scholarly journals Impact of Precision Medicine on Clinical Outcomes: A Single-Institution Retrospective Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Ryann Quinn ◽  
Rajvi Patel ◽  
Cristina Sison ◽  
Amandeep Singh ◽  
Xin-Hua Zhu
Keyword(s):  
Targeted Therapy ◽  
Precision Medicine ◽  
Clinical Outcomes ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Community Oncology ◽  
Progression Of Disease ◽  
Real Community ◽  
Oncology Practice

PurposeThe strategy of precision medicine has been widely adopted in the practice of oncology, although the efficacy remains unclear. This study assesses clinical outcomes in patients with an actionable alteration found during FoundationOne CDx™ (F1CDx) testing and who received a targeted therapy based on the results.Materials and MethodsThis is a retrospective cohort study of patients with tumors that underwent F1CDx from September 2012 to July 2018. F1CDx provided actionable alterations for patients to select appropriate therapies. The primary objective was to estimate the objective response rate (ORR) at 3 months from the start of study treatment. The secondary objectives were to estimate progression-free survival (PFS) and overall survival (OS).ResultsOne thousand patients underwent F1CDx testing. Six hundred fifty-two patients were identified as having actionable mutations. Thirty-eight patients (18 males and 20 females) received targeted therapy and were included in the study. The most common alterations were PD-1/PDL-1, high-TMB, P13K, and HER2/ERBB2. Patients received various treatments including nivolumab, pembrolizumab, trastuzumab, and everolimus. Eight (23.5%) and six (17.7%) patients achieved partial response (PR) and stable disease (SD), respectively; 20 (58.8%) had progression of disease (PD). The disease control rate was 41.2% (95% CI: 24.7% to 59.3%). The median PFS was 2.7 months (95% CI: 2.3 to 5.4 months), and median OS was 9.9 months (95% CI: 4.5 to 33.7 months).ConclusionOur results demonstrate promising data in precision medicine in real community oncology practice. It warrants further large and prospective studies in patients with actionable alterations.

Evolution of standard of care therapies used for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): A real-world analysis of patient health records from 2016 to 2019.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18728-e18728
Author(s):  
Nabil F. Saba ◽  
Soham Shukla ◽  
Kathleen M. Aguilar ◽  
Marc S. Ballas ◽  
Kelly Bell ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Real World ◽  
Data Extraction ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Treatment Discontinuation ◽  
Health Records ◽  
Treatment Regimens ◽  
Community Oncology ◽  
Oncology Practice

e18728 Background: The R/M HNSCC treatment landscape has evolved significantly in recent years, notably with the approval of 2 immuno-oncology agents (IO), pembrolizumab (second-line [2L] approval, 2016; first-line [1L] approval, 2019) and nivolumab (2L approval, 2016). Review of the literature suggests there is limited real-world (rw) data on clinical outcomes and safety associated with chemotherapy (chemo) and IO in R/M HNSCC. These analyses present a review of patient charts to assess rw clinical outcomes and safety in R/M HNSCC, stratified by patient factors. Methods: Data were derived via structured data extraction and manual review of electronic health records (EHRs; January 1, 2016–December 31, 2019) for patients with R/M HNSCC and who initiated systemic treatment at a community oncology practice in The US Oncology Network. Time-to-event endpoints were assessed by unadjusted Kaplan–Meier analyses and included death (rw overall survival [OS]), provider-assessed progression (rw progression-free survival [PFS]), rw duration of response (DoR), and treatment discontinuation (rw time-to-discontinuation [TTD]). Treatment sequences were evaluated following R/M HNSCC diagnosis. Provider-assessed response rates and adverse events (AEs) as captured in the EHRs were reported. Results: Overall, 257 patients who received 1L treatment were included in these analyses; median age was 64 years (range: 21, 90+); the majority of patients were male (77.4%) and white (74.7%), and 17.5% had evaluable PD-L1 status. The most common 1L treatment regimens were nivolumab (18.3%), carboplatin + paclitaxel (16.0%), and pembrolizumab (14.8%). Median follow-up time from treatment initiation was 7.9 months (range: 0.2, 45.9). Of the 174 patients with evaluable response to 1L treatment, overall response rate was 48.5% (95% CI: 38.3, 58.8) for chemo and 40.0% (95% CI: 28.9, 52.0) for IO. Median rwDoR was 7.6 months (95% CI: 5.8, 11.2). Median rwOS was 12.1 months (95% CI: 10.5, 16.6), and median rwPFS was 5.9 months (95% CI: 4.7, 6.8). Median rwTTD was 2.3 months (95% CI: 2.0, 3.2). The top reason for treatment discontinuation was treatment completion (38.5%) for chemo and progression (46.6.%) for IO. The most commonly reported AEs were rash (17.5%), fatigue (14.4%), and nausea (14.4%) for chemo and fatigue (12.4%), rash (7.2%), and anemia (5.2%) for IO. The percentage of AEs that did not require any intervention was 34.4% for chemo and 20.6% for IO. Conclusions: These analyses present rw clinical outcomes for patients with R/M HNSCC in community oncology practices. The proven role of IO continues to evolve, and continued work is needed to best demarcate the use of these agents, in addition to exploration of additional therapeutics for use in R/M HNSCC. Study funding: GlaxoSmithKline (GSK Study 207139).

