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Everolimus treatment for neuroendocrine tumors: latest results and clinical potential:

Everolimus treatment for neuroendocrine tumors: latest results and clinical potential: 683905 TAM0010.1177/1758834016683905Therapeutic Advances in Medical OncologyS Pusceddu, E Verzoni research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Everolimus treatment for neuroendocrine 2017, Vol. 9(3) 183 –188 DOI: 10.1177/ tumors: latest results and clinical potential © The Author(s), 2017. Reprints and permissions: http://www.sagepub.co.uk/ Sara Pusceddu, Elena Verzoni, Natialie Prinzi, Alessia Mennitto, Daniela Femia, Paolo journalsPermissions.nav Grassi, Laura Concas, Claudio Vernieri, Giuseppe Lo Russo and Giuseppe Procopio Abstract: Neuroendocrine tumors (NETs) are a heterogeneous class of diseases characterized by challenging management. Preclinical evidence shows that the PI3K/AKT/mTOR signaling pathway plays a central role in the pathogenesis and progression of NETs. Everolimus is a direct inhibitor of this pathway, and therefore this molecule appears to be a well-grounded strategy for the treatment of NETs, capable of changing clinical practice. The efficacy and safety of everolimus was demonstrated in the RADIANT trials. In this work, we comment on the results of the RADIANT trials, and other recent key evidence from fully published clinical trials on everolimus, and we discuss the current role of everolimus in the treatment of NETs. Keywords: everolimus, neuroendocrine tumors, RADIANT trials Correspondence to: Introduction safety of everolimus was demonstrated in the Giuseppe Procopio, MD Neuroendocrine tumors (NETs) are a heteroge- RADIANT trials [Yao et  al. 2010; Pavel et  al. Medical Oncology, Istituto Nazionale Tumori, Via neous class of neoplasms with increasing inci- 2011; Yao et  al. 2011, 2015]. In this work, we Venezian 1, 20100, Milan, dence worldwide [Fraenkel et  al. 2012]. Tumor comment on the results of the RADIANT trials, Italy giuseppe.procopio@ behavior and patient survival largely depend upon and other recent key evidence from fully pub- istitutotumori.mi.it a number of different factors such as tumor his- lished clinical trials on everolimus, and we dis- Sara Pusceddu, MD tology, primary site, staging and proliferative cuss the current role of everolimus in the Elena Verzoni, MD Natialie Prinzi, MD index [Panzuto et al. 2014]. treatment of NETs. Alessia Mennitto, MD Daniela Femia, MD Paolo Grassi, MD The management of NETs is challenging, and Laura Concas, MS therefore effective and safe therapeutic options Everolimus in patients with pancreatic NETs Claudio Vernieri, MD Giuseppe Lo Russo, MD for the treatment of these tumors are actively pur- The open-label, phase II RADIANT 1 trial has Medical Oncology, Istituto sued in clinical research. In particular, targeted assessed the efficacy and safety of everolimus in Nazionale Tumori, Milan, Italy therapies such as sunitinib and everolimus have patients with metastatic pancreatic NET (pNET) shown promising results and have thus entered who have progressed on prior chemotherapy [Yao clinical practice [Barbieri et al. 2014; Kulke et al. et al. 2010]. Patients were stratified according to 2008; Raymond et  al. 2011; Ito et  al. 2013; Yao the use of everolimus 10 mg/day only (n = 115), et  al. 2008, 2010; Pavel et  al. 2011; Yao et  al. or everolimus 10 mg/day + octreotide long-acting 2011, 2016]. release (LAR) (n = 45). At central analysis, the rate of partial response was 9.6% with everolimus A bulk of preclinical evidence has shown that only and 4.4% with everolimus + octreotide the PI3K/AKT/mTOR signaling pathway plays LAR; the incidence of stable disease was 67.8% a central role in the pathogenesis and progres- and 80.0%, respectively. Median progression-free sion of NETs [Manfredi et  al. 2015; Yao et  al. survival (PFS) was 9.7 months with everolimus 2008; Pusceddu et  al. 2016a; Procopio et  al. only and 16.7 months with the combination strat- 2012; Pusceddu et  al. 2016]. Everolimus is a egy. On this basis, it was suggested that everoli- direct inhibitor of this pathway, and therefore mus 10 mg/day, with or without concomitant this molecule appear to be a well-grounded octreotide LAR, presents a degree of antitumor strategy for the treatment of NETs, capable of activity in patients with advanced pNETs who changing clinical practice. The efficacy and have failed prior chemotherapy. journals.sagepub.com/home/tam 183 Therapeutic Advances in Medical Oncology 9(3) Further to the RADIANT 1 trial, the interna- Median PFS by central review, the primary end- tional randomized, placebo-controlled, phase III point of the trial, was 16.4 months in the combi- RADIANT 3 trial has evaluated patients with nation arm and 11.3 months with octreotide LAR advanced pNET (low or intermediate-grade) who only. The HR for progression between the two showed radiologic progression within the previ- groups did not reach statistical significance (0.77, ous 12 months before inclusion [Yao et al. 2012]. 