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ESMO 2024丨摘要内容公布！一文盘点KRAS突变位点抑制剂在消化道肿瘤领域的重磅研究进展

肿瘤瞭望消化时讯 发表时间：2024-10-14 14:33:46

编者按：KRAS基因是结直肠癌中常见的致癌基因突变，约40%的CRC病例存在KRAS突变。KRAS基因突变携带者往往预后不佳。由于特定的空间结构特点，KRAS一直被认为是最难成药的突变基因。2021年5月，美国FDA宣布加速批准sotorasib上市，用于治疗肿瘤携带KRAS G12C突变的晚期非小细胞肺癌患者，打破了其不可成药的“魔咒”。目前，关于KRAS突变的靶向药物研究正在如火如荼的进行中。

2024年9月13~17日，欧洲肿瘤内科学会（ESMO）年会将于西班牙巴塞罗那正式召开。当地时间9月9日00:05大会官网公布了除LBA摘要以外的其他全部摘要内容。本文特此梳理并总结了本次ESMO年会上，在消化肿瘤领域内关于KRAS突变位点抑制剂的最新药物研究进展，以飨读者。

1.第二代KRAS G12C抑制剂D3S-001治疗KRAS G12C突变晚期/转移性实体瘤的Ⅰ/Ⅱ期研究

摘要号：615MO讲者：Byoung Chul Cho（韩国首尔）

背景

D3S-001是一种第二代KRAS G12C抑制剂（G12Ci），具有更快的靶标结合动力学，能在纳摩尔水平耗尽细胞内的活性G12C，这一作用机制与更强的抗肿瘤活性相关（Cancer Discov. 2024，待发表）。2024年美国癌症研究协会（AACR）年会上首次报告了人体（FIH）剂量递增队列的初步结果，本文则报告了研究更新的分析数据结果。

方法

在正在进行的Ⅰ/Ⅱ期研究（NCT05410145）中，患者接受D3S-001（50~900 mg/日，口服）治疗，直至出现不可耐受的毒性或疾病进展。研究终点包括由研究者根据RECIST v1.1标准评估的安全性和初步疗效。

结果

截至2024年5月7日，共治疗了42例患者（25例非小细胞肺癌，13例结直肠癌，4例胰腺癌）。中位随访时间为6.8个月（范围：0.2~18.3个月），其中21例（50.0%）患者仍在研究中接受治疗。
安全性：评估期内未发生与治疗相关的剂量限制性毒性（DLT）或死亡事件。32例患者（76.2%）发生了任何级别的治疗相关不良事件（TRAE），其中7例（16.7%）为3级TRAE（无≥4级TRAE）。由于TRAE，12例患者（28.6%）调整了D3S-001剂量，但无患者因TRAE而停药。在全部42例接受给药的患者中，38例进行了基线后的肿瘤评估，其中34例为G12Ci初治患者，4例为G12Ci经治患者。
初步疗效：在34例G12Ci初治患者（21例非小细胞肺癌，9例结直肠癌，4例胰腺癌）中，总体人群中有26例（76.5%，95%CI：58.8%~89.3%）达到部分缓解（PR），确认的客观缓解率（cORR）为70.6%（95%CI：52.5%~84.9%），疾病控制率（DCR）为97.1%。6个月持续缓解率（DoR）为70.5%（95%CI：45.9%~93.0%）。6个月无进展生存率（PFS）为65.3%（95%CI：45.7%~79.3%）。
在21例非小细胞肺癌患者中，15例（71.4%，95%CI：47.8%~88.7%）达到PR，cORR为66.7%（95%CI：43.0%~85.4%），DCR为100%。6个月DoR率为70.0%（95%CI：32.9%~89.2%），6个月PFS率为64.1%（95%CI：38.7%~81.2%）。在6例伴有稳定脑转移的非小细胞肺癌患者中，观察到2例肿瘤缩小。
在9例结直肠癌患者中，7例（77.8%，95%CI：40.0%~97.2%）达到PR（均为确认），DCR为88.9%，6个月DoR率为100%。
在4例胰腺癌患者中，4例（100%）达到PR（3/4例确认）。

在4例G12Ci经治患者（2例非小细胞肺癌和2例结直肠癌）中，DCR达到100%。在31例基线ctDNA G12C阳性患者中，有18例（58.1%）在C1D8时即检测到超过90%的血浆ctDNA清除。

