In this wide ranging interview, Nicholas J. Vogelzang, MD, FASCO, FACP, shares insights, perspectives, and real-world observations from his practice following the 2018 Scientific Sessions of the American Society of Clinical Oncology. Dr Vogelzang serves as Vice Chair of the SWOG GU Committee and is Associate Director, Genitourinary Research Program, US Oncology Research, Comprehensive Cancer Centers of Nevada, in Las Vegas. He recently was recognized as one of 21 physicians for their outstanding contributions to quality care and inducted as a Giant in Cancer Care by OncLive.
Q. What impression were you left with after the 2018 ASCO meeting? Was there anything with significant translational impact?
Dr Vogelzang: I did not find any breakthroughs at this year’s meeting, nothing that I could describe as “practice changing.” With regard to CARMENA, one of the trials discussed during the Plenary Session, the data did not change my practice. I’ve always recommended a neoadjuvant TKI (tyrosine kinase inhibitor) for the last 10 years because of some traumatic experiences early on when everyone was recommending upfront nephrectomy regardless of risk factor stratification or selection considerations. In some cases, patients died before they could receive systemic therapies. I don’t recommend nephrectomy upfront unless the tumor is really small or there is minimal metastatic burden.
Q. There has been a lot of controversy surrounding this issue. There are physicians, for example, especially at academic centers like the Massachusetts General Hospital, who say that cytoreductive nephrectomy has been largely underused in the targeted therapy era and that strategies should be reconsidered. What is your opinion of these observations?
Dr Vogelzang: I think that physicians at these centers, particularly urologists, do not see the kind of kidney cancer patients whom most of us in community practice see. The problem often arising for community oncologists is that patients are sick when they come to us; they are symptomatic and should not have their kidney removed initially. It’s obvious that when you have clinical experience under your belt, the TKIs work extremely quickly to reduce pain and bleeding.
Q. Can you provide a real-world experience where this was the case?
Dr Vogelzang: Yes. A prisoner was brought to my office recently and he came in with a palpable mass and in severe pain. He had been shuttled around from one doctor to another and had undergone a biopsy but no treatment. When he walked into my office he was in shackles. After examining him, I told him, “You need to start a TKI right now.” So I went to my samples and selected Votrient, which I had available at the time. Within two days his pain was gone, his mass was smaller, evidence that the TKI was working extremely quickly. Unfortunately, the patient died because he could not find a surgeon who would operate on him because it was inoperable. The point of this case, however, is the rapidity with which TKIs reduce inflammation, the pain, and reduce peritumoral infiltrates. It is really remarkable.
Q. So to sum up the controversy on initial cytoreductive nephrectomy in the targeted therapy era, is there anything recent in the literature that can serve as a guide, aside from society or working group guidelines?
Dr Vogelzang: Yes there is. I would refer our readers to an Editorial in the New England Journal of Medicine by Motzer and Russo (June 3, 2018 DOI: 10.1056/NEJM e1806331). It reflects my views and is an excellent analysis and interpretation of the results from the CARMENA trial. It emphasizes the need to appropriately select patients for either modality.
Q. How would you frame the current discussion about the treatment algorithm for RCC after the ASCO meeting? What are some of the pitfalls in selecting various strategies?
Dr Vogelzang: Based on the ASCO meeting, the treatment paradigm is not changing yet. The biggest problem is that insurance companies are still not reimbursing for the ipi-nivo (ipilimumab and nivolumab) combination and we have no definitive data on frontline IO agents (nivolumab or pembrolizumab) given as monotherapy. The phase 2 data on pembrolizumab frontline were very encouraging. I participated in that study and I had very good results with it. So that is an encouraging step forward because we now have upfront information on this agent. We don’t have upfront nivolumab data. We have very strong upfront ipilimumab/nivolumab but a lot of us are unable to use it because of insurance issues.
Q. There was considerable speculation at ASCO about the need for using a checkpoint inhibitor as the comparator arm vs combination regimens with checkpoint inhibition. Would you agree that there is a need for such study?
Dr Vogelzang: Yes, that would be very helpful. Let’s look at the landscape of therapy: we have 2 combos (nivo/ipi and atezolizumab/bevacizumab) that are superior to sunitinib. We have a 3rd com-bo (avelumab/axitinib) that has been compared to sunitunib but not yet reported. We have five IO agents (nivolumab, pembrolizumab, atezolizumab, durvalumab and avelumab) and at least three TKIs that will template well with them. These TKIs are axitinib, lenvatinib, and cabozantinib. Cabozantinib seems to be the most difficult to give in combination with an IO. Lenvatinib is also a bit tough to administer with an IO because of adverse effects, namely hypertension and significant diarrhea. Axitinib seems clinically easiest to combine but these are my own subjective opinions.
