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Guest Editor's MemoWhen oncologists gather in late April at the 17th International Kidney Cancer Symposium (IKCS) in Prague, they will be exploring a myriad of investigative directions, options for therapy, and cutting edge concepts, in many cases, picking up on themes featured at the recent GU ASCO  meeting in San Francisco. If there was one consistent theme emerging from GU ASCO—one that has long stood at the center of the narrative on treating renal cell carcinoma (RCC)—it is the need to identify predictive biomarkers to help us determine optimal sequential and combinatorial therapies. This is often referred to as the “holy grail” of our quest for optimizing outcomes and although expectations remain high for such a discovery, the reality sets in and we know validating such biomarkers is still daunting.

Nevertheless, this will only serve to again fuel the vigorous debate that will challenge attendees at the IKCS, sponsored by the Kidney Cancer Association. Until these reliable biomarkers emerge, we need to direct much of our attention to the nuances in treatment approaches covered at GU ASCO. In that sense, I suggest we get beyond the excitement generated by recent approvals and assiduously drill down into the data to find the “devil in the details”, so to speak. And one does not need look very far. By that I mean consider all of the cautionary tales that surround the proposed “treatment paradigms” for first line and second line therapies. This is not to diminish what has been proposed by groups like the National Comprehensive Cancer Network (NCCN). It’s more a question of remaining mindful—and vigilant—of those details often overlooked when applying the data to clinical practice.

There are numerous examples of such settings. For example, consider the implications from the 2017 ESMO conference where data from CheckMate-214 emerged. If one were to unqualifiedly accept the findings without drilling down into the data, as proposed earlier, should all patients receive the combination of nivolumab and ipilimumab over sunitinib? As an Editorial in ASCO’s daily news summary suggested, unique patient-related characteristics provide a rationale for choosing one agent, or a combination of agents, over another. With due diligence, you would consider the criteria of the CheckMate-214 trial and take into account guidelines from the International mRCC Database Consortium (IMDC). Yes, the combination was superior to sunitinib in patients with intermediate- and poor-risk disease. Notably, however, the schedule modifications of sunitinib, routinely adapted in the general practice and shown to be associated with greater clinical benefit in some patients as compared to the standard 4 weeks ON 2 weeks OFF schedule, were not contemplated in the study. Furthermore, those with favorable risk disease had better results with sunitinib in terms of overall response rate and progression-free survival.

The excitement surrounding immunotherapy may obscure the compelling need to choose the most effective therapy based on evidence for a particular patient at a given time point. For example, how should clinicians consider PD-L1 expression as they contemplate the use of a checkpoint inhibitor? How many of us are mindful of data showing that improvement is likely to be more pronounced in those with tumor PD-L1 expression of 1% or more? What’s needed in the calculus is to determine how such markers not only could have an impact on therapeutic choices but on expected outcomes.

These are nuances that are all part of the exciting narrative on treatment selection as we continue to see inflection points in therapy emerge from new data. And they will remain so as the search for predictive biomarkers goes on. Until those biomarkers are revealed, an attempt to administer as many efficacious and reasonably tolerated agents will often be the “default” setting of most clinicians, based on NCCN guidelines, other widely accepted protocols and patient preference. At the same time, the need to drill down and discover the “devil in the details” will help provide an important dimension to clinical decision making and appropriate choices.

Roberto Pili, MD
Guest Editor
Robert Wallace Miller Professor of Oncology
Co-Leader, Experimental and Developmental Therapeutics Program
Director, Genitourinary Oncology
Professor of Medicine, Urology, Pharmacology and Toxicology
Indiana University School of Medicine – Simon Cancer Center
Indianapolis, Indiana