2020ASCO肺癌专题(2)

           

u ASCO| PD-1单抗联合化疗治疗转移性小细胞肺癌延长生存期

2020年5月29日,一年一度的美国肿瘤学大会(ASCO)在线召开,ASCO是全球肿瘤学领域的顶级学术会议之一,涵盖临床各个肿瘤学科领域的基础和临床研究。大医编将在近期推送系列文章,介绍今年ASCO公布的重要研究成果。

PD-1单抗作为近几年“炙手可热”的明星抗癌药,已有多项临床研究证实其在肺癌中的治疗效果。近期公布的一项Pembrolizumab联合依托泊苷和铂类在转移性小细胞肺癌一线治疗结果,显示了该药具有延长患者生存期的作用,以下是该研究主要内容。

背 景:

派姆单抗(pembro) 单药治疗在转移性小细胞肺癌的三线或后期治疗中显示出持久的抗肿瘤活性,因而获得FDA批准。KEYNOTE-604是一项派姆单抗+ 依托泊苷和铂(EP) vs安慰剂+ 依托泊苷和铂(EP)用于一线治疗广泛期小细胞肺癌 (NCT03066778)的双盲3期研究。

方 法:

对以前未接受过治疗的广泛期小细胞肺癌患者和未接受过治疗的中枢神经系统转移的符合条件的患者(pts)随机1:1分配至两组:派姆单抗200 mg (每三周给予一次)或生理盐水安慰剂进行35个周期,加4个周期标准剂量EP治疗。在第4周期后出现完全缓解或部分缓解的患者可以根据研究者的判断接受经皮冠状动脉介入治疗治疗。随机分组以铂类选择(卡铂vs顺铂)、美国东部肿瘤协作组体力状况评分(ECOG PS)(0 vs 1)和乳酸脱氢酶(≤正常上限 vs > 正常上限)进行分层。意向治疗人群的总生存期(OS)和无进展生存期(PFS) (实体肿瘤的疗效评价标准 1.1 版,盲法中央评价)为主要终点。客观缓解率、缓解持续时间和安全性是次要终点。采用分层生存分析检验评价总生存期和无进展生存期治疗差异。方案规定了两项中间分析 (IAs)和一项最终分析(FA)。预先指定的疗效边界为: IA2无进展生存期(预先指定的最终无进展生存期分析)的单侧检验P = 0.0048,与FA总生存期的单侧检验P = 0.0128。

结 果:

453名患者随机分配至两组。223/228名派姆单抗 + EP组和222/225名安慰剂+ EP组接受≥1剂量的指定治疗;派姆单抗 + EP组1名受试者错误接受安慰剂+ EP治疗。年龄中位值为65岁,74% ECOG PS评分为1级, 57% 乳酸脱氢酶 > 正常上限;派姆单抗 + EP组有更多患者出现脑转移(14% vs 10%)。在最终分析(中位随访,21.6个月)中,派姆单抗 + EP组中9%的患者和安慰剂+ EP组中1%的患者仍在研究治疗中;两组分别有12%和14%接受经皮冠状动脉介入治疗。在IA2(中位随访,13.5个月)中,派姆单抗 + EP显著改善意向治疗人群的无进展生存期 (HR 0.75 [95% CI 0.61-0.91], P = 0.0023;中位数4.5 vs 4.3个月)。在FA时,派姆单抗 + EP延长了意向治疗人群的总生存期,但未达到显著阈值(HR 0.80 [95% CI 0.64-0.98], P = 0.0164;中位数10.8 vs 9.7个月)。在经处理总生存期的事后分析中,名义P值小于显著性阈值(HR 0.78 [95% CI 0.63-0.97], P = 0.0124)。派姆单抗 + EP组在FA时的客观缓解率为71%,而安慰剂+ EP组客观缓解率为62%;中位缓解持续时间为4.2 vs 3.7 个月。观察到的不良事件符合预期;3-4级任意原因的不良事件为出现率为77% vs 75%,5级为6% vs 5%,15% vs 6%导致试验终止。

结 论:

与安慰剂+ EP相比,派姆单抗 + EP作为ES-SCLC患者的一线治疗方案可显著改善无进展生存期和延长总生存期。派姆单抗 + EP未见意外毒性反应。这些数据支持了含有派姆单抗的方案对ES-SCLC的益处。临床试验信息:NCT03066778

 

摘要原文:

Background: 

Pembro monotherapy showed durable antitumor activity as third-line or later therapy for metastatic SCLC, leading to FDA approval in that setting. KEYNOTE-604 was a double-blind, phase 3 study of pembro + EP vs placebo + EP as first-line therapy for ES-SCLC (NCT03066778).

