ASCO GU 2020: Clinically Useful Biomarkers: Ready for Prime Time in 2020? - A Urologists Report

San Francisco, CA (UroToday.com) As part of the GU ASCO 2020 renal cancer session discussing optimizing first-line systematic therapy, Dr. Martin Voss discussed clinically useful biomarkers. In his opinion, the answer to the question of “Are biomarkers ready for prime time in 2020?” his answer to his question is, no not really. There are several potential biomarkers available in the clinic/from the chart, including: PDL1 expression, histology ie. sarcomatoid features, and the neutrophil/lymphocyte ratio. Additionally, in the research setting/from the bench there are other possible biomarkers, including: genomics, RNA signatures from phase III trials, and peripheral blood markers.

In PD-L1 patients from CheckMate 214, the OS association is reversed with IO-IO therapy:

ASCO GU 2020 OS association

When we are weighing the risks and benefits in patients with imminent clinical deterioration, there is a concern for making it to second line therapy. In CheckMate 214, among all patients, there was a 42% ORR and 20% disease progression rate (1:2.1 ratio), whereas in patients with PD-L1 <1% there was ORR of 37% and 20% disease progression rate (1:1.85). However, in PD-L1 ≥ 1%, the ORR was 58% and 14% disease progression rate (1:4.14).

With regards to sarcomatoid features, the objective response rate in the treatment arm in KEYNOTE-426 was 54.9% (compared to 60.0% in the ITT population), whereas the objective response rate for sarcomatoid features in the treatment arm of CheckMate 214 was 56.7% (compared to 41.9% among all patients in the IMDC intermediate/poor risk group). Additionally, the progressive disease rate for sarcomatoid features was 13.7% in the treatment arm of KEYNOTE-426 (compared to 11.3% in the ITT population), whereas it was 25.0% in the treatment arm of CheckMate 214 (compared to 24.9% in the IMDC intermediate/poor risk group). So, in the setting of imminent deterioration (progressive disease), sarcomatoid features appears to favor pembrolizumab plus axitinib.

Several retrospective studies have assessed the impact of preoperative neutrophil-lymphocyte ratio (NLR) as a prognostic indicator. The consensus is that an NLR <4.0 is associated with improved distant metastasis rate and percent overall survival among patients undergoing nephrectomy. Furthermore, these findings were validated in the CheckMate 214 study using a cutoff of NLR <2.9, demonstrating that a lower ratio is associated with improved 24 months OS rate (79% <2.9 vs 62% >2.9) [1]. As summarized by Dr. Voss, NLR has consistently demonstrated the same prognostic association across various disease scenarios, independent of established prognostic models.

As follows is an excellent summary of the clinically relevant biomarker questions in the clinical setting:

ASCO GU 2020 clinically relevant behavior

In the research/bench setting several genomic studies have shown that PBRM1 loss is associated with improved OS in metastatic RCC. Furthermore, DDR gene deleterious alterations have been shown to significantly improve OS, with a 71% survival advantage. Finally, high mean HLA-1 evolutionary divergence (HED) expression has also been associated with OS in IO therapy in a pan-cancer cohort of 614 patients.

Given the plethora of specimens collected during recent phase III trials, several RNA signatures have emerged from these trials. A high angiogenesis signatures has demonstrated improved PFS among patients treated with sunitinib, atezolizumab + bevacizumab, and atezolizumab alone. Similarly, a myeloid inflammation signature has been tested in these trial arms, showing that high expression may be prognostic. Furthermore, high expression of the 26-gene JAVELIN Renal 101 signature was prognostic for improved PFS in the avelumab + axitinib arm, but was not so in the sunitinib control arm.

ctDNA is exciting, but definitely not ready for prime time as a biomarker according to Dr. Voss. VHL mutation rates have been assessed in ctDNA compared to primary tissue with the primary tissue identifying a mutation in 93% of cases compared to only 28% in ctDNA. Also of interest is the kynurenine/tryptophan ratio, which was assessed in CheckMate 025, showing that a lower ratio was associated with improved OS.

Finally, Dr. Voss discussed biomarker options in non-clear cell RCC patients. Among papillary RCC patients MET driven variants have shown an improved median PFS; MET driven is defined as any of the following: chromosome 7 copy gain, focal MET or HGF amplification, or MET kinase domain mutations.

To conclude Dr. Voss once again noted that biomarkers in RCC are not really ready for prime time in 2020, but we are getting there.


Presented by: Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center, New York, New York 

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

References:
1. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: Extended follow-up of efficacy and safety results from a randomized, controlled, phase 3 trial. Lancet Oncol 2019 Oct;20(10):1370-1385.