Treatment Sequencing Strategies in Advanced Neuroendocrine Tumors: A Review

Simple Summary Neuroendocrine tumors (NETs) have become increasingly common. There are several effective treatment options for advanced NETs. However, there are limited clinical trial data and published practical information on how these different treatments should be sequenced. This review assesses randomized, controlled clinical trial data in advanced NETs to provide an expert perspective on treatment sequencing for important clinical scenarios, ranging from local disease to high-volume metastatic NETs. The best practices provided in this review may be useful for clinicians considering treatment options and sequencing for their patients with advanced NETs. Abstract Neuroendocrine tumor (NET) incidence has grown. The treatment landscape for advanced NETs is rapidly evolving, but there are limited head-to-head data to guide treatment sequencing decisions. We assessed the available clinical data to aid practicing clinicians in their routine clinical decision-making. Clinical trials have demonstrated efficacy benefits for new therapies in advanced NETs. Emerging long-term data from these trials have enabled clinicians to make more accurate risk-benefit assessments, particularly for patients receiving multiple lines of therapy. However, clinical data specifically regarding treatment sequencing are limited. In lieu of definitive data, treatment sequencing should be based on disease-related factors (e.g., site of tumor origin, volume of disease) and patient-related characteristics (e.g., comorbidities, patient preferences). Clinical decision-making in advanced NETs remains highly individualized and complex; important evidence gaps regarding treatment sequencing remain. Given this, advanced NET management should be a joint effort of multidisciplinary teams at referring and high-volume centers. Additional clinical trial and real-world evidence are needed to meet the challenge of understanding how to sequence available NET therapies. Until these trials are conducted, the best practices provided in this review may serve as a guide for clinicians making treatment sequencing decisions based on the available data.


Introduction
Neuroendocrine tumors (NETs) are rare and heterogenous neoplasms with continued rising incidence [1,2]. The indolent nature of most NETs has led to high prevalence with over 170,000 patients with NETs estimated in the United States, making NETs the second most common neoplasms of gastrointestinal origin [1,3].
We review the pertinent clinical trial data of patients with advanced NETs to guide clinical decision-making and treatment sequencing.
We review the pertinent clinical trial data of patients with advanced NETs to guide clinical decision-making and treatment sequencing.

Materials and Methods
This review focuses on the management of well-differentiated advanced GEP-NETs and typical/atypical pulmonary carcinoid tumors [21,22]. Poorly differentiated neuroendocrine carcinoma, including small-cell and large-cell neuroendocrine carcinoma, were tumor types considered out of scope for this review. Medline (via PubMed) was searched for articles indexed as randomized clinical trials and their associated secondary analyses, containing the following terms: octreotide long-acting release, lanreotide, everolimus, sunitinib, 177 Lu-DOTATATE, and cytotoxic chemotherapy. Included data pertain only to eight randomized, double-blind, controlled Phase III trials (PROMID [6], CLARINET [7], SUNNET [8], RADIANT-2 [23], RADIANT-3 [9], RADIANT-4 [10], NETTER-1 [11], and SPINET [24]) along with one randomized Phase II trial that has changed standard of care over the last 5 years (ECOG E2211) [19]. Streptozocin-based regimens [25,26] are not cited as preferred regimens in clinical guidelines and thus not reviewed herein. Telotristat ethyl, an approved treatment for carcinoid syndrome diarrhea management in SSA-refractory patients based on the TELESTAR study, is also not reviewed herein as it is a symptom management drug rather than an antitumor agent.
as preferred regimens in clinical guidelines and thus not reviewed herein. Telotrista ethyl, an approved treatment for carcinoid syndrome diarrhea management in SSA-re fractory patients based on the TELESTAR study, is also not reviewed herein as it is symptom management drug rather than an antitumor agent.

