ASCO国际视野丨Dr. Gregorc点评KROCUS研究:一线KRAS G12C抑制剂与西妥昔单抗联合治疗有前景

作者:肿瘤瞭望   日期:2024/6/6 11:11:24  浏览量:695

肿瘤瞭望版权所有,谢绝任何形式转载,侵犯版权者必予法律追究。

意大利Candiolo癌症研究所Vanesa Gregorc在2024年美国临床肿瘤学会(ASCO)年会公布了II期临床试验KROCUS研究中KRAS G12C抑制剂福泽雷塞(Fulzerasib)联合西妥昔单抗用于一线非小细胞肺癌(NSCLC)治疗的数据(摘要号LBA8511)。Dr.Gregorc在《肿瘤瞭望》访谈中针对KROCUS研究结果以及KRAS靶向治疗难点分享见解。

意大利Candiolo癌症研究所Vanesa Gregorc在2024年美国临床肿瘤学会(ASCO)年会公布了II期临床试验KROCUS研究中KRAS G12C抑制剂福泽雷塞(Fulzerasib)联合西妥昔单抗用于一线非小细胞肺癌(NSCLC)治疗的数据(摘要号LBA8511)。Dr.Gregorc在《肿瘤瞭望》访谈中针对KROCUS研究结果以及KRAS靶向治疗难点分享见解。
 
福泽雷塞是首个中国自主研发的KRAS G12C抑制剂,KROCUS研究由著名肺癌专家Rafael Rosell牵头,是一项于2023年3月启动的欧洲多中心Ib/II期研究。截至今年4月19日,共有40名未经治疗的晚期KRAS G12C阳性NSCLC患者接受了福泽雷塞(600mg BID)联合西妥昔单抗治疗(500 mg/m2 Q2W)。大多数患者(95%)被诊断为IV期疾病,13名(32.5%)患有脑转移。
 
在接受至少一次治疗后肿瘤评估的33名患者中,研究者评估的客观缓解率(ORR)达到81.8%,疾病控制率(DCR)达到100%;脑转移患者的ORR为70%。中位缓解持续时间(DoR)尚未达到,88%的患者仍在接受治疗,中位随访时间为5.1个月。
 
KROCUS研究:肿瘤缓解情况
 
此外,联合治疗显示出良好的安全性/耐受性,87.5%的受试者发生治疗相关不良事件(TRAE),大多数TRAE为1-2级。约17.5%的受试者报告≥3级TRAE。没有4-5级TRAE。与单药治疗相比,未发现新的安全信号。
 
KROCUS研究:不良反应

01
《肿瘤瞭望》:根据II期KROCUS研究的数据,对于未经治疗的晚期KRAS G12C突变NSCLC患者,福泽雷塞联合西妥昔单抗的疗效如何?

Dr.Gregorc:直到五年前,KRAS还是一个“无药可治”的靶点。人们认为从药理学角度来看我们无法靶向这种蛋白质,而且我们也不确定靶向这种蛋白质是否对患者有用。幸运的是,多项研究将多个类别的KRAS抑制剂与二线化疗进行对比,其研究证据表明KRAS可能是可用药的靶点,并且可以通过药物靶向治疗。
 
目前KRAS靶向治疗出现的问题是,我们是否可以在一线使用KRAS靶向药物,特别是靶向治疗能否改善治疗效果。到目前为止,研究显示KRAS靶向疗法的反应率约为30-40%,考虑到我们习惯的EGFR抑制剂或ALK抑制剂的反应率可以达到70-80%,这个数字并不算高。
 
KROCUS研究中有两项创新性探索。首先,KROCUS研究将一种新型KRAS抑制剂福泽雷塞与西妥昔单抗相结合,以绕过耐药机制。这种联合方案有一些临床前模型的研究数据,要求在患者身上进行验证和测试。第二个创新是KROCUS研究将KRAS抑制剂用于一线治疗。KROCUS研究的策略是对的:福泽雷塞联合西妥昔单抗的总体反应率非常高,为81.8%。这非常接近EGFR抑制剂和ALK抑制剂中看到的数据,以及其他驱动基因阳性肿瘤中看到的疗效数据。KROCUS研究的疾病控制率为100%,88%的患者仍在接受治疗,所以这是非常有前景的,我们希望缓解持续时间和PFS也会很长。
 
福泽雷塞已经在中国患者中进行了探索,但KROCUS是在欧洲地区患者中进行的研究。这要感谢研究的赞助商劲方医药(GenFleet Therapeutics),以及让联合西妥昔单抗成为可能的默克公司。此外,我还要感谢所有支持这项重要研究的患者及其家属、研究人员和研究团队,例如护士和研究协调员。
 
Dr.Gregorc:Thank you very much for this question.Up until five years ago,KRAS was an“undruggable”target.It was thought that we were not able to target this protein from a pharmacological point of view,and we were also unsure if the targeting of this protein would be useful for the patients.Fortunately,different studies with different classes of agents were conducted compared to chemotherapy in the second-line,giving us evidence that KRAS may be druggable and targeted with pharmacological agents.
 