Methods: 

Eligible patients (pts) with previously untreated ES-SCLC and no untreated CNS metastases were randomized 1:1 to pembro 200 mg Q3W or saline placebo for up to 35 cycles plus 4 cycles of standard-dose EP. Pts with CR or PR after cycle 4 could receive PCI at investigator discretion. Randomization was stratified by platinum choice (carboplatin vs cisplatin), ECOG PS (0 vs 1), and LDH (≤ULN vs > ULN). Primary endpoints were OS and PFS (RECIST v1.1, blinded central review) in the ITT population. ORR, DOR, and safety were secondary endpoints. OS and PFS treatment differences were assessed by the stratified log-rank test. The protocol specified 2 interim analyses (IAs) and a final analysis (FA). Prespecified efficacy boundaries were one-sided P = 0.0048 for PFS at IA2 (prespecified final PFS analysis) and 0.0128 for OS at FA.

Results: 

453 pts were randomized. 223/228 pts assigned to pembro + EP and 222/225 assigned to placebo + EP received ≥1 dose of assigned treatment; 1 pt assigned to pembro + EP received placebo + EP in error. Median age was 65 y, 74% had ECOG PS 1, and 57% had LDH > ULN; more pts in the pembro + EP arm had baseline brain metastases (14% vs 10%). At FA (median follow-up, 21.6 mo), 9% of pts in the pembro + EP arm and 1% in the placebo + EP arm remained on study treatment; 12% and 14% received PCI. At IA2 (median follow-up, 13.5 mo), pembro + EP significantly improved PFS in the ITT population (HR 0.75 [95% CI 0.61-0.91], P = 0.0023; median 4.5 vs 4.3 mo). At FA, pembro + EP prolonged OS in the ITT population, but the significance threshold was not met (HR 0.80 [95% CI 0.64-0.98], P = 0.0164; median 10.8 vs 9.7 mo). In a post hoc analysis of OS in the as-treated population, the nominal P value was smaller than the significance threshold (HR 0.78 [95% CI 0.63-0.97], P = 0.0124). ORR at FA was 71% for pembro + EP vs 62% for placebo + EP; median DOR was 4.2 vs 3.7 mo. Observed AEs were as expected; any-cause AEs were grade 3-4 in 77% vs 75%, grade 5 in 6% vs 5%, and led to discontinuation in 15% vs 6%.

Conclusions: 

Pembro + EP significantly improved PFS and prolonged OS compared with placebo + EP as first-line therapy for pts with ES-SCLC. No unexpected toxicities were seen with pembro + EP. These data support the benefit of pembro-containing regimens for ES-SCLC. Clinical trial information: NCT03066778

参考文献:
https://meetinglibrary.asco.org/record/184545/abstract

 

 

u ASCO|ctDNA综合模型预测晚期NSCLC对一线免疫治疗和化疗+免疫治疗的疗效

一线免疫疗法(IO)和化疗免疫疗法(chemo-IO)已被批准用于表达PD-L1的晚期非小细胞肺癌(NSCLC),但PD-L1的表达不能可靠地预测治疗反应。因此,需要准确的治疗中反应评估来指导临床决策。常规放射成像是金标准,但可能无法捕获免疫介导的反应的性质和时机。我们调查了全面的循环肿瘤DNA(ctDNA)模型是否可以增强临床反应的预测效果。

方 法:

我们对一线IO或化疗IO治疗的NSCLC患者进行了血浆标本和匹配的白细胞(WBC)的靶向误差校正测序(TEC-Seq)。通过滤出在匹配的WBC中发现的克隆性造血(CH)和种系(GL)变体来鉴定血浆ctDNA变体。评估临床和病理数据,包括PD-L1肿瘤比例评分(TPS)和RECIST1.1的影像学反应。对ctDNA动态进行建模以预测持久的临床获益(6个月时),无进展生存期(PFS)和总体生存期(OS)。

结 果:

31例接受IO(n = 17)或化疗和IO(n = 14)治疗的NSCLC患者共进行143例血浆和24个白细胞样本的TEC-Seq检测。滤除CH和GL变异后,在77%(n = 24)的患者中发现了ctDNA变异,其中所有变异中占53%(n = 196/373)。在32%(n = 10)的患者中检测到了以消除ctDNA变异为标志的分子反应,并与PFS(p = 0.0004)和OS(p = 0.017)改善有关。达到分子应答的时间比达到最佳RECIST应答的时间短(中位数3比7.71周,p = 0.048,Mann-Whitney U检验)。结合分子应答,复发或出现新变异的logistic回归模型预测持久的临床获益(敏感性84%,特异性76%,AUC 0.88)优于PD-L1 TPS(AUC 0.67,p = 0.046)。

