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© 2022 EDIZIONI MINERVA MEDICA Minerva Endocrinology 2022 September;47(3):261-3

Online version at https://www.minervamedica.it DOI: 10.23736/S2724-6507.22.03879-9

EDITORIAL

Targeting receptor tyrosine kinases

in neuroendocrine neoplasm:
what’s going on with lung carcinoids?
Alessandra DICITORE 1 *, Maria C. CANTONE 2

1Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, Milan,
Italy; 2Laboratory of Geriatric and Oncologic Neuroendocrinology Research, Istituto Auxologico Italiano IRCCS,
Cusano Milanino, Milan, Italy
*Corresponding author: Alessandra Dicitore, Department of Medical Biotechnology and Translational Medicine (BIOMETRA),
University of Milan, Via Vanvitelli 32, 20129 Milan, Italy. E-mail: alessandra.dicitore@libero.it

D uring recent years there has been increased

attention for targeting receptor tyrosine ki-
nases (RTKs) as a novel approach of anticancer
treatment, particularly in tumors with high vas-
cular density.1-3 Several studies demonstrated
that well-differentiated neuroendocrine tumors
(NETs) possess a 10-fold higher intratumoral
vessel density compared with carcinomas and
are characterized by overexpression of proan-
giogenic factors including vascular endothelial
growth factor (VEGF), fibroblast growth fac-
tor (FGF), and platelet-derived growth factor
(PDGF).4, 5 Particularly in pancreatic NET, it has
been observed a higher intratumoral microvas-
cular density in low-grade than in high-grade
tumors and is associated with a higher VEGF
expression, good prognosis and prolonged sur-
vival.6 In contrast to other epithelial tumors, the
dense vascular network associated with low-
grade NETs is more likely to be a marker of
differentiation than a marker of aggressiveness.
This neuroendocrine paradox has been poorly
studied in lung carcinoids (LCs). LCs are divid-
ed in well differentiated low-grade typical car-
cinoids (TCs) and intermediate-grade atypical
carcinoids (ACs). Although their low incidence
(2% for TC and <1% for AC of primary lung tu-
mors), 30% to 40% of ACs are capable of seed-
ing regional lymph node or distant metastasis.
Most LCs can be cured by surgery and, current-
ly, there is no consensus on adjuvant therapy in
these malignancies.7 On this light, it is important
to understand if neuroendocrine paradox is trans-
latable to primary and metastatic tumors, since
antiangiogenic strategies should be indicated
mainly for the treatment of advanced LCs. In
2006, Granberg et al. demonstrated that several
RTKs are expressed in patients with LC (51%
endothelial growth factor receptor (EGFR), 23%
stem cell factor receptors (c-kit), 86% PDGF-α
and 59% PDGF-β) and in those ones with dis-
tant metastases (41% EGFR, 29% c-kit, 70%
PDGF-α and 53% PDGF-β), speculating on a
possible targeted treatment with tyrosine kinases
inhibitors (TKIs) for these patients. Indeed, sev-
eral TKIs have been used in clinical trials, alone
or in combination with standard chemotherapy
in LC patients.8 In the last years, several targeted
therapies, that directly blocked RTKs involved
in tumor-induced angiogenesis, have been used
in the therapy of these tumors with clinical ben-
efit. Sunitinib malate (VEGFR 1-3, PDGFRs,
c-kit, glial cell line-derived neurotrophic factor
receptors (GDNFRs), and fms-like tyrosine ki-
nase-3 (FLT3) inhibitor) has been evaluated in a
two-cohort Phase II clinical study of 109 patients

