Expert Weighs in on Promising New Options for Frontline Kidney Cancer

For many patients with newly-diagnosed metastatic kidney cancer, VEGF-tarted therapies have become the standard of care because of the nature of the disease, according to David McDermott, M.D., who explained that these drugs target the many new blood vessels in most clear-cell kidney cancers.

“Metastatic renal cell carcinoma is a very VEGF-driven disease, lots of blood-vessels. So, it’s not surprising that drugs that target those new blood vessels can be effective and our patients have been living significantly longer since the advent of those drugs.”

Unfortunately, most patients will eventually develop resistance to VEGF-targeted therapies within the first year, says McDermott. Therefore, there must be better approaches developed for these patients so that benefit can be extended for a longer period of time.

The phase 2 IMmotion 150 study examined the PD-L1 inhibitor Tecentriq (atezolizumab) with or without the VEGF inhibitor Avastin (bevacizumab) versus Sutent (sunitinib) in patients with untreated mRCC.

In the study, the combination of Tecentriq and bevacizumab reduced the risk of progression or death by 36 percent versus sunitinib in patients with PD-L1—positive mRCC. The median progression-free survival was 14.7 months versus 7.8 months, respectively.

Could you provide an overview of the IMmotion 150?

In an interview with CURE at the 2017 Genitourinary Cancers Symposium, McDermott, the lead IMmotion 150 study author and director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discussed the results and the significance of the IMmotion 150 trial.The IMmotion 150 study was a complicated trial that sought to go over several different goals. First of all, we don't know much about how PD-1 pathway blockade works in untreated patients. Most of the data that we had from the Opdivo (nivolumab) experiences came from patients who had failed prior VEGF therapy. So, this was the first large look at PD-L1 blockade with Tecentriq in untreated patients, and the response rates were encouraging.

These response rates were important—there were about 10 percent who had complete responses, so there were many deep responses. The reason that is important is many of those patients will be able to be alive and well at the tail of the survival curve, some of those patients can even come off treatment. The efficacy results were encouraging, and in the context of Sutent, comparable to those—but less side effects appeared in the patients getting just single agent Tecentriq alone.

Also, we tried to look at how do we extend the benefit of PD-1 or PD-L1 blockade. We know these agents have revolutionized the treatment of kidney cancer, and for may cancers, but for most patients they eventually stop working. So, one important question of this trial is if you add VEGF blockade with bevacizumab to PD-L1 blockade with Tecentriq, can you extend that benefit? The answer seems to be, “Yes,” based on this trial—it did improve outcomes for our patients, particularly in the subset of patients that had these so-called "inflamed tumors," tumors with T-cell infiltration. Tumors with PD-L1 expression seemed to do better with a combination than the all-comers populations.

In this trial, we learned several important things that will probably impact not just how we use agents in second-line, but more importantly in first-line combinations. We are going to see several phase 3 trials looking at the combination of PD-L1 and PD-1 in the frontline. We now have a sense that selection might be possible for those patients. This trial helps design the phase 3, which will look hard at this select population of tumors that express PD-L1 on their immune cells, but it almost may have implications for the adjuvant setting, too. This is because of Tecentriq’s activity and very favorable side-effect profile—it makes a lot of sense to test this drug in the adjuvant setting, and those trials will start going this year.

What adverse events have been observed?

I think we've learned a lot about kidney cancer in this trial and a lot about the future potential treatments of some of these agents. We obviously need to confirm what we found in large randomized studies and those are ongoing.Adverse events with all checkpoint-blockade are fairly consistent with the agents that are out there. We see similar things, but in many ways they are quite different from side effects with molecularly-targeted agents and with chemotherapy. They tend to come on later, so it often takes several doses for the side effects to develop. They tend to involve inflammation in body organs where the T cells are, attacking healthy issue, and they can affect almost every part of the body. Almost anything that ends with an “itus” can happen to patients getting immune checkpoint blockade. So, you have to educate your patients very well about what can happen, they have to call you when new things develop—because the sooner they call you, the more you can do about it.

Most of the side effects are reversible but not all of the side effects are reversible. We have a sense though, with early intervention, you can improve outcomes and prevent serious complication. And while serious complications are relatively less common, meaning the incident of grade 3 and 4 toxicities with this class of drugs is probably around 20 percent, maybe less, there can be rare, very dangerous side effects. Patients can actually die from these drugs, so you've got to be on top of these patients.

One thing that we've learned from Dr. Rana McKay's study is that there is this association with side effects and improved outcomes. There are patients who had side effects who have tremendous immune activation, and they can do well if they can overcome their side effects. It’s not necessarily a bad thing to have side effects; it’s also not necessarily a bad thing to intervene with the treatment of the side effects. We have this sense from bone marrow transplant experience that if you treat people with immune suppression when they are having graft versus host disease, that it might shut off the anticancer effect. It doesn't appear to do that with immune checkpoint blockade, so that kind of bolsters the argument that early intervention will prevent complications, but it does not necessarily shut off the T-cell immune response.