Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice

Neuroendocrine tumour (NET) heterogeneity poses significant challenges for management [1]. Recommended treatment options frequently target one specific pathway, often resulting in eventual escape from treatment response, such that subsequent treatment lines must address even more heterogeneous clones [2, 3]. This highlights the need for new strategies that combine drugs with different mechanisms. Somatostatin analogues (SSAs) are considered first-line systemic medical therapy by the European Neuroendocrine Tumor Society (ENETS) and in the National Comprehensive Cancer Network (NCCN) guidelines [4‐6] and are an established anti-tumour therapy for advanced locoregional disease and/or distant metastatic gastroenteropancreatic (GEP)- and lung-NETs. They target somatostatin receptors (SSTR) on NETs, exerting their anti-tumour effect through several pathways and ultimately leading to tumour-cell apoptosis [7]. Peptide receptor radionuclide therapy (PRRT), an established treatment for well-differentiated metastatic NETs, also uses SSTR overexpression on NETs to deliver a high radiation dose using an SSA radiolabelled with a β-particle-emitting radioisotope [6]. PRRT delays progression of metastatic NETs and controls hormonal symptoms in functional NETs [8‐10]. It is recommended by ENETS for grade 1/2 midgut NETs following medical therapy failure [5] and by the NCCN for progressive NETs following SSA therapy failure [6], and is being considered for lung-NETs that strongly express SSTRs [4, 5].

Anti-tumour benefits of combined PRRT–SSA therapy in patients with midgut NETs progressing under octreotide LAR (30 mg) were demonstrated in the NETTER-1 study [8]. Combination of ¹⁷⁷Lu-DOTATATE and octreotide LAR (30 mg) resulted in longer progression-free survival (PFS) and higher response rate, versus high-dose octreotide LAR monotherapy (60 mg). Consequently, ¹⁷⁷Lu-DOTATATE was approved in Europe and the USA for SSTR-positive GEP-NETs [11, 12]. Data from ERASMUS, which examined the effects of ¹⁷⁷Lu-DOTATATE in patients with bronchial or GEP-NETs [13, 14], extended the indication to include other NETs.

In the large randomised placebo-controlled CLARINET study, lanreotide autogel/depot (LAN) demonstrated anti-tumour benefits in patients with metastatic GEP-NETs and predominantly stable disease (SD) [15]. Similar benefits were observed in patients with progressive GEP-NETs in the CLARINET open-label extension and in a single-arm, open-label study [16, 17]. However, no data were available on the efficacy and safety of combined PRRT–LAN. The aim of the PRELUDE (Peptide REceptor radionuclide therapy in combination with Lanreotide aUtogel/depot in progressive Digestive and bronchopulmonary nEuroendocrine tumours) study was therefore to describe the use and investigate the effectiveness and safety of LAN combined with ¹⁷⁷Lu-DOTATOC or ¹⁷⁷Lu-DOTATATE in patients with progressive GEP- and lung-NETs. Also, at the time of study design, there were no data reporting the effects of SSA combined with, or for maintenance after, PRRT in a broader NET population (NETTER-1 recruited only patients with midgut NETs). Thus, there was a need to determine how LAN–PRRT was used in clinical practice (e.g. in which tumours, at what stage, at what doses/dosing intervals) and whether the combination treatment was beneficial. In addition, recognising the limitations of response evaluation criteria in solid tumours (RECIST) as a tool for assessing response to PRRT in slow-growing NETs, we performed a post-hoc analysis of tumour growth rate (TGR) measured using computed tomography (CT) or magnetic resonance imaging (MRI) to further assess the putative anti-tumour benefits of PRRT–LAN.