95% CI, 0.59–1.00). Those findings did not It is the largest study ever conducted in the setting match those reported at the local review of PFS, of NETs. Patients were randomly assigned to which suggested a benefit for everolimus (12.0 either everolimus 10 mg/day (n = 207) + best months versus 8.6; HR, 0.78, 95% CI, 0.62– supportive care or placebo (n = 203). Of note, 0.98). Moreover, it should be noted that World patients assigned to placebo who showed radio- Health Organization performance status was logical progression during the study (73%) were poorer in the combination arm compared with offered open-label everolimus. Median PFS was the octreotide-only group. Moreover, patients longer in the everolimus group, compared with assigned to the combination therapy presented a placebo [11.0 versus 4.6 months; hazard ratio higher incidence of pulmonary primary tumors (HR), 0.35; 95% confidence interval (CI), 0.27– and bone involvement, had higher chromogranin 0.45; p < 0.001]. Statistical analysis showed that A (CgA) values at baseline, and were more heavily the estimated proportion of patients free from pretreated. Those imbalances have contributed to progression at 18 months was 34% (95% CI, 26– the lack of statistical differences between the two 43) with everolimus and 9% (4–16) with placebo. groups in terms of PFS, as also shown at a dedi- Remarkably, the PFS advantage shown with cated multivariate analysis [Pusceddu et al. 2016; everolimus was consistent in all the subgroups Yao et al. 2012]. analyzed, independently from age, sex, ethnicity, prior exposure to somatostatin analogues (SSAs), The results of the RADIANT 2 study have led to performance status, and tumor differentiation. several subanalyses. First, a subanalysis including These findings suggest that everolimus is effective only patients with pulmonary NET (everolimus in all patients with well-differentiated or moder- + octreotide LAR, n = 33; octreotide LAR only, ately-differentiated pNET, without any parame- n = 11) showed a 2.4-fold longer PFS in the com- ter which may suggest exclusion from treatment. bination arm, associated with a 28% reduction in On the other hand, overall survival was similar in the risk of progression (13.6 versus 5.6 months; the two groups (HR, 1.05; 95% CI, 0.71–1.55), HR, 0.72; 95% CI, 0.31–1.68) [Fazio et al. 2013]. most likely due to the high number of patients In this same analysis, tumor shrinkage was who were switched to everolimus from placebo. reported by a >2-fold proportion of patients on everolimus + octreotide, compared with those Interestingly, the impact of previous chemother- assigned to octreotide LAR only (67% versus apy on the efficacy of everolimus was evaluated 27%). in a recent subanalysis of the RADIANT 3 trial [Lombard-Bohas et  al. 2015]. Among Another subgroup analysis of patients with colo- enrolled patients, 204 (50%) were chemo-naïve. rectal NET led to overall similar results [Castellano Everolimus prolonged PFS regardless of prior et  al. 2013]. In more details, the 19 patients on chemotherapy (prior chemotherapy group: 11.0 everolimus + octreotide LAR had a 4-fold pro- months with everolimus and 3.2 months with pla- longed PFS than the 20 patients assigned to octre- cebo; HR, 0.34; 95% CI, 0.25–0.48; p < 0.0001; otide monotherapy (29.9 versus 6.6; HR, 0.34; chemo-naïve group: 11.4 versus 5.4 months; HR, 95% CI, 0.13–0.89; p = 0.011). Moreover, tumor 0.42; 95% CI, 0.29–0.60; p < 0.0001). shrinkage was more frequent with combination treatment (67% versus 37%). Everolimus in patients with NET and Another recent subanalysis of the RADIANT 2 carcinoid syndrome: the RADIANT 2 trial trial has assessed the impact of previous treat- The randomized, double-blind, placebo-controlled ment with SSAs on the efficacy of everolimus phase III RADIANT 2 has evaluated the combi- treatment [Anthony et al. 2015]. The 339 patients nation of everolimus 10 mg/day and octreotide treated with everolimus and octreotide LAR had LAR compared with octreotide LAR alone in 429 longer median PFS, regardless of previous SSA patients who presented low or intermediate-grade exposure (with prior exposure: PFS 14.3 months, NET and carcinoid syndrome [Pavel et al. 2011]. 