PracticeUpdate: Haematology & Oncology

KIDNEY

24

EXPERT OPINION LAURENCE ALBIGES First-line and adjuvant therapy for RCC Interview by Sumanta Kumar Pal MD

is first-line treatment with sunitinib. So what I foresee is let’s see the full data. Let’s see once again the magnitude of the difference because that may lead to some change in the near future. I believe that if that’s the case we would like to have a larger comparison because that’s a randomised phase 2, although it’s a randomised and well-convicted academically- led study, we may want to go for a phase 3, and as you know there are other challengers in first-line setting that are coming as well. So this very specific study may change the standard of care, but we would like to see more results.

Dr Pal and Laurence Albiges, MD, PhD, discuss new data on first line treatment as well as adjuvant therapy for renal cell carcinoma at ESMO 2016.

Dr Pal : I wanted to ask you about many of the abstracts that we’re going to be seeing in renal cell carcinoma. I think clearly one that’s going to have a tangible impact when we go back to clinic next week is the S-TRAC Study. Now I know we can only speak in hypotheticals. We just have the data from press release, but how do you imagine adjuvants that might potentially play out in the clinic? Dr Albiges: Well, I think this ESMO is very important for adjuvant in RCC because what we know up to now is that we have had a large ASSURE trial that was a negative trial, which investigated both sunitinib and sorafenib versus placebo, and now we have the extra data that will be presented tomorrow indeed in the presidential session. What we know from the press release is that this study met its primary endpoint on a dif- ference on disease-free survival. So it does mean that in the study sunitinib use in an adjuvant setting in high-risk patients for 1 year did change disease-free survival compared to placebo, and I think it’s important because all of a sudden where we thought we had no adjuvant therapy for RCC, something comes into the game. However, I think that from a clinical perspective it’s way too early to change

One peculiarity, which the authors explain, is how to account for the difference with the previously reported negative ASSURE trial looking at adjuvant therapy with sunitinib and sorafenib. The authors explain that the ASSURE trial had earlier-stage patients in the trial, including 9% stage I, versus in S-TRAC, all the patients had locoregional/late-stage disease. Additionally, 21% of the patients in ASSURE had non-clear cell histology, whereas patients in the S-TRAC trial have only clear cell disease. In ASSURE, the starting dose was reduced midtrial to 37.5 mg and the subgroup analysis showed that this cohort underperformed; furthermore, in ASSURE, there was allowance for dose reduction to 25 mg, but not in S-TRAC. Thus, there is reason for optimism and a possible new standard for this patient population. The limitations and caveats include the lack of 10-year survival data yet, the cost, and the inclusion limitation to the higher-risk group. In light of the discrepancy and the toxicity of the therapy, utilisation of adjuvant sunitinib should be limited to the clear cell carcinoma, higher-risk patients as defined in the paper, and it should be given only by physicians who understand the data and are used to managing the toxicities of this therapy. design of these data because one trial out of two is positive, but the other one is strongly negative. So we cannot say, oh, we are sure we need to change our standard of care. My feeling is that we should keep with the current design, stay with the current design, and based on subsequent results be ready to amend the study if we confirm there is a signal for sunitinib adjuvant role in very high-risk patients. But up to now I think it’s a bit premature to change the design of those ongoing studies. Dr Pal: I think that’s a very pragmatic way to approach this problem. One final question. The last presentation here at ESMO, or one of the last ones in renal cell carcinoma is going to be the CABOSUN Trial led by our friend, Tony Choueiri. What do you think the implications are for that trial? The press release indicates that there’s a benefit in progression-free survival with cabozantinib. Do you feel that this trial may potentially reset our standard of care front-line? Dr Albiges: I think it’s once again a very important question. We don’t have the full data to answer it right now and having a strong difference in a progression-free survival in first- line is important and therefore, yes, we may be challenging one of the standards of care which