The PRELUDE study aimed to describe the effectiveness of LAN combined with PRRT (LAN–PRRT) and as post-PRRT maintenance therapy in patients with progressive GEP- or lung-NETs. However, there was a major recruitment shortfall; only 40 patients were enrolled: 39 with GEP-NETs and one with lung-NETs. This reflects the challenges of conducting a retrospective study in a rare-disease setting, patients’ follow-up period occurring after the time of the analysis, and the strict inclusion/exclusion criteria, which many patients did not meet. In addition, CT/MRI scans were not always obtainable (e.g. retained by patients at home). Despite the recruitment shortfall, effectiveness data in the selected population with GEP-NETs were encouraging. High PFS rates were observed at the end of the last LAN–PRRT cycle (91.7%) and at last available follow-up, 12 months post-treatment (95.0%). Diarrhoea and flushing remained stable or were improved in most patients. Few toxicities were reported, and no new safety issues were identified, indicating that LAN–PRRT combination regimen had an acceptable safety/tolerability profile. These data add to the growing body of evidence supporting the use of SSA–PRRT in NETs, from the NETTER-1 study (n = 229) [8] and retrospective analysis conducted by Yordanova et al., which assessed ¹⁷⁷Lu-octreotate plus octreotide LAR (median dose: 30 mg) or LAN (median dose: 120 mg) versus ¹⁷⁷Lu-octreotate alone in 168 patients with GEP-NETs [21]. In these studies, there were significant improvements in PFS and response rates for SSA–PRRT compared with SSA alone [8] and PRRT alone [21]. However, it should be noted that certain aspects of the Yordanova study limit interpretation of the findings. For example, the authors used adapted WHO response criteria that have not been established for PRRT; as well as partial and complete responders, patients with SD and minimal response were also included in the clinical benefit rate and ORR, respectively; there were no detailed descriptions of PRRT cycle and SSA dose interval and no explanation regarding why some patients received SSAs whilst others did not [21]. PRELUDE also builds on the findings from the Yordanova study, by describing for the first time ORR (rather than best OR) at different time points (rather than at a single time point).

PRRT is a low-dose-rate irradiation intended to slow or stop tumour progression. Slower-growing tumours are significantly more likely to remain stable or shrink post-irradiation, suggesting that pre-treatment TGR may be predictive of the tumour response to PRRT [22, 23]. Indeed, post-hoc TGR analyses suggested tumour regression in some patients before, during and after LAN–PRRT and that ORR during or after LAN–PRRT was more likely if baseline TGR was ≤ 1.18%/month and ≤ 0.33%/month, respectively. Despite the initial TGR of 0% between pre-baseline and baseline in our study, a PR was still achieved in more than 30% of patients. However, these results should be interpreted with caution as TGR measurements were based on two target tumours in most patients; in the GREPONET study, which evaluated the value of TGR as a biomarker of outcome in 222 patients with NETs, the accuracy of TGR as a prognostic factor was found to be superior if four target lesions were used for TGR calculation [24]. Nevertheless, these findings suggest that the population enrolled into PRELUDE (i.e. patients with slowly progressing disease) are probably the best candidates for LAN − PRRT. It remains to be seen if TGR provides additional predictive benefit to other proposed and somewhat established parameters like the intensity of uptake and burden of disease [25].

Our findings that diarrhoea and flushing were stable or improved with LAN–PRRT agree with the symptomatic improvements reported following ⁹⁰Y-edotreotide therapy in patients with carcinoid syndrome (CS) refractory to SSAs, and the known effectiveness of LAN for controlling CS symptoms [10, 26]. The clinical responses for diarrhoea and flushing continued to improve during treatment with LAN and during the follow-up period supporting the notion of maintenance therapy with LAN following PRRT. The adverse events reported were also consistent with published data on the use of PRRT [8, 27‐29]. Most patients (52.2%) in the GEP-NET FAS group received a LAN dosage of 120 mg every 28 days. Across all cycles, 17 to 25% of patients in the FAS received a LAN dose < 120 mg, and 20 to 27% received LAN injections greater than 28 days apart. The reasons for the use of doses lower than 120 mg every 28 days were not recorded but might reflect caution on the part of clinicians when using LAN in combination with PRRT. Indeed, a much higher percentage of patients were prescribed 120 mg every 28 days during the follow-up period when patients were treated with LAN only. As there was no increase in reported adverse drug reactions compared with LAN-only treatment, we observe that LAN–PRRT had an acceptable safety/tolerability profile.

