Multi-targeted Antiangiogenic Tyrosine Kinase Inhibitors Research Articles

Efficacy of eribulin administered in combination with an immune checkpoint inhibitor (ICI) and anlotinib as salvage treatment for patients (pts) with advanced adult soft tissue sarcoma (STS).

11572 Background: Eribulin combined with a multi-targeted antiangiogenic tyrosine kinase inhibitor has shown efficacy in STS. ICIs have also exhibited improved survival in some STS subtypes. We investigated the efficacy and safety of triple combination therapy with eribulin, an ICI and anlotinib in the treatment of advanced STS in an adult Chinese population. Methods: This study retrospectively analyzed data from patients diagnosed with advanced STS who received combination therapy with eribulin, an ICI and anlotinib at the Department of Oncology, Zhongshan Hospital affiliated to Fudan University. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) by RECIST v1.1, disease control rate (DCR), and treatment-related adverse events (TRAEs) by CTCAE v5.0. Results: Medical records from 32 pts treated between August 15, 2020 and January 31, 2023 were included; the median age was 56 years, 71.8% (23/32) were female, 75.0% (24/32) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and 25.0% (8/32) had an ECOG PS of 2. Pts had received a median of 2 (range 0-6) prior regimens and the median follow-up was 4.1 months. Among the patients, 50.0% (16/32) had liposarcomas (including 1 with pleomorphic liposarcoma and 15 with dedifferentiated liposarcoma [DDLPS]), 31.3% (10/32) had leiomyosarcomas (LMS), 3 had undifferentiated pleomorphic sarcoma (UPS), and 1 each had angiosarcoma, rhabdomyosarcoma and desmoplastic small round cell tumor. In a preliminary analysis, 29 pts were evaluable for clinical activity; partial responses (PRs) were achieved in 3 pts (2 DDLPS, 1 UPS), the ORR and DCR were 10.3% (3/29) and 62.1% (18/29) respectively, and the median PFS was 5.7 months (95% CI 2.7-9.8). Of the 15 pts with DDLPS (median 1 prior line of therapy; median follow-up 6.3 months), 13 were evaluable for clinical activity; a PR was achieved by 15.4% (2/13), the DCR was 61.5% (8/13), the median PFS was 9.8 months (95% CI 1.8-28.5) and treatment was ongoing in 46.7% of pts (n = 7). Among the 9 evaluable pts with LMS, 0 achieved a PR, the DCR was 44.4% (4/9), median PFS was 3.9 months and 3 pts were still receiving treatment. In the overall cohort (n = 32), TRAEs of any grade occurred in 56.3% of pts (n = 18), the most common were myelosuppression (28.1%), fatigue (15.6%), fever (12.5%) and rash (12.5%). Grade 3/4 TRAEs occurred in 12.5% of pts, with no grade 5 events. Conclusions: This study demonstrates the potential efficacy of combination therapy with eribulin, an ICI and anlotinib in patients with advanced STS, especially in those with the DDLPS subtype. Our data suggest that this combination has good tolerability and a prospective trial is warranted. Clinical trial information: ChiCTR2100053594.

Small Bowel Lipomatosis: An Unusual Radiological Finding in Patients With Renal Cell Cancer on Pazopanib.

Treatment for advanced renal cell carcinoma (aRCC) comprises single agent or combinations of immune checkpoint inhibitors and/or anti-angiogenic agents. Pazopanib is a multitargeted anti-angiogenic tyrosine kinase inhibitor (TKI) approved as treatment for aRCC. We noted that a number of patients receiving pazopanib developed a radiological finding of small bowel lipomatosis. To evaluate the incidence of small bowel lipomatosis in patients with aRCC on treatment with pazopanib in comparison with other tyrosine kinase inhibitors. We identified 12 out of 208 patients receiving pazopanib to have small bowel lipomatosis and compared their clinic-radiological findings with 314 patients with aRCC receiving other TKIs (sunitinib, cabozantinib, axitinib, and tivozanib). No patients receiving these TKIs developed small bowel lipomatosis. We compared the radiological findings in patients receiving pazopanib for aRCC. The presence of lipomatosis should not be considered as a clinically relevant finding in these patients. The presence of lipomatosis has no relation with the response to treatment to pazopanib and this is a unique finding seen only in patients on pazopanib. Small bowel lipomatosis is an occasional finding in patients with advanced renal cancer on pazopanib and is not seen with other TKIs.

