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Anti-tumour activity of everolimus and sunitinib in neuroendocrine neoplasms

Anti-tumour activity of everolimus and sunitinib in neuroendocrine neoplasms Comparisons between everolimus and sunitinib regarding their efficacy and safety Key Words in neuroendocrine neoplasms (NENs) are scarce. We retrospectively analysed the f neuroendocrine neoplasms clinicopathological characteristics and outcomes in 92 patients with well-differentiated f molecular targeted therapy (WD) NEN of different origin (57 pancreatic NENs (PanNENs)), treated with molecular f everolimus targeted therapy (MTT) with everolimus or sunitinib, first- (73:19) or second-line f sunitinib (sequential; 12:22) for progressive disease. Disease control rates (DCR: partial response or stable disease) at first-line were higher in all patients treated with everolimus than sunitinib (64/73 vs 12/19, P = 0.012). In PanNENs, DCR at first-line everolimus was 36/42 versus 9/15 with sunitinib (P = 0.062). Progression-free survival (PFS) at first-line everolimus was longer than sunitinib (31 months (95% CI: 23.1–38.9) vs 9 months (95% CI: 0–18.5); log-rank P < 0.0001) in the whole cohort and the subset of PanNENs (log-rank P < 0.0001). Median PFS at second-line MTT was 12 months with everolimus (95% CI: 4.1–19.9) vs 13 months with sunitinib (95% CI: 9.3–16.7; log-rank P = 0.951). Treatment with sunitinib (HR: 3.47; 95% CI: 1.5–8.3; P value: 0.005), KI67 >20% (HR: 6.38; 95% CI: 1.3–31.3; P = 0.022) and prior chemotherapy (HR: 2.71; 95% CI: 1.2–6.3; P = 0.021) were negative predictors for PFS at first line in multivariable and also confirmed at multi-state modelling analyses. Side effect (SE) analysis indicated events of serious toxicities (Grades 3 and 4: n = 13/85 for everolimus and n = 4/41 for sunitinib). Discontinuation rate due to SEs was 20/85 for everolimus versus 4/41 for sunitinib (P = 0.065). No additive toxicity of second-line MTT was confirmed. Based on these findings, and until reliable predictors of response become available, everolimus Endocrine Connections may be preferable to sunitinib when initiating MTT in progressive NENs. (2019) 8, 641–653 Introduction Neuroendocrine neoplasms (NENs) represent a the development of accurate pathologic and diagnostic heterogeneous group of tumours with variable clinical tests, but also because of the increased awareness of behaviour and unpredictable prognosis. Their incidence these tumours by clinicians (1). NEN biology has also has increased substantially in recent years, partly due to been clarified to some extent, paving the way for the https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve -19-0134 PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 642 in NENs development of novel molecular targeted therapies Subjects and methods (MTTs). MTTs with the MTOR inhibitor everolimus and the receptor tyrosine kinase (RTK) inhibitor sunitinib have Ninety-two consecutive patients with inoperable Stage been approved in clinical practice for locally advanced and IIIb and Stage IV NENs who received MTT with everolimus metastatic pancreatic NENs (PanNENs) (2, 3). In addition, or sunitinib, alone or sequentially, from 1 May 2008, to everolimus has been shown to exhibit activity in NENs 30 September 2018, were identified from a single tertiary originating from other tissues in phase III studies, whereas NEN referral centre in Athens, Greece. Patients’ files phase II studies have shown that RTK inhibitors could were chosen on the basis of a centrally reviewed biopsy- also be used in particular clinical settings in such NENs (4, proven, advanced or metastatic well-differentiated (WD) 5, 6). However, one of the main challenges regarding the NEN. Up until September 2018, patients were discussed effective treatment of NENs with these agents is related at multidisciplinary meetings and, for MTT initiation, to the paucity of validated biomarkers to select the best patients had to have disease progression as documented candidates for MTT and monitor side effects (SEs), survival by Response Evaluation Criteria in Solid Tumors (RECIST) outcomes and responses. (14). Patients were selected for MTT initiation with either In particular, the serine/threonine kinase mammalian everolimus or sunitinib after central assessment of cross- target of rapamycin (MTOR) signalling pathway plays sectional imaging. The selection of first-line MTT therapy a pivotal role in the regulation of cell proliferation was based on international guidelines, but also on the and metabolism, survival, motility and autophagy. Its presence of comorbidities, patient’s performance status and activation has been associated with a poor prognosis and preference. Hence, despite similar clinical presentation, high proliferation index (KI67) (7, 8). Everolimus interacts everolimus has been offered as first-line treatment in with the MTOR pathway and related intracellular pathways, some patients, whereas sunitinib has been offered to suppressing downstream multi-protein complexes and others. First-line MTT was administered to patients who increasing progression-free survival (PFS) across different experienced disease progression during watchful waiting sets of NENs (9, 10, 6, 3). On the other hand, angiogenesis or treatment with either somatostatin analogues (SSAs) in NENs is of paramount importance, though not yet fully or chemotherapy. Second-line (sequential) MTT with explained (11). A large placebo-controlled phase III trial sunitinib or everolimus was administered in a subset of has demonstrated that sunitinib, which is a potent multi- NEN patients after disease progression or serious toxicity targeted RTK inhibitor of VEGFR1-3, PDGFR-A, PDGFR-B while on first-line MTT with everolimus or sunitinib, and C-KIT, resulted in a PFS improvement in patients with respectively. Importantly, since neither everolimus nor metastatic pancreatic NENs (PanNENs) (2). sunitinib was officially licensed for the treatment of non- Small series on sequential use of MTT in PanNENs has pancreatic NENs before 2016, off-label administration of demonstrated similar PFS and tolerability for everolimus MTT to such patients required approval from the hospital and sunitinib at first- and second-line MTT ( 12). However, ethical/scientific committee and also the pertinent head-to-head comparison of MTT efficacy and toxicity national regulatory authority. Preliminary data in a subset is rather limited; randomized trials are lacking, whereas of 19 patients who received sequential MTT had previously there are only few small retrospective studies in PanNENs been published (12). Data on histopathology, grading and available, comparing everolimus with sunitinib (12, 13). secretory status, functional imaging properties (fluoro- Importantly, MTTs with everolimus and sunitinib have deoxyglucose positron emission tomography (FDG- distinct SE profiles, which differ from those of cytotoxic PET) and somatostatin receptor imaging (Octreoscan or chemotherapies. The continual and occasionally Ga-DOTATOC PET)), as well as prior lines of treatment prolonged nature of orally administered MTT leads to new including surgery, were retrospectively collected. challenges in their application and the management of Tumour-cell differentiation and KI67 labelling index potential additive toxicity when used sequentially. (LI) were determined from primary site, lymph node or The objectives of this study were to assess the anti- liver biopsies. Centrally, we retrospectively reassessed all tumour activity of MTT with everolimus or sunitinib the available tumour tissues according to the 2000 and administered alone or sequentially, in terms of the impact evolved 2017 WHO classification system for grading. of each drug in DCR and PFS and also to explore their Additionally, the stage of all patients was centrally SE profiles and potential additive toxicity, by means of re-evaluated based on the 8th edition of the American collecting real-world data. Joint Committee on Cancer (AJCC) classification for https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve K Daskalakis et al. Molecular targeted therapies 8:6 643 in NENs TNM staging (15, 16). Other clinicopathologic variables recorded at data entry (MTT initiation) included age, sex, genetic predisposition/family history, primary tumour site, secretory status, liver tumour load, somatostatin receptor positivity on octreoscan or Ga-PET/CT, FDG-PET/CT avidity, concomitant use of SSAs, previous treatments and the Charlson Comorbidity Index. The Charlson Comorbidity Index is a validated scale for survival (higher scores indicate more comorbidities) (17). Subsequently, all patients with NEN primaries were categorized into three groups according to the KI67 LI at the time of MTT Figure 1 initiation: Group 1: KI67 <3%, Group 2: KI67 3-20% and Markov multi-state model of cancer progression and mortality. Three possible states are considered: (1) MTT initiation, alive with progression, Group 3: KI67 >20%. (2) alive with new progression under MTT and (3) death. Duration of MTT administration, reason to stop treatment and MTT SE data were also extracted from analytical models, such as Cox’s model, but also allows patient records. SEs were graded using the National for simultaneous estimation of the effects of prognostic Cancer Institute Common Terminology Criteria for factors on the hazard of transitions between all clinically Adverse Events CTCAE v 5.0 (18). Disease progression was relevant health states of interest and avoids potentially assessed according to the Response Evaluation Criteria in important biases due to non-random censoring (20, 21). Solid Tumours (RECIST version 1.1) (14). We modelled transitions between three states: (A) MTT The study was approved by the Regional Ethics Review initiation, alive with progression at Stage IIIb or IV; (B) Board in Athens, Greece. Written informed consent was alive with new progression under MTT and (C) death obtained from all study participants. To ensure the quality (Fig.  1). The MKVPCI model allowed us to estimate of data reporting, we followed the STROBE statement (19). the separate effects of each prognostic factor: (i) new progression after first-line MTT (transition (A–B)); (ii) new progression after second-line MTT (B–B) and (iii) death Statistics after progression (B–C). In the estimation process, it was All analyses were done using the SPSS 23.0 software assumed that all cohort members were initially at risk of package (IBM SPSS Statistics, Armonk, NY, USA) and R either transition (A–B) or transition (A–C), until the time (version 3.2.4; R Foundation for Statistical Computing, of their progression (state B), death (state C) or censoring Vienna, Austria). To avoid immortal time bias, baseline at the end of follow-up (if they remained in state A). for overall survival (OS) and PFS analyses was defined Finally, shrinkage for control of confounders was applied as the first date for MTT. Preliminary analyses included between primary recorded variables and derived outcomes estimation of the chi-square test and the Kaplan–Meier in different patient states during the study period for survival curves for PFS and OS, stratified by a number the MKVPCI model (22). With the aim of eliminating of baseline variables and the log-rank testing of the validity threats to stepwise analysis, shrinkage methods differences in survival between the respective strata for applied here allowed us to address residual confounding patients receiving first-line and sequential second-line by entering each covariate in the model, along with prior MTT, respectively. Patients still receiving MTT without data that limit the size of the residual effects, e.g. when a exhibiting progression entered