编者按：黑色素瘤是一种恶性程度极高的实体肿瘤，易早期发生转移，晚期患者预后极差。近年来，黑色素瘤的发病率和死亡率日益增加并呈年轻化趋势。目前，随着对该病发病机制研究的逐步深入及生物技术的不断进展，靶向及免疫治疗为改善晚期黑色素瘤患者的预后带来了希望。在近日举办的2023年欧洲肿瘤内科学会（ESMO 2023）年会中，《肿瘤瞭望》有幸在现场采访了麻省总医院癌症中心Ryan J.Sullivan教授，Sullivan教授分享了其对“晚期黑色素瘤患者靶向治疗何时优于免疫治疗”的看法，并详细分析了两种治疗手段在副作用方面的区别。

 

Sullivan教授：这是一个非常好的问题，也是一个棘手的难题，因为一些随机数据表明，对于BRAF突变黑色素瘤患者来说，如果最初就使用免疫治疗，效果会比靶向治疗更好。但是，在某些情况下，启动免疫疗法是不现实的，或者是不可能的。

 

其中一种情况是，患者服用了非常大剂量的类固醇类药物，这种情况通常发生在出现大量脑转移的患者身上。类固醇类药物（特别是大剂量类固醇类药物）的问题在于，其会降低免疫疗法的疗效。因此，对于此类患者，启动靶向治疗确实要比尝试免疫治疗更好。

 

另一种情况是，患者的严重自身免疫性疾病在持续的免疫抑制下控制不佳，或者患者因严重的自身免疫性疾病，正在接受大量的免疫抑制治疗，此类患者需考虑靶向治疗而非免疫治疗，因为免疫抑制会降低免疫治疗的效果。如果患者有BRAF突变，我们可能会考虑让他们开始接受BRAF靶向治疗。

 

第三种情况与上述情况非常相似，但不是自身免疫性疾病，而是实体瘤移植（实体器官移植）。进行实体瘤移植（实体器官移植）的患者正处于免疫抑制状态，此时给予免疫治疗不仅可能因为免疫抑制而疗效不佳，而且还可能给移植物带来风险。所以，如果患者出现抗移植物反应，就可能会排斥移植物。如果是肾脏移植，那么情况不太好，但患者至少可以通过透析存活下来。如果是肝脏、心脏或肺脏移植，患者很可能会因移植排斥反应而死亡。

 

综上，再次强调三种情况：（1）在脑转移的情况下，对于使用非常大剂量类固醇类药物的患者，若患者有BRAF突变，我们倾向于使用BRAF靶向治疗而非免疫治疗；（2）对于使用大量免疫抑制药物或患自身免疫性疾病未得到控制的患者，如果患者有BRAF突变，我们倾向于提供BRAF靶向治疗而非免疫治疗；（3）对于进行实体瘤移植（实体器官移植）的患者，一是担心排斥反应，二是担心免疫治疗在免疫抑制的情况下可能效果不佳，我们倾向于使用BRAF靶向治疗，而非免疫治疗。

 

Oncology Frontier:Based on your extensive research，could you provide some insights on when targeted therapy might outperform immunotherapy in patients with advanced melanoma?

 

Dr.Sullivan:It’s a very good question and it’s a tough question because there’s randomized data that suggests that patients do better if they start with immunotherapy than targeted therapy and patients with BRAF mutant melanoma.However，there are some scenarios where it’s either not practical to start immunotherapy or not possible.

 

One of those scenarios are patients who are on very high dose steroids that commonly will happen in the setting of patients who have substantial brain metastases upon presentation.The problem with steroids is they’ll make，particularly at high doses，they’ll make the immunotherapy less likely to work.And so in those patients，starting targeted therapy is absolutely going to be better than trying to start immunotherapy.

 

Another setting where we begin to think about targeted therapy over immunotherapy are patients who have very severe autoimmune disease that’s not well controlled with ongoing immune suppression or who have bad autoimmune disease and are on lots of immune suppression again because immune suppression can make the immunotherapy less likely to work.If that patient has a BRAF mutation，we might think about starting them on BRAF targeted therapy.

 

A third scenario is quite similar to that scenario，but instead of autoimmune conditions，it’s actually a solid tumor transplantation(solid organ transplantation).And in patients who have solid tumor transplantation(solid organ transplantation)，they’re on lots of immune suppression and giving immunotherapy not only may not work as well because of the immune suppression，but it also may put the transplant graft at risk.And so，again，if a patient has a trigger，a reaction against their transplant graft，that patient may reject their graft.If that’s a kidney，that’s not great，but they can at least go on dialysis and survive.If it’s their liver or their heart or their lungs，those patients are very likely to die as a result of the rejection of the graft.

 

So，again，the three scenarios，patients who are in very high doses of steroids in the setting of brain metastases，we tend to use BRAF targeted therapy over immunotherapy if they have a BRAF mutation;patients who are on lots of immune suppression or have uncontrolled autoimmune disease，we tend to offer BRAF targeted therapy over immunotherapy if they have a BRAF mutation;and then patients who have a solid tumor transplantation(solid organ transplantation)for fear of one rejection and two concern that the immunotherapy may be less effective in the setting of the immune suppression we tend to favor BRAF target therapy over immunotherapy.

