Treatments for Translocation RCC Require Novel Therapeutic Targets

Yasser Mohamed Ali Ged, MBBS

Immune checkpoint inhibitors have been associated with improved outcomes for patients with metastatic translocation renal cell carcinoma (RCC); however, novel therapies and therapeutic targets are needed for patients within this histologic subset, according to Yasser Mohamed Ali Ged, MBBS.¹

Of note, patients with translocation RCC typically had better outcomes when treated with immune checkpoint inhibitors and VEGF TKI combinations. Ged, an assistant professor of oncology at Johns Hopkins University, discussed translocation RCC in a session at the 2023 International Kidney Cancer Symposium.

Translocation RCC is a rare type of RCC that is typically characterized by gene fusions involving the MiT family of transcription factors including TFE3, TFEB, TFEC, and MiTF. This disease subtype was first officially recognized in the World Health Organization (WHO) 2004 renal tumors classification and recently included in the molecularly defined renal carcinomas group within the WHO 2022 renal tumors classification. It generally impacts women at a ratio of 2:1 and accounts for up to 40% of children with RCC compared with 1.6% to 4% of adults with RCC. Ged noted that prior exposure to cytotoxic chemotherapy is a risk factor for developing translocation RCCs within the MiT family.

When diagnosing translocation RCC, Ged noted that these tumors morphologically resemble other subtypes of RCC, with the most common being papillary architecture with psammoma bodies. The disease itself is characterized by a nuclear expression of TFE3/TFE-B by immunohistochemistry, “although these can be technically challenging with high false positivity,” Ged said during the presentation. The “gold standard for diagnosis,” Ged noted, is break apart FISH assays, although RNA sequencing may help to confirm a diagnosis of translocation RCC.

There have been several efforts in recent years to understand translocation RCC tumors at the molecular level. In a study published in Clinical Cancer Research in 2020, researchers determined that these tumors have a low tumor mutational burden.²

“However, [translocation RCC tumors] have higher copy number alterations and genomic instability, which is one of the reasons for the aggressiveness of these tumors,” Ged explained.

This same study also found that the angiogenesis gene signatures in translocation RCC is higher than those found in patients with papillary RCC, though slightly lower than in patients with clear cell RCC. In addition, patients with translocation RCC also had higher PD-L1 expression compared with papillary and clear cell RCC.

Findings from another study published in Cell Report in 2022 demonstrated that translocation RCC can be characterized by frequent 9p21.3 deletion and had a distinct transcriptional signature compared with other RCCs.³ These tumors could also be characterized by the activation of the NRF2 transcriptional program, “which generally leads to resistance to targeted therapies,” Ged said.

Over the last 3 decades, there have been significant advancements in the treatment of clear cell RCC.

“The development of treatments for non-clear cell RCC has been lagging behind, and historically, clear-cell RCC treatments have been studied in non-clear cell RCC,” Ged added.

In a study published in the Journal for Immunotherapy of Cancer in 2018, researchers assessed data from a retrospective multinational cohort of 24 patients with translocation RCC, most of whom (n = 19) were treated with sunitinib (Sutent) as a firstline VEGF TKI.⁴ Of the patients who were treated with a VEGF TKI in the firstline setting, the objective response rate (ORR) was 10.5% with a median progression-free survival (PFS) of 3 months. In all of the patients in this study treated with an immune checkpoint inhibitor in the secondline setting and beyond, the ORR was 16.6 months with a median PFS of 2.5 months.

In another study published in Cell Report in 2022, researchers focused on a retrospective cohort of patients with translocation RCC treated at different lines of therapy: VEGF TKI monotherapy (n = 10) and immune checkpoint inhibitor monotherapy and combinations (n = 12). In patients treated with VEGF TKI monotherapy, there was an ORR of 0% and a median overall survival (OS) of 10.3 months. In comparison, patients treated with immune checkpoint inhibitor monotherapy and combinations had an ORR of 25% and a median OS of 62.4 months.³

“Understandably, this is a small cohort of 12 patients,” Ged said.