the analysis with PFS equal subset of patients switched from everolimus to sunitinib to the duration of treatment. Patients were censored at and vice versa (22). the time they were lost to follow-up or at the end of the study, in September 2018. Multivariable Cox regression PFS analysis was employed to assess prognostic factors Results at treatment initiation for first-line MTT. Additionally, Patient characteristics we employed the multi-state Markov piecewise constant intensities model (MKVPCI) to assess hazard ratios (HR) Ninety-two consecutive patients (34 females; mean with confidence intervals (CI) at first- and second-line MTT age ± s .d . at MTT initiation: 58 ± 14 years) with progressive and to validate the results of the Cox regression analysis. inoperable locally advanced (n = 8) or metastatic (n = 84) MKVPCI not only generalizes the single-endpoint survival well-differentiated (WD) NENs were included in the https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 644 in NENs analysis. Figure  2 presents the study flow. Patient and second-line treatment was 3.5 ± 5.4 months. Additionally, tumour characteristics are summarized in Table 1. A first- in this subset, the time interval did not differ significantly line MTT with everolimus or sunitinib was administered in either the everolimus to sunitinib group or the sunitinib in all 92 patients (everolimus, n = 73; sunitinib, n = 19). to everolimus group (P = 0.151). A second-line (sequential) MTT was administered in 34 The majority of patients had somatostatin receptor patients: in particular, 22 patients received first-line imaging (Octreoscan, Tektrotyd or Ga-DOTATOC PET) everolimus followed by sunitinib, and 12 were assigned performed prior to MTT initiation, showing a positive to first-line sunitinib followed by everolimus. Of the 92 uptake in 74 cases. FDG-PET was performed in a subset patients included in the study, 74 had sporadic tumours of 25 patients, of whom 12 had a positive uptake. and 8 familial NENs in the context of multiple endocrine neoplasia type 1 (MEN 1) syndrome. Based on primary Duration of treatment tumour location, cases were grouped into small intestinal NENs (n = 21), pancreatic NENs (PanNENs) (n = 57), lung/ Median duration of first-line MTT for the entire cohort thymic NENs (n = 7) and unknown primary origin NENs was 16.5  months (range 1–89). For everolimus, median (UPO-NENs, n = 7). Thirty-four patients had a functioning duration of first-line MTT was 21  months (range 1–89) tumour. Fifteen patients had KI67 <3%; 63 had KI67 and 6 months (range 1–27) for sunitinib. Median duration 3–20% and six had KI67 >20% (range of KI67 in these six of second-line MTT was 10  months (range 1–77) for the cases: 25–70%). In the remaining eight patients, the grade entire cohort: 10 months (range 3–77) for everolimus and was unknown. 9.5 months (range 1–59) for sunitinib. Surgery with the intention to cure or control hormonal symptoms was performed on 52 patients prior Anti-tumoural activity to MTT. First-line MTT was administered after progression while on SSAs or just observation in 65 patients. First- Disease control rate (DCR = partial response (PR) + stable line MTT constituting subsequent lines of treatment disease (SD)) during MTT administration was documented after disease progression with other chemotherapy was according to RECIST criteria at any time after MTT administered in 27 patients. Somatostatin analogues initiation. DCRs with respect to patient and tumour (SSAs) were co-administered in 86/92 patients at first- characteristics are presented in Table 2 for first-line MTT and line and 33/34 patients at second-line MTT, respectively. in Supplementary Table 2 (see section on supplementary For patients receiving sequential MTT (n = 34), the data given at the end of this article) for second-line MTT. time interval (mean ± s .d .) between the first-and the DCR was higher in patients receiving everolimus than sunitinib at first-line MTT (DCR: 64/73 (8PR-56SD) vs 12/19 (1PR-11SD); P = 0.012; Table  2). In patients with PanNEN (n = 57), DCR at first-line MTT was 36/42 with everolimus vs 9/15 with sunitinib (P = 0.062; Table  2). In the subgroup analysis of data from first-line MTT, DCR was higher in the everolimus group than the sunitinib group in patients with KI67 3–20% (45/48 vs 10/15; P = 0.039; Table 2) and advanced LTL (>10 or diffuse liver metastases; 42/49 vs 10/16; P = 0.029; Table  2). The DCR of second-line MTT did not differ significantly between patients receiving everolimus vs sunitinib (DCR: 8/12 (1PR-7SD) vs 17/22 (0PR-17SD), P = 0.687; Supplementary Table  1). Accordingly, in the subset of PanNEN patients who received second-line MTT (n = 28), DCR was 7/10 with everolimus vs 13/17 with sunitinib (P = 0.782; Supplementary Table  1). With regards to subgroup analysis for second-line MTT, no associations were evident between DCR and other potentially predictive parameters Figure 2 presented in Supplementary Table  1. With respect to Study flow diagram. MTT, molecular targeted therapy; NENs, neuroendocrine neoplasms. DCR, separate analysis was undertaken in the subset of https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve K Daskalakis et al. Molecular targeted therapies 8:6 645 in NENs Table 1 Patient characteristics at MTT initiation. Characteristics Everolimus group Sunitinib group P value Total number of patients (n = 92) No of patients (n = 73) No of patients (n = 19) Gender Male 46 12 0.991 Female 27 7 Age: mean ± s .d . 58 ± 14 56 ± 15 0.680 Inheritance Sporadic 67 17 0.751 Familial (MEN1) 6 2 Primary tumour site Pancreas 42 15 0.188 Small intestinal 19 2 Lung/thymus 7 0 Unknown primary (UPO) 5 2 Liver Tumour load No liver metastases 7 1 0.526 <5 unilobar liver metastases 11 1 5–10 unilobar liver metastases and/or 6 1 bilobar liver 49 16 metastases >10 liver metastases or diffuse liver metastases KI67 group KI67 <3% 13 2 0.645 KI67 3–20% 48 15 KI67 >20% 5 1 Secretory status Yes 29 5 0.281 No 44 14 Prior Surgery Yes 40 12 0.512 No 33 7 SRS or Ga-PET Positive 60 14 0.597 Negative 6 3 Unknown 7 2 FDG-PET FDG-PET positive 8 4 0.465 FDG-PET negative 10 3 Unknown 55 12 Previous treatment SSA or naive 56 9 0.012 Pre-treated with chemotherapy 17 10 Concomitant SSA Yes 70 16 0.100 No 3 3 CCI 0 52 13 0.406 1 14 6 2 6 0 3 1 0 Pearson chi-square test and Fisher’s exact test were conducted as appropriate. CCI, Charlson Comorbidity Index; FDG-PET, fluoro-deoxyglucose positron emission tomography; Ga, Gallium; MEN1, multiple endocrine neoplasia type 1; MTT, molecular targeted therapy; SSA, somatostatin analogue; SRS, somatostatin receptor scintigraphy. PanNENs, as presented in Supplementary Tables 2 and 3. Survival analysis of clinico-pathological prognostic As stratification by the KI67 proliferation index was linked factors at baseline with higher DCR to first-line everolimus in tumours with KI67 of 3–20%, we performed a receiver-operator curve Median PFS to first-line MTT was 31  months (95% CI: (ROC) analysis to identify non-responders (progressive 23.1–38.9) in the everolimus group versus 9  months disease (PD) recorded only) in the whole cohort and in (95% CI: 0–18.5) in the sunitinib group, respectively (log- the subset of PanNENs. However, KI67 failed to predict rank P < 0.0001; Fig.  3). Median PFS to second-line MTT treatment response in these ROC analyses (AUC = 0.57 in was 12 months (95% CI: 4.1–19.9) in the everolimus group NEN and AUC = 0.443 in PanNENs; Supplementary Figs 1 versus 13  months (95% CI: 9.3–16.7) in the sunitinib and 2). group, respectively (log-rank P = 0.951; Supplementary Functional imaging properties with respect to SRS Fig.  1). On multivariable Cox regression PFS analysis and FDG-PET avidity did not correlate with DCR in any at first-line MTT, the selection of sunitinib (HR: 3.47; subgroup (comparison: everolimus vs sunitinib; Table  2 95% CI: 1.5–8.3; P = 0.005), KI67 >20% (HR: 6.38; and Supplementary Table 1). 95% CI: 1.3–31.3; P = 0.022) and prior administration https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 646 in NENs Table 2 Disease control rates (partial response or stable disease) according to RECIST during first-line MTT. Patient characteristics (n = 92) DCR in everolimus group DCR in sunitinib group P value n = 64/73 n = 12/19 0.012 Gender Male 41/46 9/12 0.342 Female 23/27 3/7 0.061 Age: mean ± s .d . 58 ± 13.6 61 ± 15.4 0.549 Inheritance Sporadic 59/67 11/17 0.069 Familial (MEN1) 5/6 1/2 0.464 Primary tumour site Pancreas 36/42 9/15 0.062 Small intestinal 18/19 1/2 0.271 Lung/thymus 6/7 0/0 – Unknown primary (UPO) 4/5 2/2 0.999 Liver Tumour load No liver metastases 6/7 1/1 0.999 <5 unilobar liver metastases 10/11 1/1 0.999 5–10 unilobar liver metastases and/or 6/6 1/1 – bilobar liver metastases 42/49 9/16 0.039 >10 liver metastases or diffuse liver metastases KI67 Group G1 (KI67 <3%) 11/13 2/2 0.999 G2 (KI67 3–20%) 45/48 10/15 0.029 G3 (KI67 >20%) 2/5 0/1 0.999 Secretory status Yes 27/29 4/5 0.488 No 37/44 8/14 0.062 Prior surgery Yes 37/40 8/12 0.072 No 27/33 4/7 0.316 SRS or Ga-PET Positive 53/60 9/14 0.062 Negative 6/6 3/3 – Unknown 5/7 0/2 0.167 FDG-PET FDG-PET positive 5/8 2/4 0.231 FDG-PET negative 10/10 2/3 0.999 Unknown 49/55 8/2 0.099 Previous treatment SSA or naive 52/56 6/9 0.073 Pre-treated with chemotherapy 12/17 6/10 0.683 CCI 0 45/52 9/13 0.237 1 13/14 3/6 0.061 2 5/6 0/0 – 3 1/1 0/0 – Pearson chi-square test and Fisher’s exact test were conducted within subgroups as appropriate. Bold indicates statistical significance. CCI, Charlson Comorbidity Index; CI, confidence interval; FDG-PET: fluoro-deoxyglucose positron emission tomography; Ga, Gallium; HR, hazard ratio; MEN1, multiple endocrine neoplasia type 1; MTT, molecular targeted therapy; SSA, somatostatin analogue; SRS, somatostatin receptor scintigraphy. 1st line MTT B 100 2nd line MTT Everolimus Everolimus Sunitinib Sunitinib 80 ... log-rank p < 0.0001 log-rank p=0.951 Figure 3 0 (A) Progression-free survival (PFS) to first-line molecular targeted therapy (MTT) stratified by 0 10 20 30 40 0 10 20 30 MTTagent (everolimus vs sunitinib) with patient at Time from MTT initiation, months Time from 2nd line MTT initiation, months risk table below. (B) Progression-free survival No at risk No at risk (PFS) to second-line molecular targeted therapy Everolimus 73 53 40 25 16 Everolimus 12 84 2 (MTT) stratified by MTT agent (everolimus vs Sunitinib 19 64 00 Sunitinib 22 11 43 sunitinib) with patient at risk table below. https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve Progression Free Survival % Progression Free Survival % K Daskalakis et al. Molecular targeted therapies 8:6 647 in NENs of chemotherapy (HR: 2.71; 95% CI: 1.2–6.3; P = 0.021) CI: 1.59–4.75) as predictors for progression to first-line were demonstrated as negative independent prognostic MTT (Table 4). Additionally, in MKVPCI analysis, HR >1.5 factors for PFS under MTT (Table  3). For PanNENs for progression were encountered in patients with lung/ (n = 57) in particular, median PFS under first-line MTT thymic NENs and higher CCI receiving first-line MTT, as was 31  months (95% CI: 24.5–37.5) in the everolimus well as in patients with advanced LTL at second-line MTT group (n = 42) versus 9 months (95% CI: 2.3–15.7) in the (risk for progression or death, Table 4). sunitinib group (n = 15), respectively (log-rank P < 0.0001; Fig.  4). Cox regression analysis for PFS of first-line MTT Side effects in PanNENs confirmed that sunitinib treatment (HR: 4.9; 95% CI: 1.8–13.9; P = 0.002) and KI67 >20% (HR: 76.3; MTT with everolimus or sunitinib was generally well 95% CI: 5–1171; P = 0.002) were negative independent tolerated. From the entire cohort of 92 patients, 56 (61%) prognostic factors (Supplementary Table 4). experienced