Efficacy
Direct comparison between the trials is not possible because of variations in patient selection and study methodology. For instance, regarding the interventions, SUNNET patients could receive SSAs at the investigator's discretion [8], RADIANT-2 patients received IM octreotide concomitant with their randomized treatment [23], and NETTER-1 patients on 177 Lu-DOTATATE also received IM octreotide [11].
The remaining two trials, RADIANT-2 and SPINET, did not show statistically significant PFS benefits for the interventional arm. In the RADIANT-2 study of patients with advanced NETs associated with carcinoid syndrome, the combination of everolimus plus octreotide prolonged PFS versus octreotide alone, but the study primary endpoint was not met as the p value narrowly missed the prespecified boundary denoting statistical significance [23]. Nevertheless, the finding provided an initial indication of the potential PFS benefit of everolimus in patients with advanced NETs, which was subsequently confirmed in the RADIANT-3 study of patients with pNETs [9] and RADIANT-4 study of patients with nonfunctional GI or lung NETs [10]. The SPINET study (lanreotide vs. placebo) was unique by enrolling patients with somatostatin receptor-positive typical and atypical carcinoid lung NETs [24]. Enrollment was stopped early because of slow accrual, and patients without centrally assessed progression during the double-blind phase transitioned to open-label lanreotide [24]. The primary endpoint was also adapted to centrally assessed PFS during the double-blind and open-label lanreotide phases in patients initially randomized to lanreotide [24]. Median PFS was 16.6 (95% CI, 12.8-21.9) months in the lanreotide randomized group and appeared longer in the subgroup of patients with typical carcinoid lung NETs (21.9 months, 95% CI, 12.8-not calculable) than atypical carcinoid lung NETs (14.1 months, 95% CI, 5.6-16.6) [24]. In the double-blind phase, median PFS for lanreotide and placebo, respectively, was 16.6 versus 13.6 months (HR, 0.90; p = 0.769) in the entire population, 21.9 versus 13.9 months in the subgroup with typical carcinoid lung NETs, and 13.8 versus 11.0 months in the subgroup with atypical carcinoid lung NETs [24].
Per protocol exploratory analysis of PROMID [6], CLARINET [7,31], RADIANT-3 [9], RADIANT-4 [10], and NETTER-1 [11] revealed that the extended time to tumor progression or PFS in favor of the interventional arm relative to the control arm occurred irrespective of randomization stratification factors, and predefined demographic and prognostic factors.
Extensive follow-up is required to demonstrate significant gains in overall survival (OS) owing to the often indolent nature of advanced NETs. In five (PROMID [29], SUN-NET [27], RADIANT-2 [32], RADIANT-3 [28], and NETTER-1 [30]) of the nine randomized controlled Phase III trials, final OS (observed all-cause) was reported long after the cutoff date for the primary efficacy analysis, during which time multiple factors can have an influence on mortality. One of these factors is in-trial treatment crossover and post-protocol drug therapy, which affects between-group differences in OS. None of the active treatments in these five trials produced a statistically significant prolongation of OS at the time of the most recent analysis although clinically meaningful differences in median OS were observed in the SUNNET and NETTER-1 studies (Table 1).
Objective response rate was a secondary efficacy endpoint in the clinical trials. This measure is less useful than PFS for population-based treatment decision-making, given the low frequency and small range of responses observed, but measuring treatment response does have utility on an individual basis. Of the seven trials showing a benefit in time to tumor progression [6] or PFS [7][8][9][10][11]19] and reporting response data, objective response rates were lower with SSAs and everolimus (range, 2-5%) than with sunitinib (9%) [8], 177 Lu-DOTATATE (18%) [11], or CAPTEM (33%) [19].