In the journal The Oncologist in 2022, a study was published focusing on the use of cabozantinib (Cabometyx) in different lines of therapy in 52 patients with translocation RCC. Cabozantinib in multiple lines of therapy resulted in an ORR of 17.3 months, a median PFS of 6.8 months, and a median OS of 18.3 months.⁵

Another study was published in the Journal of Clinical Oncology in 2022 focused on a more contemporary treatment regimen: nivolumab (Opdivo) plus cabozantinib. This study included patients with metastatic non-clear cell RCC split into 2 different groups; 1 group (n = 40) included patients with papillary RCC, unclassified RCC, FH-deficient RCC, and translocation RCC, whereas the other group (n = 2) only included patients with translocation RCC. When all patients were assessed, the ORR was 47.5% with a median PFS of 12.5 months and a median OS of 28 months. In the patients with translocation RCC, the ORR was 50%.⁶

A phase 2 study published in Lancet Oncology in 2023 included 158 patients with metastatic non-clear cell RCC treated with pembrolizumab (Keytruda) plus lenvatinib (Lenvima). Treatment with this combination demonstrated an ORR of 49% in all patients with a median PFS of 18 months and a median OS that was not reached. In comparison, when assessed in the 6 patients with translocation RCC, the ORR was 67%.⁷

Researchers have also focused on comparing treatment with dual immune checkpoint inhibitors compared with an immune checkpoint inhibitor plus TKI combination. In a study published in The Oncologist in 2023, researchers assessed data from 29 patients with translocation RCC who were treated with immune checkpoint inhibitors at any line of therapy. For the 18 patients treated with dual immune checkpoint inhibitors, the ORR was 5.5%, with a median PFS of 2.8 months and a median OS of 17.8 months. In the 11 patients treated with an immune checkpoint inhibitor and TKI combination, the ORR was 36% with a median PFS of 5.4 months and a median OS of 30.7 months.⁸

Ged and his colleagues worked on a study, which was presented as a poster at this year’s International Kidney Cancer Symposium, with 22 patients with translocation RCC who were treated with immune checkpoint inhibitors at any line of therapy.⁹

“We observed similar efficacy outcomes in terms of higher objective response rates, better PFS in favor of the ICI plus TKI combos, but the median OS was numerically longer in the ICI plus ICI cohort,” Ged explained.

In particular, the 8 patients treated with dual immune checkpoint inhibitor therapies had an ORR of 14%, a median PFS of 1.2 months, and a median OS of 36.7 months. In comparison, 14 patients treated with an immune checkpoint inhibitor plus a TKI had an ORR of 54%, a median PFS of 6.2 months, and a median OS of 15.6 months.

References

1. Ged Y. Insights Into Variant Pathology: Translocation RCC. Presented at: 2023 International Kidney Cancer Symposium; November 9-11, 2023; Nashville, TN.
2. Marcon J DiNatale RG, Sanchez A, et al. Comprehensive Genomic Analysis of Translocation Renal Cell Carcinoma Reveals Copy-Number Variations as Drivers of Disease Progression. Clin Cancer Res. 2020;26(14):3629-3640. doi:10.1158/1078-0432.CCR-19-3283
3. Bakouny Z, Sadagopan A, Ravi P, et al. Integrative clinical and molecular characterization of translocation renal cell carcinoma. Cell Rep. 2022;38(1):110190. doi:10.1016/j.celrep.2021.110190
4. Boilève A, Carlo MI, Barthelemy P, et al. Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders. J Immunother Cancer. 2018;6(1):159. doi:10.1186/s40425-018-0482-z
5. Thouvenin J, Alhalabi O, Carlo M, et al. Efficacy of Cabozantinib in Metastatic MiT Family Translocation Renal Cell Carcinomas. Oncologist. 2022;27(12):1041-1047. doi:10.1093/oncolo/oyac158
6. Lee CH, Voss MH, Carlo MI, et al. Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. J Clin Oncol. 2022;40(21):2333-2341. doi:10.1200/JCO.21.01944
7. Albiges L, Gurney H, Atduev V, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2023;24(8):881-891. doi:10.1016/S1470-2045(23)00276-0
8. Alhalabi O, Thouvenin J, Negrier S, et al. Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas. Oncologist. 2023;28(5):433-439. doi:10.1093/oncolo/oyac262
9. Ged Y, Contreras LM, Touma A, et al. Multi-site study of treatment outcomes of metastatic mit family translocation renal cell carcinoma (tRCC) patients treated with immune-checkpoint inhibitor combinations. Presented at: 2023 International Kidney Cancer Symposium. November 9-11, 2023; Nashville, TN. Abstract 51.