any SE during first- or second-line MTT, mostly Log-rank OS analysis, did not exhibit any differences grades 1 and 2 toxicities. SEs grade >3 were encountered between patients receiving everolimus compared to in 16 patients (17.4%). Table  5 summarizes the most sunitinib as first- and second-line MTT, respectively (log- common SE and the frequency of their appearance, as rank P = 0.510 and log-rank P = 0.451, respectively; Fig. 5). well as the SE grade. Fatigue, gastrointestinal symptoms MKVPCI analysis with shrinkage of investigated (nausea, vomiting, diarrhoea, abdominal pain) and variables, confirmed the choice of sunitinib (HR: 1.88; haematological complications (reduced platelet, 95% CI: 1–3.5), KI67 >20% (HR: 4.77; 95% CI: 1.65–13.8) haematocrit and white blood cell count) were the most and prior administration of chemotherapy (HR: 2.75; 95% frequent grade 1–2 SE noticed. Twenty patients treated with Table 3 Multivariate Cox regression model for progression-free survival (PFS) for all patients receiving first-line molecular targeted therapy (MTT). Prognostic factor for PFS HR 95% CI P value MTT agent  Everolimus 1  Sunitinib 3.47 1.46–8.25 0.005 Age at baseline 0.99 0.96–1.01 0.285 Site of primary  Pancreas 1  Small intestine 0.71 0.28–1.76 0.453  Lung/thymus 1.16 0.27–5.03 0.842  Unknown primary (UPO) 1.81 0.31–10.63 0.511 Liver tumour load  No liver metastases 1 0.75  <5 unilobar liver metastases 1.98 0.31–12.55 0.467  5–10 unilobar and/or bilobar liver metastases 0.95 0.15–6.15 0.954  >10 liver metastases or diffuse liver metastases 1.51 0.32–7.13 0.603 KI67 groups  KI67 <3% 1  KI67 3–20% 0.751 0.32–1.79 0.516  KI67 >20% 6.38 1.30–31.25 0.022 SRS or Ga-PET  Negative 1 0.209  Positive 0.99 0.35–2.86 0.996  Unknown 0.31 0.06–1.57 0.158 Prior resective surgery  No 1  Yes 0.7 0.35–1.37 0.295 Prior chemotherapy  No 1  Yes 2.71 1.17–6.3 0.021 Bold indicates statistical significance. CI, confidence interval; Ga, Gallium; HR, hazard ratio; MEN1, multiple endocrine neoplasia type 1; MTT, molecular targeted therapy; SRS, somatostatin receptor scintigraphy. https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 648 in NENs AB 1st line MTT in 2nd line MTT in PanNEN PanNENs Everolimus Everolimus Sunitinib Sunitinib 80 log-rank p=0.722 log-rank p<0.0001 Figure 4 (A) Progression-free survival (PFS) to first-line 20 20 molecular targeted therapy (MTT) in patients with pancreatic neuroendocrine neoplasms (PanNEN) 0 0 stratified by MTT agent (everolimus vs sunitinib) 0 10 20 30 40 0 10 20 30 40 with patient at risk table below. (B) Progression- Time from 2nd line MTT initiation, months Time from MTT initiation, months free survival (PFS) to second-line MTT in patients No at risk No at risk with PanNENs stratified by MTT agent (everolimus Everolimus422922148 Everolimus118 42 2 Sunitinib155 30 0 Sunitinib17103 33 vs sunitinib) with patient at risk table below. everolimus manifested uncontrolled diabetes mellitus, in the sunitinib group (P value: 0.581). These figures for whereas two patients had a new onset of hypertension second-line MTT in PanNENs were 2/11 versus 7/17 for while on sunitinib treatment. Of the 16 patients who everolimus and sunitinib, respectively (P = 0.689). developed serious toxicities (grade 3 and above), SE most Finally, there was no additive toxicity at second-line commonly included bone marrow suppression, acute MTT neither for everolimus nor for sunitinib. In particular, renal failure and/or pneumonitis leading to treatment comparable SE rates were encountered between patients discontinuation. Another 12 patients discontinued MTT receiving first- (37/73) and second-line everolimus (3/12; mainly due to fatigue. All other patients who developed P = 0.122), whereas lower SE rates were demonstrated at grades 1–2 SE were given medications for symptomatic second- (5/22) compared to first-line sunitinib (14/19, relief and had MTT dosage reduction as per guidelines. P = 0.001). Previous chemotherapy administration was The discontinuation rate due to SE was as high as 20/85 not associated to additive toxicity under MTT either for everolimus versus 4/41 for sunitinib (P = 0.065). (P = 0.463). Among the 85 patients receiving everolimus as first- (n = 73) or second-line MTT (n = 12), SE were encountered in 40 patients. Thirteen patients treated with everolimus Discussion had grade 3 SE and above, mainly consisting of acute renal failure and pneumonitis. On the other hand, among the This study assessed the outcomes of patients with NENs 41 patients receiving sunitinib as first- ( n = 19) or second- receiving MTT with everolimus or sunitinib, as a first- line MTT (n = 22), SEs were encountered in 25 patients, and second-line (sequential) MTT, mainly combined with toxicity of grade 3 and above being observed in four with SSAs in a single-centre observational setting. A patients. higher PFS benefit was found after uni- and multivariable In the subset of PanNENs (n = 56), 24/41 patients analysis (HR: 3.47; 95% CI: 1.5–8.3; P = 0.005) and who received everolimus experienced any SE during first- confirmed by multi-state modelling (HR: 1.88; 95% CI: line MTT, mostly grades 1 and 2 toxicities versus 10/15 1–3.5) for patients treated with everolimus at first-line A B 100 log-rank p=0.451 log-rank=0.510 40 40 1st line MTT 2nd line MTT 20 20 Everolimus Everolimus Figure 5 Sunitinib Sunitinib (A) Overall survival (OS) from molecular targeted 0 0 therapy (MTT) initiation stratified by MTT agent 0 20 40 60 80 0 20 40 60 80 (everolimus vs sunitinib) with patient at risk table Time from 2nd MTT initiation, months Time from MTT initiation, months below. (B) Overall survival (OS) from second-line No at risk No at risk MTT initiation stratified by MTT agent (everolimus Everolimus725632168 Everolimus129 64 2 Sunitinib 14 12 11 73 Sunitinib 22 11 73 2 vs sunitinib) with patient at risk table below. https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve Cumulative Survival % Progession Free Survival % Progression Free Survival % Cumulative Survival % K Daskalakis et al. Molecular targeted therapies 8:6 649 in NENs Table 4 Results of multi-state Markov modelling of prognostic effects on progression and death. Progression under Progression under sequential 2nd line Death, 1st line Death, 2nd line 1st line MTT MTT MTT MTT Characteristics HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Total number of patients (n = 92) MTT Everolimus 1 1 1 1 Sunitinib 1.88 (1.00–3.52) 1.02 (0.43–2.41) 1.26 (0.27–5.89) 1.96 (0.55–6.98) Gender Male 1 1 1 1 Female 0.98 (0.58–1.67) 0.46 (0.18–1.18) 0.93 (0.30–2.86) 0.24 (0.05–1.06) Age Per 10 years 0.94 (0.77–1.15) 0.66 (0.50–0.89) 1.00 (0.65–1.55) 0.66 (0.46–0.95) Inheritance Sporadic 0.88 (0.38–2.06) 1.01 (0.33–3.02) 1.17 (0.15–9.03) 0.78 (0.21–2.90) Familial (MEN1) 1 1 1 1 Primary tumour site Pancreas 1 1 1 1 Small intestinal 0.71 (0.37–1.35) 0.38 (0.05–2.87) 1.38 (0.43–4.42) N/A Lung/thymus 1.90 (0.79–4.57) 1.36 (0.31–5.92) 1.47 (0.17–12.51) 1.13 (0.15–8.70) Unknown primary (UPO) 0.80 (0.24–2.62) N/A N/A N/A Liver Tumour load No liver metastases 1 1 1 1 <5 unilobar liver metastases 0.75 (0.27–2.08) 0.18 (0.02–1.69) 1.12 (0.07–18.3) 0.07 (0.01–0.92) 5–10 unilobar liver 0.48 (0.14–1.64) 5.83 (0.22–157) 1.12 (0.07–18.0) 5.26 (0.20–141) metastases and/or bilobar 0.70 (0.31–1.56) 0.14 (0.02–1.27) 1.59 (0.20–12.4) 6.38 (0.02–1.42) liver metastases >10 liver metastases or diffuse liver metastases KI67 at MTT KI67 <3% 1 1 1 1 initiation KI67 3–20% 1.00 (0.50–2.02) 0.98 (0.29–3.35) 0.32 (0.08–1.21) 0.99 (0.22–4.45) KI67 >20% 4.77 (1.65–13.8) N/A 8.07 (1.63–39.9) N/A Secretory status Yes 0.88 (0.51–1.50) 0.88 (0.36–2.19) 0.64 (0.21–1.92) 0.59 (0.21–1.71) No 1 1 1 1 Prior surgery Yes 0.77 (0.46–1.31) 0.68 (0.27–1.70) 0.84 (0.27–2.70) 0.36 (0.12–1.04) No 1 1 1 1 SRS or Ga-PET Positive 0.92 (0.48–1.78) 0.52 (0.19–1.43) 0.36 (0.11–1.20) 2.16 (0.28–16.6) Negative/unknown 1 1 1 1 FDG-PET Positive 1.04 (0.74–1.48) 0.86 (0.50–1.48) 1.13 (0.50–2.54) 0.99 (0.48–2.02) Negative 1 1 1 1 Previous treatments SSA or naive 1 1 1 1 Pre-treated with 2.75 (1.59–4.75) 0.38 (0.05–2.98) 2.38 (0.70–8.10) 0.29 (0.04–2.36) chemotherapy CCI 0 1 1 1 1 1 0.65 (0.33–1.28) 0.95 (0.31–2.95) 0.80 (0.21–2.98) 2.81 (0.94–8.43) 2 1.53 (0.60–3.91) 0.88 (0.12–6.68) 1.19 (0.15–9.54) N/A 3 N/A N/A N/A N/A CCI, Charlson Comorbidity Index; CI, confidence interval; FDG-PET, fluoro-deoxyglucose positron emission tomography; Ga, Gallium; HR, hazard ratio; MEN1, multiple endocrine neoplasia type 1; MTT, molecular targeted therapy; SRS, somatostatin receptor scintigraphy; SSA, somatostatin analogue. MTT irrespective of the tissue of origin. Overall, DCR SE was as high as 20/85 for everolimus versus 4/41 for was higher in all patients treated with everolimus vs sunitinib (P = 0.065). Foremost, no additive toxicities sunitinib (88 vs 63%, P = 0.012), whereas a similar trend at sequential MTT application were encountered in was noted for the PanNEN group (86% with everolimus this series. versus 60% with sunitinib (P = 0.062)). In addition, prior Generally, dose escalation or an increase in frequency administration of chemotherapy (HR: 2.75; 95% CI: of SSAs may be considered in G1–2 NEN patients with KI67 1.59–4.75) and a KI67 proliferation index >20% LI <10% and PD, being previously treated with a standard (HR: 4.77; 95% CI: 1.65–13.8) were identified as SSA dose (23, 24). Robust evidence based on phase III RCTs predictors for progression or death under first-line has established the role of MTT with either everolimus MTT. However, no difference in OS between the two or sunitinib in progressive WD G1 and G2 PanNENs (2, groups (everolimus versus sunitinib, first- and second- 3). In PanNENs, MTT can be first- or second-line therapy, line) was observed. Comparable safety profiles were subsequent to SSAs or chemotherapy, respectively (12, 9). evident with both agents; serious toxicities were in the However, there are few head-to-head comparisons of the range of 10–15%, and the discontinuation rate due to anti-tumour activity and safety profile of MTT in NEN. https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 650 in NENs Table 5 Adverse effects. Maximum toxicity grade 1st line everolimus 1st line sunitinib 2nd line everolimus 2nd line sunitinib Side effects Grade 1 and 2 Grade 3 Grade 1 and 2 Grade 3 Grade 1 and 2 Grade 3 Grade 1 and 2 Grade 3 Haematological 7 1 1 0 1 1 0 0 Gastrointestinal 6 0 3 0 1 0 4 0 intolerance Pneumonitis 0 4 0 1 Hepatotoxicity 2 0 0 0 0 0 0 0 Nephrotoxicity 1 6 0 0 0 0 1 0 Mucocutaneous Dermatitis 4 0 2 0 1 0 1 0 Stomatitis 7 0 1 0 1 0 1 0 Palmar-plantar 1 0 0 0 0 0 0 0 syndrome Fatigue 8 2 5 2 0 0 3 1 Diabetes mellitus 15 1 0 0 4 0 0 0 Hypertension 0 0 1 0 0 0 1 0 Hence, to date, selection of either everolimus or sunitinib ex vivo sensitivity to rapalogues (26). A recent study has been made based on local regimen availability and demonstrated that over-activation of GSK3 may be a preferences, as well as the patient’s anticipated SE profiles. potential marker of everolimus resistance in PanNEN cell Integration of other available modalities, such as peptide lines (27). Additionally, somatic mutations linked with the receptor radionuclide therapy (PRRT), may also be MTOR pathway are encountered in 15% of PanNENs (28). considered according to the availability of this treatment Regarding MTT with RTK inhibitors, SVEGFR-3, IL8 and modality. For the small intestinal and bronchial primaries, SDF-1A were recently identified as predictors of response recent randomized trials also favour the use of everolimus to sunitinib in a phase II trial (29). However, validation (10, 6). However, the results of RADIANT-4 trial were not of clinical trials and incorporation of these results in the available at MTT initiation