Debating the True Benefit of Adjuvant TKIs in High-Risk RCC

Mehrdad Alemozaffar, MD

Adjuvant therapy with tyrosine kinase inhibitors (TKIs) for patients with high-risk renal cell carcinoma (RCC) who have undergone a nephrectomy may be supported by level IIa evidence from the National Comprehensive Cancer Network (NCCN) guidelines, yet this approach is still controversial, with many physicians believing that there are not yet enough data in support of its use.

Several studies have already been completed looking at the use of adjuvant TKIs in this setting, and many more are due to release data and further findings in the near future, so this hot topic is rapidly changing as data become available supporting one side of the debate or the other.

Mehmet Asin Bilen, MD

In a debate during the 2017 Debates and Didactics in Hematology and Oncology conference, 2 oncologists argued over the current findings for and against the use of adjuvant TKI treatment in high-risk patients with RCC following surgery. Mehrdad Alemozaffar, MD, spoke in favor of adjuvant TKI therapy and Mehmet Asim Bilen, MD, argued against. Each addressed 3 trials, ASSURE, S-TRAC, and PROTECT, that all studied adjuvant TKI treatments in this setting.

FINDINGS FOR AND AGAINST

The first trial that both debaters raised was the double-blind, placebo-controlled, randomized phase III ASSURE/ECOG-ACRIN E2805 trial, which looked at 1 year of adjuvant sunitinib (Sutent), sorafenib (Nexavar), or placebo in 1943 patients with resected nonmetastatic RCC at a high risk for recurrence. The trial was looking to disease-free survival (DFS) as its primary endpoint, but no statistically significant DFS advantage was noted in this trial over placebo.¹

The median DFS for sunitinib at the primary analysis was 5.8 years (hazard ratio [HR] compared with placebo, 1.02; 97.5% CI, 0.85-1.23; P = .8038); with sorafenib the DFS was 6.1 years (HR compared with placebo, 0.97; 97.5% CI, 0.80-1.17; P = .7184); and the DFS was 6.6 years with placebo. Additionally, toxicity was increased with the TKIs, with grade ≥3 hypertension, hand-foot syndrome, rash, and fatigue all experienced at a higher rate than seen in the patients taking placebo.

However, Alemozaffar, an assistant professor in the Department of Urology at Emory University School of Medicine, believed that this was not the right trial on which to base a decision because of many issues. For example, 79.3% of patients on the trial had clear-cell RCC whereas 20.7% did not. Additionally, although the trial was intended for patients who had a high risk of recurrence, 34.7% were not characterized as high risk; they had either stage I or II disease.

Bilen, an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, pointed out that even in updated findings of the clear-cell RCC subgroup, no DFS advantage was found for either TKI at 5 years compared with placebo.²At 5 years, the DFS rate was 47.7% with sunitinib, 49.9% with sorafenib, and 50% with placebo. A difference in survival was not seen by dose quartile either.

The trial was problematic, with 43.6% patients discontinuing the trial due to toxicity-related issues.¹Investigators then had to redesign the trial and reduce the dosage of each treatment and individually bring patients back up to the original full doses if they could tolerate the lower dose. “The inadequate dosing may be responsible for the negative findings,” Alemozaffar said.

Additionally, the safety monitoring committee determined that blinded follow-up needed to be ended ahead of schedule. And finally, no central review of the primary endpoint by imaging was completed, and statistical issues were found with posthoc analyses of the trial,²including analyses of the discontinuation rates.

Alemozaffar said that the next trial, the S-TRAC trial, was the right trial for this specific setting in that there were far fewer issues associated with the trial design; this trial did show an improvement in DFS for patients treated with a TKI when compared with placebo.³

The phase III trial looked at 1 year of adjuvant sunitinib or placebo in patients with locoregional high-risk clear-cell RCC, with DFS again being the primary endpoint. The DFS with sunitinib was 6.8 years (95% CI, 5.8−not reached) compared with 5.6 years (95% CI, 3.8-6.6) in the placebo arm (HR, 0.76; 95% CI, 0.59-0.98; P = .03).

