Risk Stratification Aids Oncologists in the Management of Frontline RCC

Primo Nery Lara, Jr., MD

The best practices for systemic and local therapy selection for patients with frontline metastatic renal cell carcinoma were a topic of discussion for Primo Nery Lara, Jr., MD, who looked back on the quickly moving RCC landscape during the 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, hosted by Physicians’ Education Resource®, LLC (PER®).¹

With numerous approved combination regimens, including dual immune checkpoint inhibitor (IO) and IO/tyrosine kinase inhibitor (TKI) combinations, Lara introduced strategies for treatment selection in a crowded space.

“You need to assess carefully for eligibility for immunotherapy. If the patient is eligible for IO, they need to get combination [therapy],” said 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. “We also need to risk stratify [our patients and] involve our colleagues.”

Active Surveillance and Cytoreductive Strategies

In the treatment of clear cell RCC, Lara reviewed a treatment decision pathway that involves risk stratification according to International Metastatic RCC Database Consortium (IMDC) criteria and assessment by a multidisciplinary tumor board at the forefront of any good treatment plan.

“The question that the tumor board tackles first is whether this individual with metastatic RCC is a candidate for active surveillance. 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,” Lara said. “The question of who is a candidate for active surveillance is hard to answer because this is a bedside, gut decision.”

He turned to 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.1 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.”

Lara turned to 2 recently reported trials that showed noninferiority of systemic therapy approaches vs systemic therapy plus nephrectomy in this setting. In the phase 3 CARMENA trial (NCT00930033), sunitinib (Sutent) 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).² 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).³ 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.

Therapy With Combination Regimens in 2022

The next aspect of the treatment decision making is systemic therapy selection, a choice which Lara said hinges on whether the patient is eligible to receive IO therapy.

“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.”

After patients are deemed eligible for an IO-based combination, the clinicians should again turn to risk stratification to select the most appropriate regimen for individual patients.

In the phase 3 CheckMate 214 trial (NCT02231749) that led to the approval of nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with frontline metastatic RCC, 4-year follow-up data 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).^4,5 However, Lara noted that 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

The next trial reviewed was the pivotal phase 3 KEYNOTE-426 trial (NCT02853331) of pembrolizumab (Keytruda) plus axitinib (Inlyta) vs sunitinib. Updated data at the 42-month follow-up showed sustained OS benefit of the combination (HR, 0.73; 95% CI, 0.60-0.88). Similar to results from CheckMate 214, most of the benefit with pembrolizumab/axitinib was isolated to patients with intermediate/poor-risk disease.⁶

Moving on the phase 3 CheckMate 9ER trial (NCT03141177) that supported the approval of cabozantinib (Cabometyx) 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).⁷

Finally, the phase 3 CLEAR trial (NCT02811861) showed an advantage of lenvatinib (Lenvima) plus pembrolizumab vs sunitinib in terms of progression-free survival (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).⁸

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.”

Monotherapy Strategies

For patients who are ineligible for IO agents or VEGFR TKIs, treating clinicians must consider single-agent therapies in the setting of frontline RCC.

“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.”

For these patients who are intolerant to or who refuse IO, they may receive therapy with a single-agent VEGFR TKI. 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).⁹ 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.”

_References

_{1. 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}

_{2. 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}

_{3. 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}

_{4. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed March 14, 2022. https://bit.ly/3Jji5nm}

_{5. 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}

_{6. 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}

_{7. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed March 14, 2022. https://bit.ly/34Gb3K4}

_{8. 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}

_{9. 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}