scholarly journals Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets

2018 ◽  
Vol 7 (1) ◽  
pp. R1-R25 ◽  
Author(s):  
E T Aristizabal Prada ◽  
C J Auernhammer
Keyword(s):  
Targeted Therapy ◽  
Molecular Targeted Therapy ◽  
Histone Deacetylase Inhibitors ◽  
Neuroendocrine Tumours ◽  
Objective Response ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Beta Catenin ◽  
Cell Cycle Regulators ◽  
Preclinical Research

Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression-free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras–Raf–MEK–ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors.

scholarly journals Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial

2017 ◽  
Vol 35 (29) ◽  
pp. 3315-3321 ◽  
Author(s):  
Maria E. Cabanillas ◽  
Jonas A. de Souza ◽  
Susan Geyer ◽  
Lori J. Wirth ◽  
Michael E. Menefee ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Multikinase Inhibitor

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

Alkylating agent rechallenge in metastatic pancreatic neuroendocrine tumours

2021 ◽  
Author(s):  
Ophelie De Rycke ◽  
Thomas Walter ◽  
Marine Perrier ◽  
Olivia Hentic ◽  
Catherine Lombard-Bohas ◽  
...  
Keyword(s):  
Neuroendocrine Tumours ◽  
Objective Response ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Tumor Control ◽  
Free Survival ◽  
Mgmt Expression ◽  
Pancreatic Neuroendocrine Tumours

A rechallenge is common after initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET. Secondly, to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (Cohort A). Primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (Cohort B). We foud that cohort A included 62 patients (median Ki67 8%), for which ALK1 followed by pause achieved an objective response rate of 55%, and a PFS1 of 23.7 months (95% IC, 19.8-27.6). ALK2 achieved no objective response, and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1-11.3). At multivariable analysis, a hormonal syndrome (p=0.032) and a pause longer than 12 months (p=0.041) were associated with a longer PFS2. In the cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18-105) before ALK, to 100 (IQR 56-180) after ALK (p=0.003). We conclude that after initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain low efficacy of ALK rechallenge.

scholarly journals Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors

2020 ◽  
Vol 38 (27) ◽  
pp. 3088-3094 ◽  
Author(s):  
Anita Gul ◽  
Tyler F. Stewart ◽  
Charlene M. Mantia ◽  
Neil J. Shah ◽  
Emily Stern Gatof ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival ◽  
Metastatic Rcc

PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

Down-regulation of KRAS-interacting miRNA-143 to predict prognosis and response to EGFR-targeted agents in colorectal cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14066-e14066
Author(s):  
Florian Eisner ◽  
Michael Stotz ◽  
Hellmut Samonigg ◽  
Sigurd Lax ◽  
Gerald Hoefler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Objective Response ◽  
Progression Free Survival ◽  
Targeted Agents ◽  
Wild Type ◽  
Down Regulation ◽  
Cancer Specific Survival ◽  
Free Survival ◽  
Expression Levels

e14066 Background: MicroRNA-143 is frequently down-regulated in colorectal cancer (CRC) and influence CRC cell proliferation, apoptosis and sensitivity to 5-fluorouracil. mRNA encoded by the KRAS oncogene has been identified as a target of microRNA-143. However, the prognostic significance of microRNA-143 expression and the ability to predict the patient response to EGFR-targeted agents have not been explored yet. Methods: In this study, we analyzed 77 CRC harboring wild-type KRAS and obtaining treatment with the EGFR-targeting monoclonal antibodies cetuximab or panitumumab. MicroRNA-143 expression was measured by RT-PCR in both CRC and corresponding non-neoplastic colon tissue and the expression levels were correlated with clinico-pathological characteristics. Cancer-specific survival was calculated by uni- and multivariate analyses. The progression-free survival and objective response rates on EGFR-targeted therapy were also evaluated. Results: Down-regulation of microRNA-143 was observed in 47/77 (61%) CRC. Multivariate Cox regression analysis identified low levels of microRNA-143 expression as an independent prognostic factor with respect to cancer-specific survival (HR=1.92, CI=1.1-3.4, p=0.024). A significant difference was observed with respect to progression-free survival on EGFR-targeted therapy (p=0.031, log-rank test), but there were no significant differences with regard to the objective response rate. Conclusions: Our data suggest that microRNA-143 expression levels serve as independent prognostic biomarker for KRAS wild-type CRC patients but not as predictor for EGFR-targeted therapy. In addition, we consider microRNA-143 as a potential drug target for future therapy of CRC.

