ADJUVANT TREATMENT OF RENAL CARCINOMA?

"The jury is still out" for adjuvant treatment in high-risk resected renal cell carcinoma (RCC), say experts.

In an editorial published online September 1 in the Annals of Oncology, Giuseppe Procopio, MD, Department of Medical Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy, and colleagues point out that in the pivotal trial of the adjuvant use of sunitinib (Sutent, Pfizer Inc), the drug did not improve overall survival, although there was an increase in disease-free survival.

"The role of angiogenic inhibitors in the adjuvant setting in RCC remains under debate," they comment. This is underlined by the fact that two regulatory bodies came to two different conclusions on the basis of the same clinical data.

The US Food and Drug Administration and the European Medicines Agency had contrasting opinions on the approval of sunitinib as an adjuvant therapy, with the former in favor and the latter not.

The editorial was prompted by new data from the pivotal Sunitinib as Adjuvant Therapy for Patients at High Risk of Recurrence of Renal Cell Carcinoma Following Nephrectomy (S-TRAC) trial.

The new data were published in an article by Michael Staehler, MD, PhD, Klinikum Grosshadern, Ludwig Maximilians University of Munich, Germany, and colleagues in the the Annals of Oncology. The article gives details on safety, therapy management, and patient-reported outcomes.

The study authors show that active management of adverse events associated with sunitinb adjuvant treatment can help to prolong exposure to the drug, but the editorialists note that low-grade, symptomatic events are most likely to cause discontinuation.

The editorialists suggest that, although the adverse events did not have a clinically meaningful impact on quality of life, they still led to treatment discontinuation for many patients.

Although these latest results "represent a valuable tool for decision-making and patients' counselling," Procopio and colleagues say that "inclusion in a clinical trial represents the best management option" for patients with high-risk resected RCC.

"If no clinical trials are available, motivated high-risk patients can be informed about available evidence and make shared decisions with their physicians," they add.

Sunitinib — Only Drug to Increase DFS

Previous data from the S-TRAC trial presented at the European Society for Medical Oncology Congress in 2016 showed that, compared with placebo, sunitinib improved disease-free survival by more than 1 year, at 6.8 years vs 5.6 years (hazard ratio, 0.76; P = .03).

The editorialists point out, however, that three other trials of adjuvant therapy have shown no benefit. ASSURE, PROTECT, and ATLAS showed no improvement in disease-free survival and overall survival after 1 year of treatment with sunitinib, sorafenib (Nexavar, Bayer), pazopanib (Votrient, Novartis), or axitinib (Inlyta, PF Prism) over placebo as adjuvant treatment in patients with localized RCC at high risk for relapse after nephrectomy.

Several reasons for the difference in the results have been proposed. Among them is the suggestion that in the negative trials, lower doses were used, and the therapy was of shorter duration. This makes the current analysis from the S-TRAC study "all the more valuable," they write.

The S-TRAC study involved RCC patients at high risk for recurrence. Patients were stratified using the University of California, Los Angeles, Integrated Staging System and ECOG performance status score and were randomly assigned to receive sunitinib 50 mg/day (n = 304) or placebo (n = 306).

Treatment was planned to consist of nine cycles of 4 weeks' duration followed by 2 weeks off treatment. This protocol was continued until disease relapse, a second malignancy, significant toxicity, death, or withdrawal of consent occurred.

Adverse events were managed via single dose reductions to 37.5 mg, dose delays, and dose interruptions.

Patients continued treatment for a mean of 9.5 months in the sunitinib arm and 10.3 months in the placebo arm. In all, 71% of sunitinib patients maintained treatment for ≥8 months, and 56% completed the full year.

The most common adverse events were diarrhea, reported by 56.9% of patients in the sunitinib arm and 21.4% of patients in the placebo arm; palmar-plantar erythrodysesthesia (PPE), seen in 50.3% and 10.2%, respectively; and hypertension, which occurred in 36.9% and 11.8%, respectively.

The primary reason for treatment discontinuation was adverse events in the sunitinib arm, seen in 28.1% of patients, with PPE the most common triggering event. The median time to treatment discontinuation was 4.5 months.

Adverse events typically occurred a median of 1 month after starting sunitinib and resolved within approximately 3.5 weeks.

The team notes that 40.6% of adverse events that led to permanent discontinuation were of grade 1 or 2; of those, 87.2% either resolved or were resolving by the end of treatment.

Global health status/quality-of-life assessment using the EORTC QLQ-C30 revealed that scores were significantly lower with sunitinib vs placebo (overall mean difference, -4.76).

However, this did not reach the commonly used clinically important difference (CID) of 10 points and so was not considered by the researchers to indicate a clinically meaningful reduction in quality of life and health status.

The authors conclude: "Adverse events were predictable, manageable, and reversible, via dose interruption, dose reduction, dose delay, and/or standard supportive medical therapy.

"A proactive and effective therapy management strategy enabled many patients to remain on therapy," they add.

In their editorial, Procopio and colleagues say that they "fully concur" with this conclusion, adding that "efforts for prevention and aggressive management of side effects cannot be overemphasized," particularly in the adjuvant setting.

However, they highlight that 40% of treatment discontinuations were due to low-grade toxicities that were symptomatic and not effectively treatable, in contrast to the higher-grade but asymptomatic and treatable events, such as hypertension.

This, they say, "offers convincing evidence that patients receiving adjuvant TKIs [tyrosine kinase inhibitors] are less tolerant to low or moderate toxicities, which, nevertheless, affect their quality of life, compared to patients with active disease."

This was echoed by the patient-reported outcomes. Indeed, Procopio and colleagues argue that the application of the CID "should not override" the significant difference in quality-of-life scores between sunitinib and placebo.

"On the contrary, we believe that these results relate quite convincingly the fairly poor compliance with the side effects of therapy, which was perceived by patients as significant and led many of them to discontinue it," the editorialists comment.

They note that ongoing trials, such as the SORCE study, in which 1 year of sorafenib treatment is being compared with 3 years of sorafenib treatment over placebo, and the EVEREST trial, in which everolimus (multiple brands) is being compared with placebo, will expand the understanding of the role of targeted therapies.

"In addition, several trials testing new immunotherapy agents, inhibiting the interaction between the programmed cell death-1 receptor with its ligand are in progress," they write.

"Studies in advanced disease have suggested a more favorable toxicity profile compared to that of TKIs, suggesting that compliance of patients receiving adjuvant therapy might be improved," the editorialists add.

The S-TRAC study was sponsored by Pfizer. Dr Staehler has received honoraria, consulting fees, and research grants from Pfizer, Bayer, GlaxoSmithKline, Roche, Bristol-Myers Squibb, Novartis, Exelixis, and AVEO. Dr Procopio has received honoraria from Pfizer, Bayer, Bristol, Ipsen. Other authors have disclosed relevant financial relationships.

Ann Oncol. Published online August 23, 2018. Abstract