95% CI, 12.0–20.1; without prior exposure: 25.2 184 journals.sagepub.com/home/tam S Pusceddu, E Verzoni et al. months, 95% CI, 12.0–not recorded) compared (RECIST) criteria version 1.0, was 82.4% and with those assigned to octreotide LAR only (with: 64.9%, respectively. 11.1 months, 95% CI, 8.4–14.6; without: 13.6 months, 95% CI, 8.2–22.7). Implications for clinical practice In our opinion, everolimus does represent a major Everolimus in patients with pulmonary or advance in the therapy of NETs. In fact, according gastrointestinal NETs to the results of well-conducted clinical trials, the A phase II trial of everolimus + octreotide LAR as efficacy of everolimus has been consistently shown first-line treatment for patients with previously in well-differentiated NETs from all origins. With untreated, well-differentiated gastroenteropancre- respect to safety, the tolerability profile of everolimus atic NETs and NETs of lung origin, both function- has been consistent in all studies, with most adverse ing and not functioning, demonstrated an overall events being of mild or moderate severity; the onset response rate of 18% [2% complete response and of grade 3/4 anemia and hyperglycemia (both with a 16% partial response], with a disease control rate of rate of about 5%) must however be noticed. 92%; the responses obtained were generally dura- ble (>6 months) [Bajetta et al. 2014]. In the next paragraphs, we will discuss the role of everolimus in the different types of NETs. The efficacy of everolimus in patients with well- differentiated (G1 or G2) advanced NET of gastro- intestinal (GI) or lung origin was also evaluated in pNETs the landmark RADIANT 4 trial, a prospective, Everolimus undoubtedly represents one of the multicenter, randomized, double-blind, placebo- most effective treatments in pNET patients. controlled, phase III study [Yao et al. 2016]. Patients However, its role within the therapeutic sequence received everolimus 10 mg/day (n = 205) or placebo (e.g. in the first-line setting or at later treatment (n = 97) plus best supportive care. In total, 175 lines) remains unclear also due to the number of patients had GI NETs and 90 had lung disease. effective options in these patients with confirmed efficacy or under evaluation [sunitinib, SSAs, According to centralized analysis, patients on chemotherapy, peptide receptor radionuclide everolimus showed an almost 3-fold longer therapy (PRRT), and pazopanib]. Of note, the median PFS than those assigned to the control subgroup analysis of the RADIANT 3 study group (11.0 versus 3.9 months, HR, 0.48; 95% showed no differences in PFS between pretreated CI, 0.35–0.67; p < 0.00001). These findings were and naïve patients [Lombard-Bohas et al. 2015]. confirmed at the local evaluation (14.0 versus 5.5 The use of everolimus in the frontline setting is months) and were observed in all the analyzed also supported by a smaller study in a heterogene- subgroups, including those with pulmonary dis- ous population of patients with NETs of different ease and patients with GI NETs. However, when origin [Bajetta et al. 2014]. patients with better prognoses (appendix, caecum, jejunum, ileum, duodenum, and NETs of Given the lack of results from well-conducted unknown primary) are compared with those with head-to-head trials, we believe that everolimus worse prognoses (lung, stomach, rectum, and might be a particularly suitable first-line treat- colon except caecum), a better HR for progression ment for G2 pNET patients who show rapidly- or death was observed for patients with worse evolving disease and high disease burden, given prognosis (0.43 for everolimus versus placebo) and the antiproliferative efficacy and tolerability pro- in those with moderately-differentiated NETs G2 file of this molecule. On the other hand, everoli- patients (0.49 for everolimus versus placebo). On mus may be more useful as a second-line therapy the other hand, HR for progression or death in the in patients with G1 pNET, who frequently show ‘better prognosis’ subgroup was 0.63 for everoli- low tumor burden and indolent disease, and as mus versus placebo, and HR in patients with well- such may be effectively treated with SSAs. differentiated NETs G1 was 0.57. The rate of tumor shrinkage was 64% in the Pulmonary NETs everolimus group and 26% in the placebo