Background: CALM-NET (EudraCT 2013-002194-22; NCT02075606), a prospective, exploratory study, evaluated enumeration of pre-treatment circulating tumour cells as a predictor of symptomatic response to lanreotide autogel (LAN) in patients with functional midgut neuroendocrine tumours (NETs). Here, we describe the effect of LAN on biomarkers.
Methods: Patients, ≥18 years, with functional, well- or moderately-differentiated midgut NETs were treated with LAN 120 mg every 28 days for up to 52 weeks. Urinary and plasma 5-hydroxyindoleacetic acid (5HIAA), chromogranin A (CgA) and neurokinin A (NKA) were measured; correlations between plasma and urinary 5HIAA (baseline; Weeks 4, 16, 24; end-of-study [EOS]) were assessed. Correlations between plasma 5HIAA/CgA, plasma 5HIAA/NKA and changes in biomarkers according to symptomatic response to LAN (≥50% reduction in diarrhoea/flushing episodes, or decrease in flushing severity [mild, moderate, severe] by ≥1 level) were assessed (post-hoc analyses).
Results: Fifty patients enrolled; 40 (80%) completed. All biomarkers decreased during LAN treatment (Table 1). There was a strong correlation between plasma and urinary 5HIAA (Spearman correlation coefficients ≥0.87 [P<0.001] at all timepoints). Correlation coefficients were ≥0.68 for plasma 5HIAA/CgA and ≥0.57 for plasma 5HIAA/NKA (P<0.0001 at all timepoints). Median (95% CI) reduction in plasma 5HIAA between baseline and EOS/early withdrawal was greater in LAN symptomatic responders (−91.5 [−159.0, −16.0] ng/ml, n=34) than non-responders (−9.0 [−267.0, 79.0] ng/ml, n=5), though small sample sizes preclude statistical conclusions.
|Median (95% CI) biomarker level|
|Baseline||Change from baseline to Week 4||Change from baseline to EOS/early withdrawal|
|Urinary 5HIAA (μmol/day)||121.7 (92.5, 196.9) [n=42]||−26.4 (−64.3, −9.9) [n=38]||−41.4 (−87.1, −15.5) [n=33]|
|Plasma 5HIAA (ng/ml)||425.0 (256.0, 507.0) [n=47]||−109.5 (−172.0, −54.0) [n=46]||−83.0 (−159.0, −38.0) [n=41]|
|CgA (×ULN)||3.9 (3.1, 5.5) [n=48]||−1.7 (−2.3, −1.0) [n=46]||−1.0 (−1.7, −0.2) [n=40]|
|Neurokinin A (pg/ml)||31.0 (23.0, 42.0) [n=47]||−5.0 (−10.0, −2.0) [n=44]||−7.0 (−14.0, −3.0) [n=39]|
Conclusions: All biomarker levels decreased during LAN treatment in patients with functional midgut NETs. The study provides preliminary evidence supporting plasma 5HIAA as a biomarker for assessing response to LAN, avoiding the need for 24-h urinary 5HIAA testing, which can be cumbersome and unreliable.
02 Dec 2019
UK and Ireland Neuroendocrine Tumour Society