Inventory 2022 Professor Chen Jie: 2022 Neuroendocrine Tumor Drug Treatment Progress Inventory

About the author

Professor Chen Jie

Chief physician, professor, doctoral supervisor, chief expert of neuroendocrine oncology multidisciplinary in Fudan University Cancer Hospital, director of neuroendocrine tumor center, director of
head and neck and neuroendocrine oncology department.

He is a member of the Advisory Committee of the European Society of Neuroendocrine Oncology (ENETS), a member of the Neuroendocrine and Endocrine Oncology Group of the European Society of Medical Oncology (ESMO), a member of the Medical Advisory Committee of the International Neuroendocrine Tumor Alliance (INCA), the chairman of the Neuroendocrine Oncology Professional Committee of the Chinese Anti-Cancer Association, the leader of the Neuroendocrine Oncology Group (CSNET) of the Pancreatic Cancer Professional Committee of the Chinese Anti-Cancer Association, and the vice chairman of the Tumor Endocrinology Professional Committee of the Chinese Anti-Cancer Association.
Vice Chairman of the Pancreatic Neuroendocrine Tumor Special Committee of the Pancreatic Disease Branch of the Chinese Medical Doctor Association, Deputy Head of the Gastrointestinal Hormone and Neuroendocrine Oncology Group of the Gastroenterology Branch of the Chinese Medical Association, Standing Committee Member of the Neuroendocrine Tumor Branch of the China Association for the Promotion of International Exchanges in Healthcare, and Member of the Rare Oncology Expert Committee of the Chinese Society of
Clinical Oncology.
Senior Editorial Board Member of ENETS Official Journal of Neuroendocrinology, Editorial Board Member of Journal of Pancreatology, Editorial Board Member of Chinese Cancer Journal and Corresponding Editorial Board Member
of Chinese Journal of Digestion.

He is committed to the diagnosis, treatment and research of neuroendocrine tumors, has published more than 90 articles related to neuroendocrine tumors, and has won the National Natural Science Foundation of China Key Special Fund
for Rare Tumors.
As the main author, he participated in the formulation of the "Expert Consensus on the Diagnosis and Treatment of Gastrointestinal and Pancreatic Neuroendocrine Tumors" of the Gastrointestinal Hormone and Neuroendocrinology Group of the Gastroenterology Branch of the Chinese Medical Association and the "Guidelines for the Diagnosis and Treatment of Pancreatic Neuroendocrine Tumors in China" of the Pancreatic Surgery Group of the Surgical Branch of the Chinese Medical Association
.
As a member of the ENETS Advisory Board, he participated in the formulation of the latest edition of the INETS clinical diagnosis and treatment specifications
for neuroendocrine tumors in 2017.
As the editor-in-chief, he led the formulation
of the first edition of the Guidelines for the Integrated Diagnosis and Treatment of Neuroendocrine Tumors (2022 Edition) of the Chinese Anti-Cancer Association.

Dr.
Liang Zhen

Doctor
of Oncology, Department of Head and Neck and Neuroendocrine Oncology, Fudan University Cancer Hospital.

He served as the secretary of the Neuroendocrine Oncology Professional Committee of the Chinese Anti-Cancer Association, the secretary of the Neuroendocrine Oncology Professional Committee of the Shanghai Anti-Cancer Association, the member of the Minimally Invasive Diagnosis and Treatment Group of the Pancreatic Cancer Professional Committee of the Chinese Anti-Cancer Association, the member of the Young Elite Club of the Pancreatic Group of the Surgical Branch of the Chinese Medical Association, and the Shanghai Regional Member of
the Hepatobiliary Surgery Expert Committee of the National Telemedicine and Internet Medicine Center.

