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ESMO 2016: Pooled Analysis Shows PD-L1 Expression as a Biomarker for Nivolumab Plus Ipilimumab Response in Advanced Melanoma

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Key Points

  • In the subgroup of patients with PD-L1 expression ≥ 5%, median progression-free survival was not reached in the combination treatment arm, compared with 22 months for patients receiving sole nivolumab. However, with a minimum follow-up of 18 months, the hazard ratio was similar between both treatments, suggesting there was no difference in progression-free survival benefit between both agents.
  • In the subgroup of patients with low (< 5%) to no PD-L1 expression, median progression-free survival was 11.1 months in patients receiving nivolumab plus ipilimumab, compared with 4.9 months for nivolumab.
  • The overall response rate was higher in the combination treatment patients, regardless of PD-L1 expression. In patients with PD-L1 expression ≥ 5%, the overall response rate in patients receiving combination was 68.5% compared with 59.0% in the nivolumab group. In the subgroup of patients with < 5% PD-L1 expression, the overall response rate was also higher, at 54.9% vs 39.7%.

A pooled analysis from three clinical trials in advanced melanoma shows that although patients treated with nivolumab and nivolumab plus ipilimumab with ≥ 5% programmed death-ligand 1 (PD-L1) tumor expression have similar progression-free survival, durable response rates were higher for the combination of both agents vs nivolumab alone across all PD-L1 expression subgroups. Given that treatment-related side effects with the nivolumab plus ipilimumab combination are higher than seen with nivolumab alone, there has been interest in whether PD-L1 testing could be used to better understand the benefit risk of both treatment options. These findings were presented by Georgina Long, BSc, PhD, MBBS, FRACP, from the Melanoma Institute Australia and The University of Sydney in Sydney, Australia, at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen, Denmark (Abstract 1112PD).

CheckMate 069, 066, and 067

This large biomarker analysis used pooled data from the CheckMate 069 phase II trial and the CheckMate 066 and 067 phase III trials, wherein 832 treatment-naive patients with melanoma were randomized to nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for four cycles (n = 358) or nivolumab at 3 mg/kg every 2 weeks, followed by nivolumab at 3 mg/kg every 2 weeks (n = 474) until progression or unacceptable toxicity. Tumor tissue from primary or metastatic sites was obtained at screening prior to treatment and assessed for PD-L1 expression using a validated Dako immunohistochemistry assay.

In the combination nivolumab plus ipilimumab treatment cohort, 92 (26%) of patients had PD-L1 expression ≥ 5% and 139 (29%) patients receiving solely nivolumab had PD-L1 expression ≥ 5%. The vast majority (80%) of tumor samples with positive PD-L1 staining had PD-L1 expression levels at or below 10%. Expression did not appear to differ based on the site of biopsy collection, nor between primary and metastatic lesions. Using different thresholds (eg, > 1%, 5%, and 10% of PD-L1 expression) did not improve the ability of the test to discriminate between those patients most likely to gain a response to either treatment. In addition, using a receiver operator curve analysis did not define an optimal threshold that maximizes sensitivity and specificity for detecting responders. The area under the curve from this large number of patients treated with nivolumab was 0.6.

In the subgroup of patients with PD-L1 expression ≥ 5%, median progression-free survival was not reached in the combination treatment arm, compared with 22.0 months for patients receiving sole nivolumab. However, with a minimum follow-up of 18 months, the hazard ratio (HR = 0.99; 95% confidence interval [CI] = 0.66–1.46) was similar between both treatments, suggesting there was no difference in progression-free survival benefit between both agents.

In the subgroup of patients with low (< 5%) to no PD-L1 expression, median progression-free survival was 11.1 months in patients receiving nivolumab plus ipilimumab, compared with 4.9 months for nivolumab (HR = 0.70; 95% CI = 0.57–0.87).

By contrast to the progression-free survival results, the overall response rate was higher in the combination treatment patients, regardless of PD-L1 expression. In patients with PD-L1 expression ≥ 5%; the overall response rate in patients receiving combination was 68.5% compared with 59.0% in the nivolumab group. In the subgroup of patients with < 5% PD-L1 expression, the overall response rate was also higher, at 54.9% vs 39.7%. The median duration of response with nivolumab plus ipilimumab was not reached in both PD-L1 expression subgroups. In patients receiving only nivolumab, the duration of response was not reached vs 22.3 months in patients with ≥ 5% PD-L1 and < 5% PD-L1 subgroups, respectively.

Conclusions

The subgroup of patients having high PD-L1 demonstrated similar median progression-free survival with combination and nivolumab treatment alone. However, the overall response rate with nivolumab plus ipilimumab was numerically higher across both PD-L1 expression subgroups. The authors cautioned against using these results to assess the relative benefit of nivolumab plus ipilimumab vs nivolumab, as the overall survival data remains immature, and the use of PD-L1 as a biomarker remains problematic, as other biomarkers are emerging as potentially more important predictors of response.

Dr. Long commented that decisions about different treatment options should be made on an individual patient basis, with clinicians accepting that full understanding of PD-L1 is far from complete.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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