Treatment of advanced BP-NETS with lanreotide autogel/depot vs placebo: the phase III SPINET study

Abstract

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients' quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.

Keywords: atypical carcinoid; bronchopulmonary neuroendocrine tumors; somatostatin analog; typical carcinoid.

Figure 1

Patient disposition. Data from the OLFU phase are not reported in this article; the group comprised 19 patients who transitioned from the DB phase (as noted in the figure above) and one patient from the LAN (NPD)–LAN group who entered OLFU from the OLT phase. ^aAll 22 patients transitioned to the OLT phase after protocol amendment #5. DB, double-blind; LAN, lanreotide autogel/depot; NPD, no progressive disease; OLFU, open-label follow-up; OLT, open-label treatment; PBO, placebo; PD, progressive disease; R, randomization.

Figure 2

Centrally assessed (RECIST v1.1) progression-free survival (ITT population). (A) During double-blind or open-label treatment phase in patients randomly assigned to LAN (overall patient population). (B) During the double-blind or open-label treatment phase in patients randomly assigned to LAN (by tumor subtype). (C) During the double-blind phase in patients randomly assigned to LAN or placebo (overall patient population). (D) During the double-blind phase in patients randomly assigned to LAN or placebo (in patients with typical carcinoids). (E) During the double-blind phase in patients randomly assigned to LAN or placebo (in patients with atypical carcinoids). Data from patients who did not die and did not have confirmed disease progression were censored on the date of the last radiological assessment at which the target lesions were evaluated by central review. ^aOne patient was excluded from the analysis because their data were censored at baseline (because the baseline assessment was prior to randomization, this would have yielded a negative PFS). PFS in months was calculated as follows: (date of event – date of randomization) / 30.4375. AC, atypical carcinoid; HR, hazard ratio; ITT, intention-to-treat; LAN, lanreotide autogel/depot; NC, not calculable; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TC, typical carcinoid.

Figure 3

Time to treatment failure during the double-blind phase (ITT population). TTF was defined as the time from randomization to: documented central or local PD (defined as the minimum time to event according to central/local review using RECIST v1.1); treatment discontinuation for undocumented disease progression; treatment discontinuation for toxicity or any other reason; start of new anticancer treatment; withdrawal of consent; an AE; a protocol deviation; loss to follow-up; appearance of carcinoid syndrome or other hormone-related syndrome necessitating the initiation of SSAs (rescue octreotide and/or long-acting release SSA); death between adequate assessment visits; death before first PD assessment; prohibited medication/therapy or unblinded event. TTF in months was calculated as follows: (date of event − date of randomization)/30.4375. AE, adverse event; HR, hazard ratio; ITT, intention-to-treat; LAN, lanreotide autogel/depot; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; SSA, somatostatin analog; TTF, time to treatment failure.