Safety
Both short-and long-term safety data are required for clinicians to make more accurate risk assessments when selecting initial and subsequent therapies for advanced NETs. Adverse events (AEs) associated with each therapy over long-term use were entirely consistent with those emanating from the primary clinical trials and no new safety signals were detected during follow-up (Table 2). There was asymmetry in the duration of time when AEs were collected in the primary clinical trials, due to the efficacy of the active interventions. The clinical trial safety data were not adjusted for time on treatment, which should be considered when interpreting AE incidence data.  In SUNNET, patients received sunitinib and placebo for a median duration of 4.6 months and 3.7 months, respectively [8]. The mean relative dose intensity (i.e., the ratio of administered doses to planned doses) was 91% in the sunitinib arm and 101% in the placebo arm. At least one dose interruption was reported more often in the sunitinib arm than in the placebo arm (30% vs. 12%), primarily because of AEs [8]. Grade ≥ 3 AEs occurring more frequently with sunitinib than placebo included diarrhea (5% vs. 2%), neutropenia (12% vs. 0%), hypertension (10% vs. 1%), stomatitis (4% vs. 0%), and thrombocytopenia (4% vs. 0%), although incidence of serious AEs was lower in the sunitinib arm (26.5% vs. 41.5%) [8].
The potential for acute, subacute, and long-term AEs with 177 Lu-DOTATATE was characterized in the NETTER-1 study, which encompassed 5 years of patient follow up [11,30]. In the primary study, 77% of patients in the 177 Lu-DOTATATE arm received all four infusions of 177 Lu-DOTATATE, with 7% requiring a dose reduction. A numerically smaller proportion of patients in the 177 Lu-DOTATATE arm than control arm had AEs resulting in premature withdrawal (6% vs. 9%) [11]. Transient grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177 Lu-DOTATATE arm versus no patients in the control group [11]. During long-term follow up, the incidence of treatment-related serious AEs was 3% with none of these events occurring after the 5-year safety analysis cutoff [30]. Secondary hematologic malignancies and nephrotoxicity are AEs of interest for 177 Lu-DOTATATE. Although two of 111 patients (1.8%) in the 177 Lu-DOTATATE arm developed myelodysplastic syndrome, no patients developed myelodysplastic syndrome or acute myeloid leukemia during long-term follow-up [30]. Continued 177 Lu-DOTATATE pharmacovigilance during real-world use is required to provide more clarity on the potential for myelodysplastic syndrome and acute myeloid leukemia, especially with respect to 177 Lu-DOTATATE dose level, dose timing, and retreatment. There was no evidence of long-term nephrotoxicity in NETTER-1 [30].

Health-Related Quality of Life
Patient-reported outcome (PRO) data can reveal if the overall efficacy and safety profiles of therapy reflect patient experience and perceptions. The main PRO instrument used in PROMID [6], SUNNET [8], CLARINET [7], NETTER-1 [11], and SPINET [24] was the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and that in RADIANT-4 was the Functional Assessment of Cancer Therapy-General (FACT-G) [10]. PRO data were not reported in RADIANT-3 [9].
Only the efficacy and safety of 177 Lu-DOTATATE (in NETTER-1) translated into demonstrable improvement in health-related quality of life (HRQoL), as evidenced by a substantially longer time to clinically meaningful deterioration in EORTC QLQ-C30 scores vs. high-dose octreotide LAR [43]. Octreotide LAR, lanreotide, sunitinib, and everolimus did not show statistically significant improvement or worsening relative to placebo on the EORTC QLQ-C30 or FACT-G (except for worsening of diarrhea with sunitinib), indicating that HRQoL is maintained in these patients to a certain extent [6][7][8]44].

Translating Clinical Research into Therapeutic Strategy
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) and North American Neuroendocrine Tumor Society guidelines for advanced NETs recommend use of SSAs as first-line systemic therapy followed by targeted therapy (everolimus or sunitinib), 177 Lu-DOTATATE, or chemotherapy as later-line options depending on tumor type, grade, SSTR expression, distribution, and bulk of disease [5,13]. There are no robust categorized levels of evidence on optimal treatment strategies (i.e., order of administration, number of cycles, efficacy of combinations, and switching criteria) for scenarios often encountered in clinical practice. Currently available clinical data on treatment sequencing are restricted to a small number of retrospective studies [45].
Given the complexity of clinical decision-making under uncertainty and lack of clinical trial data, patients with advanced NETs should be referred to high-volume treatment centers. Treatment decisions should be joint efforts by the referring and high-volume treatment center and conducted by a multidisciplinary team (including the referring medical oncologist) that determines the patients' initial treatment plan and any required changes to this plan when disease control is in jeopardy. The treatment plan should be based on disease-related factors and patient-related characteristics, such as comorbidities and patient preferences. How these factors and clinical trial data may guide treatment sequencing decisions in commonly encountered disease scenarios are summarized in Table 3. In real-world clinical practice, treatment decisions are highly individualized, but the best practices given in Table 3 can serve as useful starting points in clinical decision-making. Table 3. Author opinion on treatment sequencing in advanced NETs.

