根据在2024年欧洲肺癌大会（ELCC 2024）上提交的PACIFIC-2试验的最终结果（摘要#LBA1），在不可切除的III期非小细胞肺癌（NSCLC）患者中，与单独放化疗（CRT）相比，在放化疗的同时开始免疫治疗，然后进行巩固免疫治疗，没有为患者带来显著的生存获益。《肿瘤瞭望》在布拉格现场邀请研究作者、埃默里大学医学院Jeffrey D.Bradley教授对研究结果予以解读。

 

 

在III期、随机、双盲、安慰剂对照、多中心、PACIFIC-2全球研究中，328例初治III期NSCLC患者被随机（2∶1）接受每4周1次的放化疗（CRT）加度伐利尤单抗（durvalumab）或安慰剂静脉给药，并接受度伐利尤单抗或安慰剂巩固治疗，直至疾病进展。

 

自从PACIFIC试验发布5年总生存（OS）和无进展生存（PFS）持续改善的数据，放化疗后无进展的患者接受1年度伐利尤单抗巩固治疗已经成为不可手术III期NSCLC的标准治疗（N Engl J Med 2017；377:1919-1929），然而由于同步放化疗期间或之后疾病进展、放射性肺炎或其他不良事件，多达1/3的患者不适合接受巩固治疗。

 

PACIFIC-2试验观察到度伐利尤单抗组PFS有改善趋势，但未达到统计学显著性（ELCC 2024，LBA1）

 

中位随访30.5个月时，度伐利尤单抗组的中位PFS为13.8个月，而安慰剂组为9.4个月，免疫治疗有PFS改善趋势，但未达到统计学显著性（HR=0.85；95%CI:0.65~1.12；P=0.247）（图）。据报告，度伐利尤单抗与安慰剂相比，OS无显著差异（HR=1.03；95%CI:0.78~1.39；P=0.823）。

 

在安全性方面，在同期治疗的前4个月，度伐利尤单抗组中导致死亡或停药的不良事件（AE）数量更多。两组的肺炎或放射性肺炎的发生率和严重程度相似，安全性和耐受性与每种治疗的已知特征一致。

 

Dr.Bradley：不可切除III期NSCLC患者的当前标准疗法由PACIFIC研究确立：在完成放化疗后，疾病未进展患者接受长达一年的度伐利尤单抗治疗。目前还没有研究提示在放化疗过程中更早进行免疫治疗能够获益的迹象。还有许多正在进行或已完成患者招募的试验也在问同样的问题，谁知道这些试验是否会得到与PACIFIC-2相同的结果？

 

PACIFIC-2纳入的患者群体很不一样，肿瘤体积大，中心型，患者来自全球各地，有更多来自亚洲的患者（例如，约三分之一的患者来自亚洲，约三分之一来自南美洲），所以我们不知道在另一个地理区域患者中开展研究的结果是否会相同，我们将拭目以待。

 

目前来看，不应该在放化疗期间进行免疫治疗，而是应该在放化疗结束后给药。有些人认为PD-L1并不是一个很好的肿瘤标志物，我们需要改进肿瘤标志物。例如，可能ctDNA是更好的选择，可用于确定患者需要继续免疫治疗多久（也许不到一年，也许是三个月或六个月）。所以在PACIFIC确立治疗方案后，我们仍然有很多问题可以问，但我认为，不可切除III期NSCLC治疗的骨干方案仍然是PACIFIC研究的方案。

 

Dr.Bradley:Patients with unresectable stage III NSCLC who get chemoradiation therapy today，after they complete chemoradiation，they should get durvalumab for up to a year，just like in the PACIFIC study.There is no indication right now to give it earlier during the course of chemotherapy and radiation.There are many other trials that are ongoing or have completed accrual that are asking the same question.Who knows whether those trials will have the same result as PACIFIC-2?

 

We had a very different patient population-we had large central tumors;we had worldwide distribution;we had more patients from Asia(about one-third were from Asia，and about a third from South America，for example)，so whether the results will be the same from another geographic location，we don’t know and will have to see.

 

Right now，it doesn’t look like you should give it during chemotherapy and radiation therapy，but you definitely should give it after.Some people think that PD-L1 is not such a great tumor marker，and we need to improve our tumor markers.We could do a better job perhaps with ctDNA，for example，to find out how long we need to continue this therapy.Maybe it is less than a year;maybe three months or six months.So there are many questions that we can still ask，but the backbone，I think，is still the PACIFIC study.

