McDermott Discusses Promising PD-L1/VEGF Combo Findings in Frontline mRCC

David McDermott, MD

VEGF-targeted therapies have become the standard of care for many patients with newly-diagnosed metastatic renal cell carcinoma (mRCC). This is due to the nature of the disease, says David McDermott, MD, as these drugs target new blood vessels, which are abundant in most clear-cell kidney cancer.

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

In the study, the combination of atezolizumab and bevacizumab reduced the risk of progression or death by 36% versus sunitinib in patients with PD-L1—positive mRCC. The median progression-free survival was 14.7 months versus 7.8 months, respectively (HR, 0.64; 95% CI, 0.38-1.08).

OncLive: Could you provide an overview of IMmotion 150?

In an interview with OncLive 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.McDermott: 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 nivolumab (Opdivo) experiences came from patients who had failed prior VEGF therapy. So, this was the first large look at PD-L1 blockade with atezolizumab in untreated patients, and the response rates were encouraging.

These response rates were important—there were about 10% 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 sunitinib, comparable to those—but less side effects appeared in the patients getting just single agent atezolizumab 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 atezolizumab, 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 III 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 III, 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 atezolizumab’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%, 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.

What do you hope community oncologists take away from this study?

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.I think the role of immune checkpoints for kidney cancer is likely to expand in the next several years. We've see encouraging data—really exciting data—in the second-line setting with nivolumab, but there are several other agents in development, including atezolizumab, which probably will have an impact in first-line in untreated patients. This would be exciting for patients because some of them might not need to go onto some of these other treatments if we see even better benefits in the frontline than in the second-line. This trial was encouraging in that regard with the response rates and the complete responses that we saw with single-agent atezolizumab.

Also, these agents, in many ways, make ideal drugs for the adjuvant setting because they are relatively safe and they can have long-term benefits. We've already seen the immune benefits of checkpoint blockade in the adjuvant setting in melanoma, where it improved survival. So, we're hopeful it'll improve survival in kidney cancer, and there are several important trials ongoing. If you have a patient who has just had surgery for stage III kidney cancer, look for one of those trials. There are several and they'll be open for a couple of years. If you have a patient who is untreated that is interested in immune therapy, there are also several trials to consider. We look forward to finding the answers to some of these questions in the future.

Reference

McDermott D, Atkins M, Motzer R, et al. A phase II study of atezolizumab with or without bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma patients. Abstract presented at: 2017 Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abstract 431.