Prof Ian Davis chats with Prof David Quinn about the latest research for metastatic kidney cancer and the changes we’ve seen in first line treatments.
David Ian Quinn is an international expert in the field of clinical trials and molecular correlative studies in genitourinary cancer. Dr. Quinn is the medical director of the Norris Cancer Hospital and Clinics, leader of the Developmental Therapeutics Program for the USC Norris Comprehensive Cancer Center, head of the Section of Genitourinary Medical Oncology and associate professor of Medicine in the Division of Cancer Medicine and Blood Diseases at the Keck School of Medicine of USC. He has published in the journals Cancer Research, Clinical Cancer Research, Oncogene, Proceedings of the National Academy of Science, Journal of the National Cancer Institute and Journal of Clinical Oncology. Dr. Quinn is a reviewer for more than 20 peer-reviewed journals and is on the editorial boards of the American Journal of Clinical Oncology and cancer.net (American Society of Clinical Oncology).
Talking Urology podcast transcript
ANZUP 2019 Interviews – David Quinn and Ian Davis
Ian Davis: Hi my name is Ian Davis and I’m chairman of ANZUP Cancer Trials Group and I’m speaking to you from the ANZUP Annual Scientific Meeting held in Brisbane in July 2019. It’s a great pleasure to talk today with Professor David Quinn, Medical Oncologist, at the University of Southern California and an Australian forever no matter where he lives. David great to have you here, thanks for coming to the meeting.
David Quinn: Thank you and great to see you and great to be here.
Ian: David 2019 has been a really busy year for prostate cancer and would be easy to forget that there are other genders of urinary of cancers that are of interest to ANZUP and the people watching this video. You’ve got an interest in kidney cancer, now quite a bit has been happening in that in the last few years and particularly this year as well. Could you give us your thoughts about where the current state of play is for that?
David: Sure. I think we’ve had a standard and first line metastatic renal cancer of a VEGF receptor TKI for years based upon the approval of Sunitinib now 15 years ago and that’s changed. In the last two years we’ve had the mantle of Sunitinib and another similar drugs that have been equivalent such as Pazopanib questioned initially by the CABOSUN trial randomized phase 2 study run by the alliance where Cabozantinib had a superior PFS and response rate in intermediate and poor-risk metastatic patients. And that, I think, has change practice in the US if not elsewhere.
Ian: So, what effect do you think that has had on management in 2019 and beyond?
David: Well, I think there has been some uptake of Cabozantinib in the first line for intermediate and poor-risk patients particularly those with bone metastases where Cabozantinib seems to have an advantage. So, from that perspective, a minor change but then what came after that was the advent of first line of immunotherapy in the form of Checkmate 214 where we saw Nivolumab and Ipilimumab produce a response rate and overall survival advantage over Sunitinib for once again intermediate and poor-risk patients. So, we’ve had that in the United States for a couple of years. It’s now available in most parts of the world including Australia and I think it’s been a game changer in terms of overall survival for those patients that can tolerate it. So, I think that’s a big difference.
And then the data that’s come in 2019 of being with 2 combinations of VEGF TKIs with immuno‑oncology drugs, the biggest impact that we saw was the combination of Pembrolizumab with Axitinib versus Sunitinib. In a very early analysis at about 12 months follow up, we saw an OS advantage with a hazard ratio 0.53, so a big effect, but in addition, that is also mainly in patients with intermediate and poor-risk cancer. The hazard ratios in the favorable risk, they still have overlap and they probably won’t make me change my practice. About the same time we saw data from the JAVELIN study which once again had Sunitinib as a control arm and compared that therapy to a combination of Avelumab, a PDL1inhibitor, with also Axitinib and it showed a response rate that favored the new experimental combination arm and also PFS that was heavily in favor of the new combination, but we don’t have overall survival yet. Interestingly, in that study, the PFS including unfavorable risk did favor the new combination of Avelumab and Axitinib. So, we’ve got some things that are going to question the balance of course on the two newer studies, a very brief follow up, 12 months in one, about 11 months in JAVELIN and then a further interim where we don’t have a lot of details and another one to come.
So, we going to get more data but I suspect that these combinations are going to be available in the rest of the world and they will have turned first line therapy on its head.
Ian: So, then what do we do if someone has progressed through Ipilimumab and Nivolumab or a TKI and a PD1-targeted therapy and then progress? What are we going to offer those patients?
David: Well, I think the truth is that if you follow a level one evidence, we have no idea but I think that most of us would look at giving some form of a VEGF TKI after Nivolumab and Ipilimumab. The two choices there are typically Cabozantinib where we have good level one evidence with overall survival advantage albeit over Everolimus from the METERO trial for using Cabozantinib, so Cabozantinib might be one answer. And then the other evidence-based which goes right back to the axis study, is with Axitinib as a single agent which we have a lot of experience with and might be one of the better tolerated TKI’s.
So, what becomes more complicated is if you’ve got a VEGF and I-O combinations what do you give after that? Well, you my resort to Cabozantinib but you also may resort to some of the other VEGF, TKI’s depending on what you think the tolerability is going to be in those patients. And then there’s the question of whether if a patient progresses on I-O and VEGF whether you might give a combination of Nivolumab and Ipilimumab later and we’re starting to get some data that suggests we can see a retreatment. Now, that’s expensive outside of most guidelines and is probably not going to meet approval in say, Australian and New Zealand at least anytime soon, but I think this is a time when renal cancer therapeutics in terms of what we select and the sequence of our therapy has been turned on its head.
Ian: We should say for anyone watching from Australia at the time we’re recording this in July 2019, we can’t yet use Cabozantinib on our reimbursement scheme straight after Ipilimumab and Nivolumab there has to be another TKI in between. That’s not the case in other parts of the world.
David: Well, in that setting, I don’t have a problem with people picking something else and probably my first choice would be Axitinib which I think is available in that setting in Australia but not New Zealand where they have to fund it themselves.
Ian: Okay. So, what do you think is the next big question we should be asking in renal cell carcinoma?
David: I think there’s a sequencing question. I think that we need to get longer follow up on some of these studies and we’re going to see some studies if you like, the CLEAR study which looks at Pembrolizumab and Lenvatinib, another VEGF-TKI compared to Sunitinib will be coming, and also, we have combinations of Cabozantinib with Nivolumab on the first one line that I think are going to be interesting. We’ll see whether they can produce the PFS response and overall survival data that we are seeing.
So, we’re going to be inundated with data in the first line. I think we have some novel therapies that target, for example, HIF2 and some of the metabolic pathways that are important in renal cell coming, but they’re still an early phase 2 studies at the moment to the point where we will have to do a phase 3 study is interesting. I think we also need to look at some alternatives. One particular study I think is very, very interesting is one that we’re running in ANZUP which is the KEYPAD study which looks at after initial VEGF-TKI, which is still a standard of first line therapy for a large number of patients, giving them Pembrolizumab and Denosumab where there’s a theoretical advantage of the rank ligand inhibitor in combination with PD1 inhibition. I think that’s an important study.
So, the bottom line is what we’re learning, we need to keep doing the studies and accruing to them and ANZUP is a great vehicle for doing that.
Ian: Thanks David. So, I think the take away message is that there’s still a lot of opportunities but there is still a lot to learn and the best way to do that is through clinical trials. David thank you very much for your time and for your support of ANZUP.
David: Thank you very much Ian.