Should PD-L1 Testing Be Done Before Cancer Immunotherapy?

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Should PD-L1 Testing Be Done Before Cancer Immunotherapy?

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Should PD-L1 Testing Be Done Before Cancer Immunotherapy?

Many are familiar with the need for genetic testing before using targeted therapies.

For instance, in non-small cell lung cancer, patients typically undergo testing for genes like EGFR, ALK, ROS1, RET, and others.

If a corresponding mutation is found, a targeted therapy is used.

With the increasing popularity of PD-1 immune checkpoint inhibitors, people naturally wonder:

should genetic testing also be done before immunotherapy?

And what exactly is PD-L1 testing all about?

This article will  discuss this, focusing primarily on lung cancer.

First point:

The reason genetic testing is recommended before targeted therapies is because it helps predict the effectiveness of the drug. For example, patients with EGFR mutations respond well to EGFR-targeted therapies, but those without the mutation don’t experience the same benefits.

The value of clinical biomarkers lies in tailoring treatment to the patient. Genetic testing is just one type of biomarker, with various blood indicators and tumor-expressed proteins being other examples.

The choice of biomarker during treatment is closely related to the characteristics of each drug. EGFR gene mutations can predict the effectiveness of EGFR-targeted therapies because these drugs specifically target cells carrying EGFR mutations. So, if you have the mutation, you’ll likely respond to the treatment; without it, the treatment is less effective.

However, immunotherapy is different. PD-1 immune checkpoint inhibitors target the immune system, so their mechanism of action is entirely different from targeted therapies that directly act on cancer cells, and consequently, the biomarkers are different too. Simple genetic testing has limited significance for them.

PD-L1 staining in tumors is one of the common immune biomarkers.

PD-L1 staining involves using specific antibodies to detect the expression of the PD-L1 protein in (tumor) tissue. The result is visualized under a microscope, and it looks something like this:

PD-L1 protein expression is shown in brown, with darker staining indicating more coverage of cells and stronger positivity. In the image, the leftmost tissue is negative (PD-L1 staining positive in <1% of cells), while the rightmost is strongly positive (PD-L1 staining positive in >50% of cells).

Current mainstream theories suggest that some tumor cells use high PD-L1 protein expression to bind with PD-1 protein on immune cells, suppressing the immune cells’ attacks. The action of PD-1 inhibitors, in contrast, breaks this PD-L1 and PD-1 binding, activating immune cells, especially T cells, to attack tumor cells.

Following this theory, some speculate that the more PD-L1 a tumor expresses, the better PD-1 immune checkpoint inhibitors might work. In some clinical trials, such as those for melanoma, there have been promising signs. Overall, patients with high PD-L1 expression are more likely to respond to immunotherapy.

However, this is a general trend and individual cases are much more complex. The clinical use of PD-L1 as a biomarker remains highly debated because it cannot accurately predict individual responses.

In almost all clinical trials, some PD-L1-negative patients responded to immunotherapy, and some strongly PD-L1-positive patients showed no response at all. Although PD-L1-negative patients, on average, have lower response rates, once they do respond, their outcomes are similar to those of PD-L1-positive patients. For example, in the CheckMate 057 trial, the median duration of response for non-squamous non-small cell lung cancer patients with strong PD-L1 staining (>50%) treated with Opdivo (Nivolumab) was 16 months, while for PD-L1-negative patients, it surprisingly reached 18.3 months.

The efficacy of PD-L1-negative squamous cell carcinoma patients is also clear. In the Checkmate 017 study, after a 2-year follow-up, Opdivo (Nivolumab) treatment reduced the risk of death by 42% compared to chemotherapy. For PD-L1-positive squamous cell carcinoma patients, the 2-year follow-up showed a significant 25% reduction in the risk of death compared to chemotherapy. This suggests that regardless of PD-L1 expression status, squamous cell carcinoma patients can benefit from treatment.

So, we clearly cannot tell PD-L1-negative patients that “you cannot use immunotherapy because it will definitely be ineffective.”

There is still no consensus on how to handle PD-L1 as an “immune biomarker.”