结论

D3S-001作为第二代G12Ci，在KRAS G12C突变的非小细胞肺癌、结直肠癌和胰腺癌中显示出良好的耐受性和一致且有希望的疗效。
临床试验编号：NCT05410145

2.KRAS G12C阳性实体瘤患者接受单药Divarasib治疗的长期随访

摘要号：616MO讲者：Elena Garralda（巴塞罗那，西班牙）

背景

Divarasib（GDC-6036）是一种选择性的高效口服KRAS G12C抑制剂。本研究报告了单药Divarasib治疗晚期KRAS G12C阳性实体瘤患者的长期安全性和临床活性。

方法

作为正在进行的一项Ⅰ期研究（NCT04449874）的一部分，患者接受单药口服Divarasib，剂量为每日50~400 mg，直至出现不可耐受的毒性或疾病进展。评估内容包括安全性（NCI-CTCAE v5）和初步抗肿瘤活性（RECIST v1.1）。确认的缓解定义为在至少间隔4周的两次连续肿瘤评估中达到完全或部分缓解。

结果

截至2024年1月1日，已有153例患者接受了单药Divarasib治疗（非小细胞肺癌[NSCLC]：n=65；结直肠癌[CRC]：n=61；其他实体瘤[OST]：n=27）。中位治疗持续时间为9.57个月（范围：0~37.3个月），中位既往系统治疗线数为2（范围：0~8）。没有患者接受过KRAS G12C抑制剂治疗。
在43例继续接受Divarasib治疗超过1年的患者（31例NSCLC，8例CRC，4例OST）中，有20例（47%）在1年后出现了新发TRAE。1例患者（2%）出现了新发3级TRAE（体重减轻）；没有患者出现新发4~5级TRAE。1例患者（2%）出现了新发2级TRAE（恶心），导致剂量减少。没有新发TRAE导致Divarasib停药。
对于接受400 mg Divarasib治疗的患者，初步活性（包括ORR、PFS和DOR）如表1所示。
表1. 接受400 mg Divarasib治疗患者的ORR、PFS和DOR

图片

结论

单药Divarasib治疗晚期KRAS G12C阳性实体瘤患者1年后，结果显示患者耐受性良好，新发TRAE较少，并且显示出持久的临床活性。
临床试验编码：NCT04449874

3.Sotorasib（soto）、帕尼单抗（pani）和FOLFIRI在KRAS G12C突变转移性结直肠癌（mCRC）一线治疗中的安全性和有效性分析：来自Ⅰb期CodeBreaK 101研究的数据

摘要号：505O讲者：Salvatore Siena（米兰，意大利）

背景

在Ⅰb期CodeBreaK 101（NCT04185883）研究中，将soto加帕尼单抗联合FOLFIRI治疗用于既往接受过治疗的KRAS G12C突变mCRC患者，结果显示出可接受的安全性特征和有前景的ORR（60%）。在此，我们又评估了soto、帕尼单抗和FOLFIRI在KRAS G12C突变mCRC初治患者中的安全性和有效性。

方法

在2021年7月至2024年3月期间，全球17个研究中心入组了未接受过任何针对转移性疾病的系统性治疗的KRAS G12C突变mCRC患者，并给予推荐的Ⅱ期剂量soto（960 mg，口服，每日）、帕尼单抗（6 mg/kg，静脉注射[IV]，每2周一次[Q2W]）和FOLFIRI（IV Q2W）。主要终点是安全性和耐受性，次要终点包括ORR、DCR和中位缓解时间。

结果

研究共入组并治疗了40例患者（58%为男性；中位年龄为60岁）。100%的患者发生了与治疗相关的任何级别的不良事件，53%的患者发生了3级及以上的TRAEs；未报告致死性事件。最常见的3级及以上的TRAEs包括中性粒细胞减少症（23%）、痤疮样皮炎（18%）和腹泻（10%）。30例患者获得了确认的PR，ORR为75%。soto、帕尼单抗和FOLFIRI联合治疗的DCR为93%，中位缓解时间为1.5个月。
表2. 研究者评估的Soto+pani和FOLFIRI（N=40）的缓解情况

图片

结论

本研究提供了KRAS G12C抑制剂在mCRC一线治疗中的首组数据。soto、帕尼单抗和FOLFIRI联合在初治KRAS G12C突变mCRC患者中显示出可耐受的安全性特征和有前景的ORR。目前正在进行的Ⅲ期CodeBreaK 301研究（NCT06252649）将评估这种联合方案对比标准治疗在mCRC一线治疗中的疗效。
临床试验编码：NCT04185883

