background: The phase 3 study TAGS demonstrated that the novel oraltherapy FTD/TPI (TAS-102) represents an effective treatment option with a manageable safety profile for ptswith heavily pretreated mGC. In an earlier single-arm Japanese phase 2trial in mGC, no differences were found in the pharmacokinetics of either FTDor TPI in pts with or without prior gastrectomy. We evaluated the efficacy andsafety of FTD/TPI in pts with or without prior gastrectomy within the TAGSstudy.

Methods: In this global phase 3 study of adult pts with mGC who had received ≥ 2 prior regimens ofchemotherapy, pts were randomized 2:1 to receiveFTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo, plus best supportive care. Weperformed a preplanned analysis of efficacy and safety endpoints in ptsubgroups with or without prior gastrectomy.

Results:Of 507 randomized pts, 221 (44%) had a prior gastrectomy(FTD/TPI, 147/337; placebo, 74/170). Baseline pt characteristics were balancedacross pt subgroups. FTD/TPIprolonged survival versus placebo regardless of gastrectomy (table). Thefrequency of neutropenia/leukopenia appeared to be higher among FTD/TPI-treatedpts with vs without gastrectomy, but this did not result in more treatmentdiscontinuations (table).

Conclusions: In the TAGS study, subgroup analysis demonstrated thatFTD/TPI is an effective treatment option with a manageable safety profile forpts with heavily pretreated mGC, regardless of prior gastrectomy

5 【Failed】andecaliximab 对比安慰剂联合mFOLFOX6一线治疗胃癌及胃食管交界处腺癌的GAMMA-1研究

https://meetinglibrary.asco.org/record/169297/abstract

Background: Andecaliximab (ADX) is a monoclonal antibody thatinhibits matrix metalloproteinase 9（基质金属蛋白酶9）, anextracellular enzyme involved in matrix remodeling, tumor growth, andmetastasis. A phase I/Ib study of mFOLFOX6 + ADX revealed encouraging antitumoractivity in patients (pts) with gastric or gastroesophageal junction (GEJ)adenocarcinoma (median first-line, progression-free survival [PFS] of 9.9months).

Methods: This phase 3, randomized, double-blind, multicenter studyinvestigated the efficacy and safety of mFOLFOX6 with/without ADX in pts withuntreated HER2-negative gastric or GEJ adenocarcinoma. Randomization was 1:1 tomFOLFOX6 + ADX or mFOLFOX6 + placebo (PBO). Oxaliplatin was administered onDays 1 and 15 of each 28-day treatment cycle (total of 6 cycles), followed byleucovorin and 5-fluorouracil dosing on Days 1 and 15 of each 28-day treatmentcycle until disease progression. ADX/PBO 800 mg was infused on Days 1 and 15 ofeach 28-day cycle until disease progression. The study had 85% power (one-sidedsignificance of 0.025) to detect a hazard ratio of 0.7 for overall survival(OS) by intention-to-treat analysis using the log-rank test. Secondaryendpoints were PFS, objective response rate (ORR, RECIST 1.1), and safety.

Results: Between September 2015 and May 2017, 432 pts wererandomized; 218 pts to ADX and 214 pts to PBO. Median (95% CI) OS was 12.5 (11.2, 14.0) vs 11.8 (10.3,13.5) months in the ADX and PBO groups, respectively (HR 0.93 [0.74, 1.18],two-sided p=0.56). MedianPFS was 7.5 vs 7.1 months in the ADX and PBO groups, respectively (HR 0.84[0.672, 1.038], two-sided p=0.10). Median investigator assessed ORR was 50.5% vs 41.1% in theADX and PBO groups, respectively (two-sided p=0.049). The most commontreatment-emergent adverse events were nausea, diarrhea, neutropenia, andfatigue. There were no meaningful differences in the safety profile of the ADXvs PBO groups. Subgroup analysis is ongoing.

Conclusion: Additionof ADX to mFOLFOX6 does not improve OS in pts with untreatedHER2-negative gastric or GEJ adenocarcinoma.

又是一个冒进的结果，

6 anlotinib治疗化疗难治的ESCC的随机双盲多中心2期研究

https://meetinglibrary.asco.org/record/168613/abstract

背景：化疗后进展的ESCC患者在临床上的选择依旧是不明确的：一线化疗以铂、紫衫或氟尿嘧啶的双药为主，进展后二线尚无标准。

方法：入组患者都是含铂或紫杉醇化疗后进展的晚期ESCC，2016.1.6~2018.5.22期间，中国13个中心的165名患者按2：1随机至安罗替尼组和安慰剂组。21天一个疗程，第1-14天分别给与安罗替尼（12mg QD）和安慰剂直至PD或者不可耐受毒性，主要终点PFS。

结果

最常见3-4级TRAE(>5%)：高血压(15.6%)和食欲降低(5.5%)

两组接受后续治疗的患者分别：41.2% (40/97) vs 72.7% (40/55) (P=0.0002), 包括化疗 (23.7% vs 54.6%)、PD-1 (4.1% vs 11.0%)和阿帕(10.3% vs 20.0%)，所以这个OS应该是部分受到后续治疗的影响。

结论：安罗替尼显著提升PFS和DCR，安全性可控。