for the few patients (n = 4) clinical setting are largely missing. with non-pancreatic NENs who received sequential MTT Direct comparison of MTTs with respect to their with first-line sunitinib in our study ( 6). Importantly, benefits and risks is currently incomplete. Therefore, higher DCR and prolonged PFS were encountered in to date, there are no reference standards supporting our study in all NEN patients treated with first-line the use of one over the other. Everolimus has been everolimus. Of particular interest in PanNENs (n = 57), approved as first-line therapy in all NENs, whereas DCR with everolimus achieved marginal statistical sunitinib has been approved for PanNENs only. With significance ( P = 0.062) in comparison with sunitinib, but respect to PanNENs, no randomized clinical trial has still a PFS benefit was clearly evident in these patients provided a head-to-head comparison regarding efficacy in crude and multivariable analyses. Although sunitinib and safety. Moreover, published comparative studies is not currently licensed for NENs of non-pancreatic of retrospective real-world data are scarce (13). A recent origin, primary tumour site was not demonstrated as an network meta-analysis comparing DCR for different independent predictor of PFS at first- and second-line MTT NEN therapies from all available RCTs demonstrated in multivariable Cox regression analysis. Additionally, the that single therapy with everolimus and combination rationale of the present study in terms of the included therapies were most effective (30). Specifically, everolimus patient population is also in accordance with presently alone or in combination with SSA or interferon achieved ongoing, phase I, II and III clinical trials that investigate the highest DCR, followed by single treatment with SSA, a wide range of emerging RTK inhibitors in the treatment interferon, sunitinib and placebo (30). These results are of progressive NENs from various tissues of origin (25). in accordance with the findings of our study, where using Currently, MTT selection and sequencing for NEN real-world data, everolimus alone or more commonly management is not relying on molecularly tailored in combination with SSAs was associated with longer choices due to a lack of biomarkers to predict and monitor PFS at first-line MTT compared to sunitinib. Apart from treatment response in NEN patients. Preclinical studies traditional uni- and multivariable analyses, our study have demonstrated that aberrations of PI3KCA and PTEN also applied modern statistical methods to control and elevated PAKT in the MTOR pathway may predict biases inherent in cohort studies, which confirmed that https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve K Daskalakis et al. Molecular targeted therapies 8:6 651 in NENs everolimus may be preferable to sunitinib when initiating Importantly, the seminal randomized controlled trials MTT in progressive NENs (HR: 1.88 for progression at that resulted in MTT monotherapy approval for NENs in first-line MTT). Additionally, prior administration of clinical practice do not report neither OR nor SD rates (2, chemotherapy (HR: 2.75) and KI67 >20% (HR: 4.77) 6, 3); and no studies are currently available reporting DCR were identified as predictors for progression to first-line of MTT combined with SSAs. MTT. Finally, the findings of the present study may also In the present study, the safety profile of everolimus guide future research by elucidating the role of different (as single agent or combined with SSAs) was similar to prior MTT agents and that of predictive clinicopathological reports of everolimus monotherapy and a recent phase II markers in NEN management with MTTs, thus facilitating trial on everolimus and octreotide LAR combination in appropriate trial design. gastroenteropancreatic NENs (EVERLAR trial), suggesting In the subset of PanNENs, the reasons for longer that prompt management of everolimus SE may reduce PFS (31  months) in everolimus-treated patients in our the potential toxicity of its combination with SSAs (36, study compared to the corresponding figure (11 months) 10, 6). To date, reports on the safety profile of sunitinib reported in RADIANT-3 trial could have been multifactorial combined with SSAs analogues in NEN treatment are (31). RADIANT-3 trial reports a median follow-up period lacking. Our study confirmed a SE rate of sunitinib, mainly of 17  months and a median duration of treatment with combined with SSAs in accordance with the seminal study everolimus 8.79 months (range, 0.25–27.47), as compared by Raymond et al. on sunitinib monotherapy in PanNENs with median duration of 21  months (range 1–89) in that reported approximately 30% SE rate and grade 3 or our study. Additionally, only 31% of the patients in 4 toxicity in the range of 10–12% (2). Additionally, we the everolimus group in RADIANT-3 were administered report a lack of additive toxicity related to sequential MTT treatment for a minimum of 12 months, as compared with in NEN management. Importantly, our findings on MTT 51/73 in patients treated with first-line everolimus in our safety profile should be interpreted in the light of our study study. Finally, previous chemotherapy administration was design as the duration of MTT was often prolonged, that as high as 50% in the RADIANT-3 trial, as compared to only is, until disease progression or serious toxicity occurred 17/73 in the everolimus group in our study. Importantly, and the MTT administration was sequential in a subset of prior chemotherapy administration was demonstrated to patients. However, the retrospective nature of our study be a negative independent prognostic factor of PFS and a and the lack of quantifiable information with appropriate predictor of resistance to MTT in our study. quality of life questionnaires while on MTT, limits indeed Generally, in hypervascularized WD NENs, our ability to accurately determine the safety profile of morphological changes that are clearly observed MTT agents investigated here. after exposure to MTTs such as everolimus, and most Our study has several limitations, the most important importantly to anti-angiogenic drugs, e.g. sunitinib, limitation being in its retrospective nature. This may may be poorly assessed by the currently applied RECIST explain the allocation of a different number of patients criteria, which apparently reflect tumour shrinkage or in each MTT group and differences in duration of progression in size. Several trials have challenged the treatment. Additionally, NEN heterogeneity plus the validity of traditional RECIST dimension criteria to assess inclusion of NENs originating both from the pancreas and the anti-tumoural effects of MTT, and have proposed the small intestine, as well as that of NENs of thoracic incorporating the evaluation of changes in tumour and unknown origin, may have confounded the results. density using contrast enhanced computed tomography, However, considering the distinct characteristics of dynamic contrast magnetic resonance imaging or high- PanNENs and those of other NENs, our efficacy analysis frequency Doppler ultrasonography (32, 33). Taking into for the PanNEN subset was performed separately. Finally, consideration the aforementioned limitations of RECIST the fact that the patient population in our study only criteria, we assessed DCR rather than objective responses includes referrals to a tertiary centre may include a certain in order to evaluate the effects of MTT, as PR at first- referral bias. Importantly, the MKVPCI model and the (n = 8) and second-line MTT (n = 1) were indeed only few extension of shrinkage methods to bias modelling applied in our cohort and mainly observed in patients receiving in the present study allowed us to check for variables everolimus (n = 8). Additionally, SSAs that were commonly that were known or presumed confounders, as well as for used in combination with MTT in the present study have sources of uncertainty, selection bias, misclassification stabilizing rather than shrinkage effects in NENs (34, 35); and unmeasured confounders, thus adding to the validity thus, DCR assessment seems more reasonable in this setting. of the study results (21). The main strengths of this study https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 652 in NENs survival and circulating biomarkers from the randomized, phase III are the central assessment of responses according to RADIANT-3 study. Journal of Clinical Oncology 2016 34 3906–3913. RECIST criteria and making use of centralized pathology (https://doi.org/10.1200/JCO.2016.68.0702) by dedicated radiologists and pathologists involved in the 4 Phan AT, Halperin DM, Chan JA, Fogelman DR, Hess KR, Malinowski P, Regan E, Ng CS, Yao JC & Kulke MH. Pazopanib and institutional multidisciplinary tumour board. depot octreotide in advanced, well-differentiated neuroendocrine In conclusion, our comparison of real-world data in tumours: a multicentre, single-group, phase 2 study. Lancet: patients treated with MTT suggests that, between the two Oncology 2015 16 695–703. (https://doi.org/10.1016/S1470- 2045(15)70136-1) currently approved targeted agents for NEN treatment, the 5 Strosberg JR, Cives M, Hwang J, Weber T, Nickerson M, Atreya CE, MTOR inhibitor everolimus may be preferable to the RTK Venook A, Kelley RK, Valone T, Morse B, et al. A phase II study of inhibitor sunitinib in terms of its anti-tumour activity axitinib in advanced neuroendocrine tumors. Endocrine-Related Cancer 2016 23 411–418. (https://doi.org/10.1530/ERC-16-0008) at first-line MTT; this may have important implications 6 Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, for MTT selection and sequencing in clinical practice. Raderer M, Lahner H, Voi M, et al. Everolimus for the treatment Comparable safety profiles and no additive toxicities at of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo- sequential MTT application were encountered with both controlled, phase 3 study. Lancet 2016 387 968–977. (https://doi. agents. Despite the sophisticated statistical methodology org/10.1016/S0140-6736(15)00817-X) of this study, it is clear that a prospective, randomized, 7 Capdevila J, Casanovas O, Salazar R, Castellano D, Segura A, Fuster P, Aller J, Garcia-Carbonero R, Jimenez-Fonseca P, Grande E, controlled trial will further clarify the value of MTT in et al. Translational research in neuroendocrine tumors: pitfalls NENs with respect to treatment selection and sequencing. and opportunities. Oncogene 2017 36 1899–1907. (https://doi. Importantly, as no ideal predictive markers for MTT org/10.1038/onc.2016.316) 8 Qian ZR, Ter-Minassian M, Chan JA, Imamura Y, Hooshmand SM, are available to date, one of the most important future Kuchiba A, Morikawa T, Brais LK, Daskalova A, Heafield R, et al. tasks is to incorporate the validation of such markers in Prognostic significance of MTOR pathway component expression adequately designed MTT trials. in neuroendocrine tumors. Journal of Clinical Oncology 2013 31 3418–3425. (https://doi.org/10.1200/JCO.2012.46.6946) 9 Lombard-Bohas C, Yao JC, Hobday T, Van Cutsem E, Wolin EM, Panneerselvam A, Stergiopoulos S, Shah MH, Capdevila J & Supplementary data Pommier R. Impact of prior chemotherapy use on the efficacy of This is linked to the online version of the paper at https://doi.org/10.1530/ everolimus in patients with advanced pancreatic neuroendocrine EC-19-0134. tumors: a subgroup analysis of the phase III RADIANT-3 trial. Pancreas 2015 44 181–189. 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PIK3CA/ 36 Capdevila J, Teule A, Barriuso J, Castellano D, Lopez C, Manzano JL, PTEN mutations and Akt activation as markers of sensitivity to Alonso V, Garcia-Carbonero R, Dotor E, Matos I, et al. Phase II study allosteric mTOR inhibitors. Clinical Cancer Research 2012 18 of everolimus and octreotide LAR in patients with nonfunctioning 1777–1789. (https://doi.org/10.1158/1078-0432.CCR-11-2123) gastrointestinal neuroendocrine tumors: the GETNE1003_EVERLAR 27 Aristizabal Prada ET, Spottl G, Maurer J, Lauseker M, Koziolek EJ, study. Oncologist 2019 24 38–46. (https://doi.org/10.1634/ Schrader J, Grossman A, Pacak K, Beuschlein F, Auernhammer CJ, theoncologist.2017-0622) Received in final form 17 April 2019 Accepted 24 April 2019 Accepted Preprint published online 26 April 2019 https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Endocrine Connections Bioscientifica