A single-arm, open-label, multicenter phase I/II study of the combination of panobinostat (pan) and carfilzomib (cfz) in patients (pts) with relapsed/refractory multiple myeloma (RR MM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS8115-TPS8115
Author(s):  
Jesus G. Berdeja ◽  
Joseph Mace ◽  
Ruth E. Lamar ◽  
Victor Gian ◽  
Patrick Brian Murphy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Histone Deacetylase Inhibitors ◽  
Standard Dose ◽  
Objective Response ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Current Status ◽  
Open Label ◽  
Starting Dose

TPS8115 Background: Despite novel therapies, MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM. Preclinical studies demonstrate synergistic anti-MM activity with histone deacetylase inhibitors (HDACi) and proteasome inhibitors (PI) through the dual inhibition of the proteasome and aggresome pathways. Pan is an oral pan-HDACi which has shown synergy with bortezomib in clinical studies. Cfz is a 2nd generation PI which has shown marked anti-MM activity with an improved safety profile. In this trial we evaluate the safety and efficacy of the combination of pan and cfz in pts with RR MM. Methods: This multi-center US study plans to enroll up to 52 adults with RR MM. The phase I study will determine the MTD of the combination of cfz and pan and follow a standard dose escalation design. Pan will be administered orally three times weekly during weeks 1 and 3 of each 28-day cycle (Days 1, 3, 5, 15, 17, 19) at a starting dose of 20 mg. Cfz will be administered intravenously on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cfz starting dose will be 20mg on days 1,2 of cycle 1 with escalation to the corresponding dose level beginning at 27 mg , if well tolerated. Dose modifications will not be permitted during cycle 1 unless a pt experiences a DLT. A maximum of four dose levels will be evaluated. Approximately 24 pts will be enrolled during the phase I portion to establish the MTD. In the phase II portion of this study, pts with RR MM will receive treatment with the optimal dose of pan and cfz established during phase I. Pts will be assessed for response to treatment after each cycle (4 weeks). Pts with objective response or stable disease will continue treatment until disease progression or unacceptable toxicity occurs. The primary endpoint is to establish the optimal doses of cfz and pan that can be administered to pts with RR MM (phase I) and to evaluate the overall response rate (phase II). Secondary endpoints include time-to-progression, progression-free survival, overall survival and safety. Approximately 25 pts are planned for the phase II portion. Current status: As of 1/27/12 3 patients have been enrolled.

Phase II study of apatinib combined with temozolomide in advanced melanoma patients after failure of anti-PD-1 therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22043-e22043
Author(s):  
Li Zhou ◽  
Chuanliang Cui ◽  
Lu Si ◽  
Zhihong Chi ◽  
Xinan Sheng ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Lactate Dehydrogenase Level ◽  
Advanced Melanoma ◽  
First Line Therapy ◽  
Hand Foot Syndrome ◽  
Melanoma Patients

