Insights From: Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center; Thomas Hutson, DO, PharmD, FACP, Baylor University Medical Center; Texas Oncology; James J. Hsieh, MD, PhD, Washington University School of Medicine
James J. Hsieh, MD, PhD: We are in the combination era. So, there are many, many different kinds of combinations. We started with Avastin (bevacizumab)/atezolizumab, and later on, we have axitinib/avelumab. And then we have lenvatinib/pembrolizumab. There’s another trial, that I think is very exciting to see, that is using cabozantinib/nivolumab. I love these kinds of trials because they’re using different mechanisms. Axitinib/avelumab is a VEGF/PD-1 inhibition, lenvatinib/pembrolizumab is a VEGF FGF/PD-1 inhibition, and cabozantinib/nivolumab is a VEGF c-MET/PD-1 antibody. So, these are the future, I think. It’s interesting that sunitinib got FDA-approved in 2006 because it transformed the way we treat disease, and it has become a gold standard for the past 10 years.
But not all these trials want to—in the past, some trials—beat everolimus because everolimus has extended their second-line. Not everybody wants to beat sunitinib. So, we can see how fast our field is moving toward the combination therapy.
Thomas Hutson, DO, PharmD, FACP: So, at ASCO 2017, we saw several reports of clinical studies evaluating combinations of VEGF/TKI, plus I-O agents. There was a trial, a phase I experience, combining pazopanib with pembrolizumab that showed excessive hepatotoxicity. That combination will not move further in development. Dr. Toni Choueiri has presented data on a phase I study of avelumab/axitinib, which showed some degree of efficacy, as what one would expect, but the primary focus of the phase I study was safety and tolerability. The combination was safe and tolerable, so I would expect to see that combination moving forward.
And then finally, we saw, in the “Trial in Progress” section, the reports of a trial that is launched and will begin accruing around the country. A phase III study called the CLEAR trial. And that’s a combination of lenvatinib with everolimus and lenvatinib with pembrolizumab versus sunitinib. And in that 3-arm trial, we hope to establish what the activity would be in the frontline setting of a combination of an FGF VEGF inhibitor with mTOR, that same combination that is approved in the second-line setting—lenvatinib with I-O agent, pembrolizumab—to see whether or not VEGF/FGF combined with I-O produces additive or synergist results as a frontline strategy, similar to other trials that are combining, in the frontline setting, with VEGF inhibitor/I-O versus standard of care, sunitinib. That trial will be launched not only in the United States, but around the world, and we hope that we achieve accrual within the next year and a half.
Martin H. Voss, MD: What’s unusual is that the FDA approved the combination of lenvatinib/everolimus based on a randomized phase II study. But partly, this was done under the premise that this combination will actually be tested in the phase III setting in the future. And the study’s sponsor has now set up a large randomized phase III trial that is taking things one step further. This is a triple arm trial that is comparing treatment in the first-line setting between single-agent sunitinib, the combination of lenvatinib/everolimus—which is now approved in the second-line space—and a novel combination of lenvatinib together with pembrolizumab, a PD-1 inhibitor.
This combination is very interesting because it follows the mantra of combining the old and the new VEGF-targeted therapy with lenvatinib together with immune-targeted therapy with pembrolizumab. And there are some exciting data in the preclinical space suggesting that FGFR inhibition—FGFR being one of the targets of the multitargeted kinase inhibitor, lenvatinib—can favorably manipulate the immune system toward a better response with a checkpoint inhibitor.
The phase I study for this combination, which has been conducted across multiple solid tumor malignancies, has completed its accrual for kidney cancer patients, but the data for that have not been reported. The fact that the company has jumped right into a phase III trial without even bothering to do a phase II in-between tells us that they must be very excited about this combination.
One of the combinations of heightened interest that has been studied for kidney cancer now, for some time, uses inhibition of 2 checkpoints, both inhibitory in the immune microenvironment: one being CTLA4, the other being PD-1. This has proven effective in patients with advanced melanoma where the combination of ipilimumab/nivolumab is already FDA-approved based on a randomized trial, and this avenue has been pursued aggressively in kidney cancer patients also. We have seen results reported, that are actually now in press, for the phase I study combining ipilimumab and nivolumab in kidney cancer patients. And we know that the objective response rates on this very large phase I study were significantly higher than using just 1 of these 2 agents alone. This has now led to a large randomized phase III study that is being conducted in the first-line setting where patients are being randomized to receive either standard TKI therapy with sunitinib versus the combination of these 2 checkpoint inhibitors, ipilimumab/nivolumab. This study has completed its accrual, and patients are still under investigation. We are anxiously awaiting the results for this trial, which is testing coprimary endpoints of progression-free and overall survival in the first-line setting.