Begoña Jiménez

Tyrosine kinase inhibitors and drug interactions: a review with practical recommendations.

The adverse effects associated to traditional chemotherapy are well known and broadly studied. In the recent years several tyrosine kinase inhibitors have been approved for cancer treatment and numerous are under investigation. These drugs target specific mutated/overexpressed tyrosin kinase receptors and frecuently their pharmacokinetic/pharmacodinamic behavior is not fully elucidated. These new drugs may interact with non-antineoplastic drugs leading to undesirable adverse effects. In this article, we will discuss different types of drug interactions and briefly review the pharmacokinetics and mechanisms of action of tyrosine kinase inhibitors in clinical use, with a particular emphasis on the risk of the occurrence of such interactions based on currently available scientific evidence.

Prediction of Response to Neoadjuvant Chemotherapy Using Core Needle Biopsy Samples with the Prosigna Assay.

Purpose: Most hormone receptor (HR)+/HER2− breast cancer patients respond unfavorably to neoadjuvant chemotherapy (NAC); however, genomic tests may identify those patients who are likely to benefit. Using the Prosigna assay, we first evaluated the technical performance of core needle biopsy (CNB) tissues. We then determined whether Prosigna risk of relapse (ROR) score and intrinsic subtype predicted response to NAC in HR+/HER2− patients using CNB samples. Experimental Design: Using the NanoStrings nCounter Dx analysis system and a development tissue sample set, we established tissue requirements and assay output variance. We then evaluated the concordance in subtype and correlation in ROR between CNBs and corresponding surgical resection specimens (SRS) in a second independent sample set. Finally, we analyzed 180 independent CNB samples from HR+/HER2− patients who were treated with NAC and correlated ROR and intrinsic subtype with pathologic response. Results: Intra- and interbiopsy variabilities were 2.2 and 6.8 ROR units, respectively. Subtype concordance within multiple CNBs was high for the 4- and 3-subtype classifications (k = 0.885 and 0.889, respectively). Correlation in Prosigna ROR score observed between paired CNBs and SRS was high (r ≥ 0.90), and subtype concordance was also high for the 4- and 3-subtype classifications (kappa = 0.81 and 0.91, respectively). Prosigna results obtained from the HR+/HER2− patient samples showed that both ROR (P = 0.047) and intrinsic subtype (OR LumA vs. non-LumA = 0.341, P = 0.037) were significant predictors of response to NAC. Conclusions: Prosigna ROR and intrinsic subtype are readily obtained from CNB samples in normal practice and reliably predict response to NAC in HR+/HER2− patients. Clin Cancer Res; 22(3); 560–6. ©2015 AACR.

Efficacy and safety of weekly paclitaxel combined with cetuximab in the treatment of pretreated recurrent/metastatic head and neck cancer patients

INTRODUCTION The addition of cetuximab to weekly paclitaxel has demonstrated high efficacy in the first-line treatment of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). However, this combination has been widely extended to patients who present resistance to first line chemotherapy (CT) or those who are not candidates for platinum-based CT. MATERIAL AND METHODS We have retrospectively analyzed the efficacy and safety of cetuximab in combination with weekly paclitaxel in patients with R/M-SCCHN who present disease progression after platinum schedules or those who were not candidates for platinum-based CT. Patients received weekly paclitaxel 80mg/m(2) and cetuximab 250mg/m(2) (initial dose of 400mg/m(2)) until progression or unacceptable toxicity. RESULTS Twenty-two patients were included. Median age was 58 (43-68), ECOG PS (0/1/2): 6/10/4, 19 patients had received prior platinum-based treatment (nine patients were platinum-sensitive and nine were platinum-refractory). With a median follow-up of 6.18months (range 1.3-29.7), overall response rate (ORR) was 55% (95% CI 31-76%):1 (5%) complete response and 9 (50%) partial responses. Median duration of response was 10.23months. Median progression free survival (PFS) and overall survival (OS) were 5.4 and 9.1months, respectively. There were no differences in response rate according to platinum sensitivity (66% sensitive vs 44% refractory; P=0.61). The main toxicity consisted of rash in 70% of patients (5% grade 3), with an association between rash severity and ORR (grade 0-1: 33% vs grade 2-3: 64%; P=0.03) and a trend for better PFS and OS. CONCLUSION Weekly paclitaxel in combination with cetuximab is a well tolerated and highly active second-line treatment in patients with R/MSCCHN who experience disease progression after platinum-based CT, including those who present resistant disease. Our results suggest that the efficacy of this combination is apparently superior than the published data on single agent cetuximab in this setting.

