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ONCAlert | Upfront Therapy for mRCC

Immune Component May Affect Survival after Targeted Therapy for Melanoma

Published Online: 1:38 PM, Mon June 5, 2017

Dirk Schadendorf, MD

Overall survival in advanced melanoma treated with targeted therapy had a strong association with high PD-L1 expression and high levels of tumor infiltrating lymphocytes, analysis of tissue specimens from a randomized trial showed.

Patients whose tumors had PD-L1 expression ≥20% and were treated with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) had overall survival (OS) of 86% at 12 months and 79% at 24 months. That compared with OS of 64% and 48% at 12 and 24 months, respectively, in patients who had lower levels of PD-L1 expression. A trend toward improved OS was seen in association with a higher melanoma score (derived from PD-L1 staining on tumor and adjacent mononuclear inflammatory cells).

“This effect is unlikely to be attributed to subsequent anti–PD-1 therapy, since only 1 patient with available data had both high PD-L1 expression at baseline and received a subsequent anti–PD-1 therapy,” Dirk Schadendorf, MD, the director of the Department of Dermatology and the West German Cancer Center at the University Hospital Essen in Germany, and colleagues reported in a poster presentation at the 2017 American Society of Clinical Oncology meeting in Chicago.

“These results suggest that an immune component may impact outcomes following targeted therapy,” they added. “Further analysis is required to fully characterize predictive markers.”

Studies of patients with metastatic melanoma demonstrated benefits from treatment with targeted therapies and immunotherapies. Investigation of biomarkers associated with response to anti–PD-1 therapy has identified positive associations with PD-L1 expression and immune cell infiltration. Whether clinical efficacy with targeted therapies had correlations with immunotherapy biomarkers remained unclear.

Tissue samples from patients who participated in the randomized, phase III COMBI-v trial provided an opportunity to evaluate expression of PD-L1 and CD8 and examine associations with clinical outcomes in the trial. COMBI-v demonstrated significant improvement in outcomes among patients with metastatic BRAF V600-mutant melanoma treated with the combination of dabrafenib and trametinib versus vemurafenib (Zelboraf).

The analysis involved biopsy specimens from 74 patients treated with dabrafenib and trametinib. Each specimen was assessed for expression of PD-L1 by means of immunohistochemistry and CD8 by means of an anti-CD8 antibody.

Investigators quantified PD-L1 expression in 2 ways: as a percentage of positively stained tumor cells; and by the MEL score, as previously applied in studies of patients with melanoma treated with pembrolizumab (Keytruda). A MEL score of 0 or 1 was considered negative (<1% PD-L1 staining) and scores of 2 to 5 as positive (≥1 staining).

Of the 74 evaluable patients, 54 (73%) had PD-L1–positive tumors. The distribution of MEL scores was 0 or 1 in 20 patients, 2 (≥1% to <10% staining) in 33 patients, 3 (≥10% to <33%) in 10 patients, 4 (≥33% to <66%) in 7 patients, and 5 (≥66%) in 4 patients.

Investigators found a trend toward a positive correlation between PD-L1 and CD8 expression (Spearman correlation coefficient = 0.5). Overall, PD-L1 positivity (MEL score ≥2) did not correlate with response rate, duration of response, tumor shrinkage, progression-free survival, or OS.

The 54 patients with PD-L1–positive tumors had 12- and 24-month OS of 64% and 49% and a median OS of 23 months. That compared with 79% 12-month survival and 69% 24-month survival in the 20 patients with PD-L1–negative tumors (median OS not available).

An analysis limited to patients with high PD-L1 expression (≥20%, n = 15 vs <20%, n = 59) did show an association with improved OS (HR, 2.66; 95% CI, 0.94-7.52). A similar association emerged from an analysis of MEL score ≥3 and OS (HR, 2.08; 95% CI, 0.92-4.74). A MEL score ≥3 (n = 21) associated with a 12-month OS of 80% and 24-month OS of 70%, as compared with 64% and 48% for patients with lower MEL scores.

Among patients with PD-L1–negative tumors, investigators observed improved OS in the subgroup with high CD8 expression, particularly in the stromal compartment. Patients with CD8 stromal expression ≥20% (n = 9) had 12- and 24-month OS of 100% compared with 64% and 46% for patients with lower CD8 stromal expression (n = 11).
Schadendorf D, Long GV, Grob JJ, et al. PD-L1 and CD8 expression and association with outcomes in patients (pts) with BRAF V600E/K-mutant metastatic melanoma (MM) who received dabrafenib + trametinib (D+T) in the randomized phase 3 COMBI-v study. J Clin Oncol. 2017;35 (suppl; abstr 9527).

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