New Advances in Research Pave the Way for the Treatment of Nonclear Cell RCC

David F. McDermott, MD, Professor of Medicine at Harvard Medical School and Leader of the Kidney Cancer Program at the Dana-Farber/Harvard Cancer Center talks about the recent advances in the treatment landscape for patients with nonclear cell renal cell carcinoma.

Transcript

My name is David McDermott. I'm a medical oncologist in Boston. I lead the Kidney Cancer Program at the Dana-Farber/Harvard Cancer Center, and I work at Beth Israel Deaconess Medical Center.

I'm here today to talk about the treatment of nonclear cell renal cell carcinoma (RCC). In general, most of the therapies that are available for patients with kidney cancer, or RCC, have been approved on trials that mostly included patients with what we call clear cell RCC or clear cell kidney cancer.

Clear cell kidney cancer is sort of the predominant flavor of kidney cancer, with about 70% or 80% of patients who develop kidney cancer having clear cell kidney cancer. There's about 20% or 30% of patients who are diagnosed with nonclear cell kidney cancer, which is really sort of a basket of tumors, that while they arise in the kidney, are often very different, meaning they have a very different appearance under the microscope. They often have different genetic changes that may lead to or drive the cancer.

There are many cancers that happen in small numbers of patients that are grouped together, and this is one of the reasons why advances have been slow in patients with nonclear cell kidney cancer, because it's relatively less common, and it is really multiple diseases in one basket.

So when you see some of the exciting developments over the last couple of years with new therapies both at work through the immune system, or new molecularly targeted therapies, most of the patients who've gone on these trials have been patients with clear cell cancer. To a large extent, patients with nonclear cell cancer have been excluded from these trials. So there haven't been many advances for nonclear cell patients, and we certainly have an unmet need for safe and effective treatment options for these people.

One of the exciting developments that came from pre-clinical and translational experiments that folks in my group and others have done over the last several years is they sort of set the predicate for testing immune therapies in patients with nonclear cell kidney cancer.

Traditionally, immune therapies, like cytokine therapies (eg, interleukin-2 or interferon) have worked less well in nonclear cell kidney cancer than in clear cell patients. Therefore, when the early trials with PD-1 antibodies that also work through the immune system were developed, because of the experience with cytokine therapies, patients with nonclear cell RCC were excluded from the PD-1 based trial.

That probably was a mistake. A mistake, that I mention, that other investigators are trying to correct, by first (once these drugs became available) testing them in patients with nonclear cell kidney cancer and getting a sense from small retrospective analyses that PD-1 blockade, the newer version of immunotherapy actually had some activity in nonclear cell kidney cancer. But also studying the actual patient's tumors to look at the immune infiltrate in these tumors, and to see that the ligand for PD-L1 was actually expressed on a nonclear cell kidney cancer.

So those 2 developments set the stage for clinical trials. The largest clinical trial to look at nonclear cell kidney cancer with these new immune checkpoint inhibitors, or PD-1 blockade, is the so-called KEYNOTE-427 clinical trial.

That trial was a single-arm study with 2 cohorts. The first cohort was the clear cell cohort of about 110 patients. That was presented last year at several meetings. And this year, we're excited to present the data from cohort B, which is 165 patients with exclusively nonclear cell kidney cancer, that will be presented at the GU ASCO meeting in San Francisco this weekend.

What we've known from the data that's available is it turns out that what we studied in this trial was looking at PD-1 blockade with pembrolizumab in patients with nonclear cell kidney cancer. And in those patients, the approach was actually fairly active, meaning we saw a response rate in the overall group of nonclear cell patients of 25%. I think that was higher than we would have expected in nonclear cell kidney cancer patients.

Most of the patients enrolled in the trial were papillary kidney cancer, where the response rate was also 25%. The response rate in patients with unclassified kidney cancer was 35%, and in chromophobe tumors it was less, at 10%.

In tumors that had PD-L1 staining on their surface, their response rate was higher than if they were PD-L1–negative. There was a response rate of 33% in the PD-L1–positive patients versus close to 10% in the PD-L1–negative patients, suggesting that potentially PD-L1 staining in the tumor microenvironment might be a way of predicting response.

As far as safety goes, pembrolizumab was generally well-tolerated in the KEYNOTE-427 study, similar to how it's been tolerated in other trials. There were not new side effects seen; 6% of patients actually had to stop treatment due to side effects. There were 2 treatment-related deaths on the study.

So we obviously have to monitor side effects closely, but in general, the agent was tolerated as well in non-clear cell patients as it was in clear cell patients.

So when we think about this interesting data, we obviously have to take into account all the other advances that are being made. But when you consider that there are very few, and right now no approved therapies just for non-clear cell kidney cancers, one question would be, can pembrolizumab be applied in the clinic for patients with non-clear cell disease?

The short answer is not right now. Meaning, because pembrolizumab is not approved in the US or Europe for patients with kidney cancer, but potentially in the future. So this data is interesting enough that we might consider trying to get it approved for patients in the US and in Europe and hopefully in the future there will be discussions with the FDA and the EMA about whether this is possible. That might require further studies, so for example, we might have to consider randomized trials to build on the results of the KEYNOTE-427 study, but that discussion is ongoing.

Another exciting direction in the future will be trying to expand on what we know about which patients with nonclear cell cancer respond to PD-1 blockade and which do not. There's a series of translational studies that are part of the KEYNOTE-427 study that are underway right now to try to understand which patients benefit and which do not.

Which patients with nonclear cell have benefited? Are they the same as the clear cell patients, or are they different? Meaning, are they the patients who already have an immune infiltrate in their tumors or not? Are there specific genetic factors that may predispose to a response in nonclear cell kidney cancer? And if so, what are they?

Ideally, in the future, we are rationally applying these therapies to patients more likely to benefit, and the early results of the KEYNOTE-427 study suggest that we might be able to select patients who can benefit from single-agent therapy.

Another exciting development that will be presented at the GU ASCO meeting this year is also combination based on PD-1 blockade. So, looking at molecularly targeted agents, like atezolizumab and bevacizumab, there will be data on those 2 approaches. There's also going to be data on PD-L1 blockade and another targeted therapy, called salvolitinib.

So, essentially, at least 3 trials that I'm aware of focus on can we bring immunotherapy to our non-clear cell patients. It looks like there's some hope that we can, but we're going to have to figure out how best to give it. Is it alone or in combination? Who to give it to, and how best we can get these agents available to patients who are not going on clinical trials but have these diagnoses.

I think it's clear that there is certainly hope on the horizon, but we need to be strategic in how we develop these agents so we can get them to the right patient at the right time.