Although there were much higher rates of dose reductions (34.3% vs 2%), dose interruptions (46.4% vs 13.2%), and discontinuations (28.1% vs 5.6%) in the sunitinib arm compared with the control arm, respectively, there was a similar rate of serious adverse events (AEs) in each arm (21.9% vs 17.1%, respectively).

Although a benefit with sunitinib in the S-TRAC trial, Bilen said that he would not use it in his practice, due especially to the toxicities seen in the study. Grade 3 AEs were experienced by 48.4% of patients in the sunitinib arm compared with 15.8% of those treated with a placebo, and grade 4 AEs by 12.1% and 3.6%, respectively. The most common grade ≥3 AEs experienced in the sunitinib arm included palmar-plantar erythrodysesthesia, hypertension, neutropenia, thrombocytopenia, mucosal inflammation, and fatigue. The overall survival (OS) data from the trial have not yet reached maturity, according to Alemozaffar.

In the phase III PROTECT trial, adjuvant pazopanib (Votrient) was compared with placebo in patients with locally advanced RCC following surgery.⁴Patients in the pazopanib arm first received 800 mg of pazopanib, which was later lowered to 600 mg for tolerability. In the pazopanib 600 mg intent-to-treat (ITT) group, the DFS difference was not significant (HR, 0.862; 95% CI, 0.699-1.063; P = .165). The primary endpoint of DFS for 600 mg of pazopanib was not reached in this group and OS was not increased either. Bilen found the benefits from this trial to also be negligible.

A 31% decrease in the risk of recurrence was observed, however in the 800-mg ITT group (HR, .663; 95% CI, 0.491-0.895). In the overall ITT population, the risk of recurrence was reduced by 20%. Alemozaffar found the secondary endpoint results promising in the 800-mg pazopanib arm.

AWAITING CONFIRMATION

Additional trials are looking at the use of adjuvant TKIs in this setting, including the SORCE trial (NCT00492258). The EVEREST trial is exploring 1 year of everolimus (Afinitor) treatment compared with placebo in this setting (NCT01120249). And ATLAS, which is looking at 1 year of adjuvant axitinib (Inlyta) therapy compared with 1 year of placebo in high-risk patients with RCC (NCT01599754).

Alemozaffar believed that use of the 16-gene recurrence score, which was validated in high-risk stage III patients from the S-TRAC trial,⁵could help to identify which patients are most likely to benefit from adjuvant therapy with TKIs, which should be a goal of future study.

Although he believed in the potential benefit of adjuvant therapy in this setting, Bilen noted that the research community has not yet landed on the correct treatment approach for this patient population. Bilen also considered that immunotherapy could play a role in the adjuvant setting for patients with high-risk RCC, but that this would need to be confirmed in clinical trials. The IMmotion 010 trial and the new PROSPER RCC trial are investigating immunotherapy in the adjuvant setting, with the IMmotion 010 study looking at atezolizumab (Tecentriq) and PROSPER RCC studying nivolumab (Opdivo) in high-risk patients with RCC following nephrectomy.

References:

1. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal- cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016;387(10032):2008-2016. doi: 10.1016/S0140-6736(16)00559-6.
2. Haas NB, Manola J, Dutcher JP, et al. Adjuvant treatment for high-risk clear cell renal cancer: updated results of a high-risk subset of the ASSURE randomized trial [published online March 9, 2017]. JAMA Oncol. 2017. doi: 10.1001/jamaoncol.2017.0076.
3. Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246-2254. doi: 10.1056/NEJMoa1611406.
4. Motzer RJ, Haas NB, Donskov F, et al; PROTECT investigators. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol. 2017;35(suppl; abstr 4507).
5. Escudier BJ, Rini BI, Martini J-F, et al. Phase III trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma (RCC): validation of the 16-gene Recurrence Score in stage III patients. J Clin Oncol. 2017;35(suppl 15; abstr 4508).