结 论:

ctDNA变异的综合模型可预测一线IO或化疗IO治疗的晚期NSCLC患者的临床结局,与PD-L1状态无关。通过匹配的WBC测序验证真正的ctDNA变异至关重要。可以比成像反应更早地确定分子反应,并且可以使治疗中的决策改变临床结果。

原文摘要:

Background: 

First-line immunotherapy (IO) and chemo-immunotherapy (chemo-IO) are approved for PD-L1-expressing advanced non-small cell lung cancer (NSCLC), but PD-L1 expression does not reliably predict therapeutic response. Therefore, accurate on-therapy response assessment is needed to guide clinical decision-making. Conventional radiographic imaging is the gold-standard, but may not capture the nature and timing of an immune-mediated response. We investigated whether comprehensive longitudinal circulating tumor DNA (ctDNA) dynamics could enhance prediction of clinical response.

Methods: 

We conducted targeted error correction sequencing (TEC-Seq) of longitudinal plasma specimens and matched white blood cells (WBCs) in patients with NSCLC treated with first-line IO or chemo-IO. Plasma ctDNA variants were identified by filtering out clonal hematopoiesis (CH) and germline (GL) variants found in matched WBCs. Clinical and pathological data, including PD-L1 tumor proportion score (TPS), and imaging response by RECIST1.1 were assessed. ctDNA dynamics were modeled to predict durable clinical benefit (at 6 months), progression-free survival (PFS), and overall survival (OS).

Results: 

A total of 143 longitudinal plasma and 24 white blood cell samples underwent TEC-Seq for 31 patients with NSCLC treated with IO (n = 17) or chemo-IO (n = 14). ctDNA variants were found in 77% (n = 24) of patients after filtering out CH and GL variants, which comprised 53% (n = 196 of 373) of all variants. Molecular response, signified by elimination of ctDNA variants, was detected in 32% (n = 10) of patients and associated with improved PFS (p = 0.0004, log rank) and OS (p = 0.017, log rank). Time to molecular response was shorter than time to best RECIST response (median 3 vs. 7.71 weeks, p = 0.048, Mann-Whitney U test). A logistic regression model incorporating molecular response, recrudescence, or emergence of new variants predicted durable clinical benefit (sensitivity 84%, specificity 76%, AUC 0.88) better than PD-L1 TPS (AUC 0.67, p = 0.046, bootstrap method).

Conclusions: 

Comprehensive modeling of ctDNA variant dynamics predicts clinical outcome independent of PD-L1 status in patients with advanced NSCLC treated with first-line IO or chemo-IO. Verification of bona fide ctDNA variants by matched WBC sequencing is essential. Molecular response can be identified earlier than imaging response and could enable on-therapy decision-making to alter clinical outcomes参考文献:
https://meetinglibrary.asco.org/record/184881/abstract

u ASCO|HER2抗体-药物偶联物(T-DXd; DS-8201)在HER2突变的转移性NSCLC中的研究

T-DXd是一种抗体-药物偶联物,由抗HER2抗体,可切割的基于四肽的接头和拓扑异构酶I抑制剂有效载荷组成。在一项I期试验中,接受T-DXd治疗的HER2突变的NSCLC患者(pts)的确诊客观缓解率(ORR)为72.7%(8/11)(Tsurutani等,WCLC2018)。

DESTINY-Lung01(NCT03505710)是一项正在进行的,多中心,II期研究,涉及过表达HER2或含有HER2激活突变的非鳞状非小细胞肺癌患者中使用T-DXd。在中位随访8.0 月(范围1.4-14.2 月)后,我们报告了HER2突变人群的数据。

方 法:

每3周用6.4 mg / kg T-DXd治疗Pts。主要终点通过ICR确认为ORR(完全缓解[CR] +部分缓解[PR])。其他终点是疾病控制率(DCR; CR + PR +稳定疾病),反应持续时间(DOR),无进展生存期(PFS)和安全性。

结 果:

