Biomarkers may predict response to nivolumab for urothelial cancer

CHICAGO — A combination of PD-L1 expression, circulating myeloid-derived suppressor cells and interferon gamma signatures may identify patients with urothelial carcinoma who achieve more favorable outcomes after nivolumab treatment, according to results from the CheckMate 275 trial presented at American Association for Cancer Research Annual Meeting.

The open-label phase 2 trial included 270 patients with locally advanced or metastatic urothelial carcinoma who received IV nivolumab (Opdivo, Bristol-Myers Squibb) dosed at 3 mg/kg every 2 weeks. Treatment continued until disease progression or unacceptable toxicity.

“[The trial] previously demonstrated the efficacy and manageable safety profile of nivolumab [for] patients with previously treated metastatic urothelial carcinoma,” Padmanee Sharma, MD, PhD, professor at The University of Texas MD Anderson Cancer Center, said during a presentation.

As HemOnc Today previously reported, this trial met its primary endpoint of objective response rate. PFS and OS served as secondary endpoints.

At AACR, Sharma presented updated PFS and OS results, as well as data on potential predictive biomarkers of response.

With a minimum follow-up of 21.3 months (median, 24.5 months), researchers reported median PFS of 1.9 months (95% CI, 1.9-2.3) and median OS of 8.6 months (95% CI, 6.1-11.3).

Overall, 55 patients responded to treatment. Of these:

72.7% had a response that lasted at least 6 months;
54.5% had a response that lasted at least 12 months; and
30.9% had an ongoing response at the time of analysis.

Median duration of response for all treated patients was 17.7 months (95% CI, 11.5-22). Researchers reported a 1-year OS rate of 40.3% (95% CI, 34.4-46.2) and a 2-year OS rate of 29.4% (95% CI, 23.9-35.1). They observed OS benefit across patient subgroups based tumor PD-L1 expression.

Researchers measured circulating myeloid-derived suppressor cells (MDSC) by flow cytometry at baseline. They categorized MDSC levels into tertiles of low, median and high.

Patients with low levels of MDSC achieved longer median OS (22.3 months vs. 3.7 months) than those with high levels of MDSC. Researchers also observed similar associations among patients with PD-L1 expression of less than 1% (median OS, 17 months vs. 4.3 months) and among patients with PD-L1 expression of at least 1% (median OS, not reached vs. 2 months).

The researchers assessed interferon gamma gene expression using macro-dissected samples and categorized levels as low and high based on arbitrary cutoff at median.

Patients with high tumor interferon gamma signature scores achieved prolonged OS compared with those with low scores (median OS, 22.2 months vs. 8.7 months).

Patients with high tumor interferon gamma signature scores and low MDSC levels experienced the longest OS of all the biomarker subgroups (P < 0.05).

“Baseline circulation MDSCs and tumor PD-L1 expression appear to be individual markers of clinical benefit,” Sharma said. “Composite biomarkers could help identify patients who may benefit the most from treatment with nivolumab. However, the results of these exploratory analyses will need to be confirmed in controlled trials with larger patient populations.”

Treatment with nivolumab appeared well tolerated. The most common treatment-related adverse events included fatigue (18.1%), diarrhea (12.2%), pruritus (11.5%) and decreased appetite (9.3%). – by Cassie Homer

References:

Sharma P, et al. Abstract CT178. Presented at American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.

Disclosures: Sharma reports consultant roles with Astellas, Apricity, BioAtla, BioMx, Constellation, Forty Seven Inc., Jounce, Kite Pharma, Merck, Neon, Oncolytics, Polaris and Pieris Pharmaceuticals, as well as stock holdings in Apricity, BioAtla, Constellation, Forty Seven Inc., Jounce, Neon, Oncolytics and Polaris. Please see the abstract for all other authors’ relevant financial disclosures.