Karim Rihawi

Treatment of Metastatic Breast Cancer in a Real-World Scenario: Is Progression-Free Survival With First Line Predictive of Benefit From Second and Later Lines?

INTRODUCTION Despite the availability of several therapeutic options for metastatic breast cancer (MBC), no robust predictive factors are available to help clinical decision making. Nevertheless, a decreasing benefit from first line to subsequent lines of treatment is commonly observed. The aim of this study was to assess the impact of benefit from first-line therapy on outcome with subsequent lines. METHODS We analyzed a consecutive series of 472 MBC patients treated with chemotherapy (CT) and/or endocrine therapy (ET) between 2004 and 2012. We evaluated progression-free survival (PFS) at first (PFS1), second, third, and fourth therapeutic lines, according to treatment (ET and/or CT) and tumor subtypes. RESULTS In the whole cohort, median overall survival was 34 months, and median PFS1 was 9 months. A 6-month benefit was shown by 289 patients (63.5%) at first line, 128 (40.5%) at second line, 76 (33.8%) at third line, and 34 (23.3%) at fourth line. Not having a 6-month benefit at PFS1 was associated with less chance of benefit at second line (odds ratio [OR]: 0.48; 95% confidence interval [CI]: 0.29-0.77, p = .0026) and at any line beyond first (OR: 0.39; 95% CI: 0.24-0.62, p < .0001). In the total series, after stratification for tumor subtypes, a strong predictive effect was observed among HER2-positive tumors (OR: 0.2; 95% CI: 0.05-0.73, p = .0152). CONCLUSION Our results suggest that the absence of at least a 6-month benefit in terms of PFS with first-line therapy predicts a reduced probability of benefit from subsequent therapeutic lines, especially in HER2-positive disease. IMPLICATIONS FOR PRACTICE This study supports evidence showing that the absence of a 6-month benefit in terms of progression-free survival with first-line therapy predicts a lack of benefit from subsequent therapeutic lines in metastatic breast cancer. The random distribution of benefit experienced by a subset of the cohort further spurs an interest in identifying predictive factors capable of identifying the most appropriate therapeutic strategy.

Hyperglycemia and Phosphatidylinositol 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin (PI3K/AKT/mTOR) Inhibitors in Phase I Trials: Incidence, Predictive Factors, and Management

BACKGROUND Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is implicated in human cancer growth and progression. Agents targeting this pathway are associated with hyperglycemia due to interaction with the insulin-glucose regulatory axis. Identifying the predictive factors for hyperglycemia in patients treated with these agents may help direct future management. MATERIALS AND METHODS Clinical characteristics and outcomes of patients treated consecutively with PI3K, AKT, or mTOR inhibitors in the Drug Development Unit, The Royal Marsden (RM) National Health Service (NHS) Foundation Trust, between 2007 and 2012 were recorded. Baseline variables and their association with grade 3 hyperglycemia (Common Terminology Criteria for Adverse Events, version 3.0) were analyzed by using the chi-square test and Fisher exact test for categorical variables and binary logistic regression for continuous variables. RESULTS A total of 341 patients were treated in 12 phase I trials of PI3K/AKT/mTOR inhibitors, and 298 patients (87.4%) developed hyperglycemia. Hyperglycemia was grade 1 in 217 (72.8%) and grade 2 in 61 (20.5%) patients, respectively. Grade ≥3 hyperglycemia was seen in 6.7% of patients (n = 20). According to the chi-square test, age <65 years (p = .03), history of diabetes (p = .003), and treatment with AKT and dual PI3K/mTOR inhibitors (p < .0005) predicted the occurrence of grade 3 hyperglycemia. Of 24 patients requiring intervention, 20 received metformin, 2 dietary advice, 1 insulin, and 1 both metformin and insulin. One patient required dose reduction. There were no permanent drug discontinuations, and no hyperglycemia-related dose-limiting toxicities were observed; thus, the recommended phase II dose was not affected by the hyperglycemia observed in our cohort. CONCLUSION Hyperglycemia is common in patients treated with PI3K/AKT/mTOR inhibitors; however, it is manageable with conventional treatment. Predictive factors of age, history of diabetes, and administration of AKT and dual PI3K/mTOR inhibitors warrant prospective validation. IMPLICATIONS FOR PRACTICE This study reviewed the clinical data of 341 patients treated in 12 phase I trials of agents targeting phosphatidylinositol3-kinase (PI3), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), as well as dual inhibitors. Hyperglycemia was evident in 87.4% of patients but was ≥grade 3 in just 6.7%. Age <65 years, history of diabetes, and treatment with AKT and dual PI3K/mTOR inhibitors were each associated with grade 3 hyperglycemia. Management of patients was uncomplicated, and no permanent drug discontinuations were necessary. Despite the small study size, these findings support continued caution about enrolling patients with a history of diabetes into such trials. However, clinicians may be reassured, pending prospective validation of these results, that significant hyperglycemia is not frequent and, when it occurs, is manageable.

