Anti-PD-1 Biomarker Analysis Shows Promise for MDSCs, IFN-Gamma

Published: Wednesday, Apr 18, 2018

Dr Padmanee Sharma
Padmanee Sharma, MD, PhD
A search for molecular guidance in the use of anti-PD-1 therapy in urothelial cancer pointed toward myeloid-derived suppressor cells (MDSCs) as a potentially useful biomarker, as reported at the American Association for Cancer Research meeting in Chicago, Illinois.

Analysis of the phase II CheckMate 275 trial of nivolumab (Opdivo) showed that patients with the longest overall survival (OS) had low baseline circulating MDSCs and a high interferon-gamma (IFNƴ) signature. In general, low baseline circulating MDSCs were associated with better survival as compared with higher levels.

“Baseline circulating myeloid-derived suppressor cells and tumor PD-L1 expression appear to be individual biomarkers of clinical benefit,” said Padmanee Sharma, MD, PhD, professor of genitourinary medical oncology and immunology at The University of Texas MD Anderson Cancer Center in Houston.

“Composite biomarkers could help identify patients who may benefit the most from treatment with nivolumab,” she added. “However, the results of these exploratory analyses will need to be confirmed in controlled trials with larger patient populations.”

CheckMate 275 was an open-label, single-arm clinical trial that evaluated single-agent nivolumab in patients with locally advanced or metastatic urothelial cancer that had progressed on prior platinum therapy. The trial design included a prespecified exploratory biomarker analysis of the association between PD-L1, MDSCs, and IFNƴ with overall survival (OS).

Patients received nivolumab at a dose of 3 mg/kg every 2 weeks until disease progression or development of unacceptable toxicity. The trial had a primary objective of overall response rate (ORR), as determined by a blinded independent review committee. The data analysis included 270 patients.

Results of the primary analysis of CheckMate 275 were reported at the 2017 German Society for Hematology and Medical Oncology annual meeting. Sharma reported findings from an updated analysis that reflected 9 additional complete responses since the initial report. The updated results, representing a minimum follow-up in all patients, showed an ORR of 20%, including 16% in patients whose tumors had PD-L1 expression <1% and 26% in those with higher PD-L1 expression.

Overall, 17 patients had complete responses, 38 had partial responses, and 57 had stable disease. Responses, including complete responses, were observed in patients with PD-L1 expression <1% and ≥1%. The median duration of response was 17.7 months. Sharma said 40 patients had responses lasting 6 months or longer, including 30 that persisted for 12 months or beyond.

Progression-free survival, a secondary endpoint, was 1.9 months in all patients and the PD-L1 <1% subgroup, increasing to 3.5 months in the PD-L1 ≥1% group. The median OS was 8.6 months in all patients, 6.0 months for those with PD-L1 expression <1%, and 11.9 months for patients with PD-L1 expression ≥1%.

The most common treatment-related adverse events (AEs; all grades) were fatigue (18%), diarrhea (12%), and pruritus (11%). Grade 3/4 AEs occurred in 23% of patients, led by diarrhea (3%), fatigue (2%), and asthenia (2%).

For the biomarker analysis, circulating MDSCs were measured by flow cytometry, and patients were categorized into tertiles of low, medium, and high. PD-L1 expression was determined at a central laboratory by means of the Dako IHC 28-8 assay. IFNƴ signature was determined by HTG EdgeSeq technology, using archival pretreatment biopsies, and patients were categorized as low or high on the basis of the median value.

Analysis of OS by baseline circulating MDSCs showed median values of 22.3, 8.6, and 3.7 months for patients in the low, medium, and high tertiles, respectively. Repeating the analysis by PD-L1 expression status showed median OS of 17.0, 4.1, and 4.3 for MDSCs low, medium, and high in the subgroup with PD-L1 expression <1% (n = 121). For the PD-L1 ≥1% subgroup (n = 93), the median OS was not reached for the patients in the baseline MDSCs-low group, 23.1 months for MDSCs-medium, and 2.0 for MDSCs-high.

The analysis of baseline IFNƴ showed that the high subgroup had a median OS of 22.2 months versus 8.7 months for the IFNƴ-low group. An analysis of MDSCs in the IFNƴ-low subgroup produced median OS values of 11.7, 8.6, and 7.0 months for MDSCs low, medium, and high, respectively. Repeating the analysis with the IFNƴ-high subgroup showed the median OS had yet to be reached in the patients with low baseline MDSCs, as compared with 11.6 and 4.8 months in the MDSC medium and high subgroups.
Sharma P, Baron A, Necchi A, et al. Nivolumab monotherapy in patients with advanced platinum-resistant urothelial carcinoma: efficacy and safety update and association between biomarkers and overall survival in CheckMate 275. Presented at: ACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. Abstract CT178. http://www.abstractsonline.com/pp8/#!/4562/presentation/11154.
 
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