Prediction of response to sunitinib in patients with advanced renal cell carcinoma (RCC) using mass spectrometry-based (phospho) proteomics.

e16556 Background: Sunitinib, a multi-targeted antiangiogenic tyrosine kinase inhibitor has improved the outcome of patients with advanced RCC considerably. Unfortunately, ± 30% of patients are intrinsically resistant, which underscores the urgent need to develop a clinically applicable method to select sunitinib treatment for patients. Since RCC is not single oncogene driven, but rather by multiple aberrantly activated kinase signaling pathways, we hypothesized that a functional read-out by large scale (phospho)proteomics can identify predictive biomarkers for sunitinib. Methods: Frozen tumor tissue of 26 patients (pts) with RCC, treated with sunitinib upon recurrence or progression, was obtained. Pts were classified as primary resistant (progression-free survival (PFS) < 3 months, n = 8) or sensitive (PFS ≥ 3 months, n = 18). Mass spectrometry-based tyrosine (pTyr) phosphoproteomics was performed by pTyr-immunoprecipitation followed by LC-MS/MS. Discriminatory phosphosites (p-sites) were identified (p < 0.05, fold-change (FC) > 2). Expression proteomics was performed by LC-MS/MS and differentially expressed proteins identified (p < 0.05, FC > 2, ≥ 50% data presence in group with highest abundance). Tumor biology was further analyzed by INferred Kinase Activity analysis, posttranslational modifications signature enrichment analysis (PTM-SEA, Krug et al 2019) and gene ontology mining. Results: pTyr-phosphoproteomics was successfully performed in 23 of 26 samples. Seventy-eight differential p-sites were identified, of which 22 (4 unique; BCAR3, NOP58, EIF4A2, GDI1) were upregulated in resistant and 56 in sensitive pts (35 unique). Supervised cluster analysis of these p-sites resulted in near-complete separation of the groups. EIF4A1 and its homolog EIF4A2 were differentially expressed in resistant pts both at the (phospho-)proteome and, in an independent cohort, at transcriptome level. Significantly higher inferred kinase activity of MAPK3 (p = 0.026) and EGFR (p = 0.045) was found in sensitive pts. PTM-SEA showed 3 p-site-centric signatures that were significantly enriched (p < 0.05) in resistant pts, including FGF1 and prolactin pathways. Fifteen signatures were significantly enriched (p < 0.05) in sensitive pts, including insulin, VEGF and FGF2 treatment and KIT receptor pathway. Expression proteomics revealed significantly higher expression (p < 0.05) of proteins related to vesicle mediated transport in resistant pts, while this was not the case in sensitive pts. Conclusions: This MS-based (phospho)proteomics analysis of RCC tissues revealed discriminatory phosphosite and protein signatures and differential kinase and pathway activities that are associated with sensitive and resistant tumors. These findings warrant validation in an independent cohort and the clinical utility for treatment selection remains to be demonstrated.

Pulmonary cavitation in patients with thyroid cancer receiving antiangiogenic agents

BackgroundThyroid malignancies are among the most common endocrine cancers worldwide. Owing to the angiogenic nature of these malignancies, tyrosine kinase inhibitors (TKIs) are an attractive potential treatment. However, TKIs have been associated with an increased risk of tumor cavitation, in turn linked to poor outcomes, in patients with malignancies in the lungs, where thyroid cancer commonly metastasizes.MethodWe performe d a retrospective cohort study of patients with thyroid cancer and evidence of metastatic disease to the lung that were treated with multi-targeted antiangiogenic TKIs. The primary objective of this study was to determine the incidence of pulmonary cavitation. The secondary objective was to evaluate the effect of pulmonary cavitation on survival.ResultsOf the 83 patients with pulmonary nodules, 10 developed cavitation during treatment. Of these 83 patients, two patients had to stop the treatment due to pneumothorax. Additionally, cavitation did not demonstrate any significant effect on survival.ConclusionIn patients with thyroid cancer and evidence of metastatic disease to the chest, the use of multi-targeted TKIs led to cavitations that were not uncommon but clinical consequences were marginal. Treatment was stopped only in two patients that developed pneumothorax, however the small sample is a strong limitation of our study.

