肺腺癌該用Anti-PD1? 還是不該用Anti-PD1? @ 探索癌症

下面是從cancercommons網站來的資料

https://www.cancercommons.org/2015/09/09/to-pd-l1-or-not-to-pd-l1-that-is-the-question/

雖然腫瘤呈現PD-L1是可以預測PD1抑制劑的效果但是FDA沒有規定腫瘤必須呈現PD-L1才能使用

Expression of the protein PD-L1 on tumors has been thought to be a good predictor of a patient’s response. However, none of the three FDA approvals mention expression of PD-L1 as a prerequisite for prescribing these drugs. Attempts to figure out the prognostic significance of PD-L1 are at their peak, though it is not yet clear what lies beyond. Nonetheless, it is of obvious importance: there is no compelling reason to give these very expensive drugs to patients who are not likely to benefit from them.

Here is a very brief history of this complicated connection: in 2012, the very first sensational publicationreported on the activity of nivolumab in three different cancers. The study looked at PD-L1 expression in about 15% of patients who participated in the clinical trial. Of 17 patients with PD-L1-negative (no PD-L1 detected) tumors, none had a measurable response, whereas 9 of 25 patients (36%) with PD-L1-positive tumors responded. This report certainly put PD-L1 at the center stage of anti-PD-1 development, but it was only the beginning.

在KEYNOTE-001實驗中病人腫瘤有PD-L1高度呈現 45%對治療有反應但是腫瘤沒有PD-L1的病人也有10%對治療有反應

Numerous following trials have reported that the efficacies of pembrolizumab (Keytruda) and nivolumab (Opdivo) indeed correlate with expression of PD-L1, but only to a degree. For example, in the KEYNOTE-001 trial, patients whose lung tumors had high levels of the PD-L1 protein had a response rate of 45%, but 10% patients whose tumors tested negative for PD-L1 also responded.

即使正在開發中的anti-PD-L1藥品像是atezolizumab和durvalumab 也沒有要求腫瘤有PD-L1表象但是腫瘤有PD-L1表象反應率比較高

Even the anti-PD-L1 drugs in development, atezolizumab (previously known as MPDL3280A) and durvalumab (MEDI4736), do not show a strict dependence on the presence of their target PD-L1 in tumors, as would have been expected. Across several tumor types, responses to these drugs have been observed more often in PD-L1-positive tumors, but also in a lower proportion of PD-L1-negative ones.

三年來還是沒有定論腫瘤有PD-L1表象不保証anti-PD-1藥品一定有效腫瘤沒有PD-L1表象也不表示沒反應

Three years later, there is still no consensus regarding the value of PD-L1 expression in NSCLC as a predictive marker of response. Across the board, positivity for PD-L1, while predictive of response, does not always guarantee it, and lack of PD-L1 does not exclude response. Obviously, one must conclude that PD-L1 is just one of several (many?) factors that determine the likelihood of response. To compound the PD-L1 problem, there is a lack of defined criteria about what ‘PD-L1-positive tumor’ really means:

The criteria used to define the PD-L1 status of a tumor biopsy differ vastly. In trials of nivolumab, the cutoff used is 1% to 5% of positive cells in a biopsy. For pembrolizumab, the cutoff is 1% to 50%! And for atezolizumab it is 1% to 10%.
Different companies in the checkpoint drug business use PD-L1 reagents from different commercial sources to measure its levels and, without doubt, these different reagents have different sensitivities.
Possibly the most confounding factor is that PD-L1 expression in tumors is not stable: not only can it be confined to different parts of tumors, but it can appear and disappear, depending on treatments and other poorly understood influences.

主導免疫治療發展的醫師都同意不管病人的腫瘤是否有PD-L1表象他們都會給4期肺腺癌和黑色素瘤病人anti-PD-1藥品治療這個選項

Leading clinicians agree that they would give anti-PD-1 drugs to patients with metastatic lung cancer or melanoma regardless of PD-L1 status, according to FDA guidelines. At the same time, many ongoing clinical trials testing these drugs group patients based on PD-L1 expression, or simply exclude patients without PD-L1 expression in their tumors.

今天 PD-L1表象並不是很好的生物指標因為就算腫瘤沒有PD-L1表象病人從anti-PD-1藥品得到的好處遠比使用化療要好 (David: 那是顯而易見的一個是幫助免疫系統對抗癌症一個是毒害身體殘害免疫系統)

如果肺腺癌病人有10% 到12%機會對anti-PD-1 有反應他們應該會選擇anti-PD-1 而不是傷害身體而且可能只是短期有效的化療

Right now, PD-L1 is just not a good enough biomarker to exclude patients from receiving an anti-PD-1 drug, because even PD-L1-negative patients derive more benefit from PD-1 blockade than from docetaxel (a standard chemotherapy drug). If patients with PD-L1-negative NSCLC have a 10% to 12% chance of a meaningful response, they may be strongly inclined to receive a PD-1 or a PD-L1 blocker rather than going for a harsh conventional chemotherapy that may provide only a short-lived response.

One more problem is that most trials with checkpoint blockers only accept PD-L1-positive patients. This not only deprives patients from potentially life-prolonging treatment, but precludes a meaningful analysis of what determines the possibility of response in patients with PD-L1-negative tumors.

統計至今進行過的大小20個臨床實驗1,475病人腫瘤有PD-L1表象的反應率是34.1% 腫瘤沒有PD-L1表象的反應率是19.9%

A recent study conducted a meta-analysis of 20 trials (1,475 patients) with nivolumab, pembrolizumab, and atezolizumab in NSCLC, melanoma, and genitourinary cancers. It looked at correlations between the presence of PD-L1 on tumors and patients’ responses. Significant differences were seen in NSCLC and melanoma, but not genitourinary cancers. Ignoring the different cutoffs for PD-L1 expression in different trials, responses were observed in 34.1% of PD-L1-positive and 19.9% of PD-L1-negative patients who were treated with nivolumab and pembrolizumab. This difference is obviously significant, but not tremendous.

臨床實驗排除腫瘤沒有PD-L1表象的病人是錯誤的

Excluding PD-L1-negative patients from trials of immune checkpoint inhibitors appears to be a fallacy. Ignoring many other possibilities, it is entirely probable that because of the shortcomings of reagents, and the elusive nature of PD-L1, many PD-L1-negative tumors may be ‘false-negative‘; they really do express enough PD-L1 to respond to immune checkpoint drugs.