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).
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.
OncLive: Could you provide an overview of IMmotion 150?
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.