4.ASP3082在晚期胰腺癌、结直肠癌和非小细胞肺癌成人患者中的初步安全性和临床活性研究：一种首创的KRAS G12D选择性蛋白降解剂

摘要号：608O
讲者：Wungki Park（纽约，美国）

背景

ASP3082是一种靶向KRAS G12D的新型蛋白降解剂。本研究旨在描述ASP3082单药治疗在既往接受过治疗的晚期实体瘤患者中的初步安全性和抗肿瘤活性。

方法

这是一项Ⅰ期、剂量递增的首次人体研究，纳入了患有不可切除或转移性KRAS G12D阳性实体瘤的成人患者。患者接受ASP3082单药（10~600 mg）静脉给药，每周一次，每21天为一个周期。主要终点是剂量限制性毒性（DLT）和不良事件（AE）的发生率。

结果

数据截止日期为2024年4月1日，共入组98例患者（中位年龄：64岁；男性占56%；既往系统性治疗中位线数为2[范围：1~7]），包括胰腺癌（PC，n=67）、结直肠癌（CRC，n=16）、非小细胞肺癌（NSCLC，n=13）和其他肿瘤（n=2）。
69.4%（68/98）的患者发生了TRAEs，其中5例患者为3级，无4级或5级TRAEs。≥5%患者发生的TRAEs为疲劳（15.3%）、与输注相关的反应（14.3%）、瘙痒（9.2%）、恶心（7.1%）、荨麻疹（7.1%）、天冬氨酸氨基转移酶（AST）升高（7.1%）、丙氨酸氨基转移酶（ALT）升高（6.1%）和呕吐（5.1%）。
在450 mg剂量下观察到2例DLT（3级ALT升高；3级ALT/AST升高），在600 mg剂量下观察到1例DLT（3级ALT升高）。最大耐受剂量尚未达到。根据临床前模型模拟，预测的临床有效最低剂量大于100 mg。
疗效评估包括接受10~300 mg剂量的65例患者。≤90 mg剂量组共35例患者，ORR为0%，疾病控制率（DCR）为25.7%。在140 mg剂量组（n=9），ORR为11.1%（1例PR/5例PC），DCR为33.3%（2/5例PC，1/4例CRC）。在200 mg剂量组（n=9），ORR为0%，DCR为55.6%（3/7例PC，1/1例NSCLC，1/1例CRC）。在300 mg剂量组（n=12），ORR为33.3%（3例PR/7例PC，1例PR/4例NSCLC，0例PR/1例CRC），DCR为75.0%（5/7例PC，4/4例NSCLC，0/1例CRC）。

结论

正在进行的研究表明，ASP3082作为一种新型的KRAS G12D降解剂，具有可接受的安全性特征和有前景的抗肿瘤活性，特别是在经过多线治疗的胰腺癌患者中。基于这些结果，还需要进一步的研究。
临床试验编码：NCT05382559

摘要原文

615MO - Phase I/II study of D3S-001, a second generation KRAS G12C inhibitor in advanced/metastatic solid tumors with KRAS G12C mutations

Speakers：Byoung Chul Cho (Seoul, Korea, Republic of)

Background

D3S-001 is a 2nd generation KRAS G12C inhibitor (G12Ci) with faster target engagement kinetics, depletes cellular active G12C at nanomolar levels, a MoA relevant to stronger anti-tumor activity (Cancer Discov. 2024 in press). Preliminary results of FIH dose escalation cohorts were reported at AACR 2024. Here we report the updated analyses.

Methods

In the ongoing Phase 1/2 study (NCT05410145), pts were administered D3S-001 (50-900 mg po daily) until intolerable toxicity or disease progression. Endpoints included safety and preliminary efficacy by investigators per RECIST v1.1.