Platelet function is disturbed by the angiogenesis inhibitors sunitinib and sorafenib, but unaffected by bevacizumab

IntroductionAt the clinical introduction of antiangiogenic agents as anticancer agents, no major toxicities were expected as merely just endothelial cells (ECs) in tumors would be affected. However, several (serious) toxicities became apparent, of which underlying mechanisms are largely unknown. We investigated to what extent sunitinib (multitargeted antiangiogenic tyrosine kinase inhibitor (TKI)), sorafenib (TKI) and bevacizumab [specific antibody against vascular endothelial growth factor (VEGF)] may impair platelet function, which might explain treatment-related bleedings.Materials and methodsIn vitro, the influence of sunitinib, sorafenib, and bevacizumab on platelet aggregation, P-selectin expression and fibrinogen binding, platelet–EC interaction, and tyrosine phosphorylation of c-Src was studied by optical aggregation, flow cytometry, real-time perfusion, and western blotting. Ex vivo, platelet aggregation was analyzed in 25 patients upon sunitinib or bevacizumab treatment. Concentrations of sunitinib, VEGF, and platelet and EC activation markers were measured by LC–MS/MS and ELISA.ResultsIn vitro, sunitinib and sorafenib significantly inhibited platelet aggregation (20 μM sunitinib: 71.3%, p < 0.001; 25 μM sorafenib: 55.8%, p = 0.042). Sorafenib and sunitinib significantly inhibited P-selectin expression on platelets. Exposure to both TKIs resulted in a reduced tyrosine phosphorylation of c-Src. Ex vivo, within 24 h sunitinib impaired platelet aggregation (83.0%, p = 0.001, N = 8). Plasma concentrations of sunitinib, VEGF, and platelet/EC activation markers were not correlated with disturbed aggregation. In contrast, bevacizumab only significantly impaired platelet aggregation in vitro at high concentrations, but not ex vivo.ConclusionSunitinib significantly inhibits platelet aggregation in patients already after 24 h of first administration, whereas bevacizumab had no effect on aggregation. These findings may explain the clinically observed bleedings during treatment with antiangiogenic TKIs.

Appliation of the combination of antiangiogenic agents and EGFR-TKIs in advanced NSCLC treatment

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and anti-angiogenic drugs have individually demonstrated clinical benefit in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Recent studies demonstrate that the combination of anti-EGFR and anti-angiogenesis can more significantly enhance clinical benefit, and even can remit EGFR-TKIs resistance in the treatment of advanced NSCLC. According to the different kinds of anti-angiogenesis drugs, recent clinical studies mainly include the combination of anti-vascular endothelial growth factor monoclonal antibody bevacizumab plus EGFR-TKIs and multi-targeted receptor anti-angiogenic tyrosine kinase inhibitor plus EGFR-TKIs, and the former results show a more significant improvement in terms of safety and efficacy in the treatment of advanced NSCLC. Therefore, the combination of bevacizumab plus EGFR-TKIs can be used as a new treatment standard in the treatment of some patients with NSCLC. Key words: Carcinoma, non-small-cell lung; Angiogenesis inhibitors; Epidermal growth factor receptor-tyrosine kinase inhibitors

Risk of Hypertension With Sorafenib Use in Patients With Cancer: A Meta-Analysis From 20,494 Patients.