e22043 Background: Immunotherapy is first-line therapy in advanced melanoma. Because of different subtypes and gene alterations, the efficacy of immunotherapy in Asians, mostly comprised of acral and mucosal melanoma, is lower than Caucasians. There are no standard treatment strategies after immunotherapy failure. Chemotherapy and anti-angiogenesis combination showed emerging evidence of activity in mucosal and acral melanoma. This study was to evaluate the efficacy of apatinib combined with temozolomide in advanced immunotherapy refractory melanoma patients (pts). Methods: This prospective, single-arm, phase II study recruited unresectable or metastatic melanoma pts after failure of anti-PD-1 therapy. Other treatment including targeted therapy, chemotherapy, and clinical trials were allowed. Primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). According to the dose recommended from previous phase I study, pts were given apatinib 500 mg every day and temozolomide 300mg day 1-5, 28 days for one cycle. Results: 31 pts were enrolled between Feb 2018 and Dec 2018, with 8 males, average age 55 yrs (range 24 – 69 yrs). 13 pts (41.9%) were from mucosal primaries, 9 (29.0%) acral, 5 (16.1%) cutaneous (non-acral), and 4 (12.9%) unknown primaries. One had BRAF mutation, 1 CKIT, and 3 NRAS mutations. 9 pts (29.0%) were classified as IIIc/M1a, 9 (29.0%) M1b, and 13 (41.9%) M1c. 18 pts (58.1%) had elevated lactate dehydrogenase level. All pts progressed after anti-PD-1 therapy. In addition, 29.0% pts received dacarbazine based chemotherapy, 29.0% paclitaxel or albumin-bound paclitaxel, and 3.2% had dabrafenib with trametinib. Up to Dec 2019, 30 pts can be evaluated for efficacy. Median follow-up time was 10.2 mos (2.0-23.1 mos). There were 5 confirmed PRs and 20 SDs. ORR was 16.7%, DCR 83.3%, and median PFS was 5.0 mos (95%CI 1.9-8.1 mos). Median overall survival was 10.1 mos (95%CI 4.7-15.5 mos). Common AEs were hypertension (51.6%), proteinuria (41.9%), elevated transaminase (25.8%), thrombocytopenia (16.1%), and hand-foot syndrome (16.1%). Most were grade 1-2. Grade 3-4 AEs included proteinuria (12.9%), hypertension (6.4%), and thrombocytopenia (6.4%); 10 pts required a dose reduction, and 1 had to discontinue. No treatment-related deaths were observed. Conclusions: In pts progressed after anti-PD-1 therapy, apatinib in combination with temozolomide demonstrated promising efficacy and favorable safety profile. Clinical trial information: NCT03422445.

Updated results from a randomized phase II study of cabazitaxel (CAB) versus abiraterone (ABI) or enzalutamide (ENZ) in poor prognosis metastatic CRPC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5003-5003
Author(s):  
Kim N. Chi ◽  
Sinja Taavitsainen ◽  
Nayyer Iqbal ◽  
Cristiano Ferrario ◽  
Michael Ong ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Clinical Benefit ◽  
Poor Prognosis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Pi3k Pathway ◽  
Primary Objective ◽  
Therapy Outcomes ◽  
Prognostic Criteria ◽  
Clinical Benefit Rate

5003 Background: The treatment for poor prognosis mCRPC includes taxanes and androgen receptor (AR) targeted therapy, however the optimal treatment is undefined. Methods: Patients (pts) with poor prognosis (liver metastases, early CRPC ( < 12 months from ADT start), and/or > 3 of 6 poor prognostic criteria (Chi et al, Annals of Oncol, 2016)) were randomized to receive CAB (Arm A) or AR targeted therapy (Arm B, ABI or ENZ by investigator choice) with cross over at progression. Primary objective was to determine the clinical benefit rate (CBR) (PSA decline ≥50% (PSA50), objective response (OR), or stable disease (SD) ≥ 12 weeks). Plasma was sampled serially for circulating tumour DNA (ctDNA). Results: 95 pts were randomized (Arm A: 45, Arm B: 50): 18% had liver mets, 88% early CRPC and 30% had > 3 of 6 poor prognostic criteria. 52% of pts had prior docetaxel, half for castration sensitive disease. Table summarizes 1st-line therapy outcomes. Baseline ctDNA fraction > 15% (median) was associated with shorter 1st-line progression-free survival (PFS) (median 2.8 vs 8.4 m, HR = 2.54, P < 0.001) and overall survival (OS) (median 14.0 vs 38.7 m, HR = 2.64, P = 0.001). ctDNA alterations in AR, TP53, PI3K pathway, RB1 and DNA repair were detected in 53%, 45%, 31%, 23%, and 21% of pts. Shorter PFS and OS were associated with AR gain (HR 2.57 (95% CI 1.63-4.06); HR 3.59, (1.9-6.69), respectively) and TP53 defects (HR 2.62 (CI 1.65-4.15); HR 3.33 (CI 1.8-6.14), respectively). Pts with concurrent defects in TP53 and RB1 had a trend for worse PFS/OS than pts with TP53 defect alone. AR rearrangements predicted to disrupt the ligand binding domain were detected in 6% of pts and had a shorter PFS (HR = 2.60 (1.11 - 6.09)) with a trend for shorter OS (HR = 2.27 (0.89 - 5.81)). Conclusions: In this poor prognosis cohort, 1st-line treatment with CAB had a higher clinical benefit rate than treatment with ABI/ENZA. Elevated ctDNA and genomic alterations in AR and TP53 were prognostic. Supported in part by Sanofi. Clinical trial information: NCT02254785. [Table: see text]

