More Research Is Needed for Translocation Kidney Cancer

More research is needed to develop targeted therapies for patients with translocation renal cell carcinoma.

While metastatic translocation renal cell carcinoma (RCC) — a rare subtype of kidney cancer classified by translocations of certain genes — tends to respond well to checkpoint inhibitor immunotherapy drugs, there is still a need for new drugs in the space, according to an expert.

Of note, patients with translocation RCC typically had better outcomes when treated with immune checkpoint inhibitors and VEGF tyrosine kinase inhibitor (TKI) combinations. Dr. Yasser Ged, assistant professor of oncology at Johns Hopkins University, discussed translocation RCC in a session at the International Kidney Cancer Symposium: North America.

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 approximately twice as frequently as men 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.

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.

“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, which is a set of genes that is associated with the formation of new blood vessels from previously existing ones, 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. Of note, certain checkpoint inhibitors work by targeting the PD-L1 protein.

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.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 three 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 (19 patients) were treated with Sutent (sunitinib) as a firstline VEGF TKI. Of the patients who were treated with a VEGF TKI in the firstline setting, the objective response rate (ORR; percentage of patients whose disease shrinks or disappears from treatment) was 10.5% with a median progression-free survival (PFS; time from treatment until disease worsening or death) of three 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 (10 patients) and immune checkpoint inhibitor monotherapy and combinations (12 patients). In patients treated with VEGF TKI monotherapy, there was an ORR of 0% and a median overall survival (OS; time from treatment until death of any cause) 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.

“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 Cabometyx (cabozantinib) in different lines of therapy in 52 patients with translocation RCC. Cabometyx 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.

Another study was published in the Journal of Clinical Oncology in 2022 focused on a more contemporary treatment regimen: Opdivo (nivolumab) plus Cabometyx. This study included patients with metastatic non-clear cell RCC split into two different groups; one group (40 patients) included patients with papillary RCC, unclassified RCC, FH-deficient RCC, and translocation RCC, whereas the other group (two patients) 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%.

A phase 2 study published in The Lancet Oncology in 2023 included 158 patients with metastatic non-clear cell RCC treated with pembrolizumab (Keytruda) plus Lenvima (lenvatinib). 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 six patients with translocation RCC, the ORR was 67%.

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.

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.

“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 eight 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.

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