Sorafenib is a new multikinase inhibitor; the incidence of hypertension (HTN) with sorafenib has been reported to vary substantially among clinical trials. We searched multiple databases to investigate the risk of sorafenib-induced HTN in patients with cancer. A total of 93 trials involving 20,494 patients were selected for this meta-analysis. The relative risks (RRs) of all-grade and high-grade HTN associated with sorafenib were 3.06 (P < 0.001) and 3.33 (P < 0.001). There are no significantly RRs of all-grade, 0.81 (P = 0.047), and high-grade HTN, 0.64 (P = 0.075), in sorafenib monotherapy versus other multitargeted antiangiogenic tyrosine kinase inhibitors. The incidence of sorafenib-associated all-grade and high-grade HTN was 21.3% (P < 0.001) and 5.9% (P < 0.001), respectively. The patients with renal cell carcinoma (RCC) and thyroid cancer have high incidence (≥20%) of sorafenib-associated all-grade HTN and high incidence (≥5%) of sorafenib-associated high-grade HTN. The trials with median treatment duration ≥ 4, 5, and 7 months were 21.0% (P < 0.001), 25.4% (P < 0.001), and 27.6% (P < 0.001); progression-free survival ≥ 6, 9, and 12 months were 24.5% (P < 0.001), 26.8% (P < 0.001), and 32.8% (P < 0.001); and overall survival ≥ 12, 18, and 24 months were 18.5% (P < 0.001), 22.5% (P < 0.001), and 25.9% (P < 0.001), respectively. There is a significantly high risk of sorafenib-induced HTN. In comparison between sorafenib and other multitargeted antiangiogenic tyrosine kinase inhibitors, RRs had no significance. The patients with RCC and thyroid cancer have significantly higher incidence of HTN. With prolonged treatment duration, progression-free survival, and overall survival, the incidence of all-grade HTN may increase.

Risk of treatment-related mortality with sorafenib in cancer patients: a meta-analysis of 20 randomly controlled trials : Risk of sorafenib-associated death.

Sorafenib is a relatively new multi-kinase inhibitor used to treat a wide range of cancers. As fatal adverse events from sorafenib therapy are rare, their investigation requires a meta-analysis. Aim of the review To provide a meta-analysis of sorafenib-associated fatal adverse events with the most expansive and current data. We searched Medline, EMBASE, Web of Science and Cochrane Library databases. We also searched abstracts from a number of conferences. Twenty trials of sorafenib were found in 9434 cancer patients, tested against placebos and against other drugs. We calculated relative risks and incidences for sorafenib-associated mortality. Overall incidence of sorafenib-associated mortality was 3.3 %. Patients with renal cell carcinoma (RCC) and thyroid cancer had treatment-related mortality ≥5 %. Patients treated with sorafenib had a significantly greater risk of mortality than those in placebo/control groups, with an RR of 1.75. Subgroup analyses also showed significant differences in sorafenib versus placebo (RR 1.87, 95 % CI 1.23-2.86; I (2) = 0.0 %, P = 0.865); and sorafenib + platinum-based chemotherapy (RR 2.03, 95 % CI 1.15-3.59; I (2) = 0.0 %, P = 0.654). However, sorafenib had lower risk than other multi-targeted antiangiogenic tyrosine kinase inhibitors. Patients with RCC and non-small-cell lung carcinoma were significantly more vulnerable. Sorafenib presents a significant risk of fatal adverse events (FAEs) in patients with cancer, especially for RCC or non-small-cell lung carcinoma, and in patients treated with sorafenib + platinum-based chemotherapy. However, compared with other multi-targeted antiangiogenic tyrosine kinase inhibitors, sorafenib has a lower risk of FAEs.

Improvements in progression-free and overall survival due to the use of anti-angiogenic agents in gynecologic cancers.

In ovarian cancer (OC), the best established anti-angiogenic drug, bevacizumab, has demonstrated only modest prolonged progression free survival (PFS) and no increased overall survival (OS). The unanswered question is in which clinical situation bevacizumab might benefit ovarian cancer patients most. The cost-benefit analysis in the primary treatment was found not to be favorable but the use in the recurrent OC setting might be more compelling. Multi-targeted anti-angiogenic tyrosine kinase inhibitors (TKI) such as cediranib and pazopanib have shown some therapeutic benefits with improvements of PFS and OS in patients with platinum-sensitive as well as resistant OC, in whom there is a major need for novel therapies. Very promising is also the observed improvement of PFS in recurrent OC in patients when combining cediranib with the PARP inhibitor olaparib without giving additional chemotherapy. The anti-angiogenic agent trebananib has achieved similar results like TKI, but has a favorable toxicity profile which does not overlap with those of VEGF inhibitors. In cervical cancer the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent or metastatic chemotherapy-naive disease results in a significant increase in OS. Considering the lack of therapeutic options in this difficult clinical setting, the inclusion of bevacizumab most likely will become a new standard for recurrent cervical cancer. In uterine sarcomas as very aggressive malignancies with a substantial need for better therapies the observed improved PFS with sorafenib warrants further investigation. No data showing a convincing improvement of survival in endometrial cancer have been presented yet. In view of the limited PFS and OS benefit observed with anti-angiogenics in gynecologic oncology, increased morbidity due to side effects of this treatment resulting in loss of quality of life and also substantial costs have to be taken into consideration. Thorough case selection based on molecular subgrouping of gynecologic cancers will therefore be a prerequisite for future anti-angiogenic therapy. This will require the integration of molecular diagnostics which still have to be developed and standardized.

