Low LDH May Predict Second-Line Bevacizumab CRC Response

Liam Davenport

July 07, 2016

BARCELONA — Patients with metastatic colorectal cancer (CRC) who have progressed after first-line chemotherapy plus bevacizumab (Avastin, Genentech) and who have low levels of lactate dehydrogenase (LDH) may benefit from continuation of bevacizumab alongside second-line therapy, a new analysis suggests.

A team of Italian researchers have found that patients with metastatic CRC and low LDH levels had a significant improvement in progression-free survival (PFS) when treated with second-line chemotherapy plus bevacizumab compared with those given chemotherapy alone. No such benefit with continued bevacizumab was seen in patients with high LDH levels.

The new data were presented here at the 18th World Congress on Gastrointestinal Cancer.

The researchers said, "given their potential clinical value, these data deserve prospective and retrospective confirmation in subgroup analyses of other randomized trials of second?line chemotherapy with or without an antiangiogenic."

Speaking to Medscape Medical News, lead researcher Federica Marmorino, MD, Unit of Medical Oncology 2, University Hospital of Pisa, Italy, emphasized that because the study was an analysis of trial data, the results should be interpreted with caution and "our clinical practice cannot change according to retrospective results."

Nevertheless, given the potential role of LDH levels as a predictor of the benefit from bevacizumab beyond progression, she and her colleagues are planning a study to prospectively validate the results.

Study Details

Previous studies have reported that there is an association between LDH levels and angiogenesis and that increased LDH levels suggest a worse prognosis in patients with CRC. Because there are currently no clinical or molecular predictors of benefit for second-line antiangiogenic agents in CRC, the researchers examined the utility of LDH as a prognostic and predictive biomarker.

The team analyzed data from the phase 3 Bevacizumab Beyond Progression (BEBYP) trial, in which patients with colorectal adenocarcinoma who had progressed with first-line fluoropyrimidine-based chemotherapy plus bevacizumab were randomly assigned to second-line chemotherapy with or without bevacizumab.

In all, 159 patients enrolled in BEBYP had baseline LDH levels reported. By using a cutoff of 300 U/L, the team defined 42% patients as having low LDH levels and 58% as having high levels.

There were no clinically relevant differences in baseline and disease characteristics between the high and low LDH groups.

Analysis revealed a significant interaction between LDH levels and treatment effect in terms of PFS (P = .002). Specifically, patients with low LDH levels experienced a significant improvement in PFS if they received chemotherapy plus bevacizumab vs those given chemotherapy alone, at a hazard ratio for progression of 0.39.

In contrast, there was no significant difference in PFS between the chemotherapy plus bevacizumab and chemotherapy-alone groups among patients with high LDH levels, at a hazard ratio of 1.10.

The team also found a trend for a significant interaction between LDH levels and treatment effect in terms of overall survival (P = .075), at a mortality hazard ratio of 0.55 for chemotherapy plus bevacizumab vs chemotherapy alone among patients with a low LDH level. The hazard ratio in patients with high LDH levels was 1.01.

With regard to the prognostic role of LDH, in the overall patient population, there was no significant association between LDH levels and PFS (hazard ratio for progression, 1.22 for high vs low LDH levels; P = .232). There was a trend for an association with overall survival, at a hazard ratio for mortality of 1.35 for high vs low LDH levels (P = .081).

Dr Marmorino believes that the lack of significant interaction between LDH levels and treatment effect in terms of overall survival may be due to "the number of the patients being too small to reach an adequate power to demonstrate a difference."

Furthermore, the original BEBYP trial specified PFS as the primary endpoint, with overall survival, response rate, and safety profile chosen as secondary endpoints. This, Dr Marmorino suggested, may have affected the ability of the current retrospective analysis to detect a significant difference in overall survival.

The team nevertheless concluded that patients with low LDH levels at the time of progression may benefit from the continuation of bevacizumab and that, from "a biological perspective, low LDH levels may indicate that angiogenesis inhibition by bevacizumab is still efficacious."

No funding declared. The authors have disclosed no relevant financial relationships.

18th World Congress on Gastrointestinal Cancer (WCGC). Poster PD-004. Presented July 1, 2016.

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