Precision Medicine According to Histologic Subtype in Renal Cell Carcinoma

Bradley McGregor, MD

In non-clear cell renal cell carcinoma (RCC), specific therapeutic strategies exist for most genomic subtypes. But regardless of whether physicians are utilizing VEGF inhibitors, chemotherapy, or combinations of immunotherapy, VEGF and mTOR inhibitors, the truly targeted approach for these patients, is histology-directed therapy, according to Bradley McGregor, MD.¹

During a presentation at the 2021 International Kidney Cancer Symposium: North America, McGregor discussed analyses of outcomes based on histology in major RCC clinical trials, and how this approach will shape the future of treatment.

“What we know is that unfortunately patients have worse outcomes compared with patients with clear cell [RCC],” explained McGregor during his presentation. “Certainly, this is an unmet need. Our patients need novel therapies and so we need to find new approaches to treat this. This is going to become more difficult as we start to look at the different histologic subtypes.”

In non-clear cell RCC alone, patients can have papillary, chromophobe, translation, collecting duct, medullary, or sarcomatoid histologies. Each of these different histologic subtypes can also have different cytogenetic and molecular alterations as well as pathway deregulations, according to McGregor.

The phase 2 SUPAP study of sunitinib (Sutent) in patients with locally advanced or metastatic papillary renal cell carcinoma (pRCC) (NCT00541008) showed that in 46 patients, the agent was active, but survival was impacted by whether patients had type 1 or type 2 pRCC.²

A total of 46 patients were evaluated in the study and followed for a median of 51.4 months. Patients with type 1 pRCC had a partial response rate of 13% compared with 11% in those with type 2 disease. In terms of progression-free survival (PFS), the median was 6.6 months (95% CI, 2.8-14.8) for patients with type 1 disease and 5.5 months (95% CI, 3.8–7.1) for those with type 2 disease. Finally, the overall survival (OS) was 17.8 months (95% CI, 5.7–26.1) among patients with type 1 pRCC and 2.4 months (95% CI, 8.2–14.3) months for those with type 2 histology.

Overall, the study investigators determined that sunitinib was an effective frontline option for metastatic pRCC, and later sunitinib was compared with everolimus (Afinitor) in the phase 2 ESPN clinical trial (NCT01185366).^1,2

The randomized phase 2 ESPN trial demonstrated that, overall, better therapies were needed for patients with non-clear cell RCC, as frontline everolimus was found to be nonsuperior to sunitinib in terms of PFS. Further, in the subgroups of patients with pRCC and chromophobe RCC, OS was better compared with the other histologies albeit a small cohort.³

Of the 68 patients with metastatic non-clear cell RCC, 13 patients in the everolimus arm and 14 in the sunitinib arm had papillary histology and 6 patients in each arm had chromophobe histology. These 2 histologic subgroups have better survival outcomes compared with patients who had translocated disease or clear cell histology with sarcomatoid features. Specifically, the pRCC population had a median PFS of 4.1 months (95 CI, 1.5-7.4) on treatment with everolimus compared with 5.7 months (95% CI, 1.4-19.8) with sunitinib. The median OS was 14.9 months (95% CI, 7.1-22.7) with everolimus compared with 16.6 months (95% CI, 5.9 to not assessed [NA]) with sunitinib.

In comparison, those with translocation and clear cell histologies had a median PFS and OS of 3.0 months and 1.9 months, respectively, on treatment with everolimus compared with 6.1 months and 3.5 months in the sunitinib arm. The median OS in patients with a translocation or clear cell disease was 8.1 months and 11.1 months, respectively in the everolimus arm compared with 16.1 months and 7.0 months with sunitinib.

In the open-label, multicenter phase 2 RECORD-3 trial (NCT00903175), first-line everolimus followed by sunitinib was compared with the sequence of sunitinib followed by everolimus in 471 patients with metastatic RCC.⁴

In the overall study population, the median combined PFS was 21.7 months (95% CI, 15.1-26.7) with sequential everolimus and sunitinib and 22.2 months (95% CI, 16.0-29.8) with sequential sunitinib and everolimus (HR, 1.2; 95% CI, 0.9-1.6). Further, a subgroup analysis of OS in patients with clear cell histology versus non-clear cell showed no significant difference.

Based on the study results, investigators considered sunitinib followed by everolimus at progression in patients with metastatic RCC, and this research further demonstrated the relevance of histologic subtype in outcomes for patients with metastatic RCC.

Looking forward, McGregor believes that based on research in development, the field is on track to shift toward histology-targeted RCC treatment.

_References:

_{1. McGregor B. Systemic therapy for non-clear cell: recent and future studies. Presented at 2021 International Kideny Cancer Symposium; November 5-6, 2021; Austin, Texas.}

_{2. Ravaud A, Oudard S, Frmont M,et al. First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG). Ann Oncol. 2015;26(6):1123-1128. doi:10.1093/annonc/mdv149.}

_{3. Tannir N, Jonasch E, Albiges L, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): A randomized multicenter phase 2 trial. Eur Urol. 2016;69(5):866-74. doi:10.1016/j.eururo.2015.10.049.}

_{4. Knox JJ, Barrios CH, Kim TM, et al. Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC. Ann Oncol. 2017; 28(6):1339-1345. doi:10.1093/annonc/mdx075.}