Tumor shrinkage with lanreotide Autogel 120 mg as primary therapy in acromegaly: results of a prospective multicenter clinical trial

Abstract

Context: Methodological shortcomings often compromise investigations into the effects of primary somatostatin-analog treatment on tumor size in acromegaly. There are also limited data for the long-acting lanreotide formulation.

Objective: The aim of the study was to better characterize the effects of primary lanreotide Autogel treatment on tumor size in patients with GH-secreting macroadenomas.

Design: PRIMARYS was a 48-week, multicenter, open-label, single-arm study.

Setting: The study was conducted at specialist endocrine centers.

Patients: Treatment-naïve acromegalic patients with GH-secreting macroadenomas participated in the study.

Intervention: Lanreotide Autogel 120 mg was administered sc every 28 days (without dose titration).

Outcome measures: The primary endpoint was the proportion of patients with clinically significant (≥20%) tumor volume reduction (TVR) at week 48/last post-baseline value available using central assessments from three readers. The null hypothesis (H0) for the primary endpoint was that the proportion with TVR was ≤55%. Secondary endpoints included: TVR at other time points, GH and IGF-1, acromegalic symptoms, quality of life (QoL), and safety.

Results: Sixty-four of 90 (71.1%) patients completed the study. Clinically significant TVR at 48 weeks/last post-baseline value available was achieved by 62.9% (95% confidence interval, 52.0, 72.9) of 89 patients in the primary analysis (intention-to-treat population; H0 not rejected) and 71.9-75.3% in sensitivity (n = 89) and secondary analyses (n = 63) (H0 rejected). At 12 weeks, 54.1% had clinically significant TVR. Early and sustained improvements also occurred in GH and IGF-1, acromegalic symptoms, and QoL. No patients withdrew due to gastrointestinal intolerance.

Conclusions: Primary treatment with lanreotide Autogel, administered at 120 mg (highest available dose) without dose titration, in patients with GH-secreting macroadenomas provides early and sustained reductions in tumor volume, GH and IGF-1, and acromegalic symptoms, and improves QoL.

Trial registration: ClinicalTrials.gov NCT00690898.

Figure 1.

Prespecified methodology used to ensure consistent and unbiased evaluations of tumor volume. *, Reader defined the regions of interest on images of the first and final slices of the tumor, with Life Rx software determining regions of interest on images of intervening slices. Details of how the SSRs were calculated are reported in the Supplemental Data.

Figure 2.

Flow of patients through the study. *, IGF-1 levels decreased by < 10% at week 24 vs baseline (as defined in the protocol) or investigator's judgment of insufficient response; †, patient not able to attend due to mobility issues; §, one patient had two major protocol violations.

Figure 3.

Reductions in tumor volume. A, Analyses of the proportions of patients with ≥ 20% reduction in tumor volume from baseline to week 48/LVA (primary endpoint; ITT and PP populations). B, Tumor volume reductions for individual patients (ITT population). C, Time course of changes in tumor volume reductions (ITT population) with an illustrative MRI series from one patient. The four patients with greatest increases in tumor volumes (all based on LVA measurements) in panel B had IGF-1 changes ranging from +9.8% to −40.9%. The patient with the greatest increase in tumor volume (33.1%) discontinued in the study at week 24 after discussions about the increase with the investigator. *, Primary analysis based on highest SSR; †, proportions and 95% CIs for each reader dataset were compared with the predetermined threshold of 55%; §, data are from week 48 or LVA.

Figure 4.

Proportions of patients reaching biochemical targets for GH and IGF-1 levels (secondary endpoints, ITT populations). *, The proportions of patients reaching the GH and IGF-1 combined endpoints were the same for the PP population. Normalized IGF-1 defined as IGF-1 levels within age- and sex-matched normal ranges.