Year 2022

Neuroendocrine tumor drug treatment progress inventory

introduction

Neuroendocrine neoplasms (NENs) are a rare class of tumors
that originate from a high degree of heterogeneity in neuroendocrine cells and peptidergic neurons.
The treatment of NENs includes surgery, intervention, drugs, and
radionuclides.
Pharmacotherapy includes biotherapy, targeted therapy, chemotherapy, and immunotherapy
.
In 2022, the Chinese Anti-Cancer Association organized experts in relevant fields to formulate the first version of the guidelines for the diagnosis and treatment of NENs on the basis of existing evidence-based evidence, combined with existing domestic and foreign guidelines
and consensus.
In this version of the guidelines, the drug treatment selection strategies for advanced gastrointestinal pancreas, unknown primary lesions, and lung and thymic NENs are recommended accordingly, which has clinical reference ^{value [1].}

In addition, in 2022, there are also some research progress in the field of NENs drug therapy, and this article will summarize the progress in the field of NENs drug treatment in 2022 to provide reference
for clinical treatment.

01 

Biological therapy

In terms of the application expansion of long-acting somatostatin analogues (SSAs), the results of SPINET randomized double-blind, placebo-controlled phase III studies suggest that SSAs have a certain effect
on pulmonary typical/atypical carcinoid tumors in addition to gastrointestinal pancreas and primary unknown neuroendocrine tumors (NET).
。 A total of 77 patients with advanced pulmonary typical/atypical carcinoid were included in the study, and after treatment with standard-dose lenotide, the time to treatment failure (TTF) was 13.
3 months in the lanreotide group and 9.
8 months
in the placebo group.
Among them, the progression free survival (PFS) time of typical carcinoid group can reach 21.
9 months, compared with 13.
8 months in the atypical carcinoid group and 13.
9 months and 11 months in the placebo group ^[2], suggesting that the typical carcinoid group has better
efficacy.
In addition, it is worth noting that more than 90% of patients included in the study had a liver metastatic burden ≤ 25%.

According to the results of two classical studies, RPOMID and CLARINET, the high burden of liver metastases significantly shortens the effective time of SSA drugs ^[3-4].

Therefore, for patients with large intrahepatic tumor burden, early use of surgery or hepatic artery embolization (TAE) can prolong the PFS
of drug therapy after reducing the intrahepatic tumor burden.
Our team retrospectively studied the efficacy of SSAs in combination with TAE ^[5], and included a total of 116 patients with G1/G2 liver metastases
.
The results showed that the overall median PFS time was 13.
6 months, and the effective rate of TAE could reach 78.
4%.

For patients with liver metastases burden of 25%~50% and >50%, PFS can be significantly prolonged
if TAE achieves complete or partial remission.
Subgroup analysis of the group with liver metastasis burden > 50% showed that the median PFS time of TAE combined with SSAs could reach 12.
3 months, which was much better than the 4.
6 months of SSAs monotherapy in the group with liver metastasis burden > 50% in the PROMID clinical trial ^[4], suggesting that the efficacy
of SSAs can be prolonged after intrahepatic debulking through TAE.

02 

Targeted therapy

Lenvatinib is a multi-target TKI drug, in the phase II TALENT trial for metastatic low-grade NETs, a total of 55 cases of pancreas and 56 cases of gastrointestinal NET were included, and the results showed that lenvatinib in the pancreatic group obtained an objective response rate (ORR) of 44.
2%, and the disease control rate reached 96.
2%.
The duration of the effective time can reach 19.
9 months ^[6], but because the dose of lenvatinib in this study reached 24mg/day, while the conventional dose was only 8~12mg/day, the adverse reactions were large, and 93.
7% of patients needed to reduce or terminate the dose
due to adverse reactions.
The study also analyzed the relationship between serial plasma angiogenic factors and the efficacy of lenvatinib, and showed that the levels of FGF2 and Ang2 were significantly correlated with ORR ^[7], so these two serum markers may have potential
for use in neoadjuvant or conversion therapy in the future.
With the development of radiomics research, our team's study based on CT radiomics model to predict the efficacy of anti-angiogenic targeted drug sunitinib in the treatment of pancreatic NET was also published in 2022 ^[8], showing that CT-value ratio (tumor CT value/abdominal aorta CT value of the same patient) and CT-based radiomics model can accurately predict tumor retraction and PFS
in pancreatic NET patients treated with sunitinib 。 There are also some clinical trials exploring
the use of targeted drugs in high-grade NET and neuroendocrine carcinoma (NEC).
A phase II clinical trial evaluating the efficacy and safety of cisplatin plus everolimus in advanced extrapulmonary NEC in 39 patients showed that although the DCR was 82.
1 percent, the ORR was 58.
9 percent, and the median PFS was 6.
0 months, the median survival (OS) was only 8.
7 months ^[9], overall, Targeted drugs have not yet shown satisfactory efficacy
in high-level NETs and NECs.

