ASCO 2018: Systemic Therapy in Management of High-Risk Renal Cancer

Chicago, IL (UroToday.com) In this two part educational session, Drs. Rini and Kim discuss the role of peri-operative systemic therapy for localized renal cell carcinoma. Dr. Rini discussed the current evidence and his take from a medical oncology perspective.
He first briefly discussed the experience with neoadjuvant systemic therapy, which is less established. While there were numerous retrospective studies, he focused on a few prospective studies. Two fot eh studies were done at his institution, Cleveland Clinic. All these studies assessed slightly different populations, so can’t be compared head-to-head.

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While, in general, most patients (60-100%) had some objective primary tumor shrinkage with neoadjuvant targeted therapy, the extent of shrinkage was moderate - ~10-20%, or 1-2 cm. Obviously, this limits the utility of this treatment to specific situations – he does not recommend it is used regularly. However, he and Dr. Kim agreed that they both considered its use when 1-2 cm decrease in primary tumor size may change surgical management – specifically in cases where nephron-sparing becomes feasible in patients at high risk of ESRD with radical nephrectomy. It does not have an established role in tumor thrombus shrinkage.

PADRES is a registration trial that is being initiated by Dr. Derweesh (UCSD) to evaluate this phenomenon specifically – patients in whom radical nephrectomy would place them on dialysis or severe CKD and in whom there is an imperative indication for nephron-sparing. It is a multi-institutional, non-randomized study. Patients will be treated with axitinib pre-operatively for 8 weeks and then re-staged prior to surgery. Accrual will hopefully begin in the near future.

There are obviously neoadjuvant checkpoint inhibitor studies ongoing, but results will be a few years away. One study that he emphasized with PROSPER (ASCO 2018 Abstract TPS 4597 – covered by Urotoday), a unique study that assess peri-operative nivolumab. Patients are pretreated with 2 cycles nivolumab prior to nephrectomy and the restarted on adjuvant nivolumab – the rationale being that the first two doses may prime the system. He did not the study was having some difficulty accruing and encouraged the audience to enroll patients.

He next turned his attention to adjuvant therapy, a much more controversial topic with many recent major publications. The biologic rationale for adjuvant therapy is sound – patients who recur after nephrectomy have micrometastatic disease at the time of nephrectomy. Adjuvant therapy may help treat these sites before they have a chance to progress.

Until the targeted therapy era, all prior adjuvant trials had failed to show DFS or OS benefit.
1. ASSURE (Haas NB et al Lancet 2016) was the first to report in the targeted therapy era and compared sunitinib vs sorafenib vs. placebo in a “high-risk” localized RCC population – with no DFS or OS benefit.
2. S-TRAC (Ravaud A et al. NEJM 2016), however, changed all that – in a much more selectively high-risk group of localized RCC patients after nephrectomy, the found that there was a significant DFS benefit – the curves split early and stay separate (HR 0.76). The OS data was not yet mature and did not show a difference. Based on this data, sunitib has been approved as an adjuvant therapy for high-risk RCC – albeit as a 2nd option following clinical trial enrollment.
3. PROTECT (Motzer R et al. JCO 2017) – in this study of pazopanib in an adjuvant setting, technically the study was reported as negative. However, he highlighted the dose issue in the study. Originally scheduled at 800 mg / day dose, only ~400 patients got this original dose; due to adverse events, the starting dose was reduced to 600 mg/day. In an ITT analysis using 600 mg, there was no difference. But in the 800 mg subgroup analysis, DFS was significantly improved (HR 0.66). This study highlights the importance of therapeutic dose. He feels that at the correct dose, this study would have been positive.

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In his mind, the Pro’s and Con’s of adjuvant therapy are as follows:

Pro’s:
• The SOC is observation and no intervention – which patients and physicians are uncomfortable with
• There is a DFS benefit with sunitinib – and it may be durable (OS data immature)
• There is likely an adequate window of drug exposure that balances benefit and toxicity
• You can always discontinue medication!
Cons
• The DFS benefit of sunitinib is relatively small (~5% absolute benefit)
• 1-year of therapy for modest benefit
• Adequate drug exposure may be associated with significant toxicity

However, as a recent survey of 452 kidney cancer patients found, the primary interest of patients is both DFS and OS (60% each) – toxicity is much less important (40% of respondants).

There are a few more adjuvant trials that are due to report and may add to the story and discussion – which is quite heated.

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There are also immune checkpoint inhibitor adjuvant therapy trials ongoing, which may change the field yet again. However, they are not close to reporting yet.

In his practice, he considers neoadjuvant TKI in select populations (solitary kidney, atrophic contralateral kidney, etc) if he thinks it will change surgical management and improve nephron sparing. In patients with S-TRAC high-risk pathologic characteristics, he goes to clinical trial first, but also offers sunitinib to patients when appropriate – it is FDA approved and should be discussed with patients!

Presented by: Brian Rini, MD

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA


Read the Corresponding Discussion:

Role of Surgery in Management of High-Risk Renal Cell Cancer - Presented by: Hyung Kim, MDHyung Kim, MD
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