group. The RADIANT 4 trial was the first randomized Disease control rate, assessed according to the study to show that everolimus is effective in Response Evaluation Criteria in Solid Tumors patients with pulmonary NETs, a class of disease journals.sagepub.com/home/tam 185 Therapeutic Advances in Medical Oncology 9(3) for which no treatment is established. In this everolimus with external beam radiotherapy for setting, everolimus may be particularly suitable the treatment of NET liver metastasis [Clinical as a first-line therapy for patients who present Trials.gov identifier: NCT02205515]. with aggressive disease, including those with atypical carcinoids. Moreover, data on second- Noteworthy, given the high heterogeneity of line everolimus are even stronger, also when com- NETs we believe that clinical trials on everoli- pared with those for chemotherapy and PRRT, mus in this setting should focus on single disease which were reported in small retrospective or entities, in order to provide more specific results. noncontrolled, heterogeneous series of patients. Interestingly, the efficacy of everolimus is being tested also in poorly-differentiated NETs (neu- roendocrine carcinomas (NEC) [ClinicalTrials. Gastrointestinal NETs gov identifier:NCT02687958]. Moreover, the The RADIANT 4 trial showed the efficacy of correct place of everolimus in the therapeutic everolimus in patients with well-differentiated, algorithm (e.g. frontline or second-line) requires advanced, progressive, nonfunctional GI NETs. further investigation: some hints to this respect Overall, its findings suggest that worse grade of will be provided by the ongoing SEQTOR trial differentiation and worse prognosis might be [ClinicalTrials.gov identifier: NCT02246127]. associated with higher efficacy of everolimus, This trial investigates which sequence of strep- although specific studies appear necessary to fur- tozotocin-based chemotherapy and everolimus ther evaluate those findings. gives better results in terms of second PFS in well-differentiated and advanced pNETs. At the Therefore, we believe that the use of everolimus same time, research should focus on the identifi- may be limited in the upfront setting for ‘better cation of clinical and biological biomarkers capa- prognosis’ patients with appendix, caecum, jeju- ble of discriminating between patients eligible to num, ileum, duodenum (midgut) NETs, also upfront treatment and those who may be treated because several other treatment options are avail- with everolimus at a later therapy line. able. On the other hand, everolimus may become of paramount importance for the treatment of less indolent GI carcinoids, due to the lack of effective Conclusion therapeutic opportunities other than SSAs. Treatment of NETs remains challenging, mostly because they represent a highly heterogeneous group of tumors. The international RADIANT Future perspectives trial showed the marked efficacy of everolimus in Research on everolimus in the treatment of NETs thousands of patients with different NET sub- is particularly active and at present a number of types, likely permitting to improve therapeutic studies are ongoing or are awaiting their final management and providing new evidence to results. In addition, everolimus is being investi- develop therapeutic algorithms. However, the gated within different combination regimens with identification of the optimal treatment sequence other targeted therapies including sorafenib and and the selection of patients are still to be investi- bevacizumab, temozolomide or pasireotide. An gated in controlled clinical trials. intriguing strategy, actively pursued by our group, is the combination of everolimus with metformin, Acknowledgements due to the potential antiproliferative effect of Editorial assistance for the preparation of this this small molecule and its ability to control manuscript was provided by Luca Giacomelli, hyperglycemia [Pusceddu et al. 2014b; Pusceddu PhD, and was supported by internal funds. et  al. 2016b]. The METNET1 study is investi- gating this combination [ClinicalTrials.gov Funding identifier: NCT02294006]. In addition, also the This research received no specific grant from any combination of everolimus and SSAs or everoli- funding agency in the public, commercial, or not- mus and PRRT is currently being explored, (e.g. for-profit sectors. in the ongoing Luna trial [Ferolla, 2014]), while the combination of first-line everolimus and temo- zolomide is being investigated in another study Conflict of interest statement [ClinicalTrials.gov identifier: NCT02248012]. The authors declare that there is no conflict of Another interesting pilot study is evaluating interest. 