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.

Sunitinib as first-line therapy in elderly patients (age 70 and older) with metastatic renal cell cancer.

411 Background: Many medical oncologists are still reluctant to use the standard sunitinib regimen in older patients (pts) with metastatic renal cell cancer (mRCC) because of concerns about tolerance. We assessed the routine use of first-line sunitinib in mRCC pts aged ≥70 yrs. METHODS We reviewed the clinical files of 154 pts aged ≥70 yrs with mRCC treated with first-line sunitinib in sixteen Italian Oncology Units from February 2006 to April 2011. Sunitinib 50 mg/d 4 wk on/2 wk off was considered the standard regimen (SR). All alternative schedules of sunitinib administration were considered as adapted regimens (AR). After univariate analysis a multivariate analysis was carried out by Cox regression model and included the following variables: age (<75 vs ≥75 yrs), Eastern Cooperative Oncology Group (ECOG) performance status (PS; 0-1 vs ≥2), presence of comorbidities (0 vs ≥1), lymphocytopenia (<1,000/microL vs >1,000/microL), prognostic score for VEGF-targeted agents according to Heng 2009 (good + intermediate prognosis vs poor prognosis), and treatment schedule (SR vs AR). RESULTS Median age was 74 yrs (range, 70-88 yrs). One hundred six pts (68.8%) received a SR and 48 (31.2%) received an AR consisting of 37.5 mg/d 4 wk on/2 wk off (32 cases, 67%), 25 mg/d 4 wk on/2 wk off (12 cases, 25%) and 37.5 mg continuous once-daily dosing in (4 cases, 8%). Pts treated with an AR were older than those treated with the SR (≥75 yrs, 56% vs 32%, respectively, p=0.008); with no differences for the other variables. Pts received a median of 4 sunitinib cycles with either SR or AR. Grade 3-4 toxicities occurred in 65% of SR and 42% of AR (p=0.008); dose reductions were required in 64% and 40%, respectively (p=0.005); discontinuations due to therapy-related adverse events occurred in 23% and 21%, respectively (p=0.967). Median progression-free survival (PFS) was 10.6 months (95% CI 8.7-15.3) and median overall survival (OS) was 20.1 months (95% CI 15.5-not reached). In multivariate analysis, only PS and the Heng score were predictors of either PFS or OS. CONCLUSIONS Sunitinib is active and feasible in pts with mRCC aged ≥70 yrs. AR does not appear to influence PFS and OS and has a favorable impact on toxicity.

A streamlined workflow for single-cells genome-wide copy-number profiling by low-pass sequencing of LM-PCR whole-genome amplification products

Chromosomal instability and associated chromosomal aberrations are hallmarks of cancer and play a critical role in disease progression and development of resistance to drugs. Single-cell genome analysis has gained interest in latest years as a source of biomarkers for targeted-therapy selection and drug resistance, and several methods have been developed to amplify the genomic DNA and to produce libraries suitable for Whole Genome Sequencing (WGS). However, most protocols require several enzymatic and cleanup steps, thus increasing the complexity and length of protocols, while robustness and speed are key factors for clinical applications. To tackle this issue, we developed a single-tube, single-step, streamlined protocol, exploiting ligation mediated PCR (LM-PCR) Whole Genome Amplification (WGA) method, for low-pass genome sequencing with the Ion Torrent™ platform and copy number alterations (CNAs) calling from single cells. The method was evaluated on single cells isolated from 6 aberrant cell lines of the NCI-H series. In addition, to demonstrate the feasibility of the workflow on clinical samples, we analyzed single circulating tumor cells (CTCs) and white blood cells (WBCs) isolated from the blood of patients affected by prostate cancer or lung adenocarcinoma. The results obtained show that the developed workflow generates data accurately representing whole genome absolute copy number profiles of single cell and allows alterations calling at resolutions down to 100 Kbp with as few as 200,000 reads. The presented data demonstrate the feasibility of the Ampli1™ WGA-based low-pass workflow for detection of CNAs in single tumor cells which would be of particular interest for genome-driven targeted therapy selection and for monitoring of disease progression.