Q. What are your thoughts on first-line options at this point? Once again, how does your real-world experience line up with the data being presented?
Dr Vogelzang: We have participated in the phase 2 of pembrolizumab and lenvatinib, so this combination is a contender for first line. There were quality-of-life data presented at ASCO 2018 for atezolizumab and bevacizumab that were quite promising based on a presentation by Bernard Escudier. That should be considered as a first-line therapy whether or not the patient has undergone a nephrectomy. In addition there is the avelumab/axitinib combination, and then there is nivolumab and cabozantinib. We have seen promising results reported in the JAVELIN Renal 100 Study for avelumab plus axitinib. The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced RCC seems to be manageable and consistent with that of each drug alone, and the preliminary data on antitumor activity are encouraging. This was reported by Toni Choueiri and his team in the Lancet Oncology. (Vol. 19:451–460; April 2018) A phase 3 trial is assessing avelumab and axitinib compared with sunitinib mono-therapy.
Q. Is there a consensus on which of these combinations seems to have the inside track for first line therapy?
Dr Vogelzang: These are all established regimens now and it’s very difficult to know which of them is best. When I am forced to, for one reason or another, I usually decide to use nivolumab and axitinib or nivolumab and cabozantinib. I do that because nivolumab is currently the only IO that is covered by insurance.
Q. Then to what extent are you using the ipi-nivo regimen?
Dr Vogelzang: So far I’ve only treated 2 patients because ipi-nivo is expensive, not covered by most 3rd parties and only recently was put on the NCCN compendium. Overall, the IO and TKI combinations have lived up to my expectations. As the experience has accumulated, we are all fairly convinced than an IO in combination—either IO-IO, IO-bevacizumab, or an IO-TKI is frontline, acceptable, and better.
Q. Is it safe to say there is little room now for monotherapy? That’s a big change compared to two years ago.
Dr Vogelzang: Yes, two years ago, it was Sutent and Votrient for first line. But in the immunotherapy era, Votrient could not be combined, Sutent probably cannot be combined and as a result, they are now scrambling to find a place in second or third line therapy, with some exceptions.
Q. And what might those exceptions be?
Dr Vogelzang: The one that comes to mind is the situation I mentioned previously with the prisoner who came in with pain. In his case I did not want to wait for the IO-TKI combination to be approved. I needed to put out the fire right now. A TKI is still very appropriate upfront. In another case, I had a patient in severe respiratory distress from metastatic disease. I started him on axitinib as monotherapy and when he stabilized, I added nivolumab. Now he is out of danger but has grade 2 hypertension and diarrhea. This case underscores the limi- tations in some patients of using combinations.
Q. As we move further into the era of combinatorial therapy, do you envision the possibility that a much more clearly delineated treatment algorithm will emerge or will it continue to be appropriate choices, sometimes empirically determined, from a broad spectrum of regimens?
Dr Vogelzang: I do not foresee any clear-cut algorithm. The NCCN guidelines, for example, have always directed us to a potpourri of choices and that is not going to change. Each one of us sees a different spectrum of disease and each one of us sees a different level of acuity in each patient who walks in the door. My rationale is to get the ball rolling, so to speak, and put people on a TKI with a sample I have available. Once I have initiated therapy, I know their tumors will be slowing down. Then I will apply for reimbursement for nivolumab or ipi-nivo. The only drug I can apply for with success is nivolumab. Pembrolizumab is not indicated for monotherapy, nor is atezolizumab or avelumab. The only monotherapy is nivolumab among these agents. And I would add that a clinician who treats renal cell is generally pretty happy with nivolumab—achieving long term CRs and drug-free intervals. I’ve got about 20 patients who are in CR or off the drug.
Q. With ASCO 2018 behind us, what is at the top of your list as far as unresolved issues you would like to see addressed at future meetings?
Dr Vogelzang: I’d like to see some toxicity comparisons among the various combinations. Many of my colleagues say that the ipi-nivo regimen is much easier than most of us have been led to believe. And the reason for this is that the ipilimumab dose has been reduced from 3 mg/kg to 1 mg/kg in combination with nivolumab. Secondly, it’s only four doses and nivolumab is then every four weeks. It may be that the ipi-nivo combination is the least toxic of all of these regimens. And yet, I would like to see proof of that.
Q. Have you seen any superiority among the combos in terms of complete responses?
Dr Vogelzang: I don’t think any of the five combination regimens will be superior for CR. Reasonably, we will see CR differing—ranging from 5% to 20% in all of the combinations and the differences are likely just due to patient selection. Basically, all five of the combinations are quite effective, but we have to sort out their toxicities and we have to decide which one we can afford. If ipi-nivo is the best combination, it is also the most expensive and that is not a good thing. Unfortunately, none of the TKIs are going off patent in the near future so they remain expensive as well. KCJ