03 

chemotherapy

The final results of the prospective Phase II ECOG-ACRIN E2211 clinical trial comparing the efficacy of temozolomide monotherapy and temozolomide + capecitabine combination regimen in advanced pancreatic NET were presented at the 2022 ASCO Annual Meeting, which included a total of 144 metastatic/unresectable G1/G2 grade pancreatic NETs, with overall survival OS time and ORR of 53.
8 months and 34% versus 58.
7 months and 40% in the monotherapy and combination groups, respectively, There was no statistically significant difference, but the rate of grade 3 to 4 adverse reactions was higher in the combination group than in the monotherapy group (45 versus 22 percent), and the results showed that the absence of MGMT was associated with a higher ORR, suggesting that MGMT may be a marker for predicting the efficacy of
temozolomide.
The STEM study is a multicenter phase II randomized controlled trial involving eight hospitals in China, which compares the efficacy of tigio + temozolomide with tigio + temozolomide + thalidomide in advanced or advanced pancreatic and non-pancreatic ^{NETs [10].}

The study included 80 patients with non-pancreatic NET and 60 patients with pancreatic NET, and the ORRs of 33.
1% and 17.
1% in the non-pancreatic group were 23.
1% and 17.
1%, respectively, and in the pancreatic group, the ORRs of three and two drugs, respectively, were 30% and 36.
7%.

It was suggested that the effect of three- and two-drug combinations in the treatment of pancreatic NET was better than that of non-pancreatic NET, showing a difference
.
However, for the overall participants, the PFS time of the three-drug and two-drug groups was 12.
9 months versus 11.
5 months, respectively, and there was no significant difference
.
In addition, the study also confirmed the relationship
between MGMT expression and the efficacy of temozolomide.
STEM studies showed that the ORR and PFS times of the MGMT low expression group were 36% and 19.
1 months, while the ORR and PFS times of the MGMT high expression group were 8% and 5.
4 months, which was a significant
difference.

In 2022, there are also some interesting clinical trial results
in chemotherapy combined with targeted, chemotherapy and targeted sequential therapy.
In terms of chemotherapy combined with targeting, retrospective studies of FOLFOX plus bevacizumab in the treatment of metastatic NET showed a median TTF time of 15.
5 months, in which both the pancreatic and G3 groups achieved >50% ORR, suggesting that FOLFOX plus bevacizumab could be tried as an alternative treatment regimen for alkylating agent chemotherapy in pancreatic NET and G3 ^{NETs [11].}

