肿瘤瞭望消化时讯

ASCO GI 2024丨刚刚！胃食管癌领域口头报告专场研究重磅发布！

肿瘤瞭望消化时讯

编者按：2024年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI 2024）将于当地时间2024年1月18日—20日在美国旧金山举行。作为胃肠道肿瘤领域最高水平的世界级学术盛会之一，本次大会汇集了全球的肿瘤学家汇报胃肠道肿瘤领域的研究进展。北京时间2024年1月17日上午，ASCO GI官网公布了除LBA摘要外其他全部摘要内容，本文介绍了已公布的口头报告专场胃食管癌研究，以飨读者。

SKYSCRAPER-08: A phase III, randomized, double-blind, placebo-controlled study of first-line (1L) tiragolumab (tira) + atezolizumab (atezo) and chemotherapy (CT) in patients (pts) with esophageal squamous cell carcinoma (ESCC)

SKYSCRAPER-08：一线（1L）tiragolumab（tira）+阿替利珠单抗（atezo）和化疗（CT）治疗食管鳞状细胞癌（ESCC）患者（pts）的III期、随机、双盲、安慰剂对照研究

摘要号：245

背景

TIGIT是一种新型免疫检查点抑制剂，可以通过补充PD-L1/PD-1通路进一步放大免疫反应。食管鳞状细胞癌的免疫疗法已证明其抗肿瘤活性。SKYSCRAPER-08（NCT04540211）正在评估tira（抗TIGIT）+atezo（抗PD-L1）联合CT与安慰剂+CT相比作为一线（1L）治疗（tx）在不可切除的局部晚期（LA）、不可切除的复发性或转移性（R/M）ESCC亚洲人群中的疗效和安全性。

方法

符合条件的患者（确认LA或R/M ESCC);Ecog PS 0-1分；在21天1周期（1–6周期）的第1天，1:1随机接受tira 600 mg+atezo 1200 mg+CT（紫杉醇175 mg/m2+顺铂60–80 mg/m2，当地标准治疗）或安慰剂+CT；随后是tira+atezo或安慰剂维持，直到失去临床益处/不可接受的毒性。主要终点：独立审查机构（IRF）评估的无进展生存期（PFS）和总生存期（OS)。次要终点：研究者（INV）评估的PFS、客观缓解率（ORR)、缓解持续时间（DoR）和安全性。

结果

总体而言，461例患者被随机分配(tira+atezo+CT,n=229；安慰剂+CT,n=232)。患者基线特征在两组间基本平衡。截至2022年6月15日，最低生存期随访6.5个月；经IRF评估的tira+atezo+CT组中位PFS为6.2个月，安慰剂+CT组为5.4个月（HR 0.56；95%CI：0.45-0.70；P<0.0001)。截至2023年2月13日，最短生存期随访14.5个月；OS最终分析，tira+atezo+CT组的中位OS为15.7个月，而安慰剂+CT组的中位OS为11.1个月(HR 0.70，95%CI：0.55-0.88；P=0.0024)。INV评估的PFS、IRF评估的ORR和DoR（见下表）。

结论

该研究满足了IRF评估的PFS和OS的两个主要终点，表明tira+atezo+CT组比安慰剂+CT组在PFS和OS方面有统计学意义和临床意义的改善。总的来说，包括PD-L1状态在内的各个亚组都同样观察到获益。安全性与个体的已知风险一致。

临床试验信息

NCT04540211

Pembrolizumab plus FLOT vs FLOT as neoadjuvant and adjuvant therapy in locally advanced gastric and gastroesophageal junction cancer: Interim analysis of the phase 3 KEYNOTE-585 study

帕博利珠单抗（Pembrolizumab）联合FLOT vs FLOT作为局部晚期胃癌和胃食管结癌的新辅助和辅助治疗：III期KEYNOTE-585研究的中期分析

摘要号：247

背景

3期KEYNOTE-585研究（NCT03221426）评估了新辅助/辅助帕博利珠单抗（pembro）或安慰剂（pbo）+化疗（chemo），然后辅助pembro与pbo治疗局部晚期、可切除的胃癌或胃食管交界处（G/GEJ）癌。设立了一个单独的队列评估pembro+FLOT（FLOT队列），并在第三次中期分析中报告了FLOT队列的安全性和有效性分析结果。

