Higher BMI May Be Associated With Improved Overall Survival in Patients with Metastatic Kidney Cancer

An elevated body mass index (BMI) was associated with improved overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) who were treated with PD-1/PD-L1-based immune checkpoint inhibitors (ICIs), according to data from a recent multinational analysis published in JAMA Oncology.

These findings were consistent with the clinical phenomenon referred to as the “obesity paradox”, where mRCC patients with elevated BMI tend to experience better outcomes.

In an interview with CURE®, Dr. Aly-Khan Lalani, a medical oncologist and assistant professor at McMaster University and one of the study authors, went further in depth on the findings. “Previous studies had shown that patients with a higher BMI – typically defined as a measurement of 25 kg/m2 or more – had a higher likelihood of being diagnosed with kidney cancer, but also tended to benefit more from targeted therapies for advanced disease,” Lalani said. “Our study, conducted in the immunotherapy era, also showed that mRCC patients with a higher BMI appear to have improved clinical outcomes compared to those with lower BMI.”

After a shift in the treatment landscape included ICIs for most patients, the researchers sought to determine whether patients with mRCC receiving this treatment fit with previous evidence of higher BMI as a positive prognostic factor. They also aimed to explore potential genomic alterations according to BMI status.

In their analysis, the researchers examined the association of BMI with OS, time to treatment failure (TTF) and objective response. Genomic alteration frequencies and tumor mutational burden were also compared by BMI status in patients with available next-generation sequencing data.

A total of 735 patients with mRCC were treated with a PD-1/PD-L1-based ICI. Of the participants, 229 (31%) received first-line ICI and 230 (31%) received combination ICI. At the initiation of ICI, 274 (37%) had a low BMI (of less than 25) and 461 (63%) had a high BMI (defined as 25 or greater). Median follow-up was 13.5 months.

Overall, the researchers found that patients with a high BMI showed improved OS compared to those with a low BMI (1-year OS: 79% vs 66%). Patients with higher BMIs also had numerically higher ORR (30% vs 21%) and TTF (median 7.4 months vs 4.9 months).

Of the 319 patients with available next-generation sequencing data, genomic alteration frequencies and tumor mutational burden were found to be similar between BMI groups. The authors noted that the study did have some limitations; particularly the lack of robust gene-expression profiling.

The clinical observations made in this study could be explained by several hypotheses, the authors explained. “Low fatty acid synthase gene expression, which is inversely correlated with BMI, was associated with longer OS in VEGF-treated patients,” they wrote.

Other hypotheses include that patients with obesity may have tumors with increased gene signatures denoting the development of new blood vessels. Patients with higher BMI may have adipose tissue, which stores energy in the form of fat, with increased hypoxia (low oxygen), inflammation and immune cell infiltration signatures, which could result in enhanced benefit from immunotherapy.

“Our study highlights that BMI alone is not the complete story for the patient's underlying health status,” said Lalani. “There may be other important biological underpinnings at either the tumor level or from the adipose tissue level that we need to deeply understand.”

“While BMI can be easily recorded when patients go into clinic, there are other relevant indicators of our patients’ health status such as cancer cachexia, or sarcopenia (where there's loss of muscle mass). Ultimately, our results provide further motivation to better understand the overall health status of our mRCC patients – beyond their BMI – and how we can explain and improve their responsiveness to immunotherapy.”

The authors concluded by noting that more work is necessary to explore the biological foundations for similar findings across other solid tumors treated with ICIs.

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