。 HOWEVER, THE PHASE II PROSPECTIVE CLINICAL TRIAL OF FOLFIRI VERSUS FOLFIRI+ bevacizumab for advanced nec after chemotherapy failure in ep regimen (PRODIGE 41 – BEVANEC) did not show efficacy of chemotherapy combined with targeted chemotherapy in nec
.
The results showed that PFS time and OS duration were 3.
5 months and 8.
5 months vs 3.
7 months and 7 months, respectively, in the FOLFIRI group and the combination group, with no significant differences
.
A phase II ET-NEC study explored the efficacy
of temozolomide combined with everolimus in the first-line treatment of metastatic high-grade gastrointestinal pancreatic NENs.
A total of 38 patients were enrolled, with a total ORR of 30%, PFS of 10 months, and OS of 26.
4 months
.
Subgroup analysis showed that PFS time and OS time were significantly better in the NET group than in the NEC group (12.
6 months vs 3.
4 months, 31.
4 months versus 7.
8 months), suggesting that this regimen has a certain efficacy
in NET patients.
The efficacy of chemotherapy versus targeted sequential therapy was explored in the European multicenter SEQTOR Phase III clinical study, which compared the effects
of everolimus and streptomycin (STZ) + 5-FU in pancreatic NET.
A total of 141 patients with G1/G2 pancreatic NETs were randomly enrolled 1:1 to everolimus sequential STZ+5-FU group and STZ+5FU sequential everolimus group
.
The primary endpoint was 12-month PFS rate, which showed no significant difference between the two groups of 69% and 61%, respectively, suggesting that the sequencing of chemotherapy and targeting did not affect the PFS
treated in advanced pancreatic NET.
However, in terms of ORR, the everolimus sequential STZ+5-FU group and the STZ+5FU sequential everolimus group were 11% and 30%, respectively, which showed a statistically significant difference, suggesting that for patients with neoadjuvant or transformation needs, higher ORR can be obtained with chemotherapy first, and the success rate of neoadjuvant and conversion therapy will be higher
.

In addition, the association
of long-term temozolomide use with secondary hematological tumors was reported in the ASCO GI in 2022.
Literature reviews suggest that temozolomide has an increased risk of developing secondary hematologic tumors, such as acute leukemia or myelodysplastic syndromes, beyond 12 months of treatment ^[12].

Therefore, it is recommended to continue using temozolomide for 6 months based on the evaluation of efficacy, and the duration of treatment with temozolomide should not exceed 12 months as much as possible, and it is recommended to switch to other treatments
after 12 months.
Try not to use alkylating agents such as temozolomide prematurely, and sequential or combined alkylating agents and PRRTs may lead to a higher incidence of
secondary haematological tumors.

04 

Immunotherapy

Immunotherapy is still a hot and difficult issue in the treatment of NENs, and some important clinical research results
of immunotherapy were announced in 2022.
Due to the limited efficacy of immune checkpoint inhibitors alone on NENs, researchers have carried out a series of exploratory studies
of double-free therapy, immune checkpoint inhibitors combined with targeted drugs, or combination chemotherapy 。 The final results of the DUNE study were reported at the 2022 INETS Annual Meeting, including 123 NENs, divided into four cohorts: pulmonary carcinoid/atypical carcinoid, G1/G2 gastrointestinal NET, G1/G2 pancreatic NET and G3 gastrointestinal NENs, with ORR (irORR) assessed according to irRECIST criteria being 11% and 0%, respectively , 6.
3 percent and 9.
1 percent, median PFS duration of 5.
6 months, 5.
8 months, 5.
5 months, and 2.
4 months, respectively, and median OS duration, 29.
5 months, 23.
8 months, and 5.
9 months, respectively ^[13].

The results of the study showed that the efficacy of double-exempt therapy for NENs that failed standard treatment was also very limited
.

In terms of immune combination targeted therapy, MD Anderson Cancer Center released the final results of a prospective phase II clinical trial of atezolizumab combined with bevacizumab in the treatment of advanced G1/G2 NET, the study was divided into two cohorts of pancreatic NET and non-pancreatic NET, with ORR and PFS times of 20% and 14.
9 months in the pancreatic group and 15% ORR and PFS times in the non-pancreatic group At 14.
2 months, 4 of the 5 PD-L1-positive patients in the pancreas group achieved a better ORR ^[14], suggesting that PD-L1 expression may be related to
the efficacy of immunotherapy.

In terms of immunotherapy combined with chemotherapy, the results of the international multicenter, double-blind, randomized phase III clinical study ASTRUM-005 were reported in 2022, which explored the efficacy of PD-1 antibody serplulimab combined with etoposide + carboplatin (EC) regimen in the first-line treatment of advanced small cell lung cancer (SCLC).
The results showed that the OS duration and PFS duration of 5.
7 months and 4.
3 months in the combination group and placebo group were 15.
4 months and 10.
9 months, respectively, which were statistically significant [^15].