The study was associated with several limitations but nevertheless provides important learnings related to the management of NETs in clinical practice and the conduct of future clinical trials. One limitation of the current study was the assessments used. At baseline, most patients for whom data were available did not have confirmed PD (according to RECIST v1.1) when centrally assessed, despite this being an inclusion criterion, demonstrating a discrepancy between local and central assessment. This indicates that RECIST might not be used routinely in clinical practice; instead clinicians may evaluate other scan characteristics (e.g. tumour growth or volume of multiple lesions). In addition, the reason for initiating PRRT treatment may also relate to patients’ biological, physical or general condition. In the current study, over 80% of patients were symptomatic at baseline, which may have influenced investigators’ decisions to initiate a treatment with PRRT. Limitations associated with size-based evaluations (such as RECIST) are also recognised as they may underestimate the response to some treatments [30]. Additionally, the CgA results were limited by poor assay accuracy (high false-positive and false-negative rates) and large variability (as reported previously [31]); therefore, very little can be deduced from these findings. Encouragingly, since PRELUDE was initiated, several improvements in this therapy area have been made, with the NCCN updating its guidelines to align future studies in this field [6]. Use of ¹⁷⁷Lu-DOTATATE has now been approved in Europe for adults with unresectable or metastatic, progressive, well-differentiated SSTR-positive GEP-NETs, providing clinicians with a clear posology and treatment schedule for PRRT [12].

Inherent limitations associated with retrospective studies, such as an increased risk for selection bias, necessarily apply to PRELUDE. In addition, there may have been under-reporting of treatment-related toxicities, AEs and other safety issues due to the retrospective nature of the study. However, PRELUDE was the first and only international multicentre retrospective study to use central assessment to measure PFS in a highly homogenous patient population receiving LAN–PRRT. Other limitations relate to the strict inclusion/exclusion criteria. In some cases, different combinations of PRRT (e.g. ⁹⁰Y-DOTATATE and ¹⁷⁷Lu-DOTATATE) or different doses of ¹⁷⁷Lu-DOTATATE had been used, which was reflective of real practice. Patients in whom total cumulative activity of ¹⁷⁷Lu was less than 500 mCi (18.5 GBq) also had to be excluded. In some geographies, SPECT and PET imaging had been routinely used to assess NET progression, rather than CT/MRI. Together, these findings highlight substantial differences across the community in terms of use and follow-up of non-approved treatments (LAN and PRRT in both combination and maintenance) and the lack of standardisation in nuclear medicine. The study may have been affected by ‘survivor bias’; data from deceased patients were less likely to be included because in some countries (Germany, France, UK), data collection was not allowed, investigators were reluctant to approach families to obtain consent to use the data, or authorities requested some rationale to do so. Furthermore, it was not always possible to obtain scans if results had been lost or sent to relatives.

At the time of the study, PRRT was not approved in this patient population and guidelines for practises and availability of PRRT, and standardisation of PRRT protocols were limited. Performing a retrospective study thus posed a major challenge. A lack of data sharing between centres meant diverse methods were adopted, leading to marked variability in results between centres. Disparities also arose owing to the use of PET and CT imaging and different acquisition protocols, leading to the realisation that there was no consensus on the timing for imaging assessment, imaging methods, or on how to manage the collection of CT/MRI scans. Differences in tumour assessment techniques also further limited the study. These results highlight a real need for standardisation of PRRT procedures in clinical practice.

Despite these limitations and the low number of patients enrolled, findings from PRELUDE remain robust and resonate with those reported in other studies. The low number of patients with bone metastases at baseline in this study, together with high PFS rate, concords with reported estimates of only 8 to 19% of bone metastases being associated with GEP-NETs [32‐35], and that the absence of bone metastases is associated with a longer time to progression in patients receiving PRRT [36].

In conclusion, PRELUDE provides important information for clinicians managing patients with NETs, suggesting that LAN may be effective before, during and after PRRT in patients with metastatic or locally advanced GEP-NETs. Results of the post-hoc analyses also highlight the potential role of baseline TGR to assess and predict response to LAN–PRRT. The strict inclusion criteria in PRELUDE and use of central radiological assessment to measure PFS and ORR increased the robustness of these findings. Conducting such retrospective studies in the absence of standardised or approved treatment protocols is challenging but can provide important insights into how clinical practice and future study designs can be improved. As such, a prospective study of LAN–PRRT in a larger population of patients with GEP and lung NETs, using a standardised treatment protocol, is warranted.