Nicholas J. Vogelzang, MD; Bernard Escudier, MD


June 19, 2014

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Nicholas J. Vogelzang, MD: I'm Nick Vogelzang, Professor of Medicine, University of Nevada School of Medicine and Vice Chair of the Southwest Oncology Group Genitourinary Committee. My work is in oncology research at the Comprehensive Cancer Centers in Las Vegas, Nevada.

With me today is Bernard Escudier, from the Institut Gustave Roussy in Paris. Bernard is if not the world's leading expert in kidney cancer, then nearly so. We are going to talk about the studies on renal cell carcinoma (RCC) that were presented at the 2014 meeting of the American Society of Clinical Oncology .

Bernard, you had a presentation that was one of the first in the area. Could you describe the gene signature study[1]?

Predicting Relapse in Localized RCC

Bernard Escudier, MD: We looked at whether we could predict relapse for localized kidney cancer tumor, and we used the gene signature that was discovered by the Cleveland Clinic team with Genomic Health. It's the same committee that did the Oncotype DX validation for breast, colon, and prostate cancer.

We looked at this gene signature. We prespecified the genes and took 16 of them (11 for the tumor and 5 reference genes). In our 600-plus patients, we validated that the recurrence score based on these genes very strongly predicts the risk for recurrence -- a 4-fold increase when you have an increase of 25 units. It's very good.

Dr. Vogelzang: Hopefully, that will be useful. You made a comment that it hadn't been validated yet on biopsies, and it's not yet clear that we can do anything about poor-risk RCC after resection. All we can say is that if we know that patients have poor risk, we should get them into a clinical trial.

Dr. Escudier: We do that, and also if there is a very low risk for relapse, we can reduce the number of scans that we do on our patients. There is a certain number of applications, and of course if we have an adjuvant drug (which will come), it will be very useful.

Dr. Vogelzang: The other interesting trial[2] that was reported at the prognostic/diagnostic level was the GWAS (the genome-wide association study). Could you comment on the trial done by Dr. Motzer?

Dr. Escudier: It's a very fancy and complex way to look at the genomics of the tumor and see whether you can predict the efficacy and safety of certain drugs. What they did was to look at a group of patients who were treated with pazopanib and some with sunitinib -- from the COMPARZ trial and 3 other trials.

What came out of this work, which for me is complex and still too preliminary to be applied in the clinic, is they found that some genes were associated with safety issues. They might predict, for example, liver toxicities with the genomic approach and possible efficacy of pazopanib, but not sunitinib -- maybe because they had more pazopanib patients.

It's the first approach of this type. It has to be examined further to see whether it's going to be useful. Martin Voss, the discussant, commented that the approach is interesting but still very far from application. I agree with that.

Can Genetic Markers Predict Drug Efficacy, Safety?

Dr. Vogelzang: I know that whenever I use sunitinib or pazopanib and I see an unusual side effect, such as high blood pressure, hypothyroidism, rash, or diarrhea, I say that it must be your genetic risk.

Dr. Escudier: It will be of interest if we can select the patient before treatment with the drug, either because of safety (eg, this patient should never have pazopanib or sunitinib) or to know that a patient is a better candidate to receive one drug over another.

Dr. Vogelzang: Yes, that would be ideal.

Dr. Escudier: Especially when we have so many vascular endothelial growth factor (VEGF) inhibitors, which are competitive.

Dr. Vogelzang: It seems that there is a genetic component. The Japanese, for example, rarely use sunitinib if they can avoid it because of bone marrow suppression, whereas axitinib seems to be very popular there.

Dr. Escudier: That's true, and the toxicity profile differs on the basis of patient population.

Dr. Vogelzang: That is why I was surprised that it didn't show anything.

Dr. Escudier: They did show a small difference for pazopanib, but not for sunitinib. I think it's going to come. We had a lot of single-nucleotide polymorphisms (SNPs) stories in the past, and the problem is that they looked at the SNPs compared with what has been reported before and could not find the same one, so the result is still pending.

Good Signal From Nivolumab in Pretreated Patients

Dr. Vogelzang: The big news last year and this year was the use of nivolumab in RCC. We were both at Dr. Motzer's presentation[3] when he looked at variable doses of nivolumab in patients who were fairly heavily pretreated with sunitinib and pazopanib, and in many cases with an mTOR inhibitor. What was your take on that?