Anti-tumour activity of everolimus and sunitinib in neuroendocrine neoplasms

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Abstract

Comparisons between everolimus and sunitinib regarding their efficacy and safety Key Words in neuroendocrine neoplasms (NENs) are scarce. We retrospectively analysed the f neuroendocrine neoplasms clinicopathological characteristics and outcomes in 92 patients with well-differentiated f molecular targeted therapy (WD) NEN of different origin (57 pancreatic NENs (PanNENs)), treated with molecular f everolimus targeted therapy (MTT) with everolimus or sunitinib, first- (73:19) or second-line f sunitinib (sequential; 12:22) for progressive disease. Disease control rates (DCR: partial response or stable disease) at first-line were higher in all patients treated with everolimus than sunitinib (64/73 vs 12/19, P = 0.012). In PanNENs, DCR at first-line everolimus was 36/42 versus 9/15 with sunitinib (P = 0.062). Progression-free survival (PFS) at first-line everolimus was longer than sunitinib (31 months (95% CI: 23.1–38.9) vs 9 months (95% CI: 0–18.5); log-rank P < 0.0001) in the whole cohort and the subset of PanNENs (log-rank P < 0.0001). Median PFS at second-line MTT was 12 months with everolimus (95% CI: 4.1–19.9) vs 13 months with sunitinib (95% CI: 9.3–16.7; log-rank P = 0.951). Treatment with sunitinib (HR: 3.47; 95% CI: 1.5–8.3; P value: 0.005), KI67 >20% (HR: 6.38; 95% CI: 1.3–31.3; P = 0.022) and prior chemotherapy (HR: 2.71; 95% CI: 1.2–6.3; P = 0.021) were negative predictors for PFS at first line in multivariable and also confirmed at multi-state modelling analyses. Side effect (SE) analysis indicated events of serious toxicities (Grades 3 and 4: n = 13/85 for everolimus and n = 4/41 for sunitinib). Discontinuation rate due to SEs was 20/85 for everolimus versus 4/41 for sunitinib (P = 0.065). No additive toxicity of second-line MTT was confirmed. Based on these findings, and until reliable predictors of response become available, everolimus Endocrine Connections may be preferable to sunitinib when initiating MTT in progressive NENs. (2019) 8, 641–653 Introduction Neuroendocrine neoplasms (NENs) represent a the development of accurate pathologic and diagnostic heterogeneous group of tumours with variable clinical tests, but also because of the increased awareness of behaviour and unpredictable prognosis. Their incidence these tumours by clinicians (1). NEN biology has also has increased substantially in recent years, partly due to been clarified to some extent, paving the way for the https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve -19-0134 PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 642 in NENs development of novel molecular targeted therapies Subjects and methods (MTTs). MTTs with the MTOR inhibitor everolimus and the receptor tyrosine kinase (RTK) inhibitor sunitinib have Ninety-two consecutive patients with inoperable Stage been approved in clinical practice for locally advanced and IIIb and Stage IV NENs who received MTT with everolimus metastatic pancreatic NENs (PanNENs) (2, 3). In addition, or sunitinib, alone or sequentially, from 1 May 2008, to everolimus has been shown to exhibit activity in NENs 30 September 2018, were identified from a single tertiary originating from other tissues in phase III studies, whereas NEN referral centre in Athens, Greece. Patients’ files phase II studies have shown that RTK inhibitors could were chosen on the basis of a centrally reviewed biopsy- also be used in particular clinical settings in such NENs (4, proven, advanced or metastatic well-differentiated (WD) 5, 6). However, one of the main challenges regarding the NEN. Up until September 2018, patients were discussed effective treatment of NENs with these agents is related at multidisciplinary meetings and, for MTT initiation, to the paucity of validated biomarkers to select the best patients had to have disease progression as documented candidates for MTT and monitor side effects (SEs), survival by Response Evaluation Criteria in Solid Tumors (RECIST) outcomes and responses. (14). Patients were selected for MTT initiation with either In particular, the serine/threonine kinase mammalian everolimus or sunitinib after central assessment of cross- target of rapamycin (MTOR) signalling pathway plays sectional imaging. The selection of first-line MTT therapy a pivotal role in the regulation of cell proliferation was based on international guidelines, but also on the and metabolism, survival, motility and autophagy. Its presence of comorbidities, patient’s performance status and activation has been associated with a poor prognosis and preference. Hence, despite similar clinical presentation, high proliferation index (KI67) (7, 8). Everolimus interacts everolimus has been offered as first-line treatment in with the MTOR pathway and related intracellular pathways, some patients, whereas sunitinib has been offered to suppressing downstream multi-protein complexes and others. First-line MTT was administered to patients who increasing progression-free survival (PFS) across different experienced disease progression during watchful waiting sets of NENs (9, 10, 6, 3). On the other hand, angiogenesis or treatment with either somatostatin analogues (SSAs) in NENs is of paramount importance, though not yet fully or chemotherapy. Second-line (sequential) MTT with explained (11). A large placebo-controlled phase III trial sunitinib or everolimus was administered in a subset of has demonstrated that sunitinib, which is a potent multi- NEN patients after disease progression or serious toxicity targeted RTK inhibitor of VEGFR1-3, PDGFR-A, PDGFR-B while on first-line MTT with everolimus or sunitinib, and C-KIT, resulted in a PFS improvement in patients with respectively. Importantly, since neither everolimus nor metastatic pancreatic NENs (PanNENs) (2). sunitinib was officially licensed for the treatment of non- Small series on sequential use of MTT in PanNENs has pancreatic NENs before 2016, off-label administration of demonstrated similar PFS and tolerability for everolimus MTT to such patients required approval from the hospital and sunitinib at first- and second-line MTT ( 12). However, ethical/scientific committee and also the pertinent head-to-head comparison of MTT efficacy and toxicity national regulatory authority. Preliminary data in a subset is rather limited; randomized trials are lacking, whereas of 19 patients who received sequential MTT had previously there are only few small retrospective studies in PanNENs been published (12). Data on histopathology, grading and available, comparing everolimus with sunitinib (12, 13). secretory status, functional imaging properties (fluoro- Importantly, MTTs with everolimus and sunitinib have deoxyglucose positron emission tomography (FDG- distinct SE profiles, which differ from those of cytotoxic PET) and somatostatin receptor imaging (Octreoscan or chemotherapies. The continual and occasionally Ga-DOTATOC PET)), as well as prior lines of treatment prolonged nature of orally administered MTT leads to new including surgery, were retrospectively collected. challenges in their application and the management of Tumour-cell differentiation and KI67 labelling index potential additive toxicity when used sequentially. (LI) were determined from primary site, lymph node or The objectives of this study were to assess the anti- liver biopsies. Centrally, we retrospectively reassessed all tumour activity of MTT with everolimus or sunitinib the available tumour tissues according to the 2000 and administered alone or sequentially, in terms of the impact evolved 2017 WHO classification system for grading. of each drug in DCR and PFS and also to explore their Additionally, the stage of all patients was centrally SE profiles and potential additive toxicity, by means of re-evaluated based on the 8th edition of the American collecting real-world data. Joint Committee on Cancer (AJCC) classification for https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve K Daskalakis et al. Molecular targeted therapies 8:6 643 in NENs TNM staging (15, 16). Other clinicopathologic variables recorded at data entry (MTT initiation) included age, sex, genetic predisposition/family history, primary tumour site, secretory status, liver tumour load, somatostatin receptor positivity on octreoscan or Ga-PET/CT, FDG-PET/CT avidity, concomitant use of SSAs, previous treatments and the Charlson Comorbidity Index. The Charlson Comorbidity Index is a validated scale for survival (higher scores indicate more comorbidities) (17). Subsequently, all patients with NEN primaries were categorized into three groups according to the KI67 LI at the time of MTT Figure 1 initiation: Group 1: KI67 <3%, Group 2: KI67 3-20% and Markov multi-state model of cancer progression and mortality. Three possible states are considered: (1) MTT initiation, alive with progression, Group 3: KI67 >20%. (2) alive with new progression under MTT and (3) death. Duration of MTT administration, reason to stop treatment and MTT SE data were also extracted from analytical models, such as Cox’s model, but also allows patient records. SEs were graded using the National for simultaneous estimation of the effects of prognostic Cancer Institute Common Terminology Criteria for factors on the hazard of transitions between all clinically Adverse Events CTCAE v 5.0 (18). Disease progression was relevant health states of interest and avoids potentially assessed according to the Response Evaluation Criteria in important biases due to non-random censoring (20, 21). Solid Tumours (RECIST version 1.1) (14). We modelled transitions between three states: (A) MTT The study was approved by the Regional Ethics Review initiation, alive with progression at Stage IIIb or IV; (B) Board in Athens, Greece. Written informed consent was alive with new progression under MTT and (C) death obtained from all study participants. To ensure the quality (Fig.  1). The MKVPCI model allowed us to estimate of data reporting, we followed the STROBE statement (19). the separate effects of each prognostic factor: (i) new progression after first-line MTT (transition (A–B)); (ii) new progression after second-line MTT (B–B) and (iii) death Statistics after progression (B–C). In the estimation process, it was All analyses were done using the SPSS 23.0 software assumed that all cohort members were initially at risk of package (IBM SPSS Statistics, Armonk, NY, USA) and R either transition (A–B) or transition (A–C), until the time (version 3.2.4; R Foundation for Statistical Computing, of their progression (state B), death (state C) or censoring Vienna, Austria). To avoid immortal time bias, baseline at the end of follow-up (if they remained in state A). for overall survival (OS) and PFS analyses was defined Finally, shrinkage for control of confounders was applied as the first date for MTT. Preliminary analyses included between primary recorded variables and derived outcomes estimation of the chi-square test and the Kaplan–Meier in different patient states during the study period