Limited impact of palliative chemotherapy on survival in advanced solid tumours in patients with poor performance status

AimOncologists should carefully weigh up the risks and benefits of palliative chemotherapy in patients with advanced solid tumours (AST) and poor general status from the standpoint both of medical and ethical issues and of healthcare resources required. This study is intended to assess the impact on overall survival of palliative chemotherapy in patients with AST and admitted to hospital as a result of their poor ECOG status.Materials and methodsWe performed a retrospective analysis of 92 hospitalised patients with AST, ECOG 3–4, who were treated with palliative chemotherapy. Uni- and multivariate statistical analyses were conducted to determine the impact of clinical and disease variables (number of previous chemotherapy lines, presence of comorbidities, presentation of anorexia-cachexia syndrome, delirium, dyspnoea, ascitis, brain metastases, T-cell count, albumin, haemoglobin and LDH) on survival in this patient population.ResultsMean age was 54 years (range 15–80). No chemotherapy had been given for advanced disease in 74%, 13% had received one line, 6% 2 lines and 7% ≥3 lines. Median survival, i.e., after initiation of chemotherapy to death, in these patients was 33 days (range 1–1390). The median of chemotherapy cycles was 1. In the multivariate analysis, no previous chemotherapy, and absence of anorexia-cachexia syndrome and of comorbidities was associated with significantly improved survival in patients. Forty-nine percent of patients died within 30 days of therapy, 28% died between days 30 and 90, and only 23% of patients lived longer than 90 days. Grade 3–4 toxicities mainly entailed blood disorders, namely anaemia 8%, neutropenia 13% and thrombocytopenia 8%. Six patients (5%) developed sepsis after therapy; of these, 3 died from this toxicity, 1 patient suffered cardiac toxicity, one patient leukoencephalopathy and 1 patient acute pulmonary thromboembolism.ConclusionPalliative chemotherapy given to patients with AST and ECOG 3–4 with short life expectancy provided no benefit for survival. As a result, we may be over-treating these patients and contributing to poor-quality care.

Higher Risk of Infections with PI3K–AKT–mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials

Purpose: Novel antitumor therapies against the PI3K–AKT–mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogues. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2, or multikinase inhibitors is unknown. Experimental Design: In this retrospective case–control study, we determined the incidence of infection in a group of 432 patients who were treated on 15 phase I clinical trials involving PI3K–AKT–mTOR pathway inhibitors (cases) versus a group of 100 patients on 10 phase I clinical trials of single agent non-PI3K–AKT–mTOR pathway inhibitors (controls) which did not involve conventional cytotoxic agents. We also collected data from 42 patients who were treated with phase I trials of combinations of PI3K–AKT–mTOR inhibitors and MEK inhibitors and 24 patients with combinations of PI3K–AKT–mTOR inhibitors and cytotoxic chemotherapies. Results: The incidence of all grade infection was significantly higher with all single-agent PI3K–AKT–mTOR inhibitors compared with the control group [27% vs. 8%, respectively, OR, 4.26; 95% confidence intervals (CI), 1.9–9.1, P = 0.0001]. The incidence of grade 3 and 4 infection was also significantly higher with PI3K–AKT–mTOR inhibitors compared with the control group (10.3% vs. 3%, OR, 3.74; 95% CI, 1.1–12.4; P = 0.02). Also, the combination of PI3K–AKT–mTOR inhibitors and chemotherapy was associated with a significantly higher incidence of all grade (OR, 4.79; 95% CI, 2.0–11.2; P = 0.0001) and high-grade (OR, 2.87; 95% CI, 1.0–7.6; P = 0.03) infection when compared with single-agent PI3K–AKT–mTOR inhibitors. Conclusions: Inhibitors of the PI3K–AKT–mTOR pathway can be associated with a higher risk of infection. Combinations of PI3K–AKT–mTOR inhibitors and cytotoxic chemotherapy significantly increase the risk of infection. This should be taken into consideration during the design and conduct of trials involving PI3K–AKT–mTOR pathway inhibitors, particularly when combined with chemotherapy or myelosuppressive agents. Clin Cancer Res; 21(8); 1869–76. ©2015 AACR.

