David F. McDermott, MD
The median life expectancy of patients with metastatic renal cell carcinoma (RCC) has increased with drugs targeting the VEGF receptor pathway—such as sunitinib (Sutent), pazopanib (Votrient), sorafenib (Nexavar), axitinib (Inlyta), and bevacizumab (Avastin).
However, many patients still progress on anti-VEGF therapy, and PD-1/PD-L1 inhibitors have emerged as a valuable alternative in the second-line setting.
The FDA approved the PD-1 inhibitor nivolumab (Opdivo) in November 2015 as treatment for patients with metastatic RCC following prior antiangiogenic therapy. The approval was based on the primary findings from the phase III CheckMate-025 trial, in which nivolumab improved median overall survival by 5.4 months versus everolimus (Afinitor).
A logical next step to build on this success with anti¬–PD-1/PD-L1 agents, says David F. McDermott, MD, is combination regimens with VEGF inhibitors in the frontline setting. Several such combinations are under investigation, with the most data available so far being from a phase Ib study of axitinib plus pembrolizumab that was presented at the 2016 ESMO Congress (Ann Oncol
The results reported at ESMO were for 52 patients with advanced RCC who received frontline treatment with axitinib plus pembrolizumab. The overall response rate was 67.3% (35 patients), including 2 complete responses and 33 partial responses. The researchers also reported that the combination was well tolerated.
In an interview with OncLive
, McDermott, an associate professor of Medicine at Harvard Medical School and director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discussed ongoing efforts to improve outcomes in advanced RCC through combination anti–VEGF/PD-1 regimens.
OncLive: Where are we currently with VEGF and PD-1 regimens in RCC?
: Nivolumab received FDA approval for the treatment of patients who had failed prior VEGF therapy. This represents a major improvement and a new option for our patients. However, it only works well in a subset of patients, and, for many patients, the benefit over time can wear off. How can we improve that benefit? How can we build on the progress with PD-1 and bring it to more patients?
One potential option is to combine effective therapies. We can combine 2 strategies that we know work in kidney cancer—such as combine VEGF blockades with either antibodies that target VEGF or oral tyrosine kinase inhibitors that block the signaling of VEGF with newer PD-1/PD-L1 therapies. Thus far, we have seen several different combinations and several interesting endings in early trials.
For example, there have been several different combinations tested. So far, the safety seen with these combinations seems encouraging. This means that for most of the combinations, the side effects are very familiar to what one might expect with either drug alone. However, they don’t seem to be amplified by the combination. Side effects are still an issue, but for most of the combinations that are now moving into phase III trials, safety and tolerability are reasonable.
We’re also seeing intriguing early findings on efficacy. This means that we are seeing higher response rates and encouraging PFS when you compare it with historical controls. Now, we obviously have to be very careful about doing those comparisons and it is still very early. We have very little randomized data with this, but it’s encouraging enough to propose and execute randomized trials. These are now ongoing and some of them will start to read out in 2017. The hope is that these combinations will not just extend benefits, but might also improve the immune response to the cancer.
There is a lot of data from preclinical models that suggest that high levels of VEGF can be immunosuppressive in a variety of different ways. They can inhibit dendritic cell function, for example, and can prevent T cells from coming from the blood into the tumor. A major issue is, how can you get the T cells? The hope is that by combining VEGF blockade, you can improve the immunotherapy aspect of the treatment, leading to not just more responses, but more durable responses, and an effort to improve the tail of the survival curve.
Can you give an example of these ongoing trials?
For example, axitinib is being combined with pembrolizumab (Keytruda) and avelumab. Atezolizumab (Tecentriq) is being combined with bevacizumab. Of those 3 combinations, the atezolizumab and bevacizumab combination is probably the furthest ahead. In trials, this has already gone into phase II and phase III testing; hopefully we will see results from the phase II trial in the coming year.