Vol. 47 - No. 3 Minerva Endocrinology 261

 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access COPYRIGHT 2022 EDIZIONI MINERVA MEDICA
cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
DICITORE TARGETING RECEPTOR TYROSINE KINASES IN NEUROENDOCRINE NEOPLASM
with NETs including LCs. In these patients, ob-
jective response rate (ORR) was 2.4%, with sta-
ble disease in 83%, with a time to progression
(TTP) of 10.2 months and 1-year survival rate
of 83.4.9 The PAZONET study of pazopanib, a
VEGFR, PDGFR, and c-kit inhibitor, showed a
clinical benefit in 85% of patients treated with
pazopanib, including patients with lung or thy-
mus NETs (N.=8). Median progression-free
survival (PFS) was 3.4 month.10 The epidermal
growth factor receptor (EGFR) inhibitor, erlo-
tinib, alone or in combination, is currently in
phase II studies (NCT0084 3531) whereas, re-
cently, icotinib (targeting EGFR) plus cisplatin
was administered successfully in the first patient
with pulmonary AC with EGFR mutation, pro-
viding a potential treatment mode for advanced
NETs harboring EGFR mutations.11 Axitinib, a
potent and selective inhibitor of VEGFR 1-3, at
subnanomolar concentrations, has been recently
tested in in patients with advanced G1-G2 non-
pancreatic NETs, including 71 patients with lung
NETs, randomized (1:1) to receive octreotide
LAR with axitinib or placebo (AXINET phase
II/III study). Axitinib in combination with oc-
treotide LAR showed a clinically meaningful
greater ORR than in the placebo group (17.5%
vs. 3.8%, P=0.0004), with a tolerable safety pro-
file. However, the primary endpoint of this trial,
PFS per investigator assessment, did not reach
statistical significance (median PFS 17.2 month
in axitinib arm vs. 12.3 months in place group,
Hazard Ratio (HR)=0.816, P=0.169). However,
when the study passed to a phase III multicenter
international study, the results of the secondary
endpoint was PFS by central blinded assessment
and showed a significant difference between the
group of axitinib compared with placebo (median
PFS was 16.6 months vs. 9.9 months; HR=0.71,
P=0.017).12 The SANET-ep study, conducted in
China, analyzed the efficacy and safety of suru-
fatinib, an inhibitor of VEGFR1-3, PDGFR and
the colony-stimulating factor 1 receptor (CS-
F1R), in patients with extra-pancreatic NETs,
including 23 patients with LCs (11.6%). In this
study, median PFS was 9.2 months (95% CI: 7.4-
11.1) in the surufatinib group versus 3.8 months
(3.7-5.7) in the placebo group (HR=0.33; 95%
CI: 0.22-0.50; P<0.0001).13 Surufatinib is cur-
262 Minerva Endocrinology September 2022
rently under research in an open-label phase 2
study (NCT04579679) with different cohorts of
patients with NETs, also of lung origin, in the
European population.14 Finally, several ongoing
clinical trials such as CABINET (NCT03375320)
and CABOTEM (NCT04893785) are evaluat-
ing the antitumoral activity of cabozantinib,15 a
hepatocyte growth factor receptor (MET), Re-
arranged during Transfection receptor (RET),
AXL, VEGFR2, FLT3, and c-kit inhibitor, in
advanced NETs. In conclusion, the efficacy of
TKIs remains uncertain in LCs. Although prom-
ising, they should be considered experimen-
tal. A better knowledge of the mechanisms and
regulation of tumor angiogenesis in LCs may be
clinically highly relevant to determine the best
antiangiogenic strategy for those subgroups of
patients who might benefit from these new tar-
geted therapies.
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to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,

TARGETING RECEPTOR TYROSINE KINASES IN NEUROENDOCRINE NEOPLASM DICITORE

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Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material
discussed in the manuscript.
Funding.—The study was supported by the Italian Ministry of Health (IRCCS funding Ricerca Corrente).
Authors’ contributions.—Alessandra Dicitore and Maria C. Cantone have given substantial contributions to study conception, Ales-
sandra Dicitore to manuscript writing. Both authors read and approved the final version of the manuscript.
History.—Manuscript accepted: May 23, 2022. - Manuscript received: May 9, 2022.
(Cite this article as: Dicitore A, Cantone MC. Targeting receptor tyrosine kinases in neuroendocrine neoplasm: what’s going on with
lung carcinoids? Minerva Endocrinol 2022;47:261-3. DOI: 10.23736/S2724-6507.22.03879-9)

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