Complications of hyperglycaemia with PI3K–AKT–mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials

Background:PI3K–AKT–mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients.Methods:Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups.Results:The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3–4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3–4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients.Conclusions:PI3K–AKT–mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers.

Multimodal treatment of desmoid tumours: the significance of local control

IntroductionDesmoid tumours are a rare group of tumours arising in the deep musculoaponeurotic structures and although they have no metastatic potential they can be locally aggressive with relapse rates of between 23–40%. Three sub-sites are reported: extra-abdominal, abdominal wall and intra-abdominal. The purpose of this study was to analyze patients with these tumours treated and followed at our institution and to determine factors influencing disease free survival.Material and methodsWe conducted a retrospective study of 20 patients treated between 1997 and 2009. Data was compiled to include age, gender, surgical history, familial adenomatous polyposis (FAP), contraceptives, tumour site, first-line treatment, positive margins and adjuvant radiotherapy. A descriptive and survival statistical analysis was also performed.ResultsMost patients were women, with a median age of 36 years, with abdominal wall involvement and treated with complete surgery without adjuvant radiotherapy. With a median follow-up of 35 months (range 0–188), local control at 5 years for any kind of treatment was 80%. Overall survival (OS) and 5-year progression-free survival (PFS) were 100% and 86%, respectively.ConclusionDesmoid tumours are group of rare tumours. Although complete surgical resection remains the cornerstone of treatment for resectable lesions, there is still substantial risk of recurrence. Our outcomes are comparable to those reported in the few series published to date.

Are Doses and Schedules of Small-Molecule Targeted Anticancer Drugs Recommended by Phase I Studies Realistic?

Tolerability of molecularly targeted agents (MTA) used in cancer therapeutics is determined in phase I trials. We reviewed the reported incidence of toxicity in phase III trials at doses and schedules recommended by phase I trials to evaluate whether these recommendations are realistic when drugs are used in larger populations of patients. We systematically reviewed a safety profile of small molecule (SM-MTA) and mAb MTA (MA-MTA) approved by the FDA in the last 12 years. There was a significantly increased percentage of grade 3 or 4 adverse events reported with SM-MTA compared with MA-MTA [40% vs. 27%; RR 1.5; 95% confidence interval (CI), 1.10–2.25, P = 0.038] in phase III studies. Importantly, a substantial proportion of patients (45%) treated with SM-MTA required dose modifications due to drug-related toxicity in phase III trials. However, this toxicity was associated to a definitive study drug discontinuation in only 9%. Overall, 25% of SM-MTA declared recommended phase II doses below MTD based on pharmacokinetic–pharmacodynamic data and these trials were associated with a significantly reduced number of dose modifications in registration trials (32% vs. 50%; RR 0.64; 95% CI, 0.43–0.88, P = 0.01). Tolerability is going to come into further focus due to the need for combinations of SM-MTA and other anticancer agents. There was a higher incidence of grade 3–4 toxicity in phase III trials in combinations versus single-agent SM-MTAs (64% vs. 37%; RR 1.73; 95% CI, 1.3–2.3, P = 0.001). These results indicate that phase I studies underestimate toxicity while recommending doses of SM-MTA. Clin Cancer Res; 22(9); 2127–32. ©2015 AACR.