Results

As of 07 May 2024, a total of 42 pts (25 NSCLC, 13 CRC and 4 PDAC) were treated. Median follow-up was 6.8 months (m, range 0.2-18.3m) and 21 pts (50.0%) remain on-study treatment. No treatment-related DLTs or deaths during assessment period. TRAE of any grade occurred in 32 pts (76.2%). Of which, 7 (16.7%) were Grade 3 (no ≥ Grade 4) TRAEs. D3S-001 dose was modified in 12 pts (28.6%) due to TRAE, and none had dose discontinuation. In all 42 dosed pts, 38 had post-baseline tumor assessments, of which 34 were naïve to G12Ci and 4 were G12Ci pre-treated. In 34 G12Ci naïve pts (21 NSCLC, 9 CRC and 4 PDAC), PRs were achieved in 26/34 overall population (76.5%, 95% CI 58.8, 89.3%), with a confirmed ORR (cORR) of 70.6% (95% CI: 52.5%, 84.9%) and DCR of 97.1%. The 6m DoR rate was 70.5% (95% CI: 45.9%, 93.0%). The 6m PFS rate was 65.3% (95 CI%: 45.7%, 79.3%). Among 21 NSCLC pts, 15/21 (71.4%, 95% CI: 47.8, 88.7%) achieved PR, with a cORR of 66.7% (95% CI: 43.0%, 85.4%) and DCR of 100%. The 6m DoR rate was 70.0% (95% CI: 32.9%, 89.2%). The 6m PFS rate was 64.1% (95 CI%: 38.7%, 81.2%). Tumor shrinkage was observed in 2/6 NSCLC pts with stable brain metastases. Among 9 CRC pts, 7/9 (77.8%, 95% CI: 40.0%, 97.2%) achieved PR (all confirmed), with DCR of 88.9% and 6m DoR of 100%. Among 4 PDAC pts, 4/4 (100%) achieved PRs (3/4 confirmed). DCR of 100% achieved in 4 G12Ci pre-treated pts (2 NSCLC and 2 CRC). Over 90% plasma ctDNA clearance as early as at C1D8 was detected in 18 of 31 (58.1%) baseline ctDNA G12C positive pts.

Conclusions

D3S-001, a 2G G12Ci, demonstrated favorable tolerability and consistent promising efficacy across KRAS G12C-mutated NSCLC, CRC, and PDAC.

Clinical trial identification

NCT05410145.

616MO - Long-term follow-up of single-agent divarasib in patients with KRAS G12C-positive solid tumors

Speakers：Elena Garralda (Barcelona, Spain)

Background

Divarasib (GDC-6036) is an oral, highly potent, and selective KRAS G12C inhibitor. We report the long-term safety and clinical activity of single-agent divarasib in patients with advanced KRAS G12C-positive solid tumors.

Methods

As part of an ongoing phase I study (NCT04449874), patients received single-agent oral divarasib 50-400 mg daily until intolerable toxicity or disease progression. Assessments included safety (NCI-CTCAE v5) and preliminary antitumor activity (RECIST v1.1). Confirmed response was defined as complete or partial response on 2 consecutive tumor assessments at ≥4 weeks apart.

Results

As of 1 January 2024, 153 patients had received single-agent divarasib (non-small cell lung cancer [NSCLC]: n=65; colorectal cancer [CRC]: n=61; other solid tumors [OST]: n=27). Median treatment duration was 9.57 months (range: 0-37.3) and median lines of prior systemic therapy was 2 (range: 0-8). No patients had prior KRAS G12C inhibitor treatment. Among 43 patients (31 NSCLC, 8 CRC, and 4 OST) who continued divarasib beyond 1 year, 20 (47%) experienced a new-onset treatment-related adverse event (TRAE) after a year. One patient (2%) experienced a new-onset Grade 3 TRAE (weight decreased); no patients experienced new-onset Grade 4-5 TRAEs. One patient (2%) experienced a new-onset Grade 2 TRAE (nausea) that led to dose reduction. No new-onset TRAEs led to divarasib withdrawal. Preliminary activity, including objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR), are presented in the table for patients receiving divarasib 400 mg. Table: 616MO

ORR, PFS and DOR for patients receiving divarasib 400 mg

图片

Conclusions

Single-agent divarasib was well tolerated with few new-onset TRAEs after 1 year and continued to demonstrate durable clinical activity in patients with advanced KRAS G12C-positive solid tumors.

Clinical trial identification

NCT04449874.

505O - Sotorasib (soto), panitumumab (pani) and FOLFIRI in the first-line (1L) setting for KRAS G12C–mutated metastatic colorectal cancer (mCRC): Safety and efficacy analysis from the phase Ib CodeBreaK 101 study

Speakers：Salvatore Siena (Milan, Italy)

Background

In the phase 1b CodeBreaK 101 (NCT04185883) study, the addition of soto plus pani to FOLFIRI demonstrated an acceptable safety profile and a promising response rate of 60% for patients (pts) with previously treated KRAS G12C–mutated mCRC. Here, we evaluate the safety and efficacy of soto, pani, and FOLFIRI in treatment (Tx)-naïve pts with KRAS G12C–mutated mCRC.