Scenario Multidisciplinary Perspective on Treatment Challenges and Considerations
Asymptomatic, liver metastasis a Grade 1 disease: Asymptomatic patients (especially with low bulk disease) can be safely observed with interval scans for tumor growth rate, and systemic therapy can be instituted at the time of progression; multidisciplinary team review can help determine if resection is a treatment option to cure the disease or prolong OS/PFS [46]; Grade ≥ 2 disease: Consider initiation of SSAs (especially when Ki67 > 10%) after informed discussion with the patient Frequency and timing of interval scans are not standardized; however, it is reasonable to get cross-sectional imaging every 3-6 months; Determination of the optimal time to start SSAs must be based on volume of disease, disease stability, and patient preference as it is difficult to discontinue these agents once started High-volume and/or symptomatic liver-dominant disease Discuss treatment options in a multidisciplinary setting; Based on the volume of disease, consider local therapy with surgical resection and/or liver-directed therapy (embolic therapy preferred); transplant is also an option Often, systemic treatment, especially with SSAs, can be considered in addition to local therapy in bulky disease Transplant criteria are very selective and are likely only applicable to the occasional patient Local and loco-regional disease (site agnostic) a Curative intent surgery in surgical candidates; For nonoperative candidates, the algorithm for metastatic disease can be followed Bronchial NETs a SSAs are the preferred front-line treatment for metastatic progressive SSTR+ bronchial NETs; Everolimus is an excellent second-line therapy based on RADIANT-4 data [10]. RLT can be considered in SSTR+ bronchial NETs refractory to SSAs CAPTEM can be considered in bronchial NETs refractory to standard treatment, especially atypical NETs and SSTR negative bronchial NETs [47]; Observation may be considered in certain patients (e.g., scattered lung nodules that are stable); Participation in relevant clinical trials is highly encouraged Treatment is dependent on several factors including burden of SSTR+ disease and whether there is an immediate need for response; Role of Ki-67 for bronchial NETs is controversial; The ALLIANCE trial (NCT04665739) will determine if everolimus or 177 Lu-DOTATATE is preferred DOTATATE/DOTATOC PET-CT imaging is strongly preferred to assess SSTR+ bronchial NETs (over 111 In-pentetreotide scintigraphy due to significant lower sensitivity, particularly in bronchial NETs) Low-volume or asymptomatic bronchial NETs Consider observation first; If treatment is desired, consider local therapy (SBRT) and SSAs High-volume and symptomatic bronchial NETs 177 Lu-DOTATATE preferred in SSTR+ patients. Everolimus can also be considered; CAPTEM should be reserved for very symptomatic patients requiring a rapid response, especially higher-grade tumors (atypical carcinoid) Although the role of Ki-67 scores for bronchial NETs is controversial, consider obtaining a score for patients with aggressive disease; The factors influencing the decision of when and when not to use platinum-based chemotherapy (e.g., based on Ki-67 score) are not well defined; Data are emerging for ipilimumab/nivolumab in this setting and can be an option in the refractory setting Low-volume and asymptomatic pNETs a Therapy should be based on safety and efficacy data. A therapy associated with a high ORR is not a priority. Therefore, consider SSA > everolimus, sunitinib, or 177 Lu-DOTATATE > CAPTEM as a possible rank order of therapies There is a lack of consensus on optimal treatment sequencing in this setting. Patient preference is an especially important consideration in this scenario given the lack of comparative efficacy/safety data pNETs progressing despite SSA therapy Consider everolimus, sunitinib, 177 Lu-DOTATATE (in select populations, as it is likely better tolerated than everolimus/sunitinib), or CAPTEM (choosing among these treatments depends on patient comorbidities and side-effect profiles [see Table 2]; CAPTEM or 177 Lu-DOTATATE may be especially suitable in tumors with a faster growth rate and more bulky disease if a response is needed Increase in SSA dose intensity can be considered for patients who are not able to receive other treatments Table 3. Cont.

