First-Line Immuno-Oncology Therapies Up Survival in RCC With Brain Metastases – Renal and Urology News

First-line immuno-oncology (IO)-based regimens and intensive focal therapies are associated with significantly prolonged overall survival (OS) among patients with brain metastases from renal cell carcinoma (RCC), new findings suggest.

In a real-world study, median OS was 32.7 months for patients who received first-line IO-based combination regimens compared with 20.6 months for those who received tyrosine kinase inhibitor (TKI) monotherapy, Kosuke Takemura, MD, of the Tom Baker Cancer Centre at the University of Calgary in Alberta, Canada, and colleagues reported in European Urology. Patients who received intensive focal therapies with stereotactic radiotherapy or neurosurgery have significantly longer OS compared with those who receive whole-brain radiotherapy alone or no focal therapy (31.4 vs 16.5 months).

On multivariable analysis, IO-based regimens were significantly associated with a 51% reduced risk for death compared with TKI regimens. Stereotactic radiotherapy or neurosurgery was significantly associated with a 52% lower risk for death compared with whole-brain radiotherapy alone or no focal therapy.

IMDC favorable- or intermediate-risk disease was significantly associated with a 60% lower risk for death compared with poor-risk disease.

The findings are from an analysis of data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Of 4799 patients with metastatic RCC, 389 (8.1%) had brain metastases at initiation of systemic therapy. The goal of the study was to define the clinical effectiveness of modern multi-modal cancer treatment for patients with brain metastases from RCC. The investigators did not probe the causal pathways between treatments and outcomes. 

The study included patients who received first-line IO-based combination therapy (nivolumab/ipilimumab, pembrolizumab/axitinib, avelumab/axitinib, nivolumab/cabozantinib, pembrolizumab/lenvatinib, or atezolizumab/bevacizumab) or TKI monotherapy (sunitinib or pazopanib) and had data available on brain metastases before initiation of systemic therapy. Of the 389 patients, 99 (25%) received IO-based regimens.

The patients with brain metastases were more likely to be younger (63 vs 65 years) and to have lung metastases (80% vs 67%), spleen metastases (2.0% vs 0.8%), and multiple sites of metastases (96% vs 80%). The group with brain metastases had a shorter median OS compared with patients without brain metastases (22.8 vs 34.7 months).

The study was limited by its retrospective design and absence of data on PD-L1 expression or intracranial/ extracranial disease status.

“This is a very important study and highlights that this patient population should be considered as the focus of future innovative clinical trials, and there definitely should not be an exclusion simply because they are not anticipated to have a favorable outcome,” said genitourinary surgical oncologist Philippe E. Spiess, MD, assistant chief of surgical services and high-volume kidney cancer surgeon at the Moffitt Cancer Center in Tampa, Florida. “Up until this point, these patients were never eligible for clinical trial participation, as it was thought they would do poorly, but now with promising outcomes with new treatment combinations along with site-directed brain radiation, our clinical approach to these patients needs to adapt to one offering more hope and personalization.”

In addition, the morbidity and mortality of these therapeutic modalities are improving, he said, “and now our focus should be in knowing which of these systemic therapies when used in combinations along with radiation [therapies] can offer a curative potential to a subset of patients.”

Scott S Tykodi, MD, PhD, Director of Kidney Cancer Research at the University of Washington’s Fred Hutchinson Cancer Center in Seattle, said the real-world data used in the study are informative because the outcomes are likely closer to what is seen in the clinic versus clinical trial results, which usually exclude patients with comorbidities and unfavorable disease presentations like brain metastases.

“The trends observed in the IMDC data are consistent with our expectations that front-line IO-based regimens are better than TKI monotherapy, and an oligometastatic pattern of brain metastases amenable to surgery or stereotactic radiation is a better prognosis than widespread disease managed by whole brain radiation or no localized therapy at all,” Dr Tykodi said. “While this study reinforces our usual treatment patterns, it also confirms the survival penalty associated with brain involvement by the metastatic disease burden.”

Marc A. Bjurlin, DO, MSc, Director of Clinical Trials at the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, North Carolina, said the new study provides a context in which clinicians can better counsel patients with RCC brain metastases in terms of expected OS by taking into account both focal therapy options and systemic therapy.

The IMDC database enabled investigators to capture a broad selection of clinically important and informative variables in a cohort of patients with a relatively long follow-up, Dr Bjurlin said. He pointed out, however, that there is a selection bias in that only patients who were suitable for stereotactic radiotherapy or neurosurgery were selected for those interventions, whereas those who were unable to receive these treatments due to such issues as the presence of more or larger tumors might have been steered toward whole brain radiotherapy.