Bristi Basu

Combining Antiangiogenics to Overcome Resistance: Rationale and Clinical Experience

Antiangiogenic therapies are now well established in oncology clinical practice; however, despite initial optimism, the results of late-phase trials, especially in the adjuvant setting, have largely proved disappointing. In the context of metastatic disease, resistance to antiangiogenic agents arises through a range of mechanisms, including the development of alternative angiogenic pathways. One of the proposed strategies to overcome this resistance is to combine antiangiogenic agents with different mechanisms of action. Early-phase clinical trials assessing the tolerability and efficacy of different combinations of antiangiogenic drugs, including those that target the VEGF pathway or the angiopoietins, as well as vascular disrupting agents, are increasing in number. An example of this strategy is the combination of sorafenib and bevacizumab, which has elicited major responses in different tumor types, including ovarian carcinoma and glioblastoma. However, overlapping and cumulative toxicities pose a real challenge. This review summarizes the preclinical rationale for this approach and current clinical experience in combining antiangiogenic therapies. Clin Cancer Res; 18(14); 3750–61. ©2012 AACR.

First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor, AZD2014.

Purpose: AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclinical human cancer models. Experimental Design: A rolling six-dose escalation was performed to define an MTD (part A), and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and posttreatment biopsies (part B). AZD2014 was administered orally twice a day continuously. Flow cytometry, ELISA, and immunohistochemistry were used to quantify pharmacodynamic biomarkers. Pharmacokinetic analysis was carried out by mass spectrometry. Results: A total of 56 patients were treated across a dose range of 25 to 100 mg. The MTD was 50 mg twice daily. The dose-limiting toxicities were fatigue and mucositis. At the MTD, the most common adverse events (AE) were fatigue (78%), nausea (51%), and mucositis (49%), but these were equal to or greater than grade 3 in only 5% of patients. Drug levels achieved at the MTD (AUCss 6686 ng·h/mL, Cmax ss 1,664 ng/mL) were consistent with activity in preclinical models. A reduction in p-S6 levels and Ki67 staining was observed in 8 of 8 and 5 of 9 evaluable paired biopsy samples. Partial responses were seen in a patient with pancreatic cancer and a patient with breast cancer, who were found to have a PDGFR and ERBB2 mutation, respectively. Conclusions: The recommended phase II dose for further evaluation of AZD2014 is 50 mg twice daily, and at this dose it has been possible to demonstrate pharmacologically relevant plasma concentrations, target inhibition in tumor, and clinical responses. Clin Cancer Res; 21(15); 3412–9. ©2015 AACR.

Targeting IGF-1R: throwing out the baby with the bathwater?

There are intense commercial pressures in industry to develop drugs for large unselected populations, although this remains a risky and expensive strategy. Several examples now exist where targeted treatments are utilised in molecularly defined cancer patient populations. The EGFR tyrosine kinase inhibitor (TKI) gefitinib is a case in point, failing to show a clear benefit in non-small-cell lung cancer (NSCLC) patients when given with first-line chemotherapy. Gefitinib has nevertheless re-emerged as an important therapeutic following the confirmation that mutations in the TK domain of EGFR confer sensitivity to it (Mok et al, 2009), with evidence that this population is enriched within Asian, female and never-smoker patients with adenocarcinoma (Lynch et al, 2004; Paez et al, 2004). More recently, two large-phase III trials, investigating the addition of the fully human monoclonal antibody (mAb) to the insulin-like growth factor 1 receptor (IGF-1R) figitumumab (CP-751,871, Pfizer) to carboplatin/paclitaxel (ADVIGO 1016) and to the EGFR TKI erlotinib (ADVIGO 1018), in advanced NSCLC patients have been suspended after planned interim analyses indicated futility (Jassem et al, 2010). These data raise several important questions: Was there sufficient evidence to support these phase III trials? Could we have learnt more from early-phase data to identify the patients who are most likely to benefit? Is IGF-1R a key target in NSCLC? How should we design our trials to identify predictive biomarkers that decrease the risk of such late and costly failures?

Angiogenesis in cutaneous malignant melanoma and potential therapeutic strategies

Metastatic melanoma (MM) carries a dismal prognosis, as it is largely resistant to conventional cytotoxic chemotherapy, biochemotherapy and immunotherapy. There is, therefore, a pressing need to identify new, effective treatments to improve outcomes from MM. Innovative approaches in oncology drug development include anti-angiogenic strategies, in the form of monoclonal antibodies and small-molecule kinase inhibitors. In this review we aim to present current concepts and controversies surrounding the role of angiogenesis and anti-angiogenic therapies in MM, alluding to other tumor types in which increasing knowledge may supply avenues for future directions in melanoma research and management. An overview of angiogenesis and its importance in melanoma progression is presented, highlighting the key molecules that represent potential therapeutic targets. The results of using anti-angiogenic strategies in preclinical and clinical trials are discussed and future perspectives for anti-angiogenic therapies in MM are considered.

PARP inhibitors: mechanism of action and their potential role in the prevention and treatment of cancer.

