ASCO 2013

PDL1 inhibitors in melanoma

Dr Roy Herbst - Yale Cancer Center, New Haven, USA

Cancer cells have mutations and these mutations are presented in the surface of the cell and that allows the immune system T-cells to target the cancer cell. That would be great if it really worked but what happens is cancer cells have evolved in response to T-cell stimulation, interferon gamma stimulates a protein known as PDL1 to be made on the tumour cell. This protein acts as a disguiser, it camouflages the cancer cell from the immune system because the PDL1 protein on the surface of the tumour cell binds to the T-cell and turns off the T-cell.

Why is there so much interest in PDL1?

One, it’s just extraordinary biology to understand that this checkpoint is so important for immune function and that if you release the checkpoint you then activate the T-cells and I guess the big reason is that it’s working. If you look at this meeting you can see multiple approaches, different antibodies, different companies, slightly different targets and what you can see is that we are seeing tumours respond in lung cancer and melanoma and renal cancer and head and neck cancer and breast cancer. It’s just phenomenal that we’re seeing this type of response and these durable responses with a large number of agents.

Can you modulate inhibition?

My MPDL compound that I’m presenting on behalf of a group of investigators, a Roche compound, actually targets PDL1. So it targets this disguiser protein on the surface of tumour cells.

What was the structure of your study?

This is a phase I trial being presented, 171 patients, 140 patients evaluable for efficacy. We’re seeing response rates in the mid-20% range, very durable responses. We’re seeing responses in melanoma, we’re seeing responses in kidney cancer and lung cancer, some responses also shown in head and neck cancer, as well colon cancer and we’re actually seeing that these patients are doing well. Now, one concern would be toxicity and it looks like these agents are very well tolerated.

What can you say about efficacy in patients with advanced cancers?

The fact that you can do a phase I study with 140 evaluable patients seeing response rates in the mid-20% range, seeing toxicity where only four patients had immune-related adverse events, some mild hepatitis or other problems, really tells you that we have an agent that’s here for the long-term. This is an agent where, once we identify markers, and I presented some data to show that there is a biomarker, we can target PDL1 in the tumour microenvironment and that could even make the response rate higher, bring it up to almost 40%. So I think that we now have a whole new class of drugs that’s going to be used in a host of solid tumours and that these drugs could be used either alone or in combination in the future to benefit patients.

What would it be used in combination with?

You could think about combining it with other targeted therapies, for example in lung cancer you would think that you could use it with tyrosine kinase inhibitors to target specific pathways that are addicted, such as epidermal growth factor receptor mutated patients or ALK translocated patients. You could also imagine that you might use it with agents that target MEK, for example, which is a very hot topic at this meeting; the sky’s the limit. Also studies are on-going with other agents of class looking at the drug with chemotherapy, that’s a possibility as well. So I really think that this has opened a whole new avenue; I think that in the next few years, we’ve already seen it for the last two years, immunotherapy is going to be one of the top areas of research.

We’re seeing such a high response rate you have to wonder how many of these patients are getting complete response. I think it’s still probably a minority but one of the things you never know with these agents is what’s left – is it active tumour or is it just scar tissue. So we’re going to need to do more biopsy-based studies to really figure that out. I will tell you, though, that when you have an agent that looks good in advanced disease the next step is to bring it to earlier stage disease. So I think we’re going to start seeing these agents used in the front line setting in certain cancers or as adjuvant therapy or as a maintenance therapy. Given the toxicity profile of the MPDL, I would predict in lung cancer, for example, which is the area where I treat patients most often, we’re going to start seeing this agent in the first line metastatic setting in the stage 3 patients who have locally advanced lymph nodes. Those patients are cured but to a small extent, maybe we can increase that cure rate by using the agent early, preventing tumour progression and metastases, these are all questions that remain to be asked.

Is there a possibility of any autoimmune effects?

Absolutely, that’s one of the concerns of toxicity but the nice thing about the MPDL is it targets the tumour cell, the PDL1, and it actually leaves PDL2, which is on many of the normal cells in the body, intact. And many think that PDL2 might be involved in dampening the immune system in response to inflammation and the hope would be that there would be less autoimmunity and fewer side effects. It’s too soon to tell that in an early phase trial but all the data so far are consistent with that fact.

What are the clinical implications?

Well, someone like myself who sees many patients, they come in, they have failed multiple prior therapies, the median number of prior therapies in my trial was upwards of 2. I now have a weapon to offer them, something that can make them feel better, their tumour shrinks, hopefully they live longer. It’s very promising; it makes my day much better because I’m helping more people.