来自玛格丽特公主癌症中心、多伦多大学的学者Natasha B.Leighl在2024 ASCO报告了PALOMA-3试验的主要结果：对于难治性EGFR突变晚期非小细胞肺癌（NLCLC），皮下给药比静脉给药Amivantamab（埃万妥单抗）+Lazertinib（拉泽替尼）更快、更简便，疗效令人鼓舞。

 

Amivantamab是一种靶向EGFR和MET的双特异性单克隆抗体。随机III期PALOMA-3试验比较了皮下和静脉注射Amivantamab与Lazertinib联合给药的药代动力学、疗效和安全性。2024 ASCO报道的结果显示：皮下给药在药代动力学、总体缓解率（ORR）和缓解持续时间（DoR）方面不劣于静脉给药；同时，皮下给药在总生存期（OS）、治疗时间、输液相关反应（IRR）和静脉血栓栓塞（VTE）发生率以及给药的简易性方面优于静脉给药。Dr.Leighl在《肿瘤瞭望》现场采访中进一步对PALOMA-3试验结果予以解读。

 

Dr.Leighl：Amivantamab目前已获FDA批准以静脉注射剂型用于肺癌患者，但其治疗耗时几个小时，并且输液相关反应的发生率很高。因此，PALOMA-3试验探索了皮下注射Amivantamab，以观察能否改善患者体验。PALOMA-3是一项大型、全球、随机的III期研究，在之前接受过奥希替尼和铂类化疗的局部晚期或转移性EGFR突变NSCLC患者中，比较了皮下注射和静脉注射Amivantamab，均与Lazertinib联合使用。

 

PALOMA-3试验设计

 

研究发现皮下注射Amivantamab组的药代动力学参数不劣于对照组。

 

皮下注射组的疗效结果不劣于静脉注射组，治疗应答率相似（皮下组ORR为30%，静脉注射组为33%）；皮下注射组的缓解持续时间在数值上更长（中位DoR：11.2个月vs 8.3个月；DoR≥6个月的患者比例：29%vs 14%）。

 

皮下注射组的无进展生存期有更好的趋势，PFS HR为0.84（中位PFS：6.1个月vs 4.3个月）；令人惊讶的是，皮下注射Amivantamab的总生存期有所改善，OS HR为0.62（两组的中位OS都尚未达到），具有统计学意义，P值为0.02。本试验将对OS进一步开展研究。

 

PALOMA-3试验：ORR和DoR

 

PALOMA-3试验：PFS

 

PALOMA-3试验：OS

 

皮下注射Amivantamab似乎也更安全。皮下和静脉注射组的大多数副作用相似，例如皮疹和皮肤毒性，这些副作用大多为低级别（1-2级）；然而，皮下注射Amivantamab的输液相关反应发生率显著降低（13%vs.66%）。

 

这项研究建议进行预防性抗凝治疗以避免VTE（静脉血栓栓塞症），接受预防治疗的患者中10%出现了VTE，而未接受预防治疗的患者中21%出现了VTE，预防性抗凝治疗将血栓风险降低了一半。在皮下注射组中，无论患者是否使用预防性抗凝治疗，VTE的发生率都比静脉注射组更低。

 

最后，皮下注射是否改善了患者感受？皮下给药耗时5分钟，而静脉注射首次给药则超过5个小时，后续每次静脉注射需要2小时。患者非常喜欢皮下注射方法，85%的患者认为皮下给药很便利或非常便利，其便利性远远高于静脉注射组。

 

总体而言，PALOMA-3研究表明，皮下注射治疗的效果并不逊色，疗效与静脉注射相同甚至有时更好，包括令人惊讶的OS获益，并且总体毒性特征更好，IRR和VTE发生率显著降低。此外，也许最令人称道的是，皮下注射的给药速度更快，治疗负担更少。展望未来，我们计划将皮下注射纳入所有Amivantamab适应症，以改善患者体验。

 

Dr Leighl:Amivantamab is currently approved for use in patients with lung cancer as an intravenous formulation，but this can take several hours and there is a high rate of infusion-related reactions.So in PALOMA-3 we worked with subcutaneous amivantamab to see if it could improve the patient experience.This was a large，global，randomized，phase III study.We compared patients with subcutaneous amivantamab to those receiving intravenous amivantamab，both in combination with lazertinib，in patients with EGFR-mutant lung cancer who previously received osimertinib and chemotherapy.

