Combining Surgical and Therapeutic Treatment Options in Evolving Field of RCC

During the 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, hosted by Physicians’ Education Resource®, LLC (PER®), Gennady Bratslavsky, MD, reviewed current surgical management strategies for renal cell carcinoma (RCC) across settings.

Bratslavsky, who is professor and chair of the Department of Urology and director of the Prostate Cancer Program at Upstate Medical University in Syracuse, New York, spoke about how classification of RCC tumors influences treatment options as well as the optimal standard of care management strategy for each stage of the disease.

Bratslavsky highlighted studies examining (neo)adjuvant immunotherapy in the setting of nephrectomy for locally advanced disease, such as the PROSPER (NCT03055013) and KEYNOTE-564 (NCT03142334) trials. He also revisited data from the CARMENA trial (NCT00930033), whose results initially impacted the standard of care when it was reported that treatment with sunitinib (Sutent) alone was noninferior to sunitinib plus nephrectomy in the metastatic setting.¹

Bratslavsky stressed that there is no clearly defined role of surgical management in metastatic RCC, and that strategies in the locally advanced setting are constantly changing.

Management of Small Renal Masses

Bratslavsky began his presentation by referencing a study that correlated metastatic potential with tumor histologic subtypes.² For clear cell histology, it was found that tumors measuring between 3 to 4 cm were metastatic in 1.8% of cases. For papillary histology, about 2% of those with tumors between 3 to 4 cm had metastatic disease, although the sample size was much smaller than that of the clear cell cohort. In chromophobe histology, a 2% rate of metastatic disease was reached for tumors between 6 to 7 cm.

Bratslavsky noted that while investigators have learned to stage the tumor well, information about how those data translate to prognosis for individual patients is lacking.

A recent initiative from the National Cancer Institute to improve management of small renal masses and early-stage renal cell carcinoma yielded a new trial design that may offer clarity in an uncertain space.³ The proposed study would include patients with cT1a solid renal masses of 1.5 to 3.0 cm, 65 years of age or older, and a life expectancy of 10 years or less. Patients would be enrolled to receive standard of care, either without biopsy or with mandated renal mass biopsy. Both groups would then undergo shared decision making regarding management and standard clinical follow-up.

The proposed primary end point is intervention-free survival, and the secondary end points are rates of benign disease, patient-reported outcomes, cost, progression-free survival (PFS), tumor growth rates, and biopsy adverse effects and diagnostic accuracy. To date, there has not been a follow-up meeting.

Strategies for Locally Advanced RCC

For locally advanced disease, Bratslavsky noted that there are several ongoing trials investigating the use of systemic therapies for neoadjuvant and adjuvant management of tumors undergoing nephrectomy.

The PROSPER trial is examining the role of neoadjuvant nivolumab (Opdivo) for patients with locally advanced RCC. Before randomization, patients had to receive a mandatory biopsy. A total of 766 patients were randomized 1:1 and were given either nivolumab (Opdivo) every 2 weeks for 2 doses or resection. Those receiving nivolumab then go on to have resection followed by nivolumab every 2 weeks for 3 months and then every 4 weeks for 6 months. Patients who received resection only will receive observation after surgery.

Adjuvant pembrolizumab (Keytruda) is now FDA approved for use after nephrectomy based on results of the KEYNOTE-564 trial.⁴ At the time of approval, patients saw a statistically significant improvement in disease-free survival (DFS) with pembrolizumab vs placebo (HR, 0.68; 95% CI, 0.53-0.87; P = .0010). The median DFS had not yet been reached for either arm of the study, and only 5% of deaths occurred in the overall population; follow-up is ongoing.

Metastatic RCC

The standard of care for management of RCC was previously defined by outcomes of the SURTIME trial (NCT01099423), in which patients were randomized to either receive sunitinib followed by nephrectomy or the reverse strategy of immediate nephrectomy followed by sunitinib.⁵ Results of the trial showed that patients who had immediate nephrectomy had a 28-week progression-free rate of 42% vs 42.9% in those who had therapy followed by a nephrectomy. The median overall survival (OS) with deferred nephrectomy was 32.4 months (95% CI, 14.5-65.3) vs 15.0 months (95% CI, 9.3-29.5) in the immediate nephrectomy arm (HR, 0.57; 95% CI, 0.34-0.95, P = .032).

However, results from the CARMENA trial that came out about a year later revealed that sunitinib alone was noninferior to sunitinib plus nephrectomy for OS (HR, 0.89; 95% CI, 0.71-1.10), and systemic therapy management alone became the standard-of-care in this setting.

In patients with intermediate-risk disease, the median OS was 23.4 months vs 19.0 months with sunitinib vs nephrectomy/sunitinib, respectively (HR, 0.92; 95% CI, 0.68-1.24); for those with poor-risk group disease, the median OS was 13.3 months vs 10.2 months (HR, 0.86; 95% CI, 0.62-1.17). Patients in the sunitinib-alone group experienced a median PFS of 8.3 months (95% CI, 6.2-9.9) compared with 7.2 months (95% CI, 6.7-8.5) in the nephrectomy/sunitinib group (HR, 0.82; 95% CI, 0.67-1.00).

Bratslavsky also discussed the ongoing PROBE trial (NCT04510597) which is investigating induction treatment with a checkpoint inhibitor-based combination therapy with or without surgical removal of metastatic kidney cancer. Results are ongoing.

Genetic Testing

Bratslavsky concluded the presentation by discussing a recently reported clinical consensus statement of genetic risk assessment for hereditary RCC.⁶ This study complied data on who should undergo genetic risk assessment, when assessments should be initiated, what testing should be performed, and how it should be performed.

The agreed upon statements by the panel included family history criteria, where further evaluation is needed, risk assessment for patients with bilateral or multifocal disease and/or specific histology, multigene panel testing, and counseling for patients who had experienced hereditary RCC.

Moving forward, the investigators plan to hold a second meeting to further agree upon more defining statement involving genetic risk assessment.

References

1. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675

2. Daugherty M, Sedaghatpour D, Shapiro O, Vourganti S, Kutikov A, Bratslavsky G. The metastatic potential of renal tumors: Influence of histologic subtypes on definition of small renal masses, risk stratification, and future active surveillance protocols. Urol Oncol. 2017;35(4):153.e15-153.e20. doi:10.1016/j.urolonc.2016.11.009

3. National Cancer Institute. Clinical Trials Planning Meeting on Improving Management of Small Renal Masses and Early Stage Renal Cell Carcinoma: NIG Campus, Bethesda, Maryland, January 23-24, 2020. Accessed March 15, 2022. https://bit.ly/3i89K9V

4. FDA approved pembrolizumab for adjuvant treatment of renal cell carcinoma. News Release. November 17, 2021. Accessed March 15, 2022. https://bit.ly/3ibknc0

5. Bex A, Mulders P, Jewett M, et al. Immediate versus deferred cytoreductive nephrectomy (CN) in patients with synchronous metastatic renal cell carcinoma (mRCC) receiving sunitinib (EORTC 30073 SURTIME). Annals of Oncol. 2017; 28(suppl_5):V622. Doi: 10.1093/annonc/mdx440.030

6. Bratslavsky G, Mendhiratta N, Daneshvar M, et al. Genetic risk assessment for hereditary renal cell carcinoma: Clinical consensus statement. Cancer. 2021;127(21):3957-3966. doi:10.1002/cncr.33679