Dr. Escudier: I take many things from this presentation. First, they used a different schedule than that used so far -- every 3 weeks vs every 2 weeks -- which probably means that we still don't know exactly which schedule we should use. Second, there is no clear dose effect with these agents, although they are probably going to select the dosing from the 3 doses that they tested, but these agents don't seem to have a big dose effect. Third, progression-free survival (PFS) and tumor shrinkage are probably not the ideal ways to look at this drug.

What came from the study is that the overall survival they reported seems to be much longer than what was expected compared with previous phase 3 studies. This might be a good signal, or might just be due to the selection of patients.

Dr. Vogelzang: These are people who often got to third-line therapy, and we know from the GOLD trial[4] that the third-line PFS was very close to second-line PFS and overall survival. Their overall survival was in excess of 18 months.

Dr. Escudier: Yes, the group of people at 25 months of overall survival seems to be encouraging, but it's still only 50 patients, so we should be cautious about that. Another thing I got from this presentation is that the safety profile with nivolumab alone is very good.

Dr. Vogelzang: That's true. For the practicing physicians who don't yet have PD-L1 or PD-1 antibodies, should this drug still be considered promising?

Dr. Escudier: It is very promising. Once a patient fails one line of treatment, we try to put them in a clinical trial. We still have a lot of questions about this drug, and we still have a lot of combination trials ongoing. Usually in the United States, you have a lot of access to these trials, so I would encourage that.

First-Line Nivolumab With Ipilimumab

Dr. Vogelzang: The other interesting session we heard this morning was from Dr. Hammers, in which he reported a phase 1 study[5] of nivolumab with ipilimumab. Ipilimumab is a drug that many of our readers and listeners are familiar with. Do you want to briefly summarize your 10,000-foot view of that presentation?

Dr. Escudier: What they did in a large phase 1 study is combine nivolumab and ipilimumab at 2 different doses -- a high dose of nivolumab with a low dose of ipilimumab, and vice versa. This was a relatively small study: 42 patients (21 in each arm). What came out was that there is interesting activity. The response rate was in the range of 50%, so it's quite interesting activity.

Dr. Vogelzang: Is this in newly diagnosed patients, not previously treated with sunitinib?

Dr. Escudier: These were newly diagnosed patients. The findings were quite encouraging. The duration of response is not yet impressive, but there are still a lot of patients on treatment, so we have to be careful. We don't have any idea of the survival so far. The second point is that therapy is pretty toxic.

Dr. Vogelzang: The toxicity with ipilimumab is diarrhea, diarrhea, diarrhea.

Dr. Escudier: Absolutely. Of the patients who had high doses of ipilimumab plus low-dose nivolumab, almost 70% had grade 3/4 adverse events, so that is not treatment that they are going to continue on. On 4 mg nivolumab and 1 mg ipilimumab (the lower dose of ipilimumab), the investigators said the toxicity profile was acceptable -- but 25% of patients still had grade 3/4adverse events, which is in a very selected group of patients, and I suspect that is going to be higher when they expand the cohort. These are attractive, yet very preliminary results.

Dr. Hammers said that BMS is going to launch a large phase 3 trial of first-line treatment. I am interested by the data, but a little skeptical and anxious for the patients.

First-Line Nivolumab With Pazopanib or Sunitinib

Dr. Vogelzang: In another abstract, by Dr. Amin,[6] they did first-line therapy as well, but they looked at sunitinib or pazopanib combined with nivolumab, right?

Dr. Escudier: They did, but it was not all first-line therapy, because patients who had received sunitinib could receive pazopanib plus nivolumab and vice versa. Thus, it was not strictly first-line. They did an expansion cohort in the sunitinib group. They also reported quite a high response rate: slightly higher than 40%, which is not bad.

The toxicity was a little excessive in terms of liver toxicity, especially in the sunitinib arm. They stopped the pazopanib arm because of 4 dose-limiting toxicities -- which might be a little premature, but they stopped it and expanded the sunitinib arm. They had a longer response, so it seems that there is some activity, but still a lot of toxicity.

Dr. Vogelzang: In the United States, there is an ongoing trial looking at sunitinib vs the Genentech PD-L1 agent. I remain fairly impressed with these data, but also somewhat skeptical that they are not yet ready for prime time.

