ctDNA May Guide Treatment Intensity in RCC

Circulating tumor DNA (ctDNA) may be a useful tool to inform health care professionals on whether treatment should be intensified or deescalated in patients with renal cell carcinoma (RCC), especially in the setting of treatment with immunotherapy and tyrosine kinase inhibitors (TKIs), an expert said.

Alan Tan, MD, director of genitourinary oncology at Rush University Medical Center in Chicago, discussed the use of ctDNA in RCC during the International Kidney Cancer Symposium.¹

Alan Tan, MD

“We don't want to lose these patients at the expense of trying to get that durable response,” he said during the presentation. “Some of these patients end up dying within the first 3 months of therapy. So, we might be able to monitor these patients much more closely, and we need to have more prospective clinical trials to validate ctDNA as an informative biomarker.”

Cell-free DNA is ctDNA that typically involves the spontaneous release of DNA from healthy cells, but sometimes this behaves differently in patients with cancer. In these patients, there is ctDNA which is fragments of active cancer cells undergoing apoptosis and necrosis. Tan noted that the challenge with ctDNA is that kidney cancer is an especially low shedding cancer.

“In the patients that have metastatic disease across tumor types, we usually are able to detect patients’ mutations with just liquid biopsies,” Tan explained. “But the challenge is when patients have early-stage disease, such as in the adjuvant setting like in KEYNOTE-564 (NCT03142334), these patients might not have as sensitive an opportunity to detect the disease.”

Research has been underway to determine what other methods cancer teams can use to detect earlier-stage disease. For example, in a study published in the Annals of Oncology in 2020, researchers tried using methylation signatures in cell-free DNA in different tumor types.² Although decent sensitivity was demonstrated in cancers like colorectal and esophageal for patients with stage II disease, it “really misses the mark,” Tan said, in kidney cancer. “Only in stage IV disease, there’s a high sensitivity and specificity.”

Urinary tract DNA has also been used in patients with large renal masses. Tan referred to a 61-year-old patient of his that presented with hematuria, a large renal mass and an infrahepatic IVC thrombus. The patient underwent urinary testing to complement his lung biopsy. Although his lung biopsies were negative, his urinary ctDNA returned with a VHL mutation and a SETD2 mutation, both indicating clear-cell kidney cancer.

“He was actually able to start systemic therapy without confirmed diagnosis of tissue biopsy, with the caveat that maybe he would have a delayed effect and we’d have a whole specimen to review later on,” Tan said.

A study assessing minimal residual disease (MRD) in the adjuvant setting in kidney cancer was recently presented at ESMO and focused on 61 patients with kidney cancer after undergoing surgery.³ Researchers selected 13 weeks as the window to assess MRD after surgery. Of these patients, 7 had positive ctDNA but no evidence of disease on imaging, and patients that were ctDNA negative overall in the nonadjuvant cohort had a high negative predictive value of 97%.3

“There was also some concern because 5 of the patients in the adjuvant cohort, which these investigators are selecting the highest-risk patients for adjuvant therapy, 5 of those patients were MRD negative at diagnosis, and they actually did have recurrence on scans without positive ctDNA,” Tan said. “Eventually 2 out of those 5 patients did eventually convert to positive ctDNA, but this tells me that this is probably not ready for primetime in the real-world setting in select patients for this adjuvant therapy.”

A poster that Tan and his colleagues presented at ASCO GU this year added to the knowledge base by demonstrating that ctDNA positivity was associated with worse progression-free survival (PFS). Findings from this poster also demonstrated that non-clear cell ctDNA sheds significantly higher than non-clear cell RCC.¹

Tan went on to explain how ctDNA kinetics may be used to decide whether treatment should be intensified or deescalated in patients with kidney cancer.1 He provided an example of a 77-year-old patient of his with clear cell RCC that metastasized to her thyroid. She started treatment with ipilimumab (Yervoy) and nivolumab (Opdivo), but 3 weeks later she became highly symptomatic and began to deteriorate.

“Eyeballing this patient, she was going to probably be at high risk of dying from her cancer if she didn’t have a next, so I made the decision to start on [nivolumab and cabozantinib (Cabometyx)],” Tan explained. “And pretty much immediately, we see that her calcium normalized a few weeks later.”

He added that he received a message from that patient saying how much better she was feeling after the treatment change. “She goes and has a deep molecular response and also a radiographic complete response,” Tan continued. “A year later, she’s left with a kidney mass that ends up being resected and being completely negative for any residual tumor. She had a complete pathologic response, and she has a [complete response] on scans and a molecular response. She is now off therapy and very grateful, and so is her family.”

Now, the focus has been shifted to improving the quality of life in patients with kidney cancer treated with immunotherapy plus TKI. But some studies have demonstrated that temporary discontinuation of TKIs may not impact survival, and Tan discussed whether this approach can be adopted in the immunotherapy/TKI era.

Findings from the Tide-A study, recently presented at ESMO, assessed 75 patients with clear cell RCC and measurable disease, although really high-risk patients were excluded from the study. Researchers aimed to determine whether deescalating the regimen of immunotherapy plus TKI can be done without harming patients. More than 72% of patients in this study who discontinued treatment with axitinib (Inylta) were free from progression 8 weeks later. Not only did this approach impact survival, but it also helped reduce the incidence of grade 1-3 adverse events.

Tan noted that the FDA released guidance on incorporating ctDNA into clinical trials as a way to decide upon intensifying or deescalating treatment. He also recently presented a concept at the Alliance for Clinical Trials in Oncology on how to potentially use ctDNA to adapt intermittent immunotherapy/TKI treatment in patients with metastatic RCC.

“I think this will give patients more comfort that they're still being watched carefully, and upon molecular recurrence, they're able to restart their TKI treatment,” Tan said. “You may even argue that they could stop the immunotherapy as well. So, we would give an option to stop the immunotherapy at a year if they had a good response. If they actually were ctDNA negative at diagnosis, then I argue that these patients have a good prognosis to begin with, and maybe they can be followed with just imaging and have probably the best PFS.”

^References

^{1. Tan A. Session 10: Circulating Tumor DNA: Utility for RCC in 2023. Presented at: 2023 International Kidney Cancer Symposium. November 9-11, 2022; Nashville, TN.}

^{2. Liu MC, Oxnard GR, Klein EA, et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020 Jun;31(6):745-759. doi:10.1016/j.annonc.2020.02.011}

^{3. Smigelski M, Sudhaman S, Nagpal S, et al. Utility of circulating tumor (ct)DNA testing for molecular residual disease (MRD) detection and treatment response monitoring in patients (pts) with renal cell carcinoma (RCC). Ann Oncol. 2023;34(2):1908P. doi:10.1016/annonc/annonc1312}