In the subgroup analysis of this study, PD-L1 expression was independent
of efficacy.
Phase III double-blind, placebo-controlled clinical trials (Impower133) of atezolizumab plus EC regimen for advanced SCLC and phase III randomized multicenter clinical trial (CASPIAN) of durvalumab plus etoposide + cisplatin (EP) first-line treatment of advanced SCLC compared with previously reported studies of atezolizumab plus EC regimen for first-line treatment of advanced SCLC [^16-17].
, and the OS time of serplulimab combined with EC regimen reached 15.
4 months, suggesting the potential
of serplulimab combined with chemotherapy in SCLC.
The literature reports that SCLC can be divided into four types according to the expression of its three important transcription factors ASCL1, NEUROD1 and POU2F3 and the expression of immune-related genes, namely: SCLC-A, SCLC-N, SCLC-P and SCLC-I
.
Among them, SCLC-I type is characterized by low expression of three transcription factors and high expression of immunoinflammation-related genes, and patients with this type have a better prognosis than the other three types, and can benefit more from chemotherapy combined with immunotherapy ^[18].

In a follow-up analysis of the Impower133 study reported in 2022, SCLC-I type, which accounted for 18%, was able to have a longer survival benefit from EP+PD-L1 treatment, with OS time reaching 18 months
.
Similarly, this conclusion was confirmed in a follow-up analysis of the CASPIAN study, which allowed OS duration of 17.
6 months
in the SCLC-I group 。 The results of a phase II clinical study of temozolomide combined with nivolumab in the treatment of advanced NENs were reported at the 2022 ASCO Annual Meeting, and a total of 28 patients were enrolled, including 11 bronchial NENs, 3 pancreatic NENs, and 14 other NENs, showing that the bronchial group obtained a better ORR (64%), and the study also showed that elevated peripheral blood CD8+ T lymphocyte levels after treatment may be associated with
clinical benefit 。 The Spanish multicenter phase II non-randomized open-label NICE-NEC clinical trial is the first study to evaluate the role of adding immune checkpoint inhibitors to first-line chemotherapy of G3 NENs, exploring the efficacy of nivolumab combined with cisplatin/carboplatin as a first-line treatment in advanced or unresectable gastrointestinal pancreas or NENs of unknown primary site, including 38 patients with G3 NENs, 66% Ki-67>55%, 81.
6% gastrointestinal and pancreatic NENs, and 68% NECs
。 The latest results, reported at ESMO 2022, showed limited efficacy with standard first-line platinum-containing chemotherapy combined with immune checkpoint inhibitors in G3 NENs, with an overall ORR of 54.
1%, a median PFS of 5.
7 months, and a median OS of 13.
9 months
。 ORR was slightly better in the Ki-67>55% group than in the Ki-67<55% group (59.
3 versus 46.
7 percent), and patients with gastrointestinal and pancreatic origin had better OS than in the colorectal group (gastroenteric small intestine vs pancreatic versus colorectal OS time was not achieved 14.
6 versus 6.
4 months, respectively) ^[19].

The above studies show that immunotherapy combined with chemotherapy has made some progress in lung neuroendocrine tumors, especially small cell lung cancer, but there is no breakthrough in immunotherapy for extrapulmonary neuroendocrine tumors, so further exploration
of the immune microenvironment and efficacy prediction markers of neuroendocrine tumors is required.
Our team recently published a study of the immune microenvironment of 51 thymic NETs, including PD-1, PD-L1 expression, and infiltration levels
of CD14+ monocytes, CD15+ multinucleated cells, CD4+ T cells, and CD8+ T cells.
It was found that thymic NETs were mainly presented as PD-L1+TILs+ or PD-L1-TILs+, both of which are immune subtypes with potential sensitivity to immunotherapy, and the level of CD8+ TILs in thymic NET was significantly negatively correlated with bone metastasis, which was a reliable immune marker for predicting bone metastasis ^[20].