方法

在FLOT队列中，未经治疗的局部晚期可切除G/GEJ癌症患者（pts）以1：1的比例随机分配至新辅助pembro 200 mg IV Q3W（pembro gp）或pbo（pbo gp）Q3W 3个周期+FLOT（多西他赛、奥沙利铂、亚叶酸和5-FU）Q2W，持续4个周期。手术后，pts接受辅助pembro或pbo Q3W 3个周期+FLOT Q2W 4个周期，然后辅助pembro或pbo Q3W 11个周期。评估的终点包括安全性、pCR率（BICR）、EFS（RECIST 1.1，由研究者提供）和ITT中的OS。第三次中期分析的数据截止时间为2023年2月9日。

结果

共有203例患者被随机分配（100 pembro+FLOT；103 pbo+FLOT）。其中，12例（6%）患者为cT1-T2，161例（79%）为cT3，9例（4%）为cT4。140例（69%）基线时为N+，79例（39%）患有GEJ腺癌。IA3的中位随访时间分别为31.6个月和31.1个月。99例中有94例（95%）完成了新辅助治疗，99例中有87例（87%）完成了手术阶段，77例中有45例（58%）完成了辅助治疗。pembro gp和pbo gp的R0切除率分别为79%和80%。pembro gp的pathCR率为17.0%（95%CI：10.2-25.8），pbo gp为6.8%（95%CI：2.8-13.5），估计差异为10.2%[95% CI，1.3-19.7]）。pembro gp未达到中位EFS（95%CI：28.2-NR），pbo gp未达到30.9个月（22.8-NR）（HR 0.79;95%CI：0.52-1.22）。24个月的EFS率分别为66%和57%。两组均未达到中位OS（HR 1.04；95%CI：0.66-1.66）。24个月的OS率分别为72%和73%。Pembro gp与pbo gp在所有阶段的≥3级药物相关AE的发生率分别为76%和63%，严重药物相关AE分别为42%和20%，手术相关AE分别为20%和13%。pembro gp和pbo gp分别有3例（3%）和1例（1%）患者因药物相关AE而死亡。

结论

新辅助/辅助pembro+FLOT是可行的，暂时没有新的安全问题。在未经治疗的局部晚期可切除的G/GEJ癌患者中，接受pbo+FLOT治疗的患者相比接受pbo+FLOT治疗的患者在PathCR和EFS上获益更多。

临床试验信息NCT03221426

摘要原文

SKYSCRAPER-08: A phase III, randomized, double-blind, placebo-controlled study of first-line (1L) tiragolumab (tira) + atezolizumab (atezo) and chemotherapy (CT) in patients (pts) with esophageal squamous cell carcinoma (ESCC).

Abstract：245

Background: 

Inhibition of TIGIT, a novel checkpoint inhibitor, may further amplify immune responses by complementing the PD-L1/PD-1 pathway. Anti-tumor activity has been demonstrated with cancer immunotherapy in ESCC. SKYSCRAPER-08 (NCT04540211) is evaluating the efficacy and safety of tira (anti-TIGIT) + atezo (anti-PD-L1) in combination with CT compared with placebo + CT as 1L treatment (tx) in an Asian population with unresectable locally advanced (LA), unresectable recurrent, or metastatic (R/M) ESCC. 

Methods: 

Eligible pts (confirmed LA or R/M ESCC; ECOG PS 0–1; no prior systemic tx) were randomized 1:1 to receive tira 600mg + atezo 1200mg + CT (paclitaxel 175mg/m2 + cisplatin 60–80mg/m2, local standard of care) or placebo + CT on Day 1 of each 21-day cycle (cycles 1–6); followed by tira + atezo or placebo maintenance until loss of clinical benefit/unacceptable toxicity. Primary endpoints: independent review facility (IRF)-assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints: investigator (INV)-assessed PFS, objective response rate (ORR), duration of response (DoR), and safety. 

