Researchers Poised to Expand on Exciting Advancements in RCC

Mayer Fishman, MD

The therapeutic options for renal cell carcinoma (RCC) have drastically improved over the last several years; however, work still needs to be done to determine how to optimally sequence the plethora of available agents, according to Mayer Fishman, MD.

There are other challenges that also need to be addressed, says Fishman, such as understanding triggers to therapy and identifying new biomarkers for treatments. Fishman, a medical oncologist at Moffitt Cancer Center, highlighted the most recent advances in the field of RCC during his lecture at the 2016 OncLive State of the Science Summit on Genitourinary Cancers.

OncLive: There has been a lot of excitement in kidney cancer over the last couple of years. What should be highlighted about the agents that are now available?

In an interview with OncLive during the meeting, Fishman discussed the therapeutic landscape in RCC and the next steps needed to further advance the field.Fishman: There are 3 main medicines in the kidney cancer therapies. There is the VEGF group, the immunotherapy group, and the mTOR group. There have been a few approvals in the last several months.

In the immunotherapy group, nivolumab (Opdivo) was approved as an anti—PD-1 drug. It got some other indications, and now it is approved for kidney cancer use.

In the VEGF group, cabozantinib (Cabometyx) was approved, which blocks c-MET as well as VEGF, so that is a difference. Lenvatinib (Lenvima) blocks VEGF and FGFR1, and then lenvatinib was given in combination with everolimus (Afinitor). That 2-part combination was the superior one. With those 3 treatments, each of them had been compared with everolimus; each of them showed a survival advantage. Those are some treatments that are now available.

What is a key takeaway about triggers and options for upfront therapy?

That comes in addition to other VEGF medicines that are available, such as sunitinib (Sutent), sorafenib (Nexavar), pazopanib (Votrient), axitinib (Inlyta), and bevacizumab (Avastin), and other mTOR medicines, such as everolimus and temsirolimus (Torisel), and other immunotherapies such as interleukin-2 (IL-2). There are actually 10 different medicines around for treating metastatic kidney cancer. It does make for a more complicated scene, but there are going to be select patients who do particularly well with 1 or another, so I am optimistic that that’s going to help patients.The first issue is always going to be managing symptomatic disease. If there is no symptomatic disease, some things that might become symptomatic are brain disease or an impending fracture, and the next issue is typically going to be a nephrectomy. Patients with a lot of bulk of metastatic disease will often get a deferred nephrectomy or a limited renal reserve.

On the other hand, if the dominant amount of disease were in the kidney, most of those patients would look at an upfront nephrectomy as initial treatment.

Our next issue is timing of starting medical therapy. If there is relatively rapid growth, that forces the issue. Some patients who have relatively slow growth, or is slow compared with other comorbid problems, deferring start of therapy may make more sense for them.

The trigger to start on active treatment might be a pattern of growth; it might be a sense of anxiety or missed opportunity for not starting immediately. It could be an obvious growth pattern where there’s just not going to be a long window to delay treatment. Not being on treatment, of course, has a lot of advantages as far as side effects. However, it can seem like a mixed opportunity—in fact, it can be a missed opportunity for some patients.

As far as which treatment to start with, it’s going to have to be individualized. There are going to be some patients who do well with initial treatment with immunotherapy, such as IL-2. Some patients do well with initial treatment with checkpoint inhibitor therapy, although that’s currently off-label for nivolumab as initial treatment.

We do have the research study that accommodates upfront treatment for that. Some patients will get initial therapy with the VEGF medicines. To that extent, VEGF agents have been compared directly to one another; there is not an obvious advantage with one or the other. Some of them have a label, which alludes to second-line therapy such as axitinib, lenvatinib, or cabozantinib. I don’t think anyone would expect that it wouldn’t be active as a first-line therapy, as well. I expect issue of initial or subsequent therapy to evolve.

What challenges persist with sequencing agents for patients with refractory metastatic disease?

Another part of that issue of triggers for therapy is when to change from one therapy to another. On trials, this tends to be relatively structured. On the other hand, in real life, there might be relatively slow progression and one might treat through progression for several months before changing. Or, there might be an isolated lesion that progresses, which can be treated while maintaining control of the other lesions.There are 2 perspectives. One is efficacy and the other is response. A few sequencing issues have been addressed, such as immunotherapy and VEGF therapy. Immunotherapy with IL-2 is usually used as a first-line treatment, but the question of using that after prior treatment with VEGF has been addressed in prospective studies. It looks like there may be a little bit more toxicity, but it does still have efficacy for some patients, perhaps the same patients it would have worked on regardless.

Using the VEGF therapies after IL-2 appears to be just as good as using them as upfront treatment. That is another sequencing choice that is relatively wide open. As far as nivolumab and VEGF therapy, the current label is for nivolumab to be used after VEGF therapy. I don’t think anyone thinks that patients who have nivolumab first will particularly have a different response rate to VEGF treatment, although that hasn’t really been specifically tested empirically.

Regarding mTOR therapies, the question of upfront therapy with everolimus and then sunitinib or the opposite sequence was addressed in a randomized trial. Receiving sunitinib first was found to be better. It would be unusual for everolimus to be a first-line choice, except for the situation where a known mTOR or mTOR pathway-related activated mutation had been seen in a genetic test.

As far as everolimus versus cabozantinib, or versus a combination of lenvatinib/everolimus, or versus nivolumab, since everolimus alone was the inferior arm in each of those direct comparative second-line trials, it would usually be deferred until later.

Overall, what are some of the big questions that you hope can be answered in the next 5 to 10 years?

For patients with a high-risk disease upfront who are treated with temsirolimus, there’s just some ambiguity whether initial treatment with an mTOR agent or treatment with a VEGF drug and then with an mTOR pathway drug afterwards would be better. Either of those sequences really can be on the table. That subset of patients hasn’t really been evaluated in detail the way the other groups have been. Some patients occasionally will still start with temsirolimus if they are relatively similar to the patients who are in the high-risk trial.One of the key issues is going to be finding out why some patients don’t respond to immunotherapy. The kind of easy answer about PD-L1 staining within the tumor just has not borne out at all in kidney cancer. It seems to be quite a different pattern as compared with bladder cancer, lung cancer, or melanoma—at least as far as PD-L1 infiltration. [We need to determine] a different biomarker in order to identify who doesn’t yet have a tumor that’s susceptible.

The big question is going to be how to change the way the tumor interacts with the immune system. It is not so much how the immune system interacts with the tumor, but how the tumor is blocking some component of the immune system from working. That is going to be the key to getting a bigger fraction of the patients to be responders for immune therapy, including cytokine-based and IL2-based drugs and checkpoint inhibitors, including the PD-1 drugs and others.