The findings may help screen patients who are sensitive to immunotherapy in thymic NETs, but further clinical validation
is needed.

05 

Peptide receptor radionuclide therapy (PRRT)

Preliminary results
from the first multicenter, prospective, phase II randomized controlled clinical study comparing Lu177-octreotide PRRT versus sunitinib for unresectable advanced pancreatic NENs were reported at the 2022 ESMO Annual Meeting.
A total of 84 patients were included in the study, 41 in the PRRT group and 43 in the sunitinib group, with more than 80% of patients in both groups achieving G2 and above, the proportion of patients with liver metastases greater than 25% was also more than 40%, and more than 40% of patients were after
second-line treatment.
Preliminary results suggest that PRRT has a significant PFS time advantage over sunitinib (20.
7 versus 11 months).

Other clinical studies comparing Lu177-octreotide PRRT with everolimus, Lu177-octreotide versus everolimus, CAPTEM and FOLFOX are also underway, and this series of research results may reposition PRRT in the treatment of NET
.

06 

New drug research and development

Ataxia telangiectasia mutated and Rad3-related (ATR) inhibitors can exert anti-tumor effects
through synthetic lethal mechanisms 。 A Phase II clinical study of the ATR inhibitor berzosertib combined with topotecan for the treatment of extrapulmonary small cell NEC was reported at the ASCO Annual Meeting 2022, and a total of 15 patients with an ORR of 13.
3% were included in the study, two of whom received PR for 6.
9 months and 5.
8 months
, respectively.
Another breakthrough new drug is the hypoxia-inducible factor 2α inhibitor Belzutifan
.
The mutation or deletion of tumor suppressor gene VHL will lead to the upregulation of hypoxia-inducible factor 2α and promote tumor growth and neovascularization, and belzutifan can achieve the purpose
of treating VHL gene mutation-related tumors by inhibiting hypoxia-inducible factor 2α.
The results of the phase II study were also reported at the 2022 ASCO Annual Meeting, which included a total of 61 VHL mutation-related tumors, including central angioblastoma, renal clear cell carcinoma, and pancreatic NET, of which 47 cases were pancreatic NET and obtained 90% ORR ^[21].

The drug is considered the dawn
of patients with VHL syndrome.
In addition, a basic study published by our team in 2022 showed that the high expression of the Bcl-2 protein family in gastrointestinal pancreatic NENs was negatively correlated with the prognosis of tumors ^[22], and the new drug APG-1252, which targets Bcl-xL in the Bcl-2 protein family, also showed a pro-apoptotic effect
on NENs cell lines, especially pancreatic NENs cells, in preclinical cytology experiments.
At present, the corresponding phase I clinical trial has also been launched, and the anti-apoptotic pathway may be a new target for the treatment of
NENs.

07 

summary

Summarizing the progress of NENs drug treatment in 2022, the treatment of SSAs combined with TAE to reduce the burden of liver metastases can prolong the PFS of G1/G2 NET, and it is necessary to strategically rationalize the layout of different treatment methods in clinical formation
.
How to optimize and accurately use targeted drugs is the future research direction
.
The efficacy and safety of temozolomide-based alkylating agents on pancreatic NET were further confirmed by prospective clinical studies, and the loss of expression of MGMT enzyme could predict the efficacy of temozolomide.
Oxaliplatin-based chemotherapy regimens may be used as an alternative
to temozolomide regimens.
Immunotherapy combined with chemotherapy has made progress in pulmonary small cell neuroendocrine carcinoma, but there has been no breakthrough in extrapulmonary neuroendocrine tumors, and more in-depth exploration
of the immune microenvironment and efficacy prediction markers of NENs is needed in the future.
Head-to-head controlled studies of PRRT versus various drugs are ongoing, and the results may rewrite its place
in the treatment of NET.
In terms of new drug research and development, belzutifan has made breakthroughs in the treatment of VHL gene mutation-related tumors, and the results of phase III clinical research are worth looking forward to
.

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