The question that arises is whether we can use these agents in first-line,and especially whether we can improve the results from these agents.The therapies explored till now have had a response rate of around 30-40%,which is not very high,considering what we were used to with EGFR inhibitors or ALK inhibitors that can reach 70-80%response rates.
 
In the case of the KROCUS study,we have explored two innovative things.First of all,we combined fulzerasib,which is a novel KRAS inhibitor,with cetuximab in order to bypass and contrast resistance mechanisms.This combination had some documentation from the pre-clinical models that demanded it be proven and tested in patients.The second innovative issue was that we used it in first-line.And we were right.The overall response rate in the KROCUS study was incredibly high-over 80%,in fact,82%overall response rate.This was very close to what we have been used to seeing with EGFR inhibitors and ALK inhibitors,and what we have seen in so-called addicted tumors.The disease control rate was 100%.Eighty percent of the patients are still on treatment,so this is very promising,and we hope the duration of response and PFS are also going to be very long.
 
First of all,fulzerasib has been explored in Chinese patients,but the KROCUS study has been conducted in European region patients.This is thanks to GenFleet Therapeutics who is the sponsor of the study,and also Merck who made it possible to use cetuximab.Moreover,I would like to thank all the patients and their families,the investigators and study teams,such as nurses and research coordinators,who supported this important study.

02
《肿瘤瞭望》:如何提高KRAS G12C突变晚期NSCLC的疗效,如何制定最佳序贯治疗策略?

Dr.Gregorc:我们希望将KRAS抑制剂作为一线治疗药物。关键是目前的疗效数据使其不能单药用于一线治疗。因此问题在于,与其序贯使用,如果将KRAS抑制剂与其他药物联合使用会怎样?与KRAS抑制剂联合的最佳搭档是什么?例如,最佳搭档可能是西妥昔单抗,以绕过耐药机制。我们应该使用两种不同的药物来靶向KRAS通路吗?还是应该将KRAS抑制剂与化疗或免疫疗法联合使用?目前还没有答案,相关研究正在进行中,明年将公布结果。可以肯定的是,KROCUS研究已经探索了一线治疗,因此我们知道可以期待什么,这是这项KROCUS研究的优势。
 
Dr.Gregorc:We can say that what we would like to do is go in the first-line with KRAS inhibitors.The point is that we cannot use it in monotherapy.So the question is,rather than in sequence,how do we combine them?What is the best partner to be combined with KRAS inhibitors?That might be cetuximab,for example,in order to bypass the resistance.Should we use the drugs to target the pathway with two different agents?Or should we combine the KRAS inhibitors with chemotherapy or with immunotherapy?There is still no answer to that.The studies are ongoing,and are going to reveal results next year.What is sure is that the KROCUS study has already explored the first-line setting,so we know what we can expect.This is the strength of this study.
 
03
《肿瘤瞭望》:请谈一谈KRAS G12C突变NSCLC靶向治疗的研究方向。

Dr.Gregorc:关于KRAS靶向治疗,第一个重点是我们已经用KRAS抑制剂治疗患者,这些抑制剂已显示出活性和治疗反应率,但疗效仍然有限。此外,另一个重点可能是安全性和不良事件。新型药物的活性更高,反应率更高,重点还在于安全性,不能忽视KRAS抑制剂的毒性,比如肝毒性、腹泻或干扰联合治疗的毒性。获胜者将是总体缓解率更好、安全性更高、不良事件更少的药物,如福泽雷塞。
 
Dr.Gregorc:So the point is,we have started with these KRAS inhibitors that have shown activity and a response rate,but these are still limited.Moreover,we have also seen that the point might be the safety and adverse events.The novel agents are even more active,the responses are higher,and the point is also about the safety profile,because it is very important not to ignore toxicities,such as hepatotoxicity or diarrhea or those that will interfere with the combinatory treatment.The winner is going to be the drug that has a better overall response and better safety with fewer adverse events,like fulzerasib.
 
参考文献
Gregorc V,et a.KROCUS:A phase II study investigating the efficacy and safety of fulzerasib(GFH925)in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC.2024 ASCO,abstract LBA8511.

 

版面编辑:张靖璇  责任编辑:无医学编辑

本内容仅供医学专业人士参考


肺癌

分享到: 更多