for survival curves for PFS and OS, stratified by a number the MKVPCI model (22). With the aim of eliminating of baseline variables and the log-rank testing of the validity threats to stepwise analysis, shrinkage methods differences in survival between the respective strata for applied here allowed us to address residual confounding patients receiving first-line and sequential second-line by entering each covariate in the model, along with prior MTT, respectively. Patients still receiving MTT without data that limit the size of the residual effects, e.g. when a exhibiting progression entered the analysis with PFS equal subset of patients switched from everolimus to sunitinib to the duration of treatment. Patients were censored at and vice versa (22). the time they were lost to follow-up or at the end of the study, in September 2018. Multivariable Cox regression PFS analysis was employed to assess prognostic factors Results at treatment initiation for first-line MTT. Additionally, Patient characteristics we employed the multi-state Markov piecewise constant intensities model (MKVPCI) to assess hazard ratios (HR) Ninety-two consecutive patients (34 females; mean with confidence intervals (CI) at first- and second-line MTT age ± s .d . at MTT initiation: 58 ± 14 years) with progressive and to validate the results of the Cox regression analysis. inoperable locally advanced (n = 8) or metastatic (n = 84) MKVPCI not only generalizes the single-endpoint survival well-differentiated (WD) NENs were included in the https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 644 in NENs analysis. Figure  2 presents the study flow. Patient and second-line treatment was 3.5 ± 5.4 months. Additionally, tumour characteristics are summarized in Table 1. A first- in this subset, the time interval did not differ significantly line MTT with everolimus or sunitinib was administered in either the everolimus to sunitinib group or the sunitinib in all 92 patients (everolimus, n = 73; sunitinib, n = 19). to everolimus group (P = 0.151). A second-line (sequential) MTT was administered in 34 The majority of patients had somatostatin receptor patients: in particular, 22 patients received first-line imaging (Octreoscan, Tektrotyd or Ga-DOTATOC PET) everolimus followed by sunitinib, and 12 were assigned performed prior to MTT initiation, showing a positive to first-line sunitinib followed by everolimus. Of the 92 uptake in 74 cases. FDG-PET was performed in a subset patients included in the study, 74 had sporadic tumours of 25 patients, of whom 12 had a positive uptake. and 8 familial NENs in the context of multiple endocrine neoplasia type 1 (MEN 1) syndrome. Based on primary Duration of treatment tumour location, cases were grouped into small intestinal NENs (n = 21), pancreatic NENs (PanNENs) (n = 57), lung/ Median duration of first-line MTT for the entire cohort thymic NENs (n = 7) and unknown primary origin NENs was 16.5  months (range 1–89). For everolimus, median (UPO-NENs, n = 7). Thirty-four patients had a functioning duration of first-line MTT was 21  months (range 1–89) tumour. Fifteen patients had KI67 <3%; 63 had KI67 and 6 months (range 1–27) for sunitinib. Median duration 3–20% and six had KI67 >20% (range of KI67 in these six of second-line MTT was 10  months (range 1–77) for the cases: 25–70%). In the remaining eight patients, the grade entire cohort: 10 months (range 3–77) for everolimus and was unknown. 9.5 months (range 1–59) for sunitinib. Surgery with the intention to cure or control hormonal symptoms was performed on 52 patients prior Anti-tumoural activity to MTT. First-line MTT was administered after progression while on SSAs or just observation in 65 patients. First- Disease control rate (DCR = partial response (PR) + stable line MTT constituting subsequent lines of treatment disease (SD)) during MTT administration was documented after disease progression with other chemotherapy was according to RECIST criteria at any time after MTT administered in 27 patients. Somatostatin analogues initiation. DCRs with respect to patient and tumour (SSAs) were co-administered in 86/92 patients at first- characteristics are presented in Table 2 for first-line MTT and line and 33/34 patients at second-line MTT, respectively. in Supplementary Table 2 (see section on supplementary For patients receiving sequential MTT (n = 34), the data given at the end of this article) for second-line MTT. time interval (mean ± s .d .) between the first-and the DCR was higher in patients receiving everolimus than sunitinib at first-line MTT (DCR: 64/73 (8PR-56SD) vs 12/19 (1PR-11SD); P = 0.012; Table  2). In patients with PanNEN (n = 57), DCR at first-line MTT was 36/42 with everolimus vs 9/15 with sunitinib (P = 0.062; Table  2). In the subgroup analysis of data from first-line MTT, DCR was higher in the everolimus group than the sunitinib group in patients with KI67 3–20% (45/48 vs 10/15; P = 0.039; Table 2) and advanced LTL (>10 or diffuse liver metastases; 42/49 vs 10/16; P = 0.029; Table  2). The DCR of second-line MTT did not differ significantly between patients receiving everolimus vs sunitinib (DCR: 8/12 (1PR-7SD) vs 17/22 (0PR-17SD), P = 0.687; Supplementary Table  1). Accordingly, in the subset of PanNEN patients who received second-line MTT (n = 28), DCR was 7/10 with everolimus vs 13/17 with sunitinib (P = 0.782; Supplementary Table  1). With regards to subgroup analysis for second-line MTT, no associations were evident between DCR and other potentially predictive parameters Figure 2 presented in Supplementary Table  1. With respect to Study flow diagram. MTT, molecular targeted therapy; NENs, neuroendocrine neoplasms. DCR, separate analysis was undertaken in the subset of https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve K Daskalakis et al. Molecular targeted therapies 8:6 645 in NENs Table 1 Patient characteristics at MTT initiation. Characteristics Everolimus group Sunitinib group P value Total number of patients (n = 92) No of patients (n = 73) No of patients (n = 19) Gender Male 46 12 0.991 Female 27 7 Age: mean ± s .d . 58 ± 14 56 ± 15 0.680 Inheritance Sporadic 67 17 0.751 Familial (MEN1) 6 2 Primary tumour site Pancreas 42 15 0.188 Small intestinal 19 2 Lung/thymus 7 0 Unknown primary (UPO) 5 2 Liver Tumour load No liver metastases 7 1 0.526 <5 unilobar liver metastases 11 1 5–10 unilobar liver metastases and/or 6 1 bilobar liver 49 16 metastases >10 liver metastases or diffuse liver metastases KI67 group KI67 <3% 13 2 0.645 KI67 3–20% 48 15 KI67 >20% 5 1 Secretory status Yes 29 5 0.281 No 44 14 Prior Surgery Yes 40 12 0.512 No 33 7 SRS or Ga-PET Positive 60 14 0.597 Negative 6 3 Unknown 7 2 FDG-PET FDG-PET positive 8 4 0.465 FDG-PET negative 10 3 Unknown 55 12 Previous treatment SSA or naive 56 9 0.012 Pre-treated with chemotherapy 17 10 Concomitant SSA Yes 70 16 0.100 No 3 3 CCI 0 52 13 0.406 1 14 6 2 6 0 3 1 0 Pearson chi-square test and Fisher’s exact test were conducted as appropriate. CCI, Charlson Comorbidity Index; FDG-PET, fluoro-deoxyglucose positron emission tomography; Ga, Gallium; MEN1, multiple endocrine neoplasia type 1; MTT, molecular targeted therapy; SSA, somatostatin analogue; SRS, somatostatin receptor scintigraphy. PanNENs, as presented in Supplementary Tables 2 and 3. Survival analysis of clinico-pathological prognostic As stratification by the KI67 proliferation index was linked factors at baseline with higher DCR to first-line everolimus in tumours with KI67 of 3–20%, we performed a receiver-operator curve Median PFS to first-line MTT was 31  months (95% CI: (ROC) analysis to identify non-responders (progressive 23.1–38.9) in the everolimus group versus 9  months disease (PD) recorded only) in the whole cohort and in (95% CI: 0–18.5) in the sunitinib group, respectively (log- the subset of PanNENs. However, KI67 failed to predict rank P < 0.0001; Fig.  3). Median PFS to second-line MTT treatment response in these ROC analyses (AUC = 0.57 in was 12 months (95% CI: 4.1–19.9) in the everolimus group NEN and AUC = 0.443 in PanNENs; Supplementary Figs 1 versus 13  months (95% CI: 9.3–16.7) in the sunitinib and 2). group, respectively (log-rank P = 0.951; Supplementary Functional imaging properties with respect to SRS Fig.  1). On multivariable Cox regression PFS analysis and FDG-PET avidity did not correlate with DCR in any at first-line MTT, the selection of sunitinib (HR: 3.47; subgroup (comparison: everolimus vs sunitinib; Table  2 95% CI: 1.5–8.3; P = 0.005), KI67 >20% (HR: 6.38; and Supplementary Table 1). 95% CI: 1.3–31.3; P = 0.022) and prior administration https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 646 in NENs Table 2 Disease control rates (partial response or stable disease) according to RECIST during first-line MTT. Patient characteristics (n = 92) DCR in everolimus group DCR in sunitinib group P value n = 64/73 n = 12/19 0.012 Gender Male 41/46 9/12 0.342 Female 23/27 3/7 0.061 Age: mean ± s .d . 58 ± 13.6 61 ± 15.4 0.549 Inheritance Sporadic 59/67 11/17 0.069 Familial (MEN1) 5/6 1/2 0.464 Primary tumour site Pancreas 36/42 9/15 0.062 Small intestinal 18/19 1/2 0.271 Lung/thymus 6/7 0/0 – Unknown primary (UPO) 4/5 2/2 0.999 Liver Tumour load No liver metastases 6/7 1/1 0.999 <5 unilobar liver metastases 10/11 1/1 0.999 5–10 unilobar liver metastases and/or 6/6 1/1 – bilobar liver metastases 42/49 9/16 0.039 >10 liver metastases or diffuse liver metastases KI67 Group G1 (KI67 <3%) 11/13 2/2 0.999 G2 (KI67 3–20%) 45/48 10/15 0.029 G3 (KI67 >20%) 2/5 0/1 0.999 Secretory status Yes 27/29 4/5 0.488 No 37/44 8/14 0.062 Prior surgery Yes 37/40 8/12 0.072 No 27/33 4/7 0.316 SRS or Ga-PET Positive 53/60 9/14 0.062 Negative 6/6 3/3 – Unknown 5/7 0/2 0.167 FDG-PET FDG-PET positive 5/8 2/4 0.231 FDG-PET negative 10/10 2/3 0.999 Unknown 49/55 8/2 0.099 Previous treatment SSA or naive 52/56 6/9 0.073 Pre-treated with chemotherapy 12/17 6/10 0.683 CCI 0 45/52 9/13 0.237 1 13/14 3/6 0.061 2 5/6 0/0 – 3 1/1 0/0 – Pearson chi-square test and Fisher’s exact test were conducted within subgroups as appropriate. Bold indicates statistical significance. CCI, Charlson Comorbidity Index; CI, confidence interval; FDG-PET: fluoro-deoxyglucose positron emission tomography; Ga, Gallium; HR, hazard ratio; MEN1, multiple endocrine neoplasia type 1; MTT, molecular targeted therapy; SSA, somatostatin analogue; SRS, somatostatin receptor scintigraphy. 