Navigating Frontline RCC Treatment Paths Relies on Risk Stratification

Primo Nery Lara Jr, MD

Patients who receive a diagnosis of renal cell carcinoma (RCC) are afforded a variety of treatment options ranging from active surveillance for those with low volume, indolent disease to cytoreductive nephrectomy for those who for those with favorable outcomes, to treatment with an immune-oncology (IO) agent or tyrosine kinase inhibitor (TKI). In choosing between these treatments, risk stratification at the time of diagnosis is key, according to Primo Nery Lara Jr, MD.

In a presentation during the 15th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies, Lara, who is director of the University of California Davis (UC Davis) Comprehensive Cancer Center as well as Codman-Radke Endowed Chair in Cancer Research and executive associate dean for Cancer Programs at UC Davis Health in Sacramento, provided an overview of the treatment landscape for patients with metastatic RCC.¹

A key feature to developing treatment pathways that involve risk stratification according to International Metastatic RCC Database Consortium (IMDC) criteria is to leverage a multidisciplinary tumor board. “The [first] question that the tumor board tackles is whether an individual with metastatic RCC is a candidate for active surveillance.” Lara said. From that point, several options are available including cytoreduction and combination immunotherapy-based therapy which is the standard of care for most patients.

IO Eligibility: Choosing the Right Treatment Path

With numerous approved combination regimens, including dual IO therapies and IO/TKI combinations, Lara noted that strategies for choosing between regimens goes beyond eligibility and relies on risk stratification. “The standard of care in 2022 for metastatic kidney cancer is immunotherapy-based combination therapy,” Lara said. “Most of these patients should be considered for combination therapies, and there are several combinations that we would offer depending on their risk group.”

If a patient is deemed eligible for an IO-based combination, patients with favorable-risk, intermediate-risk, and poor-risk disease have several options available including pembrolizumab (Keytruda) in combination with either axitinib (Inlyta) or lanvantanib (Lenvima), nivolumab (Opdivo) plus cabozantinib (Cabometyx), or avelumab (Bavencio) plus axitinib.¹

For those with intermediate- or poor-risk disease, Lara noted that the immunotherapy doublet of nivolumab plus ipilimumab (Yervoy) is the preferred treatment option, noting that the combination does not improve outcomes over sunitinib (Sutent) alone for those with favorable-risk disease.

Four-year follow-up data from the phase 3 CheckMate 214 trial (NCT02231749), which led to the approval of nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with frontline metastatic RCC, show advantage of the combination vs sunitinib in terms of OS for the intention-to-treat population (HR, 0.69; 95% CI, 0.59-0.81) and the intermediate/poor-risk subgroup (HR, 0.65; 95% CI, 0.54-0.78).^2,3 Patients with favorable-risk disease failed to derive an OS benefit (HR, 0.93; 0.62-1.40).

“[This combination] would be great for intermediate- and poor-risk disease, not so much for favorable risk where it was no better than sunitinib,” Lara said

Despite being recommended for all-risk groups, Lara noted that, most of the benefit with pembrolizumab/axitinib in the phase 3 KEYNOTE-426 trial (NCT02853331) was isolated to patients with intermediate/poor-risk disease. Updated data at the 42-month follow-up showed sustained OS benefit of the combination (HR, 0.73; 95% CI, 0.60-0.88; P < .001) vs sunitinib in the intention-to-treat population.⁴ The benefit was more prominent in the progression-free survival (PFS) analysis with a median PFS of 15.7 months (95% CI, 13.6-20.2) with the combination vs 11.1 months (95% CI, 8.9-12.5) with sunitinib (HR, 0.68; 95% CI, 0.58-0.80; P < .001).

In terms of the other recommended therapies, Lara highlighted the advantage of the IO combinations vs single-agent TKI for patients with all-risk disease who are eligible for this treatment pathway. In data from the phase 3 CheckMate 9ER trial (NCT03141177), which supported the approval of cabozantinib and nivolumab in this setting, Lara spotlighted OS results which showed a 40% reduction in the risk of death with the combination vs sunitnib (HR, 0.60; 98.89% CI, 0.40-0.89; P = .0010).⁵

Finally, the phase 3 CLEAR trial (NCT02811861) showed an advantage of lenvatinib plus pembrolizumab vs sunitinib in terms of PFS (HR, 0.39; 95% CI, 0.32-0.49; P < .001) and OS (HR, 0.66; 95% CI, 0.49-0.88; P = .005).⁶

Comparing results of CLEAR with the previously reviewed trials, Lara said “results superficially seem to be better if you look at the complete response rate, the median PFS, and [OS]. But you must note that this trial had the lowest percentage of poor-risk patients [vs other pivotal trials reviewed], which will drive a lot of the of the results of these trials.”

