PracticeUpdate: Haematology & Oncology

CONFERENCE COVERAGE

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EXPERT OPINION ERIC JONASCH Metastatic renal cell carcinoma review Interview by Sumanta Kumar Pal MD

Dr Pal: I’m here with Dr Eric Jonasch, who’s a world renowned expert in the disease of renal cell. Eric, I’m going to start by asking you a little bit about some of the work that you’ve done related to the mechanism of cabozantinib. Now, cabozantinib is being highly profiled here at this meeting, and I think you’ve given us a good understanding of how the drug works. Can you give us some insights? Dr Jonasch: The interesting thing about cabozantinib is it blocks not only VEGF receptors, which you see with most of the other agents that are being used for renal cell carcinoma, but also blocks MET and AXL, and these are two really, really important proteins on the surface of cells. They’ve found MET on the surface of the cancer cell, AXL on the surface of the cancer cell, and AXL can also be found on the sur- face of the immune cells. MET can also be found on the blood vessel cells, so these other proteins actually will regulate the way the cancer cell behaves. MET and AXL on the cancer cell can actually cause pro metastatic behaviour, cause epithelial- mesenchymal transformation,

was a trial that was done through the cooperative group where these num- bers usually are a little bit lower. So it really suggests that cabozantinib is doing something different; these mechanisms that I was talking about – changing the metastatic behaviour, reconfiguring if you will tooting the microenvironment – by inhibiting MET and AXL are probably one of the main reasons why this occurred. Dr Pal: That makes perfect sense. What do you think that the CAPO- SUN data establishes cabozantinib as a frontline standard? Where does cabozantinib fit now across the sea of potential frontline choices? Dr Jonasch: The interesting thing about it is they did not have good risk patients. So for this to be a universal truth, if you will, now in the frontline setting, I think is a little bit challenging. However, based on the fact that we are dealing with the majority of patients probably by looking at intermediate and core risks, I do think this is a new standard in the frontline setting. Dr Pal: Fascinating. I’m going to shift gears for a second and talk about the other high profile trial in renal cell carcinoma here at ESMO, and it’s a not a metastatic trial. It’s our adjuvant study of sunitinib, the so- called S-TRAC trial. Some really interesting results. I wonder if you could highlight those and give us your perspective on them. Dr Jonasch: That’s a 615 patient study, and this is a trial that was looking at nonmetastatic but high-risk group patients. So they tried really hard to make sure that they got people who they figured would have a high risk of relapse, T3, T4 disease, a higher grade disease and randomised them between 1 year of sunitinib and 1 year of placebo. The primary end- point was relapse free survival, and it met that endpoint, essentially a 1.2 year increase, 5.6 years to 6.8 years relapse free survival, so that’s interesting of itself.

which results in cells that can move within the tumour and also into the metastatic space. AXL is actually found on some of the members of the innate immune system, for example, the macrophages monocytes. And what it does there is it actually encourages those macrophages to do cleanup for the tumour. It shifts from those macrophages being cells that will actually attack the cancer to cells that will actually calm down inflammation, which will calm down the T-cells and cleanup garbage in the micro environment. So essentially what happens is the tumour then trains the macrophages to work for it. If you can block that with an inhibitor like MET andAXL, inhibitor like cabozantinib, you’re essentially reversing some of those effects. Dr Pal: I’ve got a feel that perhaps the work that you’ve done plays into some of the data that we’re seeing here at ESMO 2016, and in par- ticular, the CABOSUN data study. Can you perhaps give us an overview of the CABOSUN data and tell us how your work might relate to the ultimate results from the study? Dr Jonasch: This is a really interesting study. It was an Alliance study, so it was done through the coop- erative group mechanism, 157 patients, who were randomised up front without prior therapy between sunitinib and cabo- zantinib. Now, these patients were a special subset where they had intermediate or poor risk features, the vast majority intermediate. So kind of appro- priate and germane for most of the patients that we’re seeing with metastatic renal cell carci- noma. The primary endpoint was progression-free survival, which it met quite handily, so it was 8.2 months for cabozantinib versus 5.6 months for sunitinib, and the latter number kind of low. But that’s just reflecting the patient population and the fact that it