 

We found pharmacokinetic non-inferiority.We also found non-inferior efficacy outcomes，similar response，longer duration of response with subcutaneous amivantamab（just over 11 months，compared to just over 8 months），a trend to better progression-free survival with a hazard ratio of 0.84，and，to our surprise，improved overall survival with subcutaneous amivantamab with a hazard ratio of 0.62.We are looking into this further.This was statistically significant at 0.02.

 

It also appeared safer.Most side effects were the same between subcutaneous and IV，for example，rash and skin toxicity.These were mostly low grade-Grade 1 and 2-but we did see a marked reduction in the rate of infusion-related reactions with subcutaneous amivantamab-13%compared to 66%with the intravenous version.We also saw a lower rate of thrombotic events.In our study，we did recommend prophylactic anticoagulation to avoid the risk of VTE（venous thromboembolism），and we saw this cut the risk in half from 21%in patients who didn’t take it versus 10%in those who did.Also in the subcutaneous amivantamab arm，all the patients had lower rates of VTE with or without prophylaxis.

 

Finally，did we make things better for patients?We were able to give subcutaneous amivantamab in less than 5 minutes to patients in that arm，compared to over 5 hours on the first day of the intravenous arm，and of course requiring patients to come back for day two for split dosing and 2 hours for subsequent IV administrations.Patient really preferred this and 85%found it convenient or very convenient;much higher than the IV arm.

 

Overall，we showed in PALOMA-3 that treatment was non-inferior，efficacy outcomes were the same or sometimes better，including a surprising survival signal，and toxicity on balance was better with a significantly reduced rate of IRRs（infusion-related reactions）and VTE.Also，and perhaps the crowning glory，much faster administration and much less treatment burden.Moving forward，it is our plan to incorporate this across all amivantamab indications to improve the patient experience.

Dr.Leighl：自2009年起，我们开始使用EGFR-TKI作为EGFR突变NSCLC一线治疗，之后换用第二代EGFR-TKI，现在正在应用第三代EGFR-TKI，如奥希替尼。靶向治疗改善了疗效，但不幸的是，许多患者在18-19个月内病情进展，包括发生脑转移。因此，去年发布的FLAURA2和MARIPOSA试验数据以及今年报道的更多数据非常令人兴奋。

 

FLAURA2研究将化疗添加到奥希替尼中，对比单独使用奥希替尼，MARIPOSA采用类似的第三代EGFR-TKI Lazertinib联合双特异性抗体Amivantamab，这两项研究中的联合方案都带来PFS显著改善，呈现明显改善OS的趋势，但也都具有更大的毒性。

 

所以，现在我们医生与患者交谈时面临的挑战是，如何判断哪些患者需要使用FLAURA2或MARIPOSA中的联合方案进行强化治疗，哪些患者可以单独使用奥希替尼，目前可参考的高风险标志物包括：发生脑转移、转移部位更多、存在共突变（例如同时携带TP53突变）以及基线时ctDNA阳性，这类患者可能更需要强化治疗。Dr.Jänne在2024 AACR上展示了这些发现。

 

关于哪些患者需要联合方案，我们仍需要与患者的讨论，高风险人群可能确实受益于联合治疗，我们应告知患者这一点。个人认为，我们中的许多人内心仍然非常倾向于单药奥希替尼治疗或单药第三代EGFR-TKI，因此我们正在努力研究哪些患者可以安全接受这种毒性小的单药方案。

 