Multi-Targeted Antiangiogenic Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer: Meta-Analyses of 20 Randomized Controlled Trials and Subgroup Analyses

BackgroundMulti-targeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have been studied in many randomized controlled trials (RCTs) for treatment of advanced non-small cell lung cancer (NSCLC). We seek to summarize the most up-to-date evidences and perform a timely meta-analysis.MethodsElectronic databases were searched for eligible studies. We defined the experimental arm as MATKI-containing group and the control arm as MATKI-free group. The extracted data on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS) and overall survival (OS) were pooled. Subgroup and sensitivity analyses were conducted.ResultsTwenty phase II/III RCTs that involved a total of 10834 participants were included. Overall, MATKI-containing group was associated with significant superior ORR (OR 1.29, 95% CI 1.08 to 1.55, P = 0.006) and prolonged PFS (HR 0.83, 0.78 to 0.90, P = 0.005) compared to the MATKI-free group. However, no significant improvements in DCR (OR 1.08, 1.00 to 1.17, P = 0.054) or OS (HR 0.97, 0.93 to 1.01, P = 0.106) were observed. Subgroup analyses showed that the benefits were predominantly presented in pooled results of studies enrolling previously-treated patients, studies not limiting to enroll non-squamous NSCLC, and studies using MATKIs in combination with the control regimens as experimental therapies.ConclusionsThis up-to-date meta-analysis showed that MATKIs did increase ORR and prolong PFS, with no significant improvement in DCR and OS. The advantages of MATKIs were most prominent in patients who received a MATKI in combination with standard treatments and in patients who had previously experienced chemotherapy. We suggest further discussion as to the inclusion criteria of future studies on MATKIs regarding histology.

Multi-Targeted Antiangiogenic Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer: an Updated Meta-Analysis of 20 Randomized Controlled Trials and Subgroup Analyses

ABSTRACT Aim: Multi-targeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have been studied by many randomized controlled trials (RCTs) in treatments of advanced non-small cell lung cancer (NSCLC). Here we performed a timely meta-analysis to summarize the most up-to-date evidences and examined the effect of covariates on outcomes through subgroup analyses. Methods: Electronic databases were searched for eligible studies. We defined the experimental arm as MATKI-containing group while the control arm as MATKI-free group. The extracted data on objective response rates (ORR) and progression-free survival (PFS) were pooled. Subgroup analyses that stratified trials according to chemotherapy history, eligible histological type and treatment modality were conducted. Results: A total of 20 phase II/III RCTs that involved a total of 10834 participants were included. In overall, MATKI-containing group was associated with significant superior ORR (OR 1.29, 95% CI 1.08 to 1.55, P = 0.006) and prolonged PFS (HR 0.84, 0.78 to 0.90, P Outcome Subgroup No. of Arms OR/HR Effect size P ORR Overall 22 1.29 2.77 0.01 Chemo-history Chemo-Naive 12 1.12 0.85 0.40 Previous-Chemo 10 1.55 3.27 0.001 Histology All Histology 17 1.38 2.59 0.01 Non-Squamous 5 1.14 0.89 0.37 Modality Combination 17 1.45 4.61 Single agent 5 0.77 0.88 0.38 PFS Overall 21 0.84 5.02 Chemo-history Chemo-Naive 10 0.85 3.68 Previous-Chemo 11 0.82 3.72 Histology All Histology 15 0.81 4.80 Non-Squamous 6 0.90 1.50 0.13 Modality Combination 17 0.80 7.50 Single agent 5 1.00 0.02 0.99 Conclusions: This up-to-date meta-analysis showed that MATKIs could increase ORR and prolong PFS. The advantages of MATKIs were most highlighted in combination with standard treatments and in the second/third-line settings. Additionally, the inclusion criteria regarding histology in future studies on MATKIs warrants further discussed. Disclosure: All authors have declared no conflicts of interest.

