When futurist author Alvin Toffler wrote a book in 1970 called Future Shock, the title worked its way into the national lexicon as a way to describe how society was reacting to overwhelming technological change. He described it as a personal perception of “too much change in too short a period of time” or simply, information overload where we are struggling, perhaps even stressed, to keep up with the accelerated pace of new information.
Is it a bridge too far to suggest that in some respects our knowledge base in renal cell carcinoma (RCC) has left more than a few observers in “future shock,” trying to keep up with the velocity of changes that in 2018 could usher in significant changes in the strategies for frontline therapy in RCC? Perhaps “future shock” is an exaggeration, but it is certainly accurate to envision a time a few months from now, perhaps when we are all preparing for the next ASCO meeting in June, when we look forward to a calculus to help us clarify the multitude of changes proposed for frontline and second line therapy for RCC.
Recent meetings of the European Society of Medical Oncology (ESMO) and other scientific sessions such as the Society for Immunotherapy of Cancer (SITC) suggest a key turning point in frontline strategies for renal cell carcinoma (RCC). We are on the cusp of a shift in the paradigm for frontline choices. Now that cabozantinib has been approved (see page 103), and assuming that the ipilimumab-nivolumab combination will be approved in the foreseeable future, there are a wide range of questions that need to be addressed as we grapple with choices in an attempt to apply evidence-based approaches to a shifting paradigm of treatment.
The ESMO meeting of 2017 helped to move the needle on several fronts, notably with regard to data on cabozantinib. With previous data compiled by an open-label design, we needed additional evidence to support the findings from the CABOSUN trial. ESMO delivered what was expected in the form of results from an independent review board. Results from the IRC indicated that the response rate for frontline cabozantinib in intermediate- and poor-risk patients declined, but that is fairly typical of what might be expected.
We know from experience in other trials that when investigators proceed to an IRC analysis, this phase is likely to reveal a tendency in the earlier stages of the trial to be somewhat sanguine about outcomes. For example, among RCC patients who have shown, let’s say, a 25% reduction in tumor size, investigators may characterize this finding as a “partial response.” However, such responses scrutinized in the IRC analysis may be recategorized because the review suggests otherwise. This is particularly true when evaluations of whether end points have been reached are considered in a relatively subjective context.
The advantage of having an independent review board review all the radiological data was important. With regard to this IRC data, the reviewers are not aware of which patients are assigned to a drug. And they are not aware of what the investigators had said about these patients. The board simply measures the tumors and whether there was progression or reduction. The bottom line is that a major question mark regarding the validity of results previously presented through the CABOSUN trial has essentially been lifted. The robust data translate to an improvement in outcomes for patients in first line therapy who are intermediate to poor risk compared to treatment with sunitinib.
Results presented at ESMO with respect to CABOSUN were important for other reasons as well, particularly as we look for evidence on progression-free survival (PFS) and overall survival OS) to guide clinical decision making. CABOSUN did not produce definitive data on OS because the trial was not large enough for that measure. Nevertheless, CABOSUN did show an overall survival benefit trend. But with all the combi-nations emerging and undergoing study (such as a new trial investigating ipi-nivo combined with cabozantinib) we need to question the wisdom of spending years on assessing this end point with monotherapy, whether it achieves improved OS. Practically speaking, it may be superfluous and not a good investment for a pharmaceutical company’s research program to undertake this study. Why? Because it is likely that a combination of agents, including the drug for which OS has not been unequivocally determined, will produce data showing superior OS.
As we evaluate the expanded spectrum of therapy and the overarching excitement for immune-oncologic approaches, the subtext of the debate is also a cautionary tale. As impressive as the OS findings are with IO therapy, not all patients are candidates for IO. The cautionary tale reflects the fact that in many patients IO therapy may not be the appropriate first choice—particularly in those with bone metastases, autoimmune disease and the elderly whose ability to undergo infusions may be limited.
With this issue, we conclude our 15th year of publishing the Kidney Cancer Journal. Who would have known that when this publication was launched in 2003 that we would be talking about “future shock” and an overwhelming volume of information in frontline therapy? At that time there was only one drug approved for RCC Perhaps the new year will bring much in the way of a new paradigm, as much perhaps as what the situation was more than 10 years ago when the current standard of anti-VEGF therapy was about to be approved. On behalf of the journal, its Medical Advisory Board and Editorial Advisory Board, we wish you the best for the new year.
Robert A. Figlin, MD