186 journals.sagepub.com/home/tam S Pusceddu, E Verzoni et al. Manfredi, G., Dicitore, A., Gaudenzi, G., Caraglia, References M., Persani, L. and Vitale, G. (2015) PI3K/Akt/ Anthony, L., Pavel, M., Hainsworth, J., Kvols, mTOR signaling in medullary thyroid cancer: a L., Segal, S., Hörsch, D. et al. 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683905 TAM0010.1177/1758834016683905Therapeutic Advances in Medical OncologyS Pusceddu, E Verzoni research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Everolimus treatment for neuroendocrine 2017, Vol. 9(3) 183 –188 DOI: 10.1177/ tumors: latest results and clinical potential © The Author(s), 2017. Reprints and permissions: http://www.sagepub.co.uk/ Sara Pusceddu, Elena Verzoni, Natialie Prinzi, Alessia Mennitto, Daniela Femia, Paolo journalsPermissions.nav Grassi, Laura Concas, Claudio Vernieri, Giuseppe Lo Russo and Giuseppe Procopio Abstract: Neuroendocrine tumors (NETs) are a heterogeneous class of diseases characterized by challenging management. Preclinical evidence shows that the PI3K/AKT/mTOR signaling pathway plays a central role in the pathogenesis and progression of NETs. Everolimus is a direct inhibitor of this pathway, and therefore this molecule appears to be a well-grounded strategy for the treatment of NETs, capable of changing clinical practice. The efficacy and safety of everolimus was demonstrated in the RADIANT trials. In this work, we comment on the results of the RADIANT trials, and other recent key evidence from fully published clinical trials on everolimus, and we discuss the current role of everolimus in the treatment of NETs. Keywords: everolimus, neuroendocrine tumors, RADIANT trials Correspondence to: Introduction safety of everolimus was demonstrated in the Giuseppe Procopio, MD Neuroendocrine tumors (NETs) are a heteroge- RADIANT trials [Yao et  al. 2010; Pavel et  al. Medical Oncology, Istituto Nazionale Tumori, Via neous class of neoplasms with increasing inci- 2011; Yao et  al. 2011, 2015]. In this work, we Venezian 1, 20100, Milan, dence worldwide [Fraenkel et  al. 2012]. Tumor comment on the results of the RADIANT trials, Italy giuseppe.procopio@ behavior and patient survival largely depend upon and other recent key evidence from fully pub- istitutotumori.mi.it a number of different factors such as tumor his- lished clinical trials on everolimus, and we dis- Sara Pusceddu, MD tology, primary site, staging and proliferative cuss the current role of everolimus in the Elena Verzoni, MD Natialie Prinzi, MD index [Panzuto et al. 2014]. treatment of NETs. Alessia Mennitto, MD Daniela Femia, MD Paolo Grassi, MD The management of NETs is challenging, and Laura Concas, MS therefore effective and safe therapeutic options Everolimus in patients with pancreatic NETs Claudio Vernieri, MD Giuseppe Lo Russo, MD for the treatment of these tumors are actively pur- The open-label, phase II RADIANT 1 trial has Medical Oncology, Istituto sued in clinical research. In particular, targeted assessed the efficacy and safety of everolimus in Nazionale Tumori, Milan, Italy therapies such as sunitinib and everolimus have patients with metastatic pancreatic NET (pNET) shown promising results and have thus entered who have progressed on prior chemotherapy [Yao clinical practice [Barbieri et al. 2014; Kulke et al. et al. 2010]. Patients were stratified according to 2008; Raymond et  al. 2011; Ito et  al. 2013; Yao the use of everolimus 10 mg/day only (n = 115), et  al. 2008, 2010; Pavel et  al. 2011; Yao et  al. or everolimus 10 mg/day + octreotide long-acting 2011, 2016]. release (LAR) (n = 45). At central analysis, the rate of partial response was 9.6% with everolimus A bulk of preclinical evidence has shown that only and 4.4% with everolimus + octreotide the PI3K/AKT/mTOR signaling pathway plays LAR; the incidence of stable disease was 67.8% a central role in the pathogenesis and progres- and 80.0%, respectively. Median progression-free sion of NETs [Manfredi et  al. 2015; Yao et  al. survival (PFS) was 9.7 months with everolimus 2008; Pusceddu et  al. 2016a; Procopio et  al. only and 16.7 months with the combination strat- 2012; Pusceddu et  al. 2016]. Everolimus is a egy. On this basis, it was suggested that everoli- direct inhibitor of this pathway, and therefore mus 10 mg/day, with or without concomitant this molecule appear to be a well-grounded octreotide