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]

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.

Differential response rates in early-phase cancer clinical trials (EPCCT).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3133-3133
Author(s):  
Rozana Abdul Rahman ◽  
Neethu Billy Graham Mariam ◽  
Hitesh Mistry ◽  
Sreeja Aruketty ◽  
Matt Church ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Response Rates ◽  
Primary Objective ◽  
Cox Proportional Hazards ◽  
Sustained Response ◽  
Phase Ii Trials ◽  
Significant Difference

3133 Background: The primary objective of EPCCT (phase I and non-randomised phase II trials) is to determine the safety and tolerability of new therapeutic agents. Response rates (RR) in these trials have typically been reported at around 10-15%. Increasingly RR and survival outcomes are now investigated in EPCCT as primary or secondary objectives. Methods: Retrospective data analysis was performed on patients (pts) enrolled onto an EPCCT between January 2018 and December 2019 at The Christie NHS Foundation Trust, UK. Data on demographics, prior systemic treatment, sites of disease, performance status, comorbidities, types of therapy, RR, progression free survival (PFS), and overall survival (OS) were collected. Statistical analyses were performed with univariable and multivariable models. Objective response rate (ORR) was defined as the proportion of pts with complete response (CR) and partial response (PR). Duration of response (DOR) was from initial response to progressive disease (PD). Disease control rate (DCR) was defined as CR+PR+ stable disease (SD). Results: A total of 247 pts were treated across 46 EPCCTs. Median age 61 years; 57% female. Sixty-six percent of pts had ≥2 lines of treatment and the majority were ECOG PS 0/1 (98%). Eighty-one percent of pts had ≥2 sites of metastatic disease, and 13 major tumour types were included. Monotherapy trials (159 pts) were predominantly targeted therapies (TT; 60%), or immunotherapies (IO; 20%). Combination therapy trials (88 pts) were TT-based (68%) or IO-based (32%). Data for RR analyses was available for 231 pts. ORR across all trials was 15% (CR 2%) and DCR was 63%. The median DOR was 8.3 months (mos) (95% CI: 7.0 – 9.7) with 28% of pts responding for >6 mos and 7% for >12 mos. ORR in pooled IO treated pts was 27%, DCR was 65% with sustained response >6 mos seen in 37% of these pts. ORR in pooled TT treated pts was 9.4%, DCR was 60% and sustained response > 6 mos seen in 25% of pts. ORR for IO v TT treated pts was significantly different, p=0.007 (pearson chi square), but no significant difference was seen for DCR. Median PFS for all patients was 5.0 mos (95% CI: 4.1 – 6.0) and OS was 10.4 mos (95% CI: 8.4 – 13.0). OS for those with a PR is not reached (HR for PR v PD, 0.006 (95% CI: 0.002 – 0.18). Pts with SD appear to have significantly better OS compared to those with PD (14.6 v 4.2 mos, HR 0.2 (95% CI: 0.1 – 0.3). Multivariable Cox proportional hazards analysis for OS was significant for male gender (HR 1.9, p=0.002), presence of liver metastasis (HR 2.0, p=0.001), low Hb (HR 0.8, p=0.03) and log (LDH) (HR 1.9, p<0.001). Conclusions: Two-thirds of pts enrolled on EPCCTs benefitted in terms of DCR with significant OS improvement in those with PR and SD. Higher ORR were seen in pts receiving IO-based treatments however DCR was similar in IO and TT pts. Gender, presence of liver metastases, Hb count and LDH level contributed significantly to survival differences.