Multitargeted antiangiogenic tyrosine kinase inhibitors combined to chemotherapy in metastatic breast cancer: a systematic review and meta-analysis

We undertook a meta-analysis of randomized trials to evaluate the efficacy of multitargeted antiangiogenic tyrosine kinase inhibitors (MATKIs) in addition to chemotherapy in metastatic breast cancer. PubMed, Web of Knowledge databases and the ASCO meeting abstracts were searched for eligible literature published up to August 30, 2013. The endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and toxicities. Pooled hazard ratios (HRs) for survival outcomes and odds ratio (ORs) for dichotomous data with 95 % confidence intervals (CIs) were derived. Eight studies including 2,077 participants were analyzed. Compared to chemotherapy alone, adding MATKIs to chemotherapy resulted in a 14 % risk reduction of PFS events. However, the benefit did not reach statistical significance (HR 0.86; 95 % CI 0.70-1.04, P=0.126). Also, no OS benefit was observed (HR 1.03; 95 % CI 0.89-1.18, P=0.724). The addition of MATKIs significantly increased the ORR (OR 1.57; 95 % CI 1.30-1.91, P=0.000). Subgroup analysis revealed that sorafinib showed a significantly greater effect on PFS in patients with HER2 negative metastatic breast cancer (HR 0.67; 95 % CI 0.55-0.82, P=0.000) in comparison to chemotherapy alone. Additionally, sunitinib seemed to have no substantial efficacy for metastatic breast cancer. Toxicities were more frequent in patients receiving MATKIs. Overall, regimens consisting of MATKIs seemed not to be superior to chemotherapy alone in terms of PFS and OS, although significant improvement in ORR was observed. However, the addition of sorafenib significantly improved PFS. Further studies are needed to corroborate this finding.

Sorafenib relieves cell‐intrinsic and cell‐extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity

Sorafenib, a multitargeted antiangiogenic tyrosine kinase inhibitor, is the standard of care for patients with advanced hepatocellular carcinoma (HCC). Cumulating evidence suggests that sorafenib differentially affects immune cells; however, whether this immunomodulatory effect has any impact on antitumor immune responses is unknown. Using an orthotopic mouse model of HCC and tumor-free mice, we investigated the effects of sorafenib on antitumor immunity and characterized the underlying mechanisms. Sorafenib treatment inhibited tumor growth and augmented antitumor immune responses in mice bearing established orthotopic HCC. The tumor-specific effector T cell functions were upregulated, while the proportion of PD-1-expressing CD8(+) T cells and regulatory T cells (Tregs) was reduced in tumor microenvironment of sorafenib-treated mice. Mechanistically, the sorafenib-mediated effects on Tregs could be independent of its direct tumor-suppressing activities. Sorafenib treatment reduced Treg numbers by inhibiting their proliferation and inducing apoptosis. Moreover, sorafenib inhibited the function of Tregs, characterized by diminished expression of Treg-associated molecules important for their function and by their impaired suppressive capacity. These data reveal that sorafenib treatment enhanced functions of tumor-specific effector T cells as well as relieved PD-1-mediated intrinsic and Treg-mediated non-cell-autonomous inhibitions in tumor microenvironment leading to effective antitumor immune responses. In addition to the well-known tumor-inhibiting activity of sorafenib, its enhancement of antitumor immunity may also contribute to the clinical efficacy. Our findings uncover a previously unrecognized mechanism of action of sorafenib and indicate that sorafenib represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat cancer patients.

Multitargeted antiangiogenic tyrosine kinase inhibitors in advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials.