LAR, presents a degree of antitumor strategy for the treatment of NETs, capable of activity in patients with advanced pNETs who changing clinical practice. The efficacy and have failed prior chemotherapy. journals.sagepub.com/home/tam 183 Therapeutic Advances in Medical Oncology 9(3) Further to the RADIANT 1 trial, the interna- Median PFS by central review, the primary end- tional randomized, placebo-controlled, phase III point of the trial, was 16.4 months in the combi- RADIANT 3 trial has evaluated patients with nation arm and 11.3 months with octreotide LAR advanced pNET (low or intermediate-grade) who only. The HR for progression between the two showed radiologic progression within the previ- groups did not reach statistical significance (0.77, ous 12 months before inclusion [Yao et al. 2012]. 95% CI, 0.59–1.00). Those findings did not It is the largest study ever conducted in the setting match those reported at the local review of PFS, of NETs. Patients were randomly assigned to which suggested a benefit for everolimus (12.0 either everolimus 10 mg/day (n = 207) + best months versus 8.6; HR, 0.78, 95% CI, 0.62– supportive care or placebo (n = 203). Of note, 0.98). Moreover, it should be noted that World patients assigned to placebo who showed radio- Health Organization performance status was logical progression during the study (73%) were poorer in the combination arm compared with offered open-label everolimus. Median PFS was the octreotide-only group. Moreover, patients longer in the everolimus group, compared with assigned to the combination therapy presented a placebo [11.0 versus 4.6 months; hazard ratio higher incidence of pulmonary primary tumors (HR), 0.35; 95% confidence interval (CI), 0.27– and bone involvement, had higher chromogranin 0.45; p < 0.001]. Statistical analysis showed that A (CgA) values at baseline, and were more heavily the estimated proportion of patients free from pretreated. Those imbalances have contributed to progression at 18 months was 34% (95% CI, 26– the lack of statistical differences between the two 43) with everolimus and 9% (4–16) with placebo. groups in terms of PFS, as also shown at a dedi- Remarkably, the PFS advantage shown with cated multivariate analysis [Pusceddu et al. 2016; everolimus was consistent in all the subgroups Yao et al. 2012]. analyzed, independently from age, sex, ethnicity, prior exposure to somatostatin analogues (SSAs), The results of the RADIANT 2 study have led to performance status, and tumor differentiation. several subanalyses. First, a subanalysis including These findings suggest that everolimus is effective only patients with pulmonary NET (everolimus in all patients with well-differentiated or moder- + octreotide LAR, n = 33; octreotide LAR only, ately-differentiated pNET, without any parame- n = 11) showed a 2.4-fold longer PFS in the com- ter which may suggest exclusion from treatment. bination arm, associated with a 28% reduction in On the other hand, overall survival was similar in the risk of progression (13.6 versus 5.6 months; the two groups (HR, 1.05; 95% CI, 0.71–1.55), HR, 0.72; 95% CI, 0.31–1.68) [Fazio et al. 2013]. most likely due to the high number of patients In this same analysis, tumor shrinkage was who were switched to everolimus from placebo. reported by a >2-fold proportion of patients on everolimus + octreotide, compared with those Interestingly, the impact of previous chemother- assigned to octreotide LAR only (67% versus apy on the efficacy of everolimus was evaluated 27%). in a recent subanalysis of the RADIANT 3 trial [Lombard-Bohas et  al. 2015]. Among Another subgroup analysis of patients with colo- enrolled patients, 204 (50%) were chemo-naïve. rectal NET led to overall similar results [Castellano Everolimus prolonged PFS regardless of prior et  al. 2013]. In more details, the 19 patients on chemotherapy (prior chemotherapy group: 11.0 everolimus + octreotide LAR had a 4-fold pro- months with everolimus and 3.2 months with pla- longed PFS than the 20 patients assigned to octre- cebo; HR, 0.34; 95% CI, 0.25–0.48; p < 0.0001; otide monotherapy (29.9 versus 6.6; HR, 0.34; chemo-naïve group: 11.4 versus 5.4 months; HR, 95% CI, 0.13–0.89; p = 0.011). Moreover, tumor 0.42; 95% CI, 0.29–0.60; p < 0.0001). shrinkage was more frequent with combination treatment (67% versus 37%). Everolimus in patients with NET and Another recent subanalysis of the RADIANT 2 carcinoid syndrome: the RADIANT 2 trial trial has assessed the impact of previous treat- The randomized, double-blind, placebo-controlled ment with SSAs on the efficacy of everolimus phase III RADIANT 2 has evaluated the combi- treatment [Anthony et al. 2015]. The 339 patients nation of everolimus 10 mg/day and octreotide treated with everolimus and octreotide LAR had LAR compared with octreotide LAR alone in 429 longer median PFS, regardless of previous SSA patients who presented low or intermediate-grade exposure (with prior exposure: PFS 14.3 months, NET and carcinoid syndrome [Pavel et al. 2011]. 