Australasian Gastrointestinal Trials Group (AGITG) CONTROL NET Study: ¹⁷⁷Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) and capecitabine plus temozolomide (CAPTEM) for pancreas and midgut neuroendocrine tumours (pNETS, mNETS)—Final results.

Abstract

4122 Background: CAPTEM is an accepted regimen for patients (pts) with advanced pNETs. Single agent PRRT is now a standard of care for progressive WHO Grade 1/2 mNETs. High activity was seen with PRRT/CAPTEM in a single arm Phase I/II trial. This study aims to determine the activity of combining CAPTEM with PRRT in mNETs and pNETs pts. Methods: Non-comparative randomised open label parallel group phase II trial with 2:1 randomisation to PRRT/CAPTEM (experimental arm) vs. PRRT (mNETs control) and CAPTEM (pNETS control). PRRT/CAPTEM: 7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 10 every 8 weeks for 4 cycles, with concurrent oral capecitabine 750mg/m2 b.i.d. days 1-14 and temozolomide 75mg/m2 b.i.d. days 10-14 every 56 day cycle, up to 4 cycles. PRRT alone: 7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 1 every 8 weeks for 4 cycles. CAPTEM alone: Oral capecitabine 750mg/m2 b.i.d. days 1-14 and days 29-42; Oral temozolomide 75mg/m2 b.i.d. days 10-14 and 38-42 every 56 day (8w) cycle. Primary endpoint: Progression free survival (PFS). mNETS: At 15 months, assuming PFS 66.4% in control arm; target PFS ³ 80%; pNETS: At 12 months, assuming PFS 60% in control arm; target PFS ³ 75%. Secondary endpoints: Objective tumor response rate (complete or partial) (OTRR), overall survival (OS), adverse events (AEs). Results: 75 pts enrolled (Dec 2015 – Nov 2018): mNETs 33 PRRT/CAPTEM, 14 PRRT, median follow up (mFU) 60.3 months; pNETS 19 PRRT/CAPTEM, 9 CAPTEM, mFU 57.5 months (mo). Late Grade 3/4 haematologic AEs: mNETS: 2/32 (6%) PRRT/CAPTEM pts and 4/13 (31%) PRRT pts. Events included myelodysplastic syndrome (40 mo), leukaemia (60 mo), pancytopenia (50 mo), anaemia (32 mo), thrombocytopenia (7 mo). No late haematologic G3/4 AEs were reported in the pNETS cohort. No late renal toxicity was identified in all study arms. Conclusions: CONTROL NETs is the first randomized trial to demonstrate efficacy for PRRT in pNETs, in addition to a standard of care. Extended follow up confirms durable CAPTEM/PRRT activity, with superior PFS in pNETs. Late haematologic toxicity was seen in both mNET PRRT arms but was not higher with additional CAPTEM. The activity of CAPTEM/PRRT in pNETs should be tested in the phase III setting. Clinical trial information: ACTRN12615000909527. [Table: see text]

Chemotherapy in Well Differentiated Neuroendocrine Tumors (NET) G1, G2, and G3: A Narrative Review

“…TEM and CAPTEM can also be combined with PRRT to improve activity and cover the latency of PRRT effect onset [ 55 ]. Recently, the Australasian Gastrointestinal Trials Group (AGITG) CONTROL NET study, a randomized (2:1) phase II open-label trial of 177Lu-Octreotate PRRT in combination with CAPTEM, enrolled 28 patients with panNET: 19 were randomized to receive CAPTEM + PRRT, while 9 received CAPTEM alone [ 25 ]. At a median follow-up of 57.5 months, PFS rate at 27 months was higher in the CAPTEM + PRRT than in the CAPTEM arm (61.1% vs. 33.3%, respectively; HR: 0.41 [95% CI: 0.15—1.12]).…”

“…The ORR was 53%, including 15% complete responses, which was higher in patients with gastric or panNET (82%) as compared to those with siNET (26%) or lung NET (0%, the best response was stable disease in the two lung patients included). Furthermore, the AGITG CONTROL NET study randomized (2:1) patients affected by midgut NETs (N = 45) to receive PRRT + CAPTEM vs. PRRT alone in phase II randomized non-comparative trial [ 25 ]. ORR with the PRRT + CAPTEM combination was higher than with PRRT alone (34% vs. 23%); however, that did not translate into a PFS benefit (62% vs. 60% at 36 months).…”

Single-centre experience with peptide receptor radionuclide therapy for neuroendocrine tumours (NETs): results using a theranostic molecular imaging-guided approach

“…The NET MDT relies on strong morphological and functional imaging with both PET DOTATATE and FDG to guide appropriate treatment selection. The NET MDT also provides a platform for recruiting suitable subjects to clinical trials (such as CONTROL NETS-ACTRN 12615000909527 (Pavlakis et al 2022), which have the ability to generate high level clinical evidence. This evidence, in turn, feeds back into guidelines and clinical practice to give improved patient outcomes.…”

Integrating Functional Imaging and Molecular Profiling for Optimal Treatment Selection in Neuroendocrine Neoplasms (NEN)

“…Such a therapeutic strategy is under active investigation in the PARLuNET trial (NCT05053854), and NCT04086485. Patients with tumours driven by DNA repair defects might also plausibly benefit from a combination of radionuclide therapy and DNA-damaging agents used in the treatment of advanced NET including the antimetabolite capecitabine and the alkylating agent temozolomide [ 31 , 55 ].…”