1st line MTT B 100 2nd line MTT Everolimus Everolimus Sunitinib Sunitinib 80 ... log-rank p < 0.0001 log-rank p=0.951 Figure 3 0 (A) Progression-free survival (PFS) to first-line molecular targeted therapy (MTT) stratified by 0 10 20 30 40 0 10 20 30 MTTagent (everolimus vs sunitinib) with patient at Time from MTT initiation, months Time from 2nd line MTT initiation, months risk table below. (B) Progression-free survival No at risk No at risk (PFS) to second-line molecular targeted therapy Everolimus 73 53 40 25 16 Everolimus 12 84 2 (MTT) stratified by MTT agent (everolimus vs Sunitinib 19 64 00 Sunitinib 22 11 43 sunitinib) with patient at risk table below. https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve Progression Free Survival % Progression Free Survival % K Daskalakis et al. Molecular targeted therapies 8:6 647 in NENs of chemotherapy (HR: 2.71; 95% CI: 1.2–6.3; P = 0.021) CI: 1.59–4.75) as predictors for progression to first-line were demonstrated as negative independent prognostic MTT (Table 4). Additionally, in MKVPCI analysis, HR >1.5 factors for PFS under MTT (Table  3). For PanNENs for progression were encountered in patients with lung/ (n = 57) in particular, median PFS under first-line MTT thymic NENs and higher CCI receiving first-line MTT, as was 31  months (95% CI: 24.5–37.5) in the everolimus well as in patients with advanced LTL at second-line MTT group (n = 42) versus 9 months (95% CI: 2.3–15.7) in the (risk for progression or death, Table 4). sunitinib group (n = 15), respectively (log-rank P < 0.0001; Fig.  4). Cox regression analysis for PFS of first-line MTT Side effects in PanNENs confirmed that sunitinib treatment (HR: 4.9; 95% CI: 1.8–13.9; P = 0.002) and KI67 >20% (HR: 76.3; MTT with everolimus or sunitinib was generally well 95% CI: 5–1171; P = 0.002) were negative independent tolerated. From the entire cohort of 92 patients, 56 (61%) prognostic factors (Supplementary Table 4). experienced any SE during first- or second-line MTT, mostly Log-rank OS analysis, did not exhibit any differences grades 1 and 2 toxicities. SEs grade >3 were encountered between patients receiving everolimus compared to in 16 patients (17.4%). Table  5 summarizes the most sunitinib as first- and second-line MTT, respectively (log- common SE and the frequency of their appearance, as rank P = 0.510 and log-rank P = 0.451, respectively; Fig. 5). well as the SE grade. Fatigue, gastrointestinal symptoms MKVPCI analysis with shrinkage of investigated (nausea, vomiting, diarrhoea, abdominal pain) and variables, confirmed the choice of sunitinib (HR: 1.88; haematological complications (reduced platelet, 95% CI: 1–3.5), KI67 >20% (HR: 4.77; 95% CI: 1.65–13.8) haematocrit and white blood cell count) were the most and prior administration of chemotherapy (HR: 2.75; 95% frequent grade 1–2 SE noticed. Twenty patients treated with Table 3 Multivariate Cox regression model for progression-free survival (PFS) for all patients receiving first-line molecular targeted therapy (MTT). Prognostic factor for PFS HR 95% CI P value MTT agent  Everolimus 1  Sunitinib 3.47 1.46–8.25 0.005 Age at baseline 0.99 0.96–1.01 0.285 Site of primary  Pancreas 1  Small intestine 0.71 0.28–1.76 0.453  Lung/thymus 1.16 0.27–5.03 0.842  Unknown primary (UPO) 1.81 0.31–10.63 0.511 Liver tumour load  No liver metastases 1 0.75  <5 unilobar liver metastases 1.98 0.31–12.55 0.467  5–10 unilobar and/or bilobar liver metastases 0.95 0.15–6.15 0.954  >10 liver metastases or diffuse liver metastases 1.51 0.32–7.13 0.603 KI67 groups  KI67 <3% 1  KI67 3–20% 0.751 0.32–1.79 0.516  KI67 >20% 6.38 1.30–31.25 0.022 SRS or Ga-PET  Negative 1 0.209  Positive 0.99 0.35–2.86 0.996  Unknown 0.31 0.06–1.57 0.158 Prior resective surgery  No 1  Yes 0.7 0.35–1.37 0.295 Prior chemotherapy  No 1  Yes 2.71 1.17–6.3 0.021 Bold indicates statistical significance. CI, confidence interval; Ga, Gallium; HR, hazard ratio; MEN1, multiple endocrine neoplasia type 1; MTT, molecular targeted therapy; SRS, somatostatin receptor scintigraphy. https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 648 in NENs AB 1st line MTT in 2nd line MTT in PanNEN PanNENs Everolimus Everolimus Sunitinib Sunitinib 80 log-rank p=0.722 log-rank p<0.0001 Figure 4 (A) Progression-free survival (PFS) to first-line 20 20 molecular targeted therapy (MTT) in patients with pancreatic neuroendocrine neoplasms (PanNEN) 0 0 stratified by MTT agent (everolimus vs sunitinib) 0 10 20 30 40 0 10 20 30 40 with patient at risk table below. (B) Progression- Time from 2nd line MTT initiation, months Time from MTT initiation, months free survival (PFS) to second-line MTT in patients No at risk No at risk with PanNENs stratified by MTT agent (everolimus Everolimus422922148 Everolimus118 42 2 Sunitinib155 30 0 Sunitinib17103 33 vs sunitinib) with patient at risk table below. everolimus manifested uncontrolled diabetes mellitus, in the sunitinib group (P value: 0.581). These figures for whereas two patients had a new onset of hypertension second-line MTT in PanNENs were 2/11 versus 7/17 for while on sunitinib treatment. Of the 16 patients who everolimus and sunitinib, respectively (P = 0.689). developed serious toxicities (grade 3 and above), SE most Finally, there was no additive toxicity at second-line commonly included bone marrow suppression, acute MTT neither for everolimus nor for sunitinib. In particular, renal failure and/or pneumonitis leading to treatment comparable SE rates were encountered between patients discontinuation. Another 12 patients discontinued MTT receiving first- (37/73) and second-line everolimus (3/12; mainly due to fatigue. All other patients who developed P = 0.122), whereas lower SE rates were demonstrated at grades 1–2 SE were given medications for symptomatic second- (5/22) compared to first-line sunitinib (14/19, relief and had MTT dosage reduction as per guidelines. P = 0.001). Previous chemotherapy administration was The discontinuation rate due to SE was as high as 20/85 not associated to additive toxicity under MTT either for everolimus versus 4/41 for sunitinib (P = 0.065). (P = 0.463). Among the 85 patients receiving everolimus as first- (n = 73) or second-line MTT (n = 12), SE were encountered in 40 patients. Thirteen patients treated with everolimus Discussion had grade 3 SE and above, mainly consisting of acute renal failure and pneumonitis. On the other hand, among the This study assessed the outcomes of patients with NENs 41 patients receiving sunitinib as first- ( n = 19) or second- receiving MTT with everolimus or sunitinib, as a first- line MTT (n = 22), SEs were encountered in 25 patients, and second-line (sequential) MTT, mainly combined with toxicity of grade 3 and above being observed in four with SSAs in a single-centre observational setting. A patients. higher PFS benefit was found after uni- and multivariable In the subset of PanNENs (n = 56), 24/41 patients analysis (HR: 3.47; 95% CI: 1.5–8.3; P = 0.005) and who received everolimus experienced any SE during first- confirmed by multi-state modelling (HR: 1.88; 95% CI: line MTT, mostly grades 1 and 2 toxicities versus 10/15 1–3.5) for patients treated with everolimus at first-line A B 100 log-rank p=0.451 log-rank=0.510 40 40 1st line MTT 2nd line MTT 20 20 Everolimus Everolimus Figure 5 Sunitinib Sunitinib (A) Overall survival (OS) from molecular targeted 0 0 therapy (MTT) initiation stratified by MTT agent 0 20 40 60 80 0 20 40 60 80 (everolimus vs sunitinib) with patient at risk table Time from 2nd MTT initiation, months Time from MTT initiation, months below. (B) Overall survival (OS) from second-line No at risk No at risk MTT initiation stratified by MTT agent (everolimus Everolimus725632168 Everolimus129 64 2 Sunitinib 14 12 11 73 Sunitinib 22 11 73 2 vs sunitinib) with patient at risk table below. https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve Cumulative Survival % Progession Free Survival % Progression Free Survival % Cumulative Survival % K Daskalakis et al. Molecular targeted therapies 8:6 649 in NENs Table 4 Results of multi-state Markov modelling of prognostic effects on progression and death. Progression under Progression under sequential 2nd line Death, 1st line Death, 2nd line 1st line MTT MTT MTT MTT Characteristics HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Total number of patients (n = 92) MTT Everolimus 1 1 1 1 Sunitinib 1.88 (1.00–3.52) 1.02 (0.43–2.41) 1.26 (0.27–5.89) 1.96 (0.55–6.98) Gender Male 1 1 1 1 Female 0.98 (0.58–1.67) 0.46 (0.18–1.18) 0.93 (0.30–2.86) 0.24 (0.05–1.06) Age Per 10 years 0.94 (0.77–1.15) 0.66 (0.50–0.89) 1.00 (0.65–1.55) 0.66 (0.46–0.95) Inheritance Sporadic 0.88 (0.38–2.06) 1.01 (0.33–3.02) 1.17 (0.15–9.03) 0.78 (0.21–2.90) Familial (MEN1) 1 1 1 1 Primary tumour site Pancreas 1 1 1 1 Small intestinal 0.71 (0.37–1.35) 0.38 (0.05–2.87) 1.38 (0.43–4.42) N/A Lung/thymus 1.90 (0.79–4.57) 1.36 (0.31–5.92) 1.47 (0.17–12.51) 1.13 (0.15–8.70) Unknown primary (UPO) 0.80 (0.24–2.62) N/A N/A N/A Liver Tumour load No liver metastases 1 1 1 1 <5 unilobar liver metastases 0.75 (0.27–2.08) 0.18 (0.02–1.69) 1.12 (0.07–18.3) 0.07 (0.01–0.92) 5–10 unilobar liver 0.48 (0.14–1.64) 5.83 (0.22–157) 1.12 (0.07–18.0) 5.26 (0.20–141) metastases and/or bilobar 0.70 (0.31–1.56) 0.14 (0.02–1.27) 1.59 (0.20–12.4) 6.38 (0.02–1.42) liver metastases >10 liver metastases or diffuse liver metastases KI67 at MTT KI67 <3% 1 1 1 1 initiation KI67 3–20% 1.00 (0.50–2.02) 0.98 (0.29–3.35) 0.32 (0.08–1.21) 0.99 (0.22–4.45) KI67 >20% 4.77 (1.65–13.8) N/A 8.07 (1.63–39.9) N/A Secretory status Yes 0.88 (0.51–1.50) 0.88 (0.36–2.19) 0.64 (0.21–1.92) 0.59 (0.21–1.71) No 1 1 1 1 Prior surgery Yes 0.77 (0.46–1.31) 0.68 (0.27–1.70) 0.84 (0.27–2.70) 0.36 (0.12–1.04) No 1 1 1 1 SRS or Ga-PET Positive 0.92 (0.48–1.78) 0.52 (0.19–1.43) 0.36 (0.11–1.20) 2.16 (0.28–16.6) Negative/unknown 1 1 1 1 FDG-PET Positive 1.04 (0.74–1.48) 0.86 (0.50–1.48) 1.13 (0.50–2.54) 0.99 (0.48–2.02) Negative 1 1 1 1 Previous treatments SSA or naive 1 1 1 1 Pre-treated with 2.75 (1.59–4.75) 0.38 (0.05–2.98) 2.38 (0.70–8.10) 0.29 (0.04–2.36) chemotherapy CCI 0 1 1 1 1 1 0.65 (0.33–1.28) 0.95 (0.31–2.95) 0.80 (0.21–2.98) 2.81 (0.94–8.43) 2 1.53 (0.60–3.91) 0.88 (0.12–6.68) 1.19 (0.15–9.54) N/A 3 N/A N/A N/A N/A CCI, Charlson Comorbidity Index; CI, confidence interval; FDG-PET, fluoro-deoxyglucose positron emission tomography; Ga, Gallium; HR, hazard ratio; MEN1, multiple endocrine neoplasia type 1; MTT, molecular targeted therapy; SRS, somatostatin receptor scintigraphy; SSA, somatostatin analogue. MTT irrespective of the tissue of origin. Overall, DCR SE was as high as 20/85 for everolimus versus 4/41 for was higher in all patients treated with everolimus vs sunitinib (P = 0.065). Foremost, no additive toxicities sunitinib (88 vs 63%, P = 0.012), whereas a similar trend at sequential MTT application were encountered in was noted for the PanNEN group (86% with everolimus this series. versus 60% with sunitinib (P = 0.062)). In addition, prior Generally, dose escalation or an increase in frequency administration of chemotherapy (HR: 2.75; 95% CI: of SSAs may be considered in G1–2 NEN patients with KI67 1.59–4.75) and a KI67 proliferation index >20% LI <10% and PD, being previously treated with a standard (HR: 4.77; 95% CI: 1.65–13.8) were identified as SSA dose (23, 24). Robust evidence based on phase III RCTs predictors for progression or death under first-line has established the role of MTT with either everolimus MTT. However, no difference in OS between the two or sunitinib in progressive WD G1 and G2 PanNENs (2, groups (everolimus versus sunitinib, first- and second- 3). In PanNENs, MTT can be first- or second-line therapy, line) was observed. Comparable safety profiles were subsequent to SSAs or chemotherapy, respectively (12, 9). evident with both agents; serious toxicities were in the However, there are few head-to-head comparisons of the range of 10–15%, and the discontinuation rate due to anti-tumour activity and safety profile of MTT in NEN. https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 650 in NENs Table 5 Adverse effects. Maximum toxicity grade 1st line everolimus 1st line sunitinib 2nd line everolimus 2nd line sunitinib Side effects Grade 1 and 2 Grade 3 Grade 1 and 2 Grade 3 Grade 1 and 2 Grade 3 Grade 1 and 2 Grade 3 Haematological 7 1 1 0 1 1 0 0 Gastrointestinal 6 0 3 0 1 0 4 0 intolerance Pneumonitis 0 4 0 1 Hepatotoxicity 2 0 0 0 0 0 0 0 Nephrotoxicity 1 6 0 0 0 0 1 0 Mucocutaneous Dermatitis 4 0 2 0 1 0 1 0 Stomatitis 7 0 1 0 1 0 1 0 Palmar-plantar 1 0 0 0 0 0 0 0 syndrome Fatigue 8 2 5 2 0 0 3 1 Diabetes mellitus 15 1 0 0 4 0 0 0 Hypertension 0 0 1 0 0 0 1 0 Hence, to date, selection of either everolimus or sunitinib ex vivo sensitivity to rapalogues (26). A recent study has been made based on local regimen availability and demonstrated that over-activation of GSK3 may be a preferences, as well as the patient’s anticipated SE profiles. potential marker of everolimus resistance in PanNEN cell Integration of other available modalities, such as peptide lines (27). Additionally, somatic mutations linked with the