P rior reported negative adjuvant trials included treatment with both interferon and VEGF inhibitors. Adjuvant therapy in RCC was thought a dead question, looking to new trials with next-generation immunotherapies as the next big hope for the more distant future. Thus, this positive trial was a surprise for many and so yielded a cautionary acceptance. The patients in this data set were very specifically advanced-stage patients, clear cell carcinoma only, representing a more homogenously higher-risk population. Moreover, the dosing regimen started at full dose, 50 mg sunitinib for 4 weeks on, 2 weeks off; hence, more aggressive dosing on the front end. The end result displayed a median duration of disease-free survival of 6.8 years (95% CI, 5.8-not reached) in the sunitinib group vs 5.6 years (95% CI, 3.8–6.6) in the placebo group. The hazard ratio was 0.76 (P = 0.03). At 3 years, 64.9% were disease-free in the sunitinib group vs 59.5% in the placebo group. At 5 years, 59.3% were disease-free in the sunitinib group vs 51.3% in the placebo group. Overall survival data were not yet complete. However, this benefit came with a price. The sunitinib group had 34.3% dose reductions from adverse events compared with only 2% of placebo patients. There were more dose interruptions as well (46.4% vs 13.2%) and more treatment discontinuations (28.1% vs 5.6%). Despite a similar number of serious adverse events, there were significantly more frequent grade 3/4 adverse events in the sunitinib group vs the placebo group (48.4%/15.8% vs 12.1%/3.6%). our standard of care. We need to see the full data. We need to see the magnitude of the difference, and we need to ponder that with the ASSURE data which was a much larger trial who also enrolled high-risk patients at some point. So, what we would like to see is a meta-analysis of those two trials which could actually lead us to have more information, maybe on the patients’ election in very high-risk patients. But up to now my feeling is that these data will not be enough to change the standard of care. Dr Pal: I think that’s very insightful and I agree with you. I think the meta-analysis may be very helpful in terms of interpreting the data. Both on the US side and here in Europe, there’s been a lot of discussion about adjuvant PD-1 or PD-L1 directed therapies in renal cell carcinoma. Trials are being conceptualised, many have been conceived with perhaps an observation or placebo arm, what do you think of those studies? Are we going to really need to shift the design of those trials on the face of the S-TRAC data? DrAlbiges: I think it’s a true question, and I think it’s important that anyone working in this field actually really think about it. Once again in my view, it would be too early to change the

Dr Albiges is a medical oncologist in the genitourinary group of the Department of Cancer Medicine at the Institute Gustave Roussy in France. Dr Pal is an internationally recognised leader in the area of genitourinary cancers. He is the Co-Director of the City of Hope Kidney Cancer Program in California and is the head of the kidney and

bladder cancer disease team at the institution. Watch the full interview on PracticeUpdate.com

Adjuvant sunitinib increases disease-free survival in patients with high-risk RCC after nephrectomy Comment by Bradley G Somer MD

Adjuvant sunitinib in high- risk renal-cell carcinoma after nephrectomy The New England Journal of Medicine Abstract BACKGROUND Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. METHODS In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. RESULTS The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs 2%), as were dose interruptions (46.4% vs 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs 17.1% for placebo); no deaths were attributed to toxic effects. CONCLUSIONS Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. N Engl J Med 2016 Oct 10;[Epub ahead of print], Ravaud A, Motzer RJ, Pandha HS, et al.

Results from the S-TRAC trial reported in this NEJM article by Ravaud and colleagues represents the first positive study after many failed adjuvant trials for patients with clear cell carcinoma of the kidney post nephrectomy.

There is reason for optimism and a possible new standard for this patient population. The limitations and caveats include the lack of 10-year survival data yet, the cost, and the inclusion limitation to the higher-risk group.

Dr Somer is Assistant Professor, Hematology/ Oncology, University of

Tennessee Health Science Center; Senior Partner, West Clinic, Memphis, Tennessee.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY