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Current guidelines from the National Comprehensive Cancer Network for treatment of high-risk renal cell carcinoma (RCC) recommend the use of adjuvant pembrolizumab. However, the authors of a recent "Comments and Controversies" review of randomized controlled trials (RCTs) of adjuvant therapy in RCC disagree with this recommendation.

The authors caution that there is evidence of increased toxicity in RCTs of adjuvant therapy for resected RCC, but no evidence of improved overall survival (OS). "There is no proven role for adjuvant therapy with pembrolizumab or any other drug after nephrectomy for patients with high-risk RCC," Ian F. Tannock MD, PhD, of Princess Margaret Cancer Centre at the University of Toronto, and colleagues wrote in the .

Nevertheless, the team emphasized, effective adjuvant therapy is needed to improve survival in high-risk RCC, as 50% or more of patients eventually succumb to the disease.

In 2014, the FDA approved the use of adjuvant pembrolizumab for RCC based on results from the . This was followed in 2017 by FDA approval of adjuvant sunitinib based on findings from the .

Tannock and co-authors noted that although both trials reported a significant improvement in disease-free survival (DFS), the primary end point, DFS is not a valid surrogate for OS. Among other things, it can be associated with unequal loss of patients between the trial arms, and lead to in which adjuvant treatment is compared with placebo among the remaining participants. "After review of the evidence, we suggest that these [FDA] decisions were premature," the team wrote.

In addition, Tannock and co-authors noted, three trials evaluating also failed to show significant differences in DFS or OS.

In the following interview, Tannock, who chairs the board of the , a U.S.-based nonprofit focused on optimal cancer drug dosing, discussed the team's findings in greater detail.

Were any of your review findings unexpected?

Tannock: No, unfortunately clinical trials are now largely controlled by the pharmaceutical industry, and their goal is to show their products in the best light so that they can sell more drugs and increase profit. We see an increasing number of trials that have inappropriate design or analysis.

What is your take-home message for physicians?

Tannock: Adjuvant trials for RCC have not shown evidence of effects to improve survival of patients, and adjuvant therapy should not be administered for this disease.

Based on results from the S-TRAC trial evaluating adjuvant sunitinib, you recommend that FDA approval should be rescinded, and the drug should not be prescribed. Can you elaborate?

Tannock: The S-TRAC trial showed no effects of sunitinib to improve survival, and the larger ASSURE [Adjuvant Sunitinib or Sorafenib vs Placebo in Resected Unfavorable Renal Cell Carcinoma] trial was completely negative, even for the putative surrogate endpoint. Adjuvant sunitinib adds toxicity without benefit and is therefore harmful. Harmful treatments should not have FDA approval.

Do you think the confounding results from the KEYNOTE-564 trial of adjuvant pembrolizumab provide another cautionary tale about what not to do with RCT design and analysis?

Tannock: Yes, indeed. Adjuvant trials should be designed to show or rule out a difference in overall survival, should include a sensitivity analysis to determine possible effects of any informative censoring, and should require the sponsor to provide free drug to relapsing controls, if that drug has been shown to improve overall survival for patients with more advanced disease.

Do you think that similar design flaws may be common to randomized controlled trials of adjuvant therapy in other cancers?

Tannock: Yes. Our critique of the monarchE trial of adjuvant abemaciclib for estrogen receptor-positive breast cancer examined this issue recently in . It is likely that the yet-to-be-published NATALEE trial of adjuvant ribociclib probably has the same defects, and that there are similar issues with adjuvant trials in other cancers.

How would you summarize your critique?

Tannock: We noted that over the past few decades, the shift from predominantly publicly funded clinical trials to industry-funded trials has created a system geared to developing new cancer medicines at the expense of investigating novel approaches to surgery, radiotherapy, palliative care, and prevention. For this reason, we need to make sure that data from any promising new therapy is carefully analyzed to determine whether it improves overall survival.

Also, since recurrence is not experienced by all patients, it is important to keep in mind that while adjuvant therapy may improve survival in some, it represents over-treatment in others.

What's next for your research?

Tannock: I am involved with and the Optimal Cancer Care Alliance. Our aim is to promote well-designed RCTs -- and there are some of those -- but also to draw critical attention to those that lead to false claims of benefit, or which promote high doses of drugs when lower doses can achieve maximal target inhibition. With colleagues, I am developing guidelines for RCTs and hope to influence both the FDA and the EMA [European Medicines Agency] to ensure registration of drugs that work for patients.

Read the "Comments and Controversies" article here and expert commentary about it here.