8089 Background: Novel multitargeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have showed promising advantages in combination with chemotherapy or as monotherapy in treatments of advanced non-small cell lung cancer (NSCLC). Since the efficacy and safety of these small molecules have been evaluated by several phase II/III randomized controlled trials (RCTs), we seek to summarize the current evidences by performing a meta-analysis. Methods: PubMed, EMBASE, the Cochrane Library as well as the ASCO and ESMO databases were searched for eligible literatures. We defined the experimental arm as MATKI-containing group while the control arm as MATKI-free group. The endpoints being evaluated included overall survival (OS), progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR), as well as adverse events (AEs). Pooled hazard ratios (HRs) for survival outcomes and odds ratio (ORs) for dichotomous data, with 95% confidence intervals (CI) were calculated using REVMAN 5.0. Subgroup analysis was conducted according to each agent respectively. Results: Five agents (vandetanib, sunitinib, cediranib, sorafenib, motesanib) with comparable data could be analyzed. Fifteen phase II/III RCTs that involved a total of 8854 participants were included. Compared to MATKI-free group, MATKI-containing group was associated with significant longer PFS (HR 0.824, 95% CI 0.759 to 0.895, P&lt;0.001), superior ORR (OR 1.27, 95% CI 1.13 to 1.42, P&lt;0.0001) and DCR (OR 1.14, 95% CI 1.04 to 1.25, P=0.006). However, although some improvement in OS was observed, the benefit did not reach statistical significance (HR 0.962, 95% CI 0.912 to 1.015, P=0.157). In terms of subgroup results, sorafinib was revealed to yield no improvement in all endpoints. The specific AEs in patients who received these agents were rash, diarrhea and hypertension. Conclusions: Regimens consisting of multitargeted antiangiogenic TKIs were superior to those without these agents in terms of tumor response and PFS in patients with advanced NSCLC. However, no significant benefits in OS were observed. In addition, sorafinib seemed to has no substantial efficacy for NSCLC patients.

Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors or chemotherapy alone in advanced NSCLC: a meta-analysis of randomized controlled trials

Most patients with advanced non-small-cell lung cancer (NSCLC) require systemic chemotherapy. Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors (TKI; e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, axitinib) has recently been evaluated in patients with NSCLC. However, the advantage of this therapy over chemotherapy alone in patients with advanced NSCLC remains largely unknown. A meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy and toxicity of chemotherapy plus multitargeted antiangiogenic TKI with chemotherapy alone in patients with advanced NSCLC. PubMed, the ASCO and ESMO databases, and the Cochrane Library were searched for references to published articles. Two reviewers independently assessed the quality of the trials. Data were extracted, and overall response rate (ORR), pooled progression-free survival (PFS), overall survival (OS) with 95 % confidence intervals (CI), and major toxicities/adverse effects were analyzed. Six RCTs involving 3,337 patients with advanced NSCLC were ultimately analyzed. Compared to chemotherapy alone, chemotherapy plus multitargeted antiangiogenic TKI significantly increased the ORR [relative risk (RR) 1.71, 95 % CI 1.43-2.05] and PFS [hazard ratio (HR) 0.83, 95 % CI 0.76-0.90], but not OS (HR 0.93, 95 % CI 0.83-1.03). Patients who received chemotherapy plus multitargeted antiangiogenic TKI exhibited more rash, diarrhea and hypertension (OR 2.78, 95 % CI 2.37-3.26; OR 1.92, 95 % CI 1.65-2.24; OR 2.90, 95 % CI 2.19-3.84, respectively) and less nausea and vomiting (OR 0.71, 95 % CI 0.60-0.83; OR 0.75, 95 % CI 0.61-0.92, respectively). The incidence of hemorrhage, fatigue, cough, constipation, anorexia, and alopecia were comparable between the two groups. Therapy consisting of chemotherapy plus multitargeted antiangiogenic TKI was found to have specific advantages over chemotherapy alone in terms of PFS and ORR. The toxicity was comparable between the two therapies. Therefore, chemotherapy plus multitargeted antiangiogenic TKI may be a safe and valid therapeutic option for patients with advanced NSCLC.