95% CI, 12.0–20.1; without prior exposure: 25.2 184 journals.sagepub.com/home/tam S Pusceddu, E Verzoni et al. months, 95% CI, 12.0–not recorded) compared (RECIST) criteria version 1.0, was 82.4% and with those assigned to octreotide LAR only (with: 64.9%, respectively. 11.1 months, 95% CI, 8.4–14.6; without: 13.6 months, 95% CI, 8.2–22.7). Implications for clinical practice In our opinion, everolimus does represent a major Everolimus in patients with pulmonary or advance in the therapy of NETs. In fact, according gastrointestinal NETs to the results of well-conducted clinical trials, the A phase II trial of everolimus + octreotide LAR as efficacy of everolimus has been consistently shown first-line treatment for patients with previously in well-differentiated NETs from all origins. With untreated, well-differentiated gastroenteropancre- respect to safety, the tolerability profile of everolimus atic NETs and NETs of lung origin, both function- has been consistent in all studies, with most adverse ing and not functioning, demonstrated an overall events being of mild or moderate severity; the onset response rate of 18% [2% complete response and of grade 3/4 anemia and hyperglycemia (both with a 16% partial response], with a disease control rate of rate of about 5%) must however be noticed. 92%; the responses obtained were generally dura- ble (>6 months) [Bajetta et al. 2014]. In the next paragraphs, we will discuss the role of everolimus in the different types of NETs. The efficacy of everolimus in patients with well- differentiated (G1 or G2) advanced NET of gastro- intestinal (GI) or lung origin was also evaluated in pNETs the landmark RADIANT 4 trial, a prospective, Everolimus undoubtedly represents one of the multicenter, randomized, double-blind, placebo- most effective treatments in pNET patients. controlled, phase III study [Yao et al. 2016]. Patients However, its role within the therapeutic sequence received everolimus 10 mg/day (n = 205) or placebo (e.g. in the first-line setting or at later treatment (n = 97) plus best supportive care. In total, 175 lines) remains unclear also due to the number of patients had GI NETs and 90 had lung disease. effective options in these patients with confirmed efficacy or under evaluation [sunitinib, SSAs, According to centralized analysis, patients on chemotherapy, peptide receptor radionuclide everolimus showed an almost 3-fold longer therapy (PRRT), and pazopanib]. Of note, the median PFS than those assigned to the control subgroup analysis of the RADIANT 3 study group (11.0 versus 3.9 months, HR, 0.48; 95% showed no differences in PFS between pretreated CI, 0.35–0.67; p < 0.00001). These findings were and naïve patients [Lombard-Bohas et al. 2015]. confirmed at the local evaluation (14.0 versus 5.5 The use of everolimus in the frontline setting is months) and were observed in all the analyzed also supported by a smaller study in a heterogene- subgroups, including those with pulmonary dis- ous population of patients with NETs of different ease and patients with GI NETs. However, when origin [Bajetta et al. 2014]. patients with better prognoses (appendix, caecum, jejunum, ileum, duodenum, and NETs of Given the lack of results from well-conducted unknown primary) are compared with those with head-to-head trials, we believe that everolimus worse prognoses (lung, stomach, rectum, and might be a particularly suitable first-line treat- colon except caecum), a better HR for progression ment for G2 pNET patients who show rapidly- or death was observed for patients with worse evolving disease and high disease burden, given prognosis (0.43 for everolimus versus placebo) and the antiproliferative efficacy and tolerability pro- in those with moderately-differentiated NETs G2 file of this molecule. On the other hand, everoli- patients (0.49 for everolimus versus placebo). On mus may be more useful as a second-line therapy the other hand, HR for progression or death in the in patients with G1 pNET, who frequently show ‘better prognosis’ subgroup was 0.63 for