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PD-1 Inhibitors for Kidney Cancer

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I wanted to update the audience at Cancer GRACE with some really interesting developments at the American Society of Clinical Oncology meeting this year. Dr Charles Drake, from Johns Hopkins University, presented data related to the agent nivolumab, a so-called PD-1 inhibitor. I’m quite sure that PD-1 inhibitors are going to be drugs you’ll be hearing a lot about in coming years, along with PD-L1 inhibitors. These are drugs that work at the interface between immune-based cells called T-cells as well the cancer cell. Essentially, what they do is they stimulate the body’s own immune response to fight cancer.

There’s been a lot of talk related to some data from a Phase I clinical trial of nivolumab that encompasses a number of cancer types, including lung cancer and melanoma, as well as patients with kidney cancer. I wanted to mention specifically the data related to kidney cancer that has been presented to date. Specifically, Dr. Drake reported results from a total of 34 patients that were treated one of two doses of nivolumab, either 1 mg/kg or 10 mg/kg. In this total cohort of 34 patients, it was noted that 29% of patients had responses. The median delay in cancer progression, also known as progression-free survival, was 7.3 months. Now this in and of itself might not seem shocking, but what I will say is that patients in this trial were very heavily pre-treated. About half of patients in this study had 3 or more prior therapies. In my experience, it is relatively rare to see patients who have had this extent of prior therapy respond so well. What might be even more impressive than the response data or the delay in cancer progression is the survival data. That, so far, indicates that about 70% of patients on the trial lived to 1 year, and about half of patients are still alive at 2 years and beyond.

So what’s the way forward for PD-1 inhibitors such as nivolumab? Well, nivolumab is right now being compared in a large phase III trial against the agent everolimus, which is an agent that is commonly used in the second or third line setting for the treatment of metastatic  renal cell carcinoma after failure of one or two prior VEGF directed-therapies. This trial has the primary endpoint of overall survival; if this demonstrates an improvement in overall survival, I’m quite confident that this will lead to the approval of nivolumab in this clinical setting. Of course, one of the challenges is that now patients get multiple therapies beyond the second-line or third-line setting. So beyond nivolumab and everolimus, as delivered on the clinical trial, patients may be getting sunitinib, pazopanib, axitnib, and a whole host of other drugs afterwards. So I’m curious to see how this will cloud the interpretation of survival in this study.

I’m also excited about a phase I clinical trial which nivolumab is being combined with sunitinib or pazopanib. A recently added arm to this study is exploring nivolumab in combination with the agent Ipilimumab. The interest in this arm in particular is that ipilimumab is another immune-modulating agent that may potentially have an immune stimulatory effect in patients with kidney cancer. While nivolumab is certainly a drug that I and many other investigators are excited about, I will heed some caution right now that data is very early. The data that we have to-date is limited to primarily the studies that I have noted here. I will say that there was exciting data for another PD-L1 inhibitor currently known as MPDL3280A. This drug also shows promise. The response rates in association with this agent and a small study were more modest, but having said that, there were prolonged periods of stable disease in patients that received this class of drugs.

I’d love to get a sense from the audience here at GRACE regarding their sentiments on the data for PD-1 so far. I’d also be happy to address any questions related to these sorts of agents.


2 Responses to PD-1 Inhibitors for Kidney Cancer

  • slimer says:

    Dr. Pal,

    Because I might be heading for the MK3475 trial depending on my scan in a few weeks, I have been researching. I have gotten different answers from trial sites regarding PD-1 and PDL-1, specifically on what the required biopsy is testing for!

    My simplified understanding is the following: the PD-1 receptor is on the immune T cell. The cancer cells have a small protein called a ligand on their surface. It’s called PDL-1. It is the joining together of PD-1 & PDL-1 that hides the cancer cells from the immune system. There actually are 2 immunotherapies in clinical trials, one involving anti-PD-1 and one involving anti-PDL-1. The anti-PD-1 drug blocks the receptor on the immune cell so the tumor cell can’t bind to it. The other drug, anti-PDL-1, binds to the cancer cell’s PDL-1 & that also prevents the cancer cell & the immune cell from joining. In order for the cancer cell to hide from the immune system, PD-1 & PDL-1 must join together. Blocking either one prevents them from joining & allows the immune system to “see” the cancer cells.

    But if the cancer cell expresses PDL-1, and the MK3475 is an Anti-PD-1 drug, what is the biopsy testing the tumor for? I’ve been told they will test for PD-1 by one site, and PDL-1 by another. Can you help clarify? I’m heading for a collapsed lung with the biopsy, so I want to make sure the trial sites really know their stuff and I at least know what the heck the biopsy is testing for. And do the Anti-PDL-1 trials ALSO test the tumor, and conversely, what would they be testing for?

  • Dr. Pal says:

    Dear “slimer”,

    Thanks very much for your post. You ask a great question, and to be very frank with you, I’d need to read the full protocol associated with the clinial trial you are enrolling on in order to answer it. As such, I’d refer you to your treating phsyician to understand precisely what they are looking for with the biopsy assessments.

    I will say that there’s good rationale to begin looking at PD-L1 more globally in clinical trials. From the phase I trial of nivolumab, there was some indication that a greater response rate was observed in the group of patients with higher PD-L1 expression on their tumors.

    Best of luck,

    Dr. Pal

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