Ramucirumab for the treatment of gastric cancers, colorectal adenocarcinomas, and other gastrointestinal malignancies

ABSTRACT Introduction: The use of antiangiogenic strategy in the treatment of advanced colorectal cancers has been largely evidence-based. More recently, novel vascular endothelial growth factor receptor (VEGFR) inhibitors have been studied in other gastrointestinal diseases. Ramucirumab, a recombinant monoclonal antibody that binds to VEGFR2 extracellular domain with a much greater affinity compared to its natural ligand, showed second-line effectiveness for patients with gastric or colorectal carcinomas. Areas covered: We perform a narrative literature review. The aims of our work are to recall the current evidence of its efficacy in the treatment of gastric, hepatocellular and colorectal cancers and to present the ongoing studies enrolling gastrointestinal cancer patients in which ramucirumab is being tested. Expert commentary: The landscape of angiogenesis-inhibition for the treatment of GI malignancies is rapidly evolving. The results of the REGARD and RAINBOW trials renewed the interest for antiangiogenic agents in gastric cancer and determined a swift change in the treating paradigm for this disease. Accordingly, ramucirumab was shown to be effective in pretreated colorectal cancer patients and it is being tested in other gastrointestinal malignancies.

Timing and extent of response in colorectal cancer: critical review of current data and implication for future trials.

The identification of new surrogate endpoints for advanced colorectal cancer is becoming crucial and, along with drug development, it represents a research field increasingly studied. Although overall survival (OS) remains the strongest trial endpoint available, it requires larger sample size and longer periods of time for an event to happen. Surrogate endpoints such as progression free survival (PFS) or response rate (RR) may overcome these issues but, as such, they need to be prospectively validated before replacing the real endpoints; moreover, they often bear many other limitations. In this narrative review we initially discuss the role of time-to-event endpoints, objective response and response rate as surrogates of OS in the advanced colorectal cancer setting, discussing also how such measures are influenced by the tumor assessment criteria currently employed. We then report recent data published about early tumor shrinkage and deepness of response, which have recently emerged as novel potential endpoint surrogates, discussing their strengths and weaknesses and providing a critical comment. Despite being very compelling, the role of such novel response measures is yet to be confirmed and their surrogacy with OS still needs to be further investigated within larger and well-designed trials.

Phase I clinical trials in patients with advanced non-small cell lung cancer treated within a Drug Development Unit: What have we learnt?

OBJECTIVES Despite advances in novel drug development for patients with advanced non-small cell lung cancer (NSCLC), there are still only a limited number of approved treatments. We therefore evaluated the clinical outcomes of patients with advanced NSCLC referred to a dedicated phase I clinical trials unit assessed baseline clinical factors associated with successful enrollment onto phase I trials. MATERIAL AND METHODS We conducted a retrospective study involving patients with advanced NSCLC referred to the Drug Development Unit at the RMH between January 2005 and December 2013. RESULTS 257 patients with advanced NSCLC were referred for consideration of phase I trials, of which only 89 (35%) patients successfully commenced phase I trials. The commonest reasons for not entering study included poor ECOG performance status and rapid disease progression. A multivariate analysis identified that ECOG performance status (0-1) and RMH prognostic score (0-1) were associated with successful enrollment onto phase I trials (p<0.001). Single agent therapies included novel agents against the phosphatidylinositol-3 kinase pathway, insulin growth factor-1 receptor and pan-HER family tyrosine kinases. These trial therapies were well tolerated and mainly associated with grade 1-2 adverse events, with a minority experiencing grade 3 toxicities. Nine (10%) patients, 4 with known EGFR or KRAS mutations, achieved RECIST partial responses. Median time to progression was 2.6 months and median overall survival was 8.1 months for patients enrolled. CONCLUSIONS Phase I trial therapies were generally well tolerated with potential antitumor benefit for patients with advanced NSCLC. Early referral to drug development units at time of disease progression should be considered to enhance the odds of patient participation in these studies.

Maintenance Therapy in Colorectal Cancer: Moving the Artillery Down While Keeping an Eye on the Enemy

The survival improvement in metastatic colorectal cancer, achieved with more intensive chemotherapy regimens, has recently led clinicians to question the optimal duration of therapies and to consider the role of maintenance. Indeed, patients whose disease is controlled after induction chemotherapy may benefit from continuing a less intensive regimen in order to reinforce the results achieved with up-front treatment. In addition, the more favorable toxicity profile of maintenance approaches would ensure a better quality of life. After discussing the rationale and the difference of pursuing a maintenance strategy with chemotherapeutic and/or biologic agents, we present significant available data from the literature and comment on the current implications and future directions of maintenance therapy. The current roles of depotentiated treatment schedules, antiangiogenic compounds, epidermal growth factor receptor inhibitors, and novel targeted therapies are also reviewed. Finally, we address elements that may foster clinical and social debate on this topic, suggesting potential aspects that need to be further investigated.