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Rinke 2009 - PROMID Trial

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tagsneuroendocrine, net, rct, promid, somatostatin-analogue, octreotide

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Rinke 2009 — PROMID Trial

Citation: Rinke A, Müller HH, Schade-Brittinger C, et al; PROMID Study Group. Placebo- Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic Neuroendocrine Midgut Tumors: A Report From the PROMID Study Group. J Clin Oncol. 2009;27(28):4656-4663. doi:10.1200/JCO.2009.22.8510.

Study design

  • Randomised, double-blind, placebo-controlled, phase IIIB trial — 18 German academic centres. 85 patients randomised (42 octreotide LAR / 43 placebo), March 2001–January 2008; treatment-naive patients (median time since diagnosis only 4.3 months — an early-disease population, unlike CLARINET’s more heterogeneous cohort).
  • Population: locally inoperable or metastatic, well-differentiated midgut NET (or unknown-origin tumour believed midgut in origin), Karnofsky performance status >60%, no curative options. Functionally active (carcinoid syndrome, 39%) and inactive tumours both included. 95% had Ki-67 ≤2% (i.e., near-exclusively low-grade/grade-1 disease).
  • Intervention: octreotide LAR 30 mg IM every 28 days vs placebo, until tumour progression.
  • Primary endpoint: time to tumour progression (TTP). This report reflects a planned interim analysis (67 progressions, 16 deaths) — the trial stopped enrollment early given the clear positive effect and slow accrual, without reaching its originally planned 121-death survival analysis.

Key findings

  • Median TTP: 14.3 months (octreotide LAR) vs 6.0 months (placebo); HR 0.34 (95% CI 0.20–0.59); p=.000072 (conservative intent-to-treat analysis). Per-protocol analysis: HR 0.24 (0.13–0.45); p=.0000036.
  • Treatment effect similar in functionally active (HR 0.23) and inactive (HR 0.25) tumours.
  • Subgroup analysis suggested the most favourable effect in patients with low (≤10%) hepatic tumour burden and a resected primary tumour — per-protocol HR 0.16 for resected-primary patients vs 0.84 (i.e., near-null effect) for unresected-primary patients, a substantial interaction.
  • Overall survival: HR 0.81 (95% CI 0.30–2.18); p=.77 — not statistically significant. Only 16 deaths had occurred at the time of this interim analysis (7 octreotide, 9 placebo); the authors explicitly state survival analysis was not confirmatory given the low event count, and stopped further enrollment/analysis at this interim point rather than continuing to the planned 121-death survival endpoint.
  • WHO tumour response at 6 months: stable disease in 66.7% (octreotide) vs 37.2% (placebo).
  • Safety: no treatment-related deaths; GI and haematologic serious adverse events were the most common in both arms; bile stones recorded in 6 patients overall, 5 of them in the octreotide group.

Limitations

  • Small trial (85 patients), stopped early at a planned interim analysis — never reached its originally planned enrollment (162) or survival-analysis event target (121 deaths). The authors are explicit that the OS finding is not confirmatory.
  • Near-exclusively low-grade (Ki-67 ≤2%) population — does not address efficacy in higher-Ki-67 (grade 2, 3–10%) midgut NETs, a gap CLARINET was later designed to partly address (though CLARINET itself excluded pure midgut-only enrichment).
  • Extensive post-study crossover — most placebo-group patients received subsequent somatostatin analogue therapy after progression, further limiting any long-term survival inference from this trial alone.
  • Midgut-only population — does not speak to pancreatic or hindgut NETs (addressed later by CLARINET’s broader enteropancreatic population).

Relevance

Closes the primary-literature gap flagged in Small Bowel Neuroendocrine Tumors (NETs)‘s Open items for octreotide/PROMID — that page previously narratively summarized this trial via a textbook chapter without specific TTP figures. The precise numbers here (median TTP 14.3 vs 6.0 months; HR 0.34) should replace the previously unsourced qualitative statement. PROMID is the first placebo-controlled evidence for a somatostatin analogue’s antiproliferative (not just symptomatic) effect in NETs, and its narrow population (near-exclusively low-grade midgut disease) is explicitly why Caplin 2014 - CLARINET Trial’s authors designed CLARINET to test a broader enteropancreatic, higher-Ki-67 population — the two trials should be read as complementary rather than duplicative.

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