Biomarkers predict benefit of adjuvant nivolumab in resected melanoma
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Key takeaways:
- Four biomarkers appeared associated with longer RFS with nivolumab but not placebo.
- More research will examine the effect of additional biomarkers, as well as biomarker combinations.
CHICAGO — Several biomarkers predicted outcomes with adjuvant nivolumab vs. placebo for patients with resected stage IIB or IIC melanoma, according to study results presented at ASCO Annual Meeting.
In contrast to prior findings in melanoma, no biomarkers appeared prognostic for RFS among patients who received placebo.
“Typical findings associated with metastatic melanoma in terms of biomarkers and anti-PD-1 efficacy are consistent in nonmetastatic melanoma,” study co-author Brian Gastman, MD, who conducted this research at Cleveland Clinic and serves as adjunct professor of surgery there, told Healio.
“[This is] quite interesting as the therapy is being given after all known disease is resected and, thus, any gross or even microscopic tumor microenvironment should be eradicated, [and this] is commonly thought to be the location of where biomarkers make the most difference.”
Background and methods
Results of the randomized phase 3 Checkmate -76K trial showed adjuvant therapy with nivolumab (Opdivo, Bristol Myers Squibb) — a PD-1 immune checkpoint inhibitor — significantly extended RFS vs. placebo among patients with stage IIB or IIC melanoma (HR = 0.42; 95% CI, 0.3-0.59). The benefit persisted across all T stages.
Gastman and colleagues — including presenting author Georgina Long, AO, FRACP, co-medical director of Melanoma Institute Australia — assessed select biomarkers and their association with RFS among patients with early-stage melanoma treated with nivolumab.
Researchers analyzed baseline primary tumor and serum biomarkers, including interferon gamma-related gene expression signature, tumor mutational burden, BRAF mutation status, percentage of intratumoral CD8-positive T cells, serum C-reactive protein levels and tumor cell PD-L1 expression.
“Given that many patients in this cohort will benefit from surgery alone and some won’t benefit from surgery plus nivolumab — understanding which patients are ideal candidates is key,” Gastman said. “These data are critical to optimize who should or should not get this therapy, and they help establish a more accurate risk-benefit [ratio] for this patient population.”
Results
Analysis of continuous biomarker levels identified four variables linked to longer RFS with nivolumab but not placebo — higher interferon gamma-related gene expression signature (nivolumab, HR = 0.59; 95% CI, 0.41-0.86; placebo, HR = 0.91; 95% CI, 0.65-1.27), higher tumor mutational burden (nivolumab, HR = 0.66; 95% CI, 0.49-0.9; placebo, HR = 1.2; 95% CI, 0.89-1.61), higher percentage of CD8-positive T cells (nivolumab, HR = 0.6; 95% CI, 0.39-0.9; placebo, HR = 0.97; 95% CI, 0.71-1.33) and lower serum C-reactive protein level (nivolumab, HR = 1.37; 95% CI, 1-1.88; placebo, HR = 0.92; 95% CI, 0.69-1.24).
Analyses by which biomarkers were dichotomized by median or prespecified cutoffs revealed the same correlations.
Results showed longer RFS among nivolumab-treated patients than those assigned placebo across all levels of biomarkers, as well as regardless of BRAF mutation status.
Results showed no association between PD-L1 expression and RFS (nivolumab, HR = 0.82; 95% CI, 0.6-1.12; placebo, HR = 0.99; 95% CI, 0.87-1.12).
Next steps and implications
“[Because] most of these biomarkers and anti-PD-1 have only been studied in either stage IV unresectable disease or locoregional metastatic stage III disease, seeing the results in nonmetastatic disease — where there is still high risk for relapse — was quite interesting,” Gastman told Healio. “Ultimately, more research and more complex biomarkers and biomarker analysis will need to ensue to bring these types of data to clinical reality.”
There is “active research” examining combinations of the biomarkers studied, and findings related to other biomarkers that have not yet been studied — such as circulating tumor DNA — will be reported, Gastman said.
“Anti-PD-1 therapy works for patients without known metastatic disease, essentially on high-risk primary tumors,” Gastman said. “What anti-PD-1 would do to these tumors without surgery may be important to study — say, in a neoadjuvant context. Further, while these cases were all sentinel node biopsy negative and benefited, the benefit is not as powerful as the same patient with sentinel node biopsy-positive pathology; thus, the need for sentinel node biopsy to have a rational conversation and rational workup is ever more important.”
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Long G, et al. Abstract 9504. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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