Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study

Abstract

Purpose: Evaluate the activity of everolimus (RAD001) in combination with octreotide long-acting repeatable (LAR) in patients with advanced low- to intermediate-grade neuroendocrine tumors.

Methods: Treatment consisted of RAD001 5 mg/d (30 patients) or 10 mg/d (30 patients) and octreotide LAR 30 mg every 28 days. Thirty carcinoid and 30 islet cell patients were enrolled.

Results: Intent-to-treat response rate was 20%. Per protocol, there were 13 with partial responses (22%), 42 with stable disease (SD; 70%), and five patients with progressive disease (8%). Overall median progression-free survival (PFS) was 60 weeks. Median PFS for patients with known SD at entry was longer than for those who had progressive disease (74 v 50 weeks; P < .01). Median overall survival has not been reached. One-, 2-, and 3-year survival rates were 83%, 81%, and 78%, respectively. Among 37 patients with elevated chromogranin A, 26 (70%) achieved normalization or more than 50% reduction. Most common toxicity was mild aphthous ulceration. Grade 3/4 toxicities occurring in >or= 10% of patients included hypophosphatemia (11%), fatigue (11%), and diarrhea (11%). Treatment was associated with a dose-dependent rise in lactate dehydrogenase (LDH). Those with lower than 109 U/L rise in LDH at week 4 had shorter PFS (38 v 69 weeks; P = .01). Treatment was also associated with a decrease in proliferation marker Ki-67 among patients who underwent optional paired pre- and post-treatment biopsy (P = .04).

Conclusion: RAD001 at 5 or 10 mg/d was well tolerated in combination with octreotide LAR, with promising antitumor activity. Confirmatory studies are ongoing.

Fig 1.

Serial tumor measurements. Percentage change in the sum of target lesion diameters by course for (A) all patients and (C) for those in the 5-mg and (D) 10-mg cohorts. (B) The percentage change as the best response in each patient is shown as a waterfall plot. Maximum tumor reduction was achieved after several courses of therapy in many patients. BL, baseline.

Fig 2.

Kaplan-Meier analysis of progression-free survival (PFS). (A) For all 60 patients, 6- and 12-month PFS rates were 80% and 59%. (B) PFS by disease subgroups. Six- and 12-month PFS rates were 86% and 69% for the carcinod group, and were 73% and 48% for the islet cell group (P = .46). (C) PFS by dose group. Six- and 12-month PFS rates were 68% and 46% for the 5-mg group and were 90% and 70% for 10-mg group (P = .19). (D) PFS by disease status at entry. Six- and 12-month PFS rates were 68% and 49% for those with progressive (n = 39) and were 100% and 81% for those with stable disease (n = 16) at study entry (P = .01). RAD001, everolimus.

Fig 3.

(A) Changes in mean (± standard deviation) plasma lactate dehydrogenase (LDH) levels during treatment for the 5-mg and 10-mg dose groups. (B) Kaplan-Meier analysis of progression-free survival (PFS) for patients in the lowest (< 109 U/L) and higher three quartiles (≥ 109 U/L) for changes in plasma LDH levels during treatment. Patients in the higher three quartiles had a significantly longer PFS than the 25% with the lowest increases in plasma LDH during treatment (P = .01). RAD001, everolimus.

Fig 4.

Changes in Ki-67 measurements. Patients consenting to optional biopsy had prospective sampling of metastases by image guided core needle biopsy at baseline and week 2. Mean tumor Ki-67 decreased from 6.7% (± 2.6) to 2.1% (± 0.5). The decrease was statistically significant (P = .04) by Wilcoxon signed rank test. PFS, progression-free survival, PD, progressive disease; SD, stable disease.