Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma - PubMed (original) (raw)

Clinical Trial

doi: 10.1007/s00262-014-1528-9. Epub 2014 Mar 8.

Bianca Heemskerk, Harm van Tinteren, Rob R H van den Brom, Geke A P Hospers, Alfonsus J M van den Eertwegh, Ellen W Kapiteijn, Jan Willem B de Groot, Patricia Soetekouw, Rob L Jansen, Edward Fiets, Andrew J S Furness, Alexandra Renn, Marcin Krzystanek, Zoltan Szallasi, Paul Lorigan, Martin E Gore, Ton N M Schumacher, John B A G Haanen, James M G Larkin, Christian U Blank

Affiliations

Clinical Trial

Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma

Sander Kelderman et al. Cancer Immunol Immunother. 2014 May.

Abstract

Introduction: Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit.

Methods: Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes.

Results: A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK.

Conclusion: In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy.

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Conflict of interest statement

G. A. P. Hospers, A. J. M. van den Eertwegh, E. W. Kapiteijn, J. W. de Groot, P. Lorigan, M. E. Gore, J. B. A. G. Haanen, J. M. G. Larkin and C. U. Blank have participated in advisory board meetings of Bristol-Myers Squibb for which the faculty has received compensation. P Lorigan has received support for travel and compensation for educational and speaker bureau activities. J. M. G. Larkin and M. E. Gore acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. J. B. A. G. Haanen and T. N. M. Schumacher are members of the Bristol-Meyers Squibb Immuno-Oncology network and have furthermore received a grant for translational research from Bristol-Meyers Squibb. C. U. Blank receives funding for an investigator-initiated study from Bristol-Myers Squibb. All other authors declared that they have no conflict of interest.

Figures

Fig. 1

Fig. 1

Kaplan–Meier curves for progression-free survival and OS of NL and UK cohort. Progression-free survival curve for a the NL cohort and OS curves for b the NL and c UK patient cohorts are shown

Fig. 2

Fig. 2

Kaplan–Meier curves for OS stratified by blood parameters. OS is shown when stratifying for blood values of a baseline absolute lymphocyte count (ALC), b ALC at week 6, c slope of ALC after two infusions, d baseline lactate dehydrogenase (LDH), e S100 and f baseline erythrocyte sedimentation rate (ESR). ULN upper limit of normal. P < 0.05 is statistically significant

Fig. 3

Fig. 3

Patient selection based on baseline LDH for NL and UK cohort. Upper part of panel a shows the stratification of patients based on their upper limit of normal (ULN) baseline values of serum lactate dehydrogenase (LDH) in the NL cohort. For six patients, baseline LDH values were not available and these were excluded from further analyses. Lower part shows patients grouped by their response to therapy and the occurrence of toxicities. A statistically significant difference in OS was observed when stratifying by 1× ULN baseline LDH. However, seven patients with a clinical response upon ipilimumab treatment would have been missed when implementing this cut-off. Only two patients with a clinical response remained in the LDH-high subgroup when stratifying by 2× ULN of baseline LDH. Toxicities in the high and low LDH subgroups were similar. Panel b shows the stratification by baseline LDH values of patients from the UK cohort. At a cut-off of 1× ULN of baseline LDH, there is no significant influence on OS. Stratification by 2× ULN baseline LDH does significantly increase OS, and no patients in the LDH-high subgroup survive beyond the first year after treatment initiation. Percentages may not add up to 100 due to rounding. HR hazard ratio, CR complete response, PR partial response, SD stable disease, PD progressive disease, NE non-evaluable

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