Methods

Pts with KRAS G12C–mutated mCRC who had not received any prior systemic Tx for metastatic disease were enrolled at 17 global sites (between Jul 2021 and Mar 2024) and received the recommended phase 2 dose of soto (960 mg, oral, daily), pani (6 mg/kg, intravenous [IV], once every 2 weeks [Q2W]), and FOLFIRI (IV Q2W). Primary endpoint was safety and tolerability. Secondary endpoints included objective response rate, disease control rate, and median time to response.

Results

Forty pts were enrolled and treated (58% male; median age: 60 years). Tx-related adverse events (TRAEs) of any grade occurred in 100% of pts, and grade ≥ 3 TRAEs occurred in 53% of pts; no fatal event was reported. The most common grade ≥ 3 TRAEs included neutropenia (23%), dermatitis acneiform (18%), and diarrhea (10%). 30 pts had confirmed partial responses, with an overall response rate of 75%. Treatment with soto, pani, and FOLFIRI resulted in a disease control rate of 93% and median time to response of 1.5 months. Table: 505O

图片

∗Data are presented as n (%) unless indicated otherwise.

Conclusions

This study provides the first data set on the use of a KRASG12C inhibitor in 1L mCRC. The combination of soto, pani, and FOLFIRI demonstrated a tolerable safety profile and promising response rates in pts with Tx-naïve KRAS G12C–mutated mCRC. CodeBreaK 301 (NCT06252649), a phase 3 study, is currently enrolling to evaluate this combination in 1L mCRC against standard of care.

Clinical trial identification

NCT04185883

608O - Preliminary safety and clinical activity of ASP3082, a first-in-class, KRAS G12D selective protein degrader in adults with advanced pancreatic (PC), colorectal (CRC), and non-small cell lung cancer (NSCLC)

Speakers：Wungki Park (New York, United States of America)

Background

ASP3082 is a novel protein degrader selectively targeting KRAS G12D. Here, we describe the preliminary safety and antitumor activity of ASP3082 monotherapy in patients (pts) with previously treated advanced solid tumors.

Methods

In this phase 1, dose-escalation, first-in-human study, adults with unresectable or metastatic KRAS G12D-positive solid tumors were included. Pts received escalating doses of ASP3082 monotherapy (10–600 mg) intravenously once weekly over a 21-day cycle. Primary endpoints were incidence of dose-limiting toxicities (DLTs) and adverse events (AEs).

Results

Data cutoff was 1 April 2024, with 98 pts enrolled (median age: 64 years; 56% male; median [range] prior lines of systemic therapy: 2 [1–7]) who had PC (n=67), CRC (n=16), NSCLC (n=13), or other cancers (n=2). Treatment-related AEs (TRAEs) occurred in 68/98 (69.4%) pts, including 5 pts with grade (Gr) 3 and 0 pts with Gr 4 or 5 events. TRAEs occurring in ≥5% of pts were fatigue (15.3%), infusion-related reactions (14.3%), pruritus (9.2%), nausea (7.1%), urticaria (7.1%), aspartate aminotransferase (AST) increased (7.1%), alanine aminotransferase (ALT) increased (6.1%), and vomiting (5.1%). DLTs were observed in 2 pts at 450 mg (Gr 3 ALT increased; Gr 3 ALT/AST increased) and 1 pt at 600 mg (Gr 3 ALT increased). The maximum tolerated dose has not been reached. Based on a preclinical modeling simulation, the predicted lowest dose for clinical efficacy was >100 mg. Efficacy evaluation included 65 pts receiving 10–300 mg. A total of 35 pts received ≤90 mg; objective response rate (ORR) was 0% and disease control rate (DCR) was 25.7%. At 140 mg (n=9), ORR was 11.1% (1 partial response [PR]/5 PC) and DCR was 33.3% (2/5 PC, 1/4 CRC). At 200 mg (n=9), ORR was 0% and DCR was 55.6% (3/7 PC, 1/1 NSCLC, 1/1 CRC). At 300 mg (n=12), ORR was 33.3% (3 PR/7 PC, 1 PR/4 NSCLC, 0 PR/1 CRC) and DCR was 75.0% (5/7 PC, 4/4 NSCLC, 0/1 CRC).

Conclusions

The ongoing study suggests that ASP3082, a novel KRAS G12D degrader, has an acceptable safety profile and promising antitumor activity, especially in pts with heavily pretreated PC. Based on these results, further studies are needed.

Clinical trial identification

NCT05382559.

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