Dr. Escudier: PD-L1 is a little different from PD-1. There is a lot of explanation for that. The activity might be a little different. In RCC, there is an ongoing randomized phase 2 trial, which might turn out to be a phase 3 trial later on, looking at PD-L1 alone or plus bevacizumab[7] (which seems to be an effectiveagent) vs sunitinib. We will learn a lot from this frontline study. It's very attractive option, and it pushes us to put patients in clinical trials.

Dr. Vogelzang: For the practicing physician, would you encourage them to refer patients for these immunotherapy trials?

Dr. Escudier: I have put quite a large number of patients on them. Patients love these drugs; they are very safe. Combinations are another issue, but they are very safe and some patients respond very well. I am sure you have seen some of these patients. This therapy is easy to give. The question now is about the combinations.

Dr. Vogelzang: Hopefully, the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) will give us some clearance on these soon.

Dr. Escudier: For PD-L1, they were very encouraging.

Non-Clear Cell RCC: Need to Focus on Papillary

Dr. Vogelzang: Let's turn briefly to the last 2 abstracts. The abstract that Dr. Tannir[8] presented today was on non-clear cell RCC, and he compared sunitinib with everolimus up front. The trial accrued 70-80 patients. What was your take-home message on that? This is a disease that practicing physicians will see regularly.

Dr. Escudier: Yes; for all of us, this is 15%-20% of our patients. First of all, this was a very heterogeneous group of patients: papillary, chromophobe, sarcomatoid, and so on. These are very different diseases. The beauty of this trial was to try to group them together because it's non-clear cell disease, and the commentator said that we should never do any trial with all non-clear cell cases together.

Dr. Vogelzang: He was saying that we should stick to papillary and not try to do everything at once.

Dr. Escudier: Papillary is the most common one. The main messages from this presentation? First, the drugs that we have are not very active in non-clear cell RCC, and once again, we have to test new strategies in this histology. Second, sunitinib is probably the best drug among the bad drugs that we have.

Dr. Vogelzang: In other words, sunitinib sort of beat everolimus here.

Dr. Escudier: Yes, there is a small advantage to using sunitinib over everolimus -- although I'm not sure that it makes a big difference if you use one or the other.

Immunotherapy Promising in Bladder Cancer

Dr. Vogelzang: I would like to turn now to the bladder story. What was your take on the bladder study[9]? I was one of the authors, so I will let you tell me what you thought.

Dr. Escudier: For the first time, we have seen a very interesting new approach in bladder cancer, which we have not had for many years now. This came from the PD-L1 study, and you are going to comment on that. I have seen 2 patients in this phase 1 study with impressive results, so I'm happy that it turned out to be positive. What did you find?

Dr. Vogelzang: I treated about a dozen patients, and Tom Powles presented the data.[9] We had 68 patients, and it was very impressive. There were no side effects to speak of and a response rate that was 50% and durable, going on well over 1 year and in patients who previously had chemotherapy. Now I must admit that they were in the healthiest group, who were node-positive; those with liver metastasis did not do as well, but the patients with lung metastases seemed to do well. It was interesting that in their hands, Genentech examined both the tumor PD-L1 and the immune cell PD-L1 level, and the immune cell PD-L1 did seem to predict who would benefit.

Dr. Escudier: This is easier to get than the tumor, which makes it interesting.

Dr. Vogelzang: Right. But I also remain fairly skeptical because sometimes these were archival specimens -- they weren't always done within 1 year or so. In my opinion, however, it's a real paradigm shift.

Dr. Escudier: Do you think they are going to go to first-line therapy in comparison with chemotherapy now?

Dr. Vogelzang: They are opening up a 300- to 400-patient phase 2 trial; about 100 of these patients will be treatment naïve, platinum-ineligible, and the others it will have previously received platinum treatment. They are also thinking about adjuvant therapy and are talking about unresectable, locally advanced cancers, such as these high-grade papillary cancers that no longer can be removed but are still popping up all the time.

Dr. Escudier: For the people who are listening, does this mean that the drug is going to be available very soon?

Dr. Vogelzang: No; it means that we will hopefully have a new drug within the next 2 years.

Dr. Escudier: Two years? I was thinking it would be 6 months.

Dr. Vogelzang: No, not that fast. I thought it was a pretty impressive result for them.

I'd like to again thank everybody for coming today. This is Medscape Oncology Insights on genitourinary cancer, and Dr. Escudier and I are here at the 2014 annual meeting of the American Society of Clinical Oncology. Bernard, thank you for being here today.

Dr. Escudier: Thank you, Nick.


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