Association of the neutrophil to eosinophil ratio with response to immunotherapy-based combinations in metastatic renal cell carcinoma.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 341-341
Author(s):  
Matthew D Tucker ◽  
Katy Beckermann ◽  
Kristin Kathleen Ancell ◽  
Kerry Schaffer ◽  
Renee McAlister ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Clinical Outcomes ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Progression Free Survival ◽  
Rank Test ◽  
Cancer Center ◽  
Exact Test

341 Background: Neutrophilia is known to be associated with worse prognosis in metastatic renal cell carcinoma (mRCC); however, less is known about the role of eosinophils in the response to immunotherapy (IO). We investigated the association of the baseline neutrophil to eosinophil ratio (NER) with outcomes to IO-based combination treatment in mRCC. Methods: Patients with mRCC treated with ipilimumab plus nivolumab, pembrolizumab plus axitinib, or avelumab plus axitinib at the Vanderbilt-Ingram Cancer Center were retrospectively identified. Patients on >10mg prednisone and patients with prior IO were excluded. Baseline NER (at time of first IO) and association with progression free survival (PFS), overall survival (OS), and objective response rate (ORR) were investigated. Data cutoff was 9/1/2020. Analysis for PFS and OS was performed using the log-rank test and Mantel-Haenszel method, and analysis of the odds ratio for ORR was performed using Fischer’s exact test. Results: Sixty-one patients were identified: 89% clear cell histology, 74% prior nephrectomy, 69% IMDC intermediate risk, and 72% treatment-naïve. Patients with baseline NER < median (N=31) had improved clinical outcomes compared to patients with baseline NER > median (N=30) (Table). Improvement in PFS by NER was maintained when stratified by anti-PD-1/CTLA-4 and anti-PD(L)-1/VEGF (p= 0.0062 and p= 0.049); however, differences in OS and ORR were no longer significant. The median baseline NER among patients with partial response (PR) was significantly lower at 22.7 (95% CI 18.9-31.1) vs. 51.6 (95% CI 39.5-93.1) among those with progressive disease (PD) (p= 0.0054). For comparison, the median neutrophil to lymphocyte ratio was not significantly different between PR (2.60) and PD (3.84, p= 0.056). Conclusions: Patients with a low baseline NER treated with IO-based combinations had improved clinical outcomes compared to patients with a high baseline NER. Additional investigation of this parameter in larger cohorts is warranted. [Table: see text]

scholarly journals Observational study of clinical outcomes of eribulin mesylate in metastatic breast cancer after cyclin-dependent kinase 4/6 inhibitor therapy

2019 ◽  
Vol 15 (34) ◽  
pp. 3935-3944 ◽  
Author(s):  
Sarah S Mougalian ◽  
Bruce A Feinberg ◽  
Edward Wang ◽  
Karenza Alexis ◽  
Debanjana Chatterjee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Outcomes ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Cyclin Dependent Kinase ◽  
Eribulin Mesylate ◽  
Free Survival

Aim: To examine the effectiveness of eribulin mesylate for metastatic breast cancer post cyclin-dependent kinase inhibitor (CDKi) 4/6 therapy. Materials & methods: US community oncologists reviewed charts of patients who had received eriublin from 3 February 2015 to 31 December 2017 after prior CDKi 4/6 therapy and detailed their clinical/treatment history, clinical outcomes (lesion measurements, progression, death) and toxicity. Results: Four patient cohorts were created according to eribulin line of therapy: second line, third line, per US label and fourth line with objective response rates/clinical benefit rates of 42.2%/58.7%, 26.1%/42.3%, 26.7%/54.1% and 17.9%/46.4%, respectively. Median progression-free survival/6-month progression-free survival (79.5% of all patients censored) by cohort was: 9.7 months/77.3%, 10.3 months/71.3%, not reached/70.4% and 4.0 months/0.0%, respectively. Overall occurrence of neutropenia = 23.5%, febrile neutropenia = 1.3%, peripheral neuropathy = 10.1% and diarrhea = 11.1%. Conclusion: Clinical outcome and adverse event rates were similar to those in clinical trials and other observational studies. Longer follow-up is required to confirm these findings.

scholarly journals Pharmacogenetic Association between XRCC1 Polymorphisms and Response to Platinum-Based Chemotherapy in Asian Patients with NSCLC: A Meta-Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Ningning Zhang ◽  
Yushu Ouyang ◽  
Jianlan Chang ◽  
Ping Liu ◽  
Xiangyang Tian ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Gene Dosage ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Gene Dosage Effect ◽  
Asian Patients ◽  
Hazard Ratios ◽  
Platinum Based Chemotherapy ◽  
Study Heterogeneity