everoli- low tumor burden and indolent disease, and as mus versus placebo, and HR in patients with well- such may be effectively treated with SSAs. differentiated NETs G1 was 0.57. The rate of tumor shrinkage was 64% in the Pulmonary NETs everolimus group and 26% in the placebo group. The RADIANT 4 trial was the first randomized Disease control rate, assessed according to the study to show that everolimus is effective in Response Evaluation Criteria in Solid Tumors patients with pulmonary NETs, a class of disease journals.sagepub.com/home/tam 185 Therapeutic Advances in Medical Oncology 9(3) for which no treatment is established. In this everolimus with external beam radiotherapy for setting, everolimus may be particularly suitable the treatment of NET liver metastasis [Clinical as a first-line therapy for patients who present Trials.gov identifier: NCT02205515]. with aggressive disease, including those with atypical carcinoids. Moreover, data on second- Noteworthy, given the high heterogeneity of line everolimus are even stronger, also when com- NETs we believe that clinical trials on everoli- pared with those for chemotherapy and PRRT, mus in this setting should focus on single disease which were reported in small retrospective or entities, in order to provide more specific results. noncontrolled, heterogeneous series of patients. Interestingly, the efficacy of everolimus is being tested also in poorly-differentiated NETs (neu- roendocrine carcinomas (NEC) [ClinicalTrials. Gastrointestinal NETs gov identifier:NCT02687958]. Moreover, the The RADIANT 4 trial showed the efficacy of correct place of everolimus in the therapeutic everolimus in patients with well-differentiated, algorithm (e.g. frontline or second-line) requires advanced, progressive, nonfunctional GI NETs. further investigation: some hints to this respect Overall, its findings suggest that worse grade of will be provided by the ongoing SEQTOR trial differentiation and worse prognosis might be [ClinicalTrials.gov identifier: NCT02246127]. associated with higher efficacy of everolimus, This trial investigates which sequence of strep- although specific studies appear necessary to fur- tozotocin-based chemotherapy and everolimus ther evaluate those findings. gives better results in terms of second PFS in well-differentiated and advanced pNETs. At the Therefore, we believe that the use of everolimus same time, research should focus on the identifi- may be limited in the upfront setting for ‘better cation of clinical and biological biomarkers capa- prognosis’ patients with appendix, caecum, jeju- ble of discriminating between patients eligible to num, ileum, duodenum (midgut) NETs, also upfront treatment and those who may be treated because several other treatment options are avail- with everolimus at a later therapy line. able. On the other hand, everolimus may become of paramount importance for the treatment of less indolent GI carcinoids, due to the lack of effective Conclusion therapeutic opportunities other than SSAs. Treatment of NETs remains challenging, mostly because they represent a highly heterogeneous group of tumors. The international RADIANT Future perspectives trial showed the marked efficacy of everolimus in Research on everolimus in the treatment of NETs thousands of patients with different NET sub- is particularly active and at present a number of types, likely permitting to improve therapeutic studies are ongoing or are awaiting their final management and providing new evidence to results. In addition, everolimus is being investi- develop therapeutic algorithms. However, the gated within different combination regimens with identification of the optimal treatment sequence other targeted therapies including sorafenib and and the selection of patients are still to be investi- bevacizumab, temozolomide or pasireotide. An gated in controlled clinical trials. intriguing strategy, actively pursued by our group, is the combination of everolimus with metformin, Acknowledgements due to the potential antiproliferative effect of Editorial assistance for the preparation of this this small molecule and its ability to control manuscript was provided by Luca Giacomelli, hyperglycemia [Pusceddu et al. 2014b; Pusceddu PhD, and was supported by internal funds. et  al. 2016b]. The METNET1 study is investi- gating this combination [ClinicalTrials.gov Funding identifier: NCT02294006]. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Mar 1, 2017

Keywords: everolimus; neuroendocrine tumors; RADIANT trials

References