Scenario Multidisciplinary Perspective on Treatment Challenges and Considerations
High-volume and symptomatic pNETs Consider CAPTEM first line for efficient cytoreduction; Alternatively, RLT can be considered for SSTR+ disease when disease shrinkage is desired. RLT is also ideal for widespread bony metastatic disease; Everolimus is a good second-line option for low-volume disease; Sunitinib should be reserved for third-line and later treatment owing to its side-effect profile and availability of more tolerable alternative options; SSAs are usually added; however, ORRs with SSAs are modest (<5%); For liver-dominant disease, consider liver-directed therapy (which can be sequenced with systemic therapy) Metastatic pNETs with high-volume symptomatic disease or risk of rapid progression require an objective response or tumor shrinkage; The A022001 trial (NCT05247905) will determine if CAPTEM or 177  It should be acknowledged that there are several evidence gaps that hinder wellinformed clinical decision-making in certain contexts. For example, there are currently limited head-to-head data for continuation of SSAs beyond disease progression, use of combination therapy, optimal treatment sequences, and potential for retreatment with 177 Lu-DOTATATE. Despite these gaps, the current clinical data and our clinical experience have allowed us to provide a framework for treatment sequencing decisions across many different clinical scenarios, but more data are needed to fully support well-informed clinical decision-making for patients with NETs.

Conclusions
NETs have seen a significant advance in therapeutic drug development in the last decade. This has ushered us into a new era in which "how to sequence therapies" is a foremost challenge. New and emerging clinical trial data of agents for advanced NETs have demonstrated improved PFS versus control, with efficacy benefits preserved across clinically relevant patient subgroups. Long-term clinical trial follow-up has also evaluated the safety profile of each agent comprehensively, enabling clinicians to make more accurate risk assessments when selecting therapy. Clinical trial data and real-world data are now needed to meet the challenge of understanding how to use these valuable medicines optimally, and several studies are ongoing that may fill important knowledge gaps (Figure 3). In the meantime, continuing medical education and multidisciplinary team collaboration is important to ensure that clinicians continue to have the acumen and resources to make treatment sequencing decisions based on clinical trial data in conjunction with a full patient risk assessment. NETs have seen a significant advance in therapeutic drug development in the last decade. This has ushered us into a new era in which "how to sequence therapies" is a foremost challenge. New and emerging clinical trial data of agents for advanced NETs have demonstrated improved PFS versus control, with efficacy benefits preserved across clinically relevant patient subgroups. Long-term clinical trial follow-up has also evaluated the safety profile of each agent comprehensively, enabling clinicians to make more accurate risk assessments when selecting therapy. Clinical trial data and real-world data are now needed to meet the challenge of understanding how to use these valuable medicines optimally, and several studies are ongoing that may fill important knowledge gaps (Figure 3). In the meantime, continuing medical education and multidisciplinary team collaboration is important to ensure that clinicians continue to have the acumen and resources to make treatment sequencing decisions based on clinical trial data in conjunction with a full patient risk assessment. Supplementary Materials: The following supporting information can be downloaded at: www.mdpi.com/xxx/s1, Figure S1: Images of common clinical scenarios encountered in the management of NETs.
Author Contributions: A.C. had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Authors confirm that they meet ICMJE authorship criteria and that no one who would qualify for authorship has been excluded. Funding: Novartis Pharmaceuticals Corporation provided funding for medical writing assistance. Acknowledgments: Ashfield MedComms, an Inizio Company, provided medical writing and editorial assistance, which was funded by Novartis Pharmaceuticals Corporation. Neither Novartis Pharmaceuticals Corporation nor Ashfield MedComms influenced the content of this manuscript, nor did the authors receive financial compensation for authorship.
Author Contributions: A.C. had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Authors confirm that they meet ICMJE authorship criteria and that no one who would qualify for authorship has been excluded.