Combination Therapy Is Promising for Kidney Cancer, Expert Says

Thanks to drugs that target the VEGF receptor pathway — such as Sutent (sunitinib), Votrient (pazopanib), Nexavar (sorafenib), Inlyta (axitinib) and Avastin (bevacizumab) – the median life expectancy of patients with metastatic renal cell carcinoma (RCC) is longer than before.

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 Opdivo (nivolumab) 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 3 CheckMate-025 trial, in which Opdivo improved median overall survival by 5.4 months versus Afinitor (everolimus).

A logical next step to build on this success with anti—PD-1/PD-L1 agents, says David F. McDermott, M.D., 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 1b study of Inlyta plus Keytruda (pembrolizumab) that was presented at the 2016 ESMO Congress (Ann Oncol. 2016;27[6]:266-295.)

The results reported at ESMO were for 52 patients with advanced RCC who received frontline treatment with Inlyta plus Keytruda. The overall response rate was 67.3 percent (35 patients), including 2 complete responses and 33 partial responses. The researchers also reported that the combination was well tolerated.

Where are we currently with VEGF and PD-1 regimens in RCC?

In an interview with CURE, 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.Opdivo 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 two 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 3 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.

Can you give an example of these ongoing trials?

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.For example, Inlyta is being combined with Keytruda and avelumab. Tecentriq (atezolizumab) is being combined with bevacizumab. Of those three combinations, the Tecentriq and bevacizumab combination is probably the furthest ahead. In trials, this has already gone into phase 2 and phase 3 testing; hopefully we will see results from the phase 2 trial in the coming year.

We have seen some interesting early data of that combination. We have done some trials where we have done biopsies on patients before treatment and on treatment and have seen some interesting changes in their tumors. We’ve seen examples — admittedly in a small number of patients — of these T cells getting into the tumor better when the combination is given than with either drug alone, so that is encouraging.

What are some commonly observed side effects?

The combination with the most reported data is the combination of Inlyta and Keytruda. They have enrolled over 50 patients and saw a response rate close to 70 percent, which is interesting and is higher than you would expect with either drug alone. We will have to see how durable those responses are and what the survival looks like. However, both combinations make a lot of sense for testing in randomized trials. With many of these oral VEGF agents, we see a consolation of symptoms; for example, we see fatigue, diarrhea and skin issues, such as rash or hand-and-foot syndrome. Those are some of the common side effects; you certainly see those with these combinations.

What we haven’t seen yet is an amplification of those side effects. We need to watch closely and we need to watch long term. However, in the short term and small trials, we haven’t seen more hypertension than we would expect. Or, more importantly, we haven’t seen more diarrhea than we might otherwise anticipate. That is an important issue because PD-1 blockade can cause some of those side effects. PD-1 blockade can cause diarrhea, for example, or it can cause liver inflammation.

If these side effects increase, that will present a clinical challenge for many physicians, such as determining which drug is causing the diarrhea. In the case of VEGF blockade, if patients have diarrhea, physicians could give Imodium or they could stop the drug. In the case of immunotherapy-induced diarrhea, physicians could stop the treatment but you sometimes need to go beyond that and give immune-suppressant medication. Those side effects will pose a challenge.

Thus far, the side effect that has increased in early trials was from the combination of pazopanib with Keytruda. We saw more liver inflammation than what we might expect with just pazopanib or Keytruda alone. We’re still trying to work on ways to combine those agents but not every combination will work as well as others, since the two together may not mix well.