Secon point:

PD-L1’s less-than-ideal status as a biomarker is due to technical issues, particularly with staining. For instance, different antibodies can yield different results, and variations in sample processing can also lead to different outcomes.

Beyond this, there are more significant biological reasons for PD-L1’s limitations as a biomarker, primarily two:

Firstly, uneven distribution: PD-L1 is not uniformly distributed within tumors. In the same tumor tissue, some areas may express PD-L1 positively, while others may express it negatively. This randomness can lead to issues because sampling might capture either positive or negative expression. A tissue section deemed “PD-L1 negative” could potentially become “positive” if sampled from a different location.

Secondly, expression instability: PD-L1 protein expression is influenced by many molecular signals and can dynamically change. Tumor tissue that appears to have low expression one day might exhibit high expression the next.

All of these factors create significant interference when determining whether PD-L1 is positive or negative.

What about other markers?

In addition to PD-L1, many other markers have been explored, such as tumor mutation burden (TMB) and immune scores.

However, to date, there is no perfect standalone marker.

The relationship between the immune system and tumors is incredibly complex and influenced by many factors. Recent research even suggests that gut microbiota and dietary habits can impact the effectiveness of immunotherapy.

Therefore, the prevailing belief is that predicting the efficacy of immunotherapy may require a combination of multiple markers rather than a single one, unlike targeted therapies.

For example, the paper published in “Science” explores the possibility of using multiple markers together. While the predictive performance is better than using a single marker, it is still not ideal.

Third point:

So, should PD-L1 testing be done in clinical practice?

It depends on various factors.

Firstly, it depends on the type of tumor.

Some tumors show some correlation between treatment efficacy and PD-L1 expression, such as melanoma related to UV damage. In such cases, PD-L1 testing might be considered. However, for some tumors, like classical Hodgkin’s lymphoma, overall expression is generally high, so testing may not be necessary.

Secondly, it depends on whether it’s first-line or second-line treatment.

In lung cancer, if immune drugs are used as monotherapy in the first-line setting, testing can be considered because research has found that patients with strong PD-L1 positivity (>50%) benefit the most. But for second-line treatment, it’s currently not recommended. On one hand, some studies have found that PD-L1-negative patients can still benefit, and on the other hand, second-line patients have limited treatment options, with chemotherapy results being suboptimal. So, the value of using PD-L1 for selection in this context is limited.

Thirdly, it depends on whether it’s monotherapy or combination therapy.

In first-line clinical trials for lung cancer, if PD-1 inhibitors are used as monotherapy, PD-L1-negative patients hardly benefit, making testing valuable. However,

when immunotherapy is combined with chemotherapy in the first-line setting, even PD-L1-negative patients can benefit, so testing is not necessary.

Fourthly, it depends on the hospital.

While PD-L1 testing is relatively quick, it involves over 20 manual steps. Many pathology departments in hospitals have not yet established a stable PD-L1 staining quality control system, so testing currently holds limited significance.

Fifthly, it depends on economic considerations.

Any testing, whether for PD-L1, tumor mutation burden, or immune scores, incurs costs. When economic conditions allow, and when other options are suboptimal, a pragmatic approach is to try immune checkpoint inhibitor drugs for a period without prior testing to see how the patient responds.

Forth Point:

In the era of precision medicine, the goal is to use drugs on patients who are most likely to benefit. Therefore, research into biomarkers that can predict treatment efficacy is crucial.

However, at present, there is still no universally accepted and highly effective biomarker for immunotherapy. Whether PD-L1 testing or other tests should be done depends on many factors. In addition to scientific considerations, factors such as the patient’s disease progression, overall health status, family financial situation, and more must also be taken into account.

We hope that better markers will be discovered and that more immunotherapy methods will be validated, benefiting a wider range of patients.

Should PD-L1 Testing Be Done Before Cancer Immunotherapy?

References:

1. Peripheral and tumor immune correlates in patients with advanced melanoma treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) monotherapy or in combination with ipilimumab. J Transl Med 2014;12:O8.

2. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol Cancer Ther. 2015 Apr;14(4):847-56.

(source:internet, reference only)

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