Results: 

Overall, 461 pts were randomized (tira + atezo + CT, n= 229; placebo + CT, n=232). Pt characteristics were generally balanced between arms. As of 15 June 2022 (minimum survival follow-up 6.5 months [mo]; PFS primary analysis), median IRFassessed PFS was 6.2 mo for tira + atezo + CT vs 5.4 mo for placebo + CT (HR 0.56; 95% CI: 0.45, 0.70; P,0.0001). As of 13 Feb 2023 (minimum survival follow-up 14.5 mo; OS final analysis), median OS was 15.7 mo for tira + atezo + CT vs 11.1 mo for placebo + CT (HR: 0.70; 95% CI: 0.55, 0.88; P= 0.0024). INV-assessed PFS, IRF-assessed ORR and DoR are presented in Table. Treatment-related adverse events (TRAEs) occurred in 98.2% of pts (both arms); Grade 3/4 TRAEs in 59.6% (tira + atezo + CT) and 56.4% (placebo + CT) of pts; Grade 5 TRAEs in 2.6% (tira + atezo + CT) and 0.9% (placebo + CT) of pts. 

Conclusions: 

The study met both primary endpoints of IRF-assessed PFS and OS, demonstrating statistically significant and clinically meaningful improvements in PFS and OS for tira + atezo + CT over placebo + CT. Generally consistent benefit was observed across subgroups, including PD-L1 status. The safety profile was consistent with the known risks of the individual tx. Clinical trial information: NCT04540211. 

Pembrolizumab plus FLOT vs FLOT as neoadjuvant and adjuvant therapy in locally advanced gastric and gastroesophageal junction cancer: Interim analysis of the phase 3 KEYNOTE-585 study

Abstract：247

Background: 

The phase 3 KEYNOTE-585 study (NCT03221426) evaluated neoadjuvant/adjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo) followed by adjuvant pembro vs pbo in locally advanced, resectable gastric or gastroesophageal junction (G/GEJ) cancer. A separate cohort evaluated pembro + FLOT (FLOT cohort). We report results from safety and efficacy analyses of the FLOT cohort at third interim analysis. 

Methods: 

In the FLOT cohort, patients (pts) with untreated, locally advanced, resectable G/GEJ cancer were randomized 1:1 to neoadjuvant pembro 200 mg IV Q3W (pembro gp) or pbo (pbo gp) Q3W for 3 cycles + FLOT (docetaxel, oxaliplatin, leucovorin, and 5-FU) Q2W for 4 cycles. After surgery, pts received adjuvant pembro or pbo Q3W for 3 cycles + FLOT Q2W for 4 cycles, then adjuvant pembro or pbo Q3W for 11 cycles. Endpoints evaluated included safety, pathCR rate (BICR), EFS (RECIST 1.1, by investigator), and OS in the ITT. Data cut-off at third interim analysis was 09 Feb 2023. 

Results: 

A total of 203 pts were randomized (100 pembro + FLOT; 103 pbo + FLOT). Among these, 12 (6%) pts had cT1-T2, 161 (79%) had cT3, and 9 (4%) had cT4. 140 (69%) had N+ disease, and 79 (39%) had GEJ adenocarcinoma at baseline. Median follow-up was 31.6 months (mo) and 31.1 mo, respectively, at IA3. A total of 94 of 99 (95%) pts completed the neoadjuvant phase, 87 of 99 (87%) completed the surgery phase, and 45 of 77 (58%) completed adjuvant treatment. The R0-resection rate was 79% vs 80% in the pembro gp vs pbo gp, respectively. The pathCR rate was 17.0% (95% CI, 10.2-25.8) in the pembro gp and 6.8% (95% CI, 2.8-13.5) in the pbo gp, estimated difference (10.2% [95% CI, 1.3-19.7]). Median EFS was not reached (95% CI, 28.2-NR) in the pembro gp and 30.9 mo (22.8-NR) in the pbo gp (HR 0.79; 95% CI, 0.52-1.22). The 24-mo EFS rates were 66% and 57%, respectively. Median OS was not reached in either group (HR 1.04; 95% CI, 0.66-1.66). The 24-mo OS rates were 72% and 73%, respectively. Grade $ 3 drug-related AE rates in all phases combined were 76% and 63% in the pembro vs pbo gp, with serious drug-related AEs in 42% vs 20%, and surgery-related AEs in 20% vs 13%, respectively. A total of 3 (3%) vs 1 (1%) pt in the pembro vs pbo gp died due to a drug-related AE. 

Conclusions: 

Neoadjuvant/adjuvant pembro + FLOT was feasible with no new safety concerns.

PathCR and EFS favored pembro + FLOT vs pbo + FLOT in pts with untreated, locally advanced resectable G/GEJ cancer. Clinical trial information: NCT03221426. 

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