receptor radionuclide therapy (PRRT), may also be MTOR pathway are encountered in 15% of PanNENs (28). considered according to the availability of this treatment Regarding MTT with RTK inhibitors, SVEGFR-3, IL8 and modality. For the small intestinal and bronchial primaries, SDF-1A were recently identified as predictors of response recent randomized trials also favour the use of everolimus to sunitinib in a phase II trial (29). However, validation (10, 6). However, the results of RADIANT-4 trial were not of clinical trials and incorporation of these results in the available at MTT initiation for the few patients (n = 4) clinical setting are largely missing. with non-pancreatic NENs who received sequential MTT Direct comparison of MTTs with respect to their with first-line sunitinib in our study ( 6). Importantly, benefits and risks is currently incomplete. Therefore, higher DCR and prolonged PFS were encountered in to date, there are no reference standards supporting our study in all NEN patients treated with first-line the use of one over the other. Everolimus has been everolimus. Of particular interest in PanNENs (n = 57), approved as first-line therapy in all NENs, whereas DCR with everolimus achieved marginal statistical sunitinib has been approved for PanNENs only. With significance ( P = 0.062) in comparison with sunitinib, but respect to PanNENs, no randomized clinical trial has still a PFS benefit was clearly evident in these patients provided a head-to-head comparison regarding efficacy in crude and multivariable analyses. Although sunitinib and safety. Moreover, published comparative studies is not currently licensed for NENs of non-pancreatic of retrospective real-world data are scarce (13). A recent origin, primary tumour site was not demonstrated as an network meta-analysis comparing DCR for different independent predictor of PFS at first- and second-line MTT NEN therapies from all available RCTs demonstrated in multivariable Cox regression analysis. Additionally, the that single therapy with everolimus and combination rationale of the present study in terms of the included therapies were most effective (30). Specifically, everolimus patient population is also in accordance with presently alone or in combination with SSA or interferon achieved ongoing, phase I, II and III clinical trials that investigate the highest DCR, followed by single treatment with SSA, a wide range of emerging RTK inhibitors in the treatment interferon, sunitinib and placebo (30). These results are of progressive NENs from various tissues of origin (25). in accordance with the findings of our study, where using Currently, MTT selection and sequencing for NEN real-world data, everolimus alone or more commonly management is not relying on molecularly tailored in combination with SSAs was associated with longer choices due to a lack of biomarkers to predict and monitor PFS at first-line MTT compared to sunitinib. Apart from treatment response in NEN patients. Preclinical studies traditional uni- and multivariable analyses, our study have demonstrated that aberrations of PI3KCA and PTEN also applied modern statistical methods to control and elevated PAKT in the MTOR pathway may predict biases inherent in cohort studies, which confirmed that https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve K Daskalakis et al. Molecular targeted therapies 8:6 651 in NENs everolimus may be preferable to sunitinib when initiating Importantly, the seminal randomized controlled trials MTT in progressive NENs (HR: 1.88 for progression at that resulted in MTT monotherapy approval for NENs in first-line MTT). Additionally, prior administration of clinical practice do not report neither OR nor SD rates (2, chemotherapy (HR: 2.75) and KI67 >20% (HR: 4.77) 6, 3); and no studies are currently available reporting DCR were identified as predictors for progression to first-line of MTT combined with SSAs. MTT. Finally, the findings of the present study may also In the present study, the safety profile of everolimus guide future research by elucidating the role of different (as single agent or combined with SSAs) was similar to prior MTT agents and that of predictive clinicopathological reports of everolimus monotherapy and a recent phase II markers in NEN management with MTTs, thus facilitating trial on everolimus and octreotide LAR combination in appropriate trial design. gastroenteropancreatic NENs (EVERLAR trial), suggesting In the subset of PanNENs, the reasons for longer that prompt management of everolimus SE may reduce PFS (31  months) in everolimus-treated patients in our the potential toxicity of its combination with SSAs (36, study compared to the corresponding figure (11 months) 10, 6). To date, reports on the safety profile of sunitinib reported in RADIANT-3 trial could have been multifactorial combined with SSAs analogues in NEN treatment are (31). RADIANT-3 trial reports a median follow-up period lacking. Our study confirmed a SE rate of sunitinib, mainly of 17  months and a median duration of treatment with combined with SSAs in accordance with the seminal study everolimus 8.79 months (range, 0.25–27.47), as compared by Raymond et al. on sunitinib monotherapy in PanNENs with median duration of 21  months (range 1–89) in that reported approximately 30% SE rate and grade 3 or our study. Additionally, only 31% of the patients in 4 toxicity in the range of 10–12% (2). Additionally, we the everolimus group in RADIANT-3 were administered report a lack of additive toxicity related to sequential MTT treatment for a minimum of 12 months, as compared with in NEN management. Importantly, our findings on MTT 51/73 in patients treated with first-line everolimus in our safety profile should be interpreted in the light of our study study. Finally, previous chemotherapy administration was design as the duration of MTT was often prolonged, that as high as 50% in the RADIANT-3 trial, as compared to only is, until disease progression or serious toxicity occurred 17/73 in the everolimus group in our study. Importantly, and the MTT administration was sequential in a subset of prior chemotherapy administration was demonstrated to patients. However, the retrospective nature of our study be a negative independent prognostic factor of PFS and a and the lack of quantifiable information with appropriate predictor of resistance to MTT in our study. quality of life questionnaires while on MTT, limits indeed Generally, in hypervascularized WD NENs, our ability to accurately determine the safety profile of morphological changes that are clearly observed MTT agents investigated here. after exposure to MTTs such as everolimus, and most Our study has several limitations, the most important importantly to anti-angiogenic drugs, e.g. sunitinib, limitation being in its retrospective nature. This may may be poorly assessed by the currently applied RECIST explain the allocation of a different number of patients criteria, which apparently reflect tumour shrinkage or in each MTT group and differences in duration of progression in size. Several trials have challenged the treatment. Additionally, NEN heterogeneity plus the validity of traditional RECIST dimension criteria to assess inclusion of NENs originating both from the pancreas and the anti-tumoural effects of MTT, and have proposed the small intestine, as well as that of NENs of thoracic incorporating the evaluation of changes in tumour and unknown origin, may have confounded the results. density using contrast enhanced computed tomography, However, considering the distinct characteristics of dynamic contrast magnetic resonance imaging or high- PanNENs and those of other NENs, our efficacy analysis frequency Doppler ultrasonography (32, 33). Taking into for the PanNEN subset was performed separately. Finally, consideration the aforementioned limitations of RECIST the fact that the patient population in our study only criteria, we assessed DCR rather than objective responses includes referrals to a tertiary centre may include a certain in order to evaluate the effects of MTT, as PR at first- referral bias. Importantly, the MKVPCI model and the (n = 8) and second-line MTT (n = 1) were indeed only few extension of shrinkage methods to bias modelling applied in our cohort and mainly observed in patients receiving in the present study allowed us to check for variables everolimus (n = 8). Additionally, SSAs that were commonly that were known or presumed confounders, as well as for used in combination with MTT in the present study have sources of uncertainty, selection bias, misclassification stabilizing rather than shrinkage effects in NENs (34, 35); and unmeasured confounders, thus adding to the validity thus, DCR assessment seems more reasonable in this setting. of the study results (21). The main strengths of this study https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve PB–13 K Daskalakis et al. Molecular targeted therapies 8:6 652 in NENs survival and circulating biomarkers from the randomized, phase III are the central assessment of responses according to RADIANT-3 study. Journal of Clinical Oncology 2016 34 3906–3913. RECIST criteria and making use of centralized pathology (https://doi.org/10.1200/JCO.2016.68.0702) by dedicated radiologists and pathologists involved in the 4 Phan AT, Halperin DM, Chan JA, Fogelman DR, Hess KR, Malinowski P, Regan E, Ng CS, Yao JC & Kulke MH. Pazopanib and institutional multidisciplinary tumour board. depot octreotide in advanced, well-differentiated neuroendocrine In conclusion, our comparison of real-world data in tumours: a multicentre, single-group, phase 2 study. Lancet: patients treated with MTT suggests that, between the two Oncology 2015 16 695–703. (https://doi.org/10.1016/S1470- 2045(15)70136-1) currently approved targeted agents for NEN treatment, the 5 Strosberg JR, Cives M, Hwang J, Weber T, Nickerson M, Atreya CE, MTOR inhibitor everolimus may be preferable to the RTK Venook A, Kelley RK, Valone T, Morse B, et al. A phase II study of inhibitor sunitinib in terms of its anti-tumour activity axitinib in advanced neuroendocrine tumors. Endocrine-Related Cancer 2016 23 411–418. (https://doi.org/10.1530/ERC-16-0008) at first-line MTT; this may have important implications 6 Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, for MTT selection and sequencing in clinical practice. Raderer M, Lahner H, Voi M, et al. Everolimus for the treatment Comparable safety profiles and no additive toxicities at of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo- sequential MTT application were encountered with both controlled, phase 3 study. Lancet 2016 387 968–977. (https://doi. agents. Despite the sophisticated statistical methodology org/10.1016/S0140-6736(15)00817-X) of this study, it is clear that a prospective, randomized, 7 Capdevila J, Casanovas O, Salazar R, Castellano D, Segura A, Fuster P, Aller J, Garcia-Carbonero R, Jimenez-Fonseca P, Grande E, controlled trial will further clarify the value of MTT in et al. Translational research in neuroendocrine tumors: pitfalls NENs with respect to treatment selection and sequencing. and opportunities. Oncogene 2017 36 1899–1907. (https://doi. 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(https://doi.org/10.1634/ Schrader J, Grossman A, Pacak K, Beuschlein F, Auernhammer CJ, theoncologist.2017-0622) Received in final form 17 April 2019 Accepted 24 April 2019 Accepted Preprint published online 26 April 2019 https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0134 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 12:32:33AM via Deepdyve

Journal

Endocrine Connections – Bioscientifica

Published: Jun 1, 2019

Keywords: neuroendocrine neoplasms

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