Abstract 1374: Cross-resistance and sensitivity of sunitinib resistant tumor cells

Abstract Background: Resistance to sunitinib, a multi-targeted anti-angiogenic tyrosine kinase inhibitor (TKI) approved for clinical use in advanced renal cell cancer, gastrointestinal stromal tumors and pancreatic neuroendocrine tumors, represents a major clinical problem. Previously we have shown that tumor cells acquire resistance in vitro by continuous incubation with sunitinib and found that acidic lysosomal sequestration of sunitinib mediates its resistance. In this study, we investigated whether sunitinib resistant tumor cells are cross-resistant to other clinically relevant inhibitors and whether agents interfering with lysosomal function can modulate resistance. Methods: Continuous exposure to sunitinib for more than 12 months resulted in drug resistance in 786-O (RCC) and HT-29 (colorectal cancer) cell lines. Using these cells, cross-resistance to other clinically available TKIs such as sorafenib, pazopanib and erlotinib, and to the mTOR inhibitor everolimus, was determined in proliferation assays (MTT). In addition, modulation of sunitinib resistance by the lysosomal inhibitors (LIs) chloroquine and bafilomycin A1 was studied using proliferation assays. The effect of LIs on phosphorylation of key signaling proteins was determined by western blotting. Results: Compared to parental cell lines, proliferation assays revealed that sunitinib resistant cell lines were cross-resistant to pazopanib and erlotinib, while no significant decrease in sensitivity to sorafenib or everolimus was observed. Both chloroquine and bafilomycin A1 were able to modulate sunitinib resistance. Western blot analysis revealed that phosphorylation of key signaling proteins including Akt and p44/42-MAPK was inhibited in sunitinib resistant cells upon co-incubation with chloroquine, while sunitinib alone did not inhibit phosphorylation of these kinases. Conclusion: We found that sunitinib resistant tumor cells are cross-resistant to pazopanib and erlotinib, but remain sensitive to sorafenib and everolimus. Furthermore, combination with the lysosomal inhibitor chloroquine resulted in inhibition of key signaling proteins in sunitinib resistant cells. Taken together, we envision that these findings are relevant for clinical treatment strategies in patients with renal cell cancer resistant to sunitinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1374. doi:1538-7445.AM2012-1374

Antiangiogenic Agents in Combination With Chemotherapy for the Treatment of Epithelial Ovarian Cancer

The purpose of this review was to provide an overview of angiogenesis, including the rationale for targeting angiogenesis as a treatment strategy for epithelial ovarian cancer (EOC) and to discuss available clinical trial data with antiangiogenic agents in EOC, with a focus on combinations with chemotherapy. This was a literature review of clinical studies evaluating select antiangiogenic agents in combination with traditional cytotoxic chemotherapy for the treatment of EOC. Several therapies that target angiogenesis-specific pathways are undergoing clinical development for EOC. Although some of these agents have demonstrated single-agent activity for EOC, there is considerable interest in combining this treatment strategy with chemotherapy in an effort to potentially improve treatment benefits in this patient population. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the most studied antiangiogenic agent in EOC and has shown efficacy as monotherapy and combined with chemotherapy in both the relapsed/recurrent and first-line settings. However, results from recent phase 3 trials raise questions regarding patient selection and optimal dose, schedule, and duration of bevacizumab therapy. Other agents in various phases of testing include aflibercept (VEGF Trap), a fusion protein that binds all isoforms of VEGF; multitargeted antiangiogenic tyrosine kinase inhibitors (eg, BIBF 1120, cediranib, pazopanib, sorafenib); and AMG 386, a selective angiopoietin inhibitor. Toxicities associated with VEGF inhibition are also a concern with antiangiogenic therapy, including hypertension, proteinuria, thromboses, and gastrointestinal perforation. Results from recently completed and ongoing clinical trials combining antiangiogenic agents with chemotherapy are awaited in hopes of expanding therapeutic options for patients with EOC.

Antiangiogenic Agents in Combination with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC.

Cellular and physiological rationale for trimodal combination of chemotherapy, antiangiogenesis and radiotherapy

Cellular and physiological rationale for trimodal combination of chemotherapy, antiangiogenesis and radiotherapy