截至数据截止(2019年11月25日),有42名患者(64.3%女性)接受了T-DXd治疗。中位年龄为63.0岁(范围34-83岁; <65岁,59.5%);  45.2%有中枢神经系统转移;ECOG绩效状态为23.8%的患者为0,76.2%的患者为1。HER2突变主要位于激酶结构域(90.5%)。大多数患者(90.5%)曾接受铂类化学疗法,而54.8%曾接受过抗PD-1或PD-L1治疗。先前治疗线的中位数为2(范围为1-6)。中位治疗时间为7.75 月(范围0.7-14.3 月);45.2%的患者仍在接受治疗。ICR确诊的42例患者的ORR为61.9%(95%CI,45.6%-76.4%); 数据截止时未达到中值DOR;  

26名反应者中有16名在数据截止时仍在接受治疗;DCR为90.5%(95%CI,77.4%-97.3%); 估计PFS中位数为14.0 月(95%CI,6.4-14.0 月)。所有患者(42/42)均出现治疗紧急不良事件(TEAE)。≥3级者占64.3%(与药物有关的52.4%),其中中性粒细胞减少(26.2%)和贫血(16.7%)。由一个独立委员会诊断出5例(11.9%)药物相关性间质性肺疾病(ILD)(均为2级,≥3级),还有1例1级ILD尚待诊断。TEAEs导致25例(59.5%)的剂量中断,16例(38.1%)剂量减少和10 pts(23.8%)的治疗中断。

结 论:

T-DXd在具有HER2突变的NSCLC的患者中有高ORR和持久的疗效。安全性概况通常与先前报道的研究一致。

临床试验信息:NCT03505710。

原文摘要:

Background: 

T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. In a phase I trial, patients (pts) with HER2-mutated NSCLC who received T-DXd had a confirmed objective response rate (ORR) of 72.7% (8/11) (Tsurutani et al, WCLC 2018). DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase II study of T-DXd in pts with non-squamous NSCLC overexpressing HER2 or containing a HER2-activating mutation. We report data for the cohort with HER2 mutations after a median follow-up of 8.0 mo (range, 1.4-14.2 mo).

 

Methods: 

Pts were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was confirmed ORR (complete response [CR] + partial response [PR]) by ICR. Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety.

Results: 

At data cutoff (25 Nov 2019), 42 pts (64.3% female) had received T-DXd. Median age was 63.0 years (range, 34-83 years; < 65 y, 59.5%); 45.2% had central nervous system metastases; ECOG performance status was 0 in 23.8% of pts and 1 in 76.2%. HER2 mutations were predominantly in the kinase domain (90.5%). Most pts (90.5%) had prior platinum-based chemotherapy and 54.8% had anti–PD-1 or –PD-L1 treatment; median number of prior treatment lines was 2 (range, 1-6). Median treatment duration was 7.75 mo (range, 0.7-14.3 mo); 45.2% of pts remained on treatment. Confirmed ORR by ICR among the 42 pts was 61.9% (95% CI, 45.6%-76.4%); median DOR was not reached at data cutoff; 16 of 26 responders remained on treatment at data cutoff; DCR was 90.5% (95% CI, 77.4%-97.3%); estimated median PFS was 14.0 mo (95% CI, 6.4-14.0 mo). All pts (42/42) had treatment-emergent adverse events (TEAEs); 64.3% were grade ≥ 3 (52.4% drug-related), including decreased neutrophil count (26.2%) and anemia (16.7%). There were 5 cases (11.9%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (all grade 2, no grade ≥ 3) and 1 case of grade 1 ILD is pending adjudication. TEAEs led to dose interruption in 25 pts (59.5%), dose reduction in 16 pts (38.1%), and treatment discontinuation in 10 pts (23.8%).

Conclusions: 

T-DXd demonstrated promising clinical activity with high ORR and durable responses in pts with HER2-mutated NSCLC. The safety profile was generally consistent with previously reported studies. Clinical trial information: NCT03505710.

参考文献:
https://meetinglibrary.asco.org/record/184803/abstract



u ASCO|PD-1和CTLA-4单抗与铂类双药化疗一线治疗晚期NSCLC研究

在3期CheckMate 227第1部分(NCT02477826;最少随访,29.3个月)中,与未接受化疗的aNSCLC和肿瘤PD-L1患者(pts)相比,1L NIVO + IPI显着提高了总生存期(OS)表达≥1%(初步分析)或<1%(预先描述性分析)。

在这里,我们报告的数据至少需要3年的随访。

方 法:

将IV期/复发性NSCLC和PD-L1≥1%(n = 1189)的患者按1:1的比例随机分为NIVO(3 mg / kg Q2W)+ IPI(1 mg / kg Q6W),NIVO(240毫克(Q2W)或化学疗法。PD-L1 <1%(n = 550)的患者被随机分为NIVO + IPI,NIVO(360 mg Q3W)+化学或化学。主要终点是PD-L1≥1%的患者的NIVO + IPI vs化疗。在6个月时根据反应状态(CR / PR,SD,PD)对患者的OS进行了探索性分析。

结 果:

在平均随访43.1个月(数据库截止2020年2月28日)之后,PD-L1≥1%的患者继续从NIVO + IPI与化学治疗中获益(HR:0.79; 95%CI,0.67– 0.93); 3-y OS发生率为33%(NIVO + IPI),29%(NIVO)和22%(chemo)。在3年时,用NIVO + IPI治疗的PD-L1≥1%的患者中,有18%的患者无进展,而NIVO和化学性的患者分别为12%和4%。在3 y时,NIVO + IPI组仍然有38%的已确认应答者响应,而在NIVO组中则为32%,在化学组中为4%。在PD-L1 <1%的患者中,NIVO + IPI与化学疗法的OS HR为0.64(95%CI,0.51-0.81); 3-y OS发生率分别为34%(NIVO + IPI),20%(NIVO +化学)和15%(化疗);分别有13%,8%和2%的患者无进展;分别有34%,15%和0%的已确认应答者仍在应答中。PD-L1≥1%且CR / PR≥6 mo的患者继发NIVO + IPI的OS较化疗更长;治疗后6个月时SD或PD的患者在治疗后的OS一般相似(表);将显示PD-L1 <1%pts的结果。在用NIVO + IPI治疗的所有患者中,观察到任何级别/ 3-4级治疗相关的AE,在化学治疗中观察到了82%/ 36%的所有患者。

结 论:

通过最少3年的随访,NIVO + IPI作为一线治疗给aNSCLC患者带来持久和长期的OS益处。PD-L1≥1%且在6个月时达到CR / PR的患者,NIVO + IPI与化疗相比具有明显的OS获益。NIVO + IPI没有新确定的安全信息。

临床试验信息:NCT02477826

原文摘要:

Background: 

In the phase 3 CheckMate 227 Part 1 (NCT02477826; minimum follow-up, 29.3 mo), 1L NIVO + IPI significantly improved overall survival (OS) vs chemo in treatment-naive patients (pts) with aNSCLC and tumor PD-L1 expression ≥ 1% (primary analysis) or < 1% (pre-specified descriptive analysis). Here we report data with 3-y minimum follow-up.

Methods: 

Pts with stage IV / recurrent NSCLC and PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO (240 mg Q2W) alone, or chemo. Pts with PD-L1 < 1% (n = 550) were randomized to NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. Primary endpoint was OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1%. An exploratory analysis of OS in pts by response status (CR/PR, SD, progressive disease [PD]) at 6 mo was conducted.

Results: 

After a median follow-up of 43.1 mo (database lock, 28 Feb 2020), pts with PD-L1 ≥ 1% continued to derive OS benefit from NIVO + IPI vs chemo (HR: 0.79; 95% CI, 0.67–0.93); 3-y OS rates were 33% (NIVO + IPI), 29% (NIVO), and 22% (chemo). At 3 y, 18% of pts with PD-L1 ≥ 1% treated with NIVO + IPI remained progression-free vs 12% with NIVO and 4% with chemo; 38% of confirmed responders remained in response in the NIVO + IPI arm at 3 y vs 32% in the NIVO arm and 4% in the chemo arm. In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 3-y OS rates were 34% (NIVO + IPI), 20% (NIVO + chemo), and 15% (chemo); 13%, 8%, and 2% of pts remained progression-free; and 34%, 15%, and 0% of confirmed responders remained in response, respectively. Pts with PD-L1 ≥ 1% with either CR/PR at 6 mo had longer subsequent OS with NIVO + IPI vs chemo; pts with SD or PD at 6 mo had generally similar subsequent OS between treatments results in PD-L1 < 1% pts will be presented. Any-grade / grade 3–4 treatment-related AEs were observed in 77% / 33% of all pts treated with NIVO + IPI, and 82% / 36% with chemo.

Conclusions: 

With 3 y minimum follow-up, NIVO + IPI continued to provide durable and long-term OS benefits vs chemo for pts in 1L aNSCLC. Pts with PD-L1 ≥ 1% who achieved CR/PR at 6 mo had marked OS benefit with NIVO + IPI vs chemo. No new safety signals were identified for NIVO + IPI. Clinical trial information: NCT02477826

参考文献:
https://meetinglibrary.asco.org/record/184651/abstract



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