Dr.Leighl:It has been since 2009 when we first started using EGFR kinase inhibitors as our frontline therapy.Since then，we have moved to second-generation and now third-generation drugs，like osimertinib.It has really been a fantastic story.But unfortunately，many of our patients progress by 18-19 months，including in the brain.So it is very exciting to see data last year and more data this year looking at FLAURA2，where chemotherapy was added to osimertinib compared to osimertinib alone，and also the MARIPOSA study，where lazertinib，a similar third-generation EGFR kinase inhibitor was added to amivantamab，a bispecific antibody.Both of these showed marked improvements in progression-free survival.They have both shown clear trends to improved overall survival.Of course，they both have more toxicity，so now the challenge，when we talk to our patients，is who needs intensified therapy with either FLAURA2 or MARIPOSA versus who can just have osimertinib alone.We know some of the markers of high risk include:brain metastasis;more sites of metastasis;patients with co-mutations，such as co-mutant TP53;and there are also，of course，other factors，including ctDNA positivity at baseline that might favor intensified treatment versus non-intensified treatment.Dr Jänne showed those at AACR this year.

 

So I think it is still a discussion with patients.I think we know that our high risk patients probably do benefit from combinations，and we should talk to them about that.I think，at heart，many of us still really like single agent osimertinib or single agent third-generation TKIs，so we are working very hard to see which of our patients can receive that safely with less toxicity.

 

Dr.Leighl：这是一个激动人心的时刻。我们已经从第一代EGFR-TKI发展到第二代EGFR-TKI，现在是第三代EGFR-TKI，以及EGFR-TKI联合化疗或双特异性抗体（比如Amivantamab），还有许多关于新药的研究——阿美替尼、Lazertinib和许多其他药物——真正试图改善世界各地获得第三代EGFR-TKI治疗的机会。

 

为了继续改善这类患者的治疗，我们现在面对的问题是：如何利用这些新治疗策略为患者提供最好的服务？如何确保最高风险的患者得到强化治疗，而较低风险的患者能避免强化治疗的毒性和更高成本，从奥希替尼单药治疗中获得良好效果。我认为这是一个新兴的研究领域。此外，前期放疗的作用也非常重要。目前正在进行NORTHSTAR这类的研究（II期NORTHSTAR旨在确定在未经治疗或TKI耐药的转移性EGFR突变型NSCLC患者中，如果在奥希替尼诱导治疗6-12周后病情未出现进展，则先进行局部巩固治疗[LCT；放疗+/-手术切除]，然后接受奥希替尼治疗，与单独使用奥希替尼相比是否可以延长PFS）。我认为这些都是非常令人兴奋的治疗方法。此外，研究人员正在探索ctDNA的作用，评估血浆检测能否指导治疗，在中国和其他地方正在进行一些很棒的研究，探讨如何使用这项伟大的新技术。

 

Dr.Leighl:It has been such an exciting time.We have gone from first-generation to second-generation，and now third-generation EGFR kinase inhibitors，now combination therapies adding chemotherapy or adding bispecific antibodies，like amivantamab.There are also a number of studies of novel drugs-almonertinib，lazertinib，and many other drugs-really trying to improve access to third-generation kinase inhibitors around the world.

 

I think moving forward，the questions now are:how do we do the best for our patients with these new strategies?How do we make sure the highest risk patients get intensified therapies，and lower risk patients avoid those toxicities and cost，but still do well on osimertinib?I think this is an area of emerging investigation.Also the role of up-front radiotherapy is very important.There are studies like NORTHSTAR that are currently accruing，where patients get induction osimertinib and then randomized to either continue or have surgery or radiotherapy.I think these are all very exciting approaches.Also，what about ctDNA?Can we use plasma testing to help us direct therapy?There are some great studies ongoing in China and other places，looking at how we can use this great new technology.

 

参考文献

Leighl NB，et al.Subcutaneous amivantamab vs intravenous amivantamab，both in combination with lazertinib，in refractory EGFR-mutated，advanced non-small cell lung cancer(NSCLC):primary results，including overall survival(OS)，from the global，phase 3，randomized controlled PALOMA-3 trial.J Clin Oncol.2024;42(suppl 17):LBA8505.doi:10.1200/JCO.2024.42.17_suppl.LBA8505