 

Dr.Bradley：根据你的问题，患者已经完成了化疗和放疗的整个疗程，并完成了长达一年的免疫治疗。这位患者可能是在完成免疫治疗之前，也就是在免疫治疗期间发生疾病进展，也可能是在免疫治疗停止后疾病进展。在这种情况下，需要重新对患者进行肿瘤分期。

 

*如果PACIFIC方案治疗进展后，出现一处孤立的转移，应该非常积极地治疗，并考虑手术或局部放疗。

 

*如果发生多个转移，应该从头开始，重新给病人做活检，检测分子异常和突变情况；如果检测出有靶向药可用的靶点，则为患者提供一种靶向疗法，否则给予化疗/免疫治疗。对于PACIFIC方案失败后的治疗，患者存在很多不同的情况。

 

具有讽刺意味的是，在PACIFIC-2研究中，大约一半的患者没有接受任何后续治疗。这也是PACIFIC-2的不同之处，我没有在2024 ELCC展示数据。试验中一半的患者在治疗失败后没有接受后续治疗，我认为现实世界中大多数患者会接受二线治疗。

 

Dr Bradley:Your question might indicate the patient has competed a full course of chemotherapy and radiation，and completed，let’s say，up to a year of immunotherapy.Maybe its before completion and they progress during immunotherapy or maybe after the immunotherapy has stopped.You would re-stage that patient.If they have one isolated metastasis，you should treat that very aggressively，and consider surgery or localized radiation therapy.If they have multiple metastases，I think you start from scratch.You re-biopsy the patient.You test for molecular abnormalities and mutations.You then deliver a treatment that might need a targeted therapy if there is an actual target，or give chemotherapy and immunotherapy.There are a lot of different scenarios where you might add more treatment to patients who fail on the PACIFIC study regimen.

 

Ironically，in our study，about half the patients didn’t get any subsequent therapy.That is something that is also different about PACIFIC-2.I didn’t show the data，but half the patients after they failed didn’t get a subsequent therapy.Today，I think most patients would get second-line treatment.

 

Dr.Bradley：我是一名放射肿瘤学家，当你问我未来会怎样，我想到的是临床试验以及我们可以做些什么来改善患者的结果。我来举例说明：

 

*我们可以探索不同的放疗技术，比如开展质子治疗的试验，中国有研究质子治疗的单位，正在为质子治疗的试验招募患者。对于肺癌患者而言，可回避淋巴细胞和心脏的质子治疗存在优势。

 

*我们有一项关于能量肿瘤的试验（我是能量肿瘤委员会主席，这是美国的一个协作组），该试验研究了针对原发肿瘤进行立体定向放射治疗，针对淋巴结进行放化疗。

 

*我今天在ELCC会议又听说了另一个探索方向——人们正在尝试做心脏回避治疗计划，使放射疗法不再施加在心脏，这似乎在许多试验中都是一个问题，可能包括PACIFIC-2。

 

我认为对于局部晚期NSCLC患者的治疗，未来我们可以探索和关注的内容有很多。

 

Dr.Bradley:I am a radiation oncologist，so when you ask a question about what does the future hold，that makes me think about clinical trials and what we can do to improve the outcomes for patients.There are different radiation techniques we can explore.There are trials in proton therapy.You have proton therapy units in China，and you are accruing to trials on proton therapy in China.In lung cancer，missing lymphocytes with protons and missing the heart with protons could be an advantage for patients.We have a trial with Energy Oncology(I am the Committee Chair for Energy Oncology，which is a cooperative group in the United States)where the trial investigated stereotactic radiation therapy to the primary tumor and chemoradiation to the nodes.Those are two examples.I learned of another one today-people are trying to do cardiac avoidance treatment planning，so we don’t treat a portion of the heart with radiation therapy，which looks to be an issue in a number of trials，perhaps including PACIFIC-2.So I think there are lots of things we can look at in the future for our patients with locally advanced disease.

 

参考文献：

Bradley JD，et al.Durvalumab in Combination with Chemoradiotherapy for Patients with Unresectable，Stage III NSCLC:Final Results from PACIFIC-2.European Lung Cancer Congress 2024，LBA1