The use of poly(ADP-ribose) polymerase (PARP) inhibitors provided proof-of-concept for a synthetic lethal anticancer strategy as a result of their efficacy and favourable toxicity profile in BRCA1/2 mutation carriers. Efforts are underway to identify a broader group of patients with genomic susceptibility that may benefit from these agents. In an endeavour to enhance anti-tumour effects, PARP inhibitors have been combined with traditional cytotoxic therapy and radiotherapy; however, optimization of dosing schedules for these combination regimens remains key to maximizing benefit whilst mitigating the potential for increased toxicity. With ongoing clinical experience of PARP inhibition, mechanisms of resistance to these therapies are being elucidated and specific challenges to long-term administration of these drugs will need to be addressed. Development of robust predictive biomarkers of response for optimal patient selection and rational combination strategies must be pursued if the full potential of these agents is to be realized.

A phase 2 study of vatalanib in metastatic melanoma patients

BACKGROUND A phase 2 study of vatalanib (PTK787/ZK222584) an oral tyrosine kinase inhibitor of VEGFR 1, 2 and 3 was undertaken in patients with metastatic melanoma. METHODS Adults with pathologically confirmed metastatic melanoma, WHO Performance status 0-2, and adequate haematological, hepatic and renal function, were treated with vatalanib until disease progression. The trial used Flemings single stage design. RESULTS Tumour control rate (CR+PR+SD) was 35% at 16 weeks, with objective response seen in only 1 patient. Median progression-free survival was 1.8 months (95% CI 1.8-3.7 months) and median overall survival was 6.5 months (95% CI 3.9-10.2 months). CONCLUSION Vatalanib stabilised disease in a proportion of patients, although overall survival was disappointing.

Safety and Efficacy of Modified FOLFIRINOX for Advanced Pancreatic Adenocarcinoma: A UK Single-Centre Experience

Objectives: The combination of 5-fluorouracil (5-FU), irinotecan and oxaliplatin (FOLFIRINOX) is considered the first-line chemotherapy for fit patients with advanced pancreatic ductal adenocarcinoma (PDAC) but carries an unfavourable adverse event (AE) profile. We retrospectively evaluated the tolerability and efficacy of a modified FOLFIRINOX (mFOLFIRINOX) regimen: intravenous oxaliplatin 85 mg/m2, irinotecan 135 mg/m2, folinic acid 400 mg/m2 and 5-FU infusion 2,400 mg/m2 over 46 h, with routine subcutaneous filgrastim on a 14-day cycle. Methods: Records of 18 patients with advanced PDAC who received treatment with mFOLFIRINOX were reviewed. Imaging of measurable disease was assessed for response, and survival was measured from the date of commencing chemotherapy to disease progression and/or death. Results: Grade 3 or 4 AEs (n; %) included vomiting (5; 28), nausea (4; 22), diarrhoea (3; 17) and non-neutropaenic fever (3; 17). For patients with stage IV disease, 12/15 (80%) achieved at least stable disease as the best radiological response, with 7/15 (47%) objective responses. In this subgroup, median overall and progression-free survival were 9.3 months (95% CI 8.3-10.4) and 7.2 months (95% CI 4.7-9.6), respectively. Conclusion: Compared to full-dose FOLFIRINOX, our modified regimen resulted in lower haematological but only marginally improved non-haematological toxicity rates, with comparable efficacy outcomes. Prospective studies are required to validate these findings.

The role of angiogenesis inhibitors in the management of melanoma.

Metastatic melanoma has a very poor prognosis and systemic therapies - both cytotoxic and biological - have not improved outcome in this disease so far. For this reason, novel therapeutic strategies are urgently required. Angiogenesis represents a relevant process to modulate in melanoma, as pro-angiogenic ligands and their receptors are overexpressed and have been found to correlate with disease progression and prognosis. The angiogenic axis may be targeted at many different levels, which are still being defined. This article presents an overview of the importance of angiogenesis in melanoma and draws attention to some of the key molecules that are currently being targeted rationally within clinical studies. We discuss a number of anti-angiogenic and anti-vascular agents and their mechanisms of action. An overview of the efficacy and toxicity of these treatments in clinical trials performed so far in melanoma is presented and future directions for anti-angiogenic strategies in melanoma are considered.

Targeting Insulin-Like Growth Factor Signaling: Rational Combination Strategies

Activation of the insulin-like growth factor (IGF) pathway, by binding of the growth factors IGF-I and IGF-II to the receptors IGF-IR and insulin receptor (IR), triggers complex signaling cascades that regulate cell growth, survival, proliferation, and differentiation. There has been intense

Targeting angiogenesis in melanoma: prospects for the future.

Angiogenesis has been identified as a relevant target for melanoma experimental therapeutics, based on preclinical and clinical studies. A variety of angiogenesis inhibitors are currently being tested in both metastatic and adjuvant melanoma clinical trials. To date, the most promising evidence of benefit is based on a statistically nonsignificant trend in survival gain reported in a randomized phase II trial combining bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, with cytotoxic chemotherapy. Larger phase III studies are required to determine the true extent of clinical benefit with this class of agents. Key to these clinical trials is the need to include translational endpoints, since correlation of biological and clinical data will provide the opportunity to identify biomarkers predictive of treatment response. These biological studies will also aid our, as yet, poor understanding of the mechanism of action of angiogenesis inhibitors, as well as drug-related side effects. Finally, if these trials show meaningful clinical benefit, then careful consideration will need to be given when designing second-generation trials, in the light of novel gene-directed therapies currently showing promise in melanoma.