Single-Agent Solutions

Patients who undergo risk stratification and are not eligible for IO therapy, TKIs including sunitinib or pazopanib are preferred treatment options for those with favorable-risk disease. OS outcomes for patients with favorable-risk disease had a median survival time of 37 month with sunitinib vs 9.4 months among those with poor-risk disease.

“Those who have active autoimmune disease should probably not risk [treatment with] a checkpoint inhibitor. Those with a history of solid organ transplantation and those on supraphysiologic corticosteroids are not your best candidates, or those with illnesses that require chronic immune suppressive therapy,” Lara said. “Sometimes there will be a patient who will have a personal preference [to avoid intravenous] therapy or who doesn’t want to go to your clinic because it is too far to drive; they’re not eligible for immunotherapy for those practical reasons.”

In patients with bone-only metastases, cabozantinib monotherapy may be preferential based on results of the phase 1 CABOSUN trial (NCT02496208), which showed a PFS advantage vs sunitinib in the indicated patient subset (0.54; 95% CI, 0.31-0.95).⁷ Similarly, Lara said he would use single-agent cabozantinib for patients with non–clear cell papillary RCC and perhaps for those with favorable-risk disease.

“Favorable-risk patients treated with pembrolizumab plus axitinib didn’t seem to benefit from that doublet, so maybe those patients ought to get a VEGFR TKI and then reserved immunotherapy for later,” Lara said.

Conversely, some patients may only be suitable for treatment with single-agent immunotherapy. “For those who are ineligible for or refuse to receive a VEGFR TKI–containing combination or those patients who [want to avoid] ipilimumab toxicities, single-agent checkpoint inhibitors are reasonable.” However, Lara noted that this should be limited to few patients with single-agent HD IL-2 and mTOR inhibitors representing 2 treatment options that have little justification for use in an era or more active, life-prolonging therapies.¹

Surveillance Vs Nephrectomy

Other branches of the decision tree for patients with metastatic RCC include active surveillance and cytoreduction for patients with favorable-risk disease.

“There is a subset of patients with advanced kidney cancer for whom you could watch [and wait] until such time comes when you do need to treat them with systemic therapies that have adverse effects. The question of who is a candidate for active surveillance is hard to answer because this is a bedside, gut decision.”

Lara reviewed data from a phase 2 prospective trial of 52 patients that showed surveillance could be a viable treatment option for certain patients with metastatic RCC.⁸ Median time to treatment initiation was 14.9 months (95% CI, 10.6-25.0) overall, with shortened surveillance associated with adverse risk factors (P = .0403) and higher numbers of metastatic disease sites (P = .0414).

“The other question that tumor boards often tackle is whether a cytoreductive approach is necessary,” Lara said. “Most favorable-risk patients and some of those with intermediate-risk disease remain candidates for a cytoreductive nephrectomy, especially those with large and/or symptomatic primary tumors and a low burden of metastatic disease.”

Recently reported data from 2 trials showed noninferiority of systemic therapy approaches vs systemic therapy plus nephrectomy in this setting. In the phase 3 CARMENA trial (NCT00930033), sunitinib alone was found to produce noninferior overall survival (OS) vs sunitinib plus nephrectomy in patients with intermediate- or poor-risk disease (HR, 0.89; 95% CI, 0.71-1.10).⁹ In the phase 3 SURTIME trial (NCT01099423), deferred cytoreductive nephrectomy after 3 cycles of sunitinib improved OS vs immediate nephrectomy (HR, 0.57; 95% CI, 0.34-0.95; P = .03).¹⁰ He noted that decisions must be individualized according to risk.

“Many intermediate- and most poor-risk patients should start on systemic therapy first,” Lara said.

As for metastasectomy, Lara said patients with a good performance status, isolated or oligometastatic disease, a disease-free interval of 2 years following nephrectomy, no lymph node involvement, or lung-only disease may benefit from local ablative approaches.

References

1. Lara P. Frontline systemic therapy for renal cell carcinoma: immunotherapy and tyrosine kinase inhibitors. Presented at: 15th Annual Interdisciplinary Prostate Cancer® and other GU Malignancies Congress. March 11-12, 2022. New York, NY.
2. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed March 14, 2022. bit.ly/3Jji5nm
3. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079
4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500
5. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed March 14, 2022. https://bit.ly/34Gb3K4
6. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
7. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591-597. doi:10.1200/JCO.2016.70.7398
8. Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 2016;17(9):1317-1324. doi:10.1016/S1470-2045(16)30196-6
9. 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
10. Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 2019;5(2):164-170. doi:10.1001/jamaoncol.2018.5543