Background. Platinum-based chemotherapy plays an antitumor role by damaging DNA. X-ray repair crosscomplementing protein 1 (XRCC1) participates in DNA repair and thus affects the sensitivity to platinum drugs. Two polymorphisms of XRCC1, rs25487 (Arg399Gln) and rs1799782 (Arg194Trp), have been widely studied for the association with clinical outcomes of platinum-based chemotherapy in Asian patients with non-small-cell lung cancer (NSCLC), but the results remain inconclusive. Thus, we performed the present meta-analysis. Methods. Literature search was performed in PubMed, Web of Science, and EMBASE up to June 2019. Odds ratios (ORs) for objective response ratio (ORR), Cox proportional hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS), and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association strengths between XRCC1 polymorphisms and clinical outcomes. Comparisons were performed in homozygous, heterozygous, dominant, and recessive models. Results. Finally, a total of 23 studies involving 5567 patients were included in the meta-analysis. Compared to ArgArg of rs25487, GlnGln ( OR = 1.71 , 95% CI: 1.16-2.52, p = .007 , I 2 = 56.8 % ) and GlnArg ( OR = 1.23 , 95% CI: 1.07-1.40, p = .003 , I 2 = 29.0 % ) were associated with higher ORR. Meanwhile, GlnGln indicated a favorable OS ( HR = 0.60 , 95% CI: 0.40-0.88) and PFS ( HR = 0.64 , 95% CI: 0.46-0.90). We also found positive associations between rs1799782 and ORR in all comparison models with low between-study heterogeneity. The association strength increased with the number of variant alleles (TrpTrp vs. ArgArg: OR = 1.73 , 95% CI:1.31-2.27; TrpArg vs. ArgArg: OR = 1.28 , 95% CI: 1.06-1.55), suggesting a gene dosage effect. In addition, TrpTrp predicted a longer OS. Conclusion. Our results showed that rs25487 and rs1799782 of XRCC1 are potential markers to predict clinical outcomes of platinum-based chemotherapy in Asian patients with NSCLC.

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.

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.

A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma

2017 ◽  
Vol 35 (16) ◽  
pp. 1764-1769 ◽  
Author(s):  
Moshe C. Ornstein ◽  
Laura S. Wood ◽  
Paul Elson ◽  
Kimberly D. Allman ◽  
Jennifer Beach ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Initial Therapy ◽  
Primary Objective ◽  
Intermittent Therapy

Purpose Sunitinib is a standard initial therapy in metastatic renal cell carcinoma (mRCC), but chronic dosing requires balancing toxicity with clinical benefit. The feasibility and clinical outcome with intermittent sunitinib dosing in patients with mRCC was explored. Patients and Methods Patients with treatment-naïve, clear cell mRCC were treated with four cycles of sunitinib (50 mg once per day, 4 weeks of receiving treatment followed by 2 weeks of no treatment). Patients with a ≥ 10% reduction in tumor burden (TB) after four cycles had sunitinib held, with restaging scans performed every two cycles. Sunitinib was reinitiated for two cycles in those patients with an increase in TB by ≥ 10%, and again held with ≥ 10% TB reduction. This intermittent sunitinib dosing continued until Response Evaluation Criteria in Solid Tumors-defined disease progression while receiving sunitinib, or unacceptable toxicity occurred. The primary objective was feasibility, defined as the proportion of eligible patients who underwent intermittent therapy. Results Of 37 patients enrolled, 20 were eligible for intermittent therapy and all patients (100%) entered the intermittent phase. Patients were not eligible for intermittent sunitinib because of progressive disease (n = 13), toxicity (n = 1), or consent withdrawal (n = 3) before the end of cycle 4. The objective response rate was 46% after the first four cycles of therapy. The median increase in TB during the periods off sunitinib was 1.6 cm (range, −2.9 to 3.4 cm) compared with the TB immediately before stopping sunitinib. Most patients exhibited a stable sawtooth pattern of TB reduction while receiving sunitinib and TB increase while not receiving sunitinib. Median progression-free survival to date is 22.4 months (95% CI, 5.4 to 37.6 months) and median overall survival is 34.8 months (95% CI, 14.8 months to not applicable). Conclusion Periodic extended sunitinib treatment breaks are feasible and clinical efficacy does not seem to be compromised.

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