Exploratory endpoints in a FARETES study of the efficacy of testosterone in metastatic renal cell carcinoma (mRCC) patients.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 574-574 ◽  
Author(s):  
Ilya Tsimafeyeu ◽  
Pavel Borisov ◽  
Ruslan Zukov ◽  
Kristina Zakurdaeva ◽  
Anastasia Bondarenko ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Symptom Control ◽  
Objective Response ◽  
Progression Free Survival ◽  
Control Group ◽  
Testosterone Undecanoate ◽  
Male Patients ◽  
New Treatment ◽  
Grade 3 ◽  
October 17

574 Background: In multicenter randomized phase 2 study (FARETES) we showed that male patients with mRCC receiving targeted therapy had significantly less fatigue and better symptom control with testosterone undecanoate (T) (MASCC 2018, LBA004). Here we described exploratory endpoints in FARETES study. Methods: Sixty male patients with clear cell mRCC, normal PSA level, low testosterone level and no evidence of hypothyroidism receiving first-line sunitinib or pazopanib with fatigue were randomly assigned (1:1) to either T (Nebido, 1,000 mg) and targeted therapy or targeted therapy alone (control group). T was injected intramuscular deeply on Day 1 of a new treatment cycle. Exploratory endpoints included rate of adverse events (AE) of targeted therapy, duration of targeted therapy, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: As of the data cutoff on October 17, 2018, median (range) follow-up was 15.2 (9.9 -16.5) months. No unexpected toxicity of T was observed. Grade 3-4 targeted therapy-related AE occurred in 11 (37%) and 3 (10%) patients in the control group and T group, respectively. Discontinuation due to AE was observed in 3% (1/30) of patients in the T group and in 17% (5/30) of patients in the control group. ORR and PFS were significantly better in the T group (all P < 0.05, Table). Median OS was not reached in either group. Clinical trial information: NCT03379012. Conclusions: T therapy could decrease rate of serious AE of targeted therapy. Male mRCC patients receiving T had longer duration of targeted therapy, better PFS and ORR. Larger trials are needed to evaluate efficacy of T in this group of patients.[Table: see text]

Lenvatinib for Hepatocellular Carcinoma Patients with Nonviral Infection Who Were Unlikely to Respond to Immunotherapy: A Retrospective, Comparative Study

Oncology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Takeshi Hatanaka ◽  
Satoru Kakizaki ◽  
Tamon Nagashima ◽  
Masashi Namikawa ◽  
Takashi Ueno ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Viral Infection ◽  
Objective Response ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Advanced Hepatocellular Carcinoma ◽  
Infection Group ◽  
Significant Difference

<b><i>Aim:</i></b> Atezolizumab plus bevacizumab (atezo + bev) shows a good overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients. However, the OS of patients with nonviral infection is quite worse than that in those with viral infection. The present study investigated the efficacy and safety of lenvatinib in patients with nonviral infection, who were unlikely to obtain benefit from atezo + bev. <b><i>Methods:</i></b> We conducted a multicenter retrospective study that included 139 advanced HCC patients treated with lenvatinib between March 2018 and September 2020. <b><i>Results:</i></b> The median age was 72 years, and 116 patients (83.5%) were male. Based on the etiology of liver disease, 84 (60.4%) and 55 patients (39.6%) were assigned to the viral infection and nonviral infection groups, respectively. The significant extents in patient characteristics were not observed in both groups. The objective response rate per mRECIST and progression-free survival (PFS) did not differ significantly between the viral infection and nonviral infection groups (36.0 vs. 33.0%, <i>p</i> = 0.85; and 7.6 vs. 7.5 months, <i>p</i> = 0.94, respectively). The 1-year survival rates were 68.7% (95% confidence interval [CI] 57.7–79.7%) in the viral infection group and 59.5% (95% CI 45.2–73.8%) in the nonviral infection group. The viral infection group was not a significant factor associated with the PFS or OS in a multivariate analysis. <b><i>Conclusions:</i></b> Lenvatinib shows no significant difference in response between patients with and without viral infection. Treatment strategies based on the etiology of liver disease may lead to good clinical outcome.

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