Cross-sensitivity between taxanes in patients with breast cancer

AimThis study was a retrospective analysis of our experience with severe cross-hypersensitivity reactions (HSR) to the taxanes paclitaxel (P) and docetaxel (D) in patients with breast cancer.Patients and methodsWe evaluated patients with breast cancer treated with P or D who experienced severe HSR to one of the two taxanes. Severe HSR was defined as any reaction severe enough to warrant discontinuation of the drug. Initial intravenous premedication for paclitaxel was dexamethasone (20 mg), ranitidine (50 mg) and dexchlorpheniramine (10 mg). For docetaxel, dexamethasone (4 mg) orally every 12 hours was administered the day before infusion and dexamethasone (20 mg) was administered intravenously prior to infusion. After severe HSR to the taxane and 30 minutes before infusion of another taxane, we administered dexamethasone (20 mg), ranitidine (50 mg) and dexchlorpheniramine (10 mg) iv as a premedication, and we also increased the time of the infusion.ResultsBetween March 2009 and April 2010, 23 patients experienced an initial severe HSR to taxane (12 P, 11 D). Substitution of another taxane was conducted in 17 patients in the two weeks following the initial HSR. Eight patients had an initial HSR with P, and three had a cross-HSR to D. Nine patients had an initial HSR to D, and four of these patients had a cross-HSR to P. Among the 17 patients who received both taxanes, 7 (41%) had a cross-HSR. All cross-HSRs were sufficiently severe (grade 3–4) to suspend taxane treatment permanently. In the remaining 6 patients, a desensitisation protocol to taxanes was performed by increasing the dose of the diluted drug (4 P, 2 D), which resulted in administration of the drug without complications in all cases. There were no treatment-related deaths.ConclusionSevere cross-HSR between P and D occurred in a significant proportion of our patients with breast cancer, so care must be taken when substituting taxanes (paclitaxel and docetaxel). A desensitisation protocol can be an effective alternative to decrease the risk of a new HSR.

468PPHASE I MULTICENTRE TAX-TORC TRIAL OF THE DUAL MTORC1/2 INHIBITOR AZD2014 (A) PLUS WEEKLY PACLITAXEL (P) IN PATIENTS (PTS) WITH SOLID TUMOURS (CRUKD/12/013)

ABSTRACT Aim: Activation of the PI3 kinase-AKT-mTOR pathway is hypothesized to contribute to resistance to chemotherapy and targeted agents in many cancers. Enhanced PI3 kinase pathway signaling has been shown in ovarian cancer cell lines and ascitic cells from pts showing chemoresistance. In a previous phase I trial the maximum tolerated dose (MTD) of the dual mTORC1/2 inhibitor AZD2014 (A) as monotherapy was defined as 50 mg bd 7/7. Preclinically, when A is combined with P, additive apoptosis is observed. Therefore, the combination of A and P was evaluated in a multicentre Phase I trial in patients with solid tumours (EudraCT 2012-003896-20). Study aims were to determine the MTD and recommended dose for the combination of fixed dose weekly P with two intermittent schedules of A, based on safety, tolerability, pharmacokinetics (PK) profile, pharmacodynamics (PD) and antitumour activity. Methods: A was administered orally bd either 3 days on 4 days off (3/7 schedule) or 2 days on 5 days off (2/7 schedule) starting on the same day as fixed dose weekly intravenous P 80mg/m2. A cycle comprised 6 weekly treatments every 49 days. A 3 + 3 dose escalation design was employed. Results: 17 pts have been treated in the study so far. On the 3/7 schedule (12 treated), 2 pts had dose-limiting toxicities (DLT) of grade (Gr) 3 fatigue and mucositis at 75 mg bd of A. On the 2/7 schedule (5 treated), 2 pts had DLT of Gr 3 rash at 100mg bd of A. Frequently observed adverse events of any grade were fatigue, diarrhoea, anaemia, mucositis and anorexia. PK and PD data for the 2 schedules will be presented. To date, 3/5 pts with taxane-pretreated ovarian cancer have achieved RECIST and/or GCIG CA125 partial response (PR). 2/2 pts with taxane-pretreated squamous NSCLC and 1/2 pts with EGFR-mutant lung adenocarcinoma have shown significant necrosis of their tumours and PR by RECIST. Conclusions: The MTD for the 3/7 schedule is P 80 mg/m2 plus A 50 mg bd. For the 2/7 schedule, 100mg bd A + weekly P is declared non-tolerated, based on 2 DLTs of Gr 3 rash. Expansions in relapsed ovarian cancer and squamous cell lung cancer are now planned. The study is supported by AstraZeneca, Cancer Research UK, Experimental Cancer Medicine Centre and NIHR Biomedical Research Centre Initiatives. It is co-sponsored by the Institute of Cancer Research/Royal Marsden NHS Foundation Trust. Disclosure: S. Banerjee, S.B. Kaye and J.S. De Bono: Served on Advisory Board for AstraZeneca. All other authors have declared no conflicts of interest.