 

Sullivan教授：从副作用的角度来看，它们非常不同。靶向治疗与我们通常认为人类服用的其他药物非常相似。当药物在体内的浓度足够高时，会同时产生好的和坏的影响。如果继续服药，药物的副作用往往会持续。如果停药，随着药物暴露量的减少，副作用会在可预测的时间内好转。然后你可以采用较低的剂量继续治疗，或者有时如果副作用足够严重，你必须停止治疗。我们看到的副作用类型也不同。

 

靶向治疗的副作用类型更多的是毒性药物的常见副作用（如引起胃部不适或腹泻），通常会引起皮疹、疲倦、乏力，其中大部分是口服片剂，因此也会引起味觉改变。这就是一般的副作用特征，在副作用何时开始、何时消失、何时停药以及降低剂量和减少剂量的可能性方面，它们更容易预测。

 

至于免疫治疗，副作用往往会在任何时候出现，也就是说，它们并不是总在服药三小时后出现。副作用出现的原因在于药物对T细胞产生的反应，而T细胞才是免疫疗法的真正药物。每当这些T细胞被激活，然后通过解除检查点而被释放出来时，副作用就会出现。所以，其副作用的可预测性要比化疗低一些，因为化疗时，我们几乎能够迅速获知患者接受化疗后的感受。因此，其副作用的发生有一定的随机性。副作用本质上是炎症性的，也就是说，这些副作用是免疫细胞进入组织并与组织发生负面作用的结果。但另一个问题是，如果停止用药，细胞仍然存在，仍然会被激活。免疫系统往往会产生这种前馈或正反馈调控。因此，你会出现炎症，炎症会不断加剧。而停药不足以让副作用消失。所以，我们通常需要通过免疫抑制来治疗副作用。然后再将其作为一个独立的问题来处理，逐渐减少类固醇类药物或最终使用的其他免疫抑制药物。

 

因此，靶向治疗的可预测性要高得多，就像我们给患者服用的大多数药物一样，停药后就会好转。如有必要，还可以减少剂量。免疫治疗在时间上的可预测性较差。如果患者病情严重，往往需要进行免疫抑制。而且，与靶向治疗相比，免疫治疗的毒性更可能是永久性的。

 

Oncology Frontier:In your studies，you’ve explored the development of novel molecular therapeutic agents for malignant melanoma.How do these targeted therapies compare to immunotherapies in terms of efficacy and potential side effects?

 

Dr.Sullivan:Yeah，so they’re very different from a side effects standpoint.Targeted therapy is very much like any other drug that we tend to think about humans taking.The drug gets in the system at a high enough level，it causes effects both good and bad.The side effects from drugs tend to continue if you continue the drug.If you stop the drug，the side effects get better within a predictable amount of time as the drug exposure is reducing.And then you can resume therapy at a lower dose or sometimes you have to stop therapy if the side effect was severe enough.The types of side effects we see also are different.

 

The types of side effects with targeted therapy are much more of the common side effects of sort of toxic agents like they cause stomach upset or diarrhea.They commonly cause rash，tiredness，fatigue，most of these are pills so they can also cause alterations of taste.That’s the general side effect profile，they’re much more predictable in terms of when the side effects will start and when they’ll go away when you stop the drug and then how likely are to lower the dose and come in with a dose reduction.

 

With regards to immune therapy，those side effects tend to happen whenever they happen，meaning it’s not quite，they always happen three hours after you take the dose，no.It’s like the cause of the side effects is a reaction that the drugs are having on the T cell，which is the actual drug of our immune therapies.So whenever those T cells get activated and then released by the relieving of the checkpoints that are placed upon them，that’s when the side effects kick in.So it’s a little less predictable than，say，chemotherapy，where we can know by the minute almost how a patient’s going to feel once they get dose of chemotherapy.So they happen a little bit，it’s a little seemingly more random when they happen.The side effects are inflammatory in nature，meaning that they occur as a result of immune cells getting into and interacting in a negative way to a tissue.The other issue about that，however，is if you stop the drug，the cells are still there and they’re still activated.The immune system tends to have this feed-forward or positive feedback loop.So you get inflammation，which gets more inflammation，which gets more inflammation.And so stopping the drug isn’t enough to have the side effect go away.And so very commonly we have to give immune suppression to treat the side effect.And then deal with that as its own issue with tapering the steroids or whatever immune suppression we end up using.

 

So targeted therapy，much more predictable，much more like most of the drugs we give to patients get better when you stop the drug.And you tend to be able to come back in with dose reductions if necessary.Immunotherapy，they tend to be a little bit less predictable in terms of timing.They tend to require，if they’re severe enough，immune suppression.And they also are more likely to be permanent than，say，a targeted therapy toxicity.

 

Ryan J.Sullivan

麻省总医院癌症中心血液学/肿瘤学副教授

Ryan J.Sullivan是一名临床和转化研究者，他的主要研究领域是开发治疗恶性黑色素瘤的新型分子治疗药物、将有前景的临床前研究成果转化为早期临床试验，以及为这些研究和标准治疗方法开发预测性生物标志物。

Dr.Sullivan是麻省总医院黑色素瘤中心（Center for Melanoma）和Teermer靶向治疗中心（Teermer Center for Targeted Therapy）的成员，也是Dana-Farber/哈佛癌症中心（DFHCC）黑色素瘤项目的成员，还是DFHCC机构审查委员会成员。