Immunotherapy in Oncology and the Role of the PD-L1 Biomarker

Antoni Ribas, MD, PhD: It’s quite clear by now that immuno-oncology is in a new pillar of therapy for advanced cancers. We’ve known a long time that the immune system could attack the cancer, but it only worked anecdotally. By understanding the biology of how the immune system relates to the cancer, we now have drugs that actually unleash the immune response to get in the immune system to attack cancer specifically. We’re seeing unprecedented levels of long-lasting responses in patients in multiple cancers, including the ones for which the PD-1 class of drugs are being approved—melanoma, lung cancer, Hodgkin’s disease, renal cell carcinoma. There are at least 15 cancers where there’s activity, and these drugs are being tested in many more.

The broad applicability of immunotherapy at this time for cancer is the PD-1 or PD-L1—blocking antibodies. By themselves, as single agents, they have very low toxicity profiles. They compare favorably to any other treatment that I have tested to chemotherapy, to radiation therapy. These are low-toxicity agents. They very specifically unleash T cells that are attacking the tumor, as opposed to T cells that attack other parts of the body.

A prior generation of these agents, the CTLA4-blocking antibodies, had broader toxicity, because they work upstream. They work when the immune system has been turned on. So, they can turn on immune cells that can attack different parts of the body, including the cancer. The PD-1—blocking antibodies act at the site of the T cells inside the tumor and are only unleashed then. That’s why the toxicity profile ranges from 10% to 15% of grade 3 to 4 toxicities. It’s much better than it was with the older immunotherapies.

The premise of immunotherapy is that once we get the immune response to attach the cancer, it should have memory leading to long-lasting responses because the immune system remembers. We were interested in immunotherapy for cancer for many years, but it only worked anecdotally. With the PD-1 and PD-L1—blocking antibodies, we’re seeing higher frequencies of the durable long-lasting responses. In my clinic, it’s made a big difference. I work in melanoma. I used to have a clinic that had a steady number of patients. Unfortunately, whenever I had new patients, the other patients were no longer coming anymore. Now, my clinic [volume] is going up. I’m accumulating a lot of patients that keep coming back and coming back, getting treatments or now off treatment, and instead of having a deadly disease [my patients] are seeming to be having a normal life for 3, 4 years, and going on.

Biomarkers for activity of PD-1 and PD-L1—blocking antibodies are obviously of great interest. We were able to select one-third of patients who respond to single-agent PD-1–blocking antibodies—either pembrolizumab, nivolumab, or the PD-L1–blocking antibodies—in melanoma, and we were able to achieve then 100% response rates. I think we have information to do this, but it’s hard to apply to clinic. Because, it’s not only PD-L1. PD-L1 is important when it’s reactive to the presence of T cells in the tumor.

So, if you’re looking for PD-L1, the next question is, are there immune system cells to be unleashed? If there’s PD-L1 and no immune system cells, there’s no point in unleashing them. If there are immune system cells that do not trigger the protection of the tumor by PD-L1, also there’s no need to unleash them. But, then the immune system cells need to find something that’s wrong in the cancer, need to differentiate the cancer cells from the normal cells. Then we start thinking about biomarkers that are within the cancer, like mutational load. The more mutations, the more likely the immune system has tried to attack the cancer specifically. We should be able to put it together, but there’s no assay that’s ready for clinical use, at this time at least. The PD-L1 biomarker alone is not enough. And it only gives only partial information that can enrich for the population for response, but will not tell us which patient is going to respond or not.

In melanoma, the FDA approvals of pembrolizumab and nivolumab have been, regardless of the biomarker of PD-L1. This is because early on, it was clear that patients with PD-L1 negative tumors could respond. And, also, we could see a percentage of patients with PD-L1—positive tumors who did not respond. I think that’s because it doesn’t capture all of the complexity; we need both PD-L1, and the presence of the immune system cells to be able to make sense of what PD-L1—positive or –negative means.

Also, the scoring of PD-L1 is usually done on the whole slide, as opposed to looking specifically in the area of where the immune system is trying to attack the cancer. And the cancer can try to protect itself through PD-L1. So, I think it’s a biomarker, that is not used in the field of melanoma, not only because of the clinical experience that is not supported, but also I think the biology of PD-L1 does not support using it as a single marker.