There are rumours that overall survival really has not been affected. So now what we’re left with is individuals who are going to be treated for a year with an agent that’s essentially going to instead of upfront, outback delay relapse but maybe not improve overall survival. So I think it leaves the community with a bit of a quandary; what’s the value of that 1.2 years of enhanced relapse-free survival if we’re not really getting a survival endpoint. We’re not really using this to cure people but delaying the inevitable, and they’re dealing with the toxicity up front. I think it’s going to be an interesting conversation in the weeks and months to come whether this is an advance for patients with renal cell carcinoma. Dr Pal: What’s your message to the community based oncologists who might be tempted to treat that patient with high risk sunitinib therapy? Dr Jonasch: Well, first of all, we’re going to have to figure out whether this is going to get approved by regu- latory agencies. We’re going to have to see how it’s viewed by the various compendia, and were it to be avail- able, it really requires a conversation with the patient do you want to trade up front toxicity for a possibility of a delay in your metastatic disease or do you want to enjoy the quality of life you have now.

Dr Pal and Eric Jonasch, MD, discuss key renal cell carcinoma studies and treatments at ESMO 2016.

Dr Jonasch is Professor in the Department of Genitourinary

Medical Oncology, Division of Cancer Medicine, at the MD

Anderson Cancer Center of The University of Texas in Houston, where he is also Co-Chair of the Renal Cancer Program.

Watch the full interview at PracticeUpdate.com

© ESMO 2016

Patients with advanced renal cell carcinoma able to remain on axitinib for extended periods Among patients with advanced renal cell carcinoma who are treated with first-line axitinib, a substantial proportion remained on therapy for a prolonged period of time. T his conclusion, based on results of a important to understand factors associated with long-term response.”

(25.0% vs 18.4%), diarrhoea (14.5% vs 4.4%), and weight decrease (11.2% vs 3.2%), respectively. Factors associated with a longer duration of therapy were: • Eastern Cooperative Oncology Group per- formance status 0 • Platelet count ≤ the upper limit of normal • Neutrophil count ≤ the upper limit of normal • Haemoglobin (male >13 g/dL or female >11.5) • Absence of bone or liver metastases • Baseline tumour burden below the overall median sum of longest diameter (96 mm). Dr Rini concluded that among patients with advanced renal cell carcinoma who are treated with first-line axitinib, a substantial proportion remained on therapy for a prolonged period of time. Longer axitinib treatment duration (>18 months) was associated with an increased objective response rate and increased fre- quency of early tumour shrinkage. He added, “We hope to continue to opti- mise titration of this drug to achieve the opti- mal dose to achieve maximal clinical effect in patients with renal cell carcinoma.”

had shorter duration of therapy. Overall, 119 (29.6%) received over 2 years of therapy, 71 (17.7%) over 3 years, and 28 (7.0 %) over 4 years. The median (range) duration of ther- apy was 34.7 (18.4–60.1) months for longer duration of therapy versus 6.5 (0.1–17.7) months for shorter duration of therapy. Objective response rate was 75% for longer duration of therapy versus 24.4% for shorter duration of therapy (50.6% difference; 95%CI 41.9–59.3%; P < 0.0001). More patients had early ≥ 10% tumour shrinkage in the longer duration of therapy group (74.8%) than in the shorter duration of therapy group (55.3%; difference: 19.6%, 95% CI 10.1–29.0%; P = 0.0001). Grade 3 adverse events were more frequent for longer duration of therapy than shorter duration of therapy and included hypertension

retrospective analysis of patients treated in phase 2 or 3 clinical trials of the drug. B.I. Rini, MD, of the Cleveland Clinic, Ohio, explained that axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors approved globally in advanced renal cell carcinoma. A subset of patients treated with axitinib achieve long-term disease control. Dr Rini and colleagues set out to characterise the duration of treatment and clinical outcome of patients with advanced renal cell carcinoma who achieved a duration of treatment over 18 months on axitinib therapy. “We undertook the analysis,” said Dr Rini, “to try to understand which patients might continue to respond to axitinib long term. It is

Data were reviewed from 402 treatment- naive patients with advanced renal cell car- cinoma treated with axitinib in phase 2 or 3 clinical trials. Data on treatment duration, objective response rate per Response Evaluation Criteria in Solid Tumors v1, and early tumour shrinkage ( ≥ 10% shrinkage at first scan) were compared between patients with a duration of treatment over 18 months (longer duration of treatment) versus those who had duration of treatment 18 months or less (shorter duration of treatment). The analysis was conducted to identify baseline characteristics associated with longer duration of treatment. Of the 402 patients, 152 (37.8%) had longer duration of therapy and 250 (62.2%)

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