Thomas J. Semrad

Geographic variation of racial/ethnic disparities in colorectal cancer testing among medicare enrollees

The Medicare population has documented racial/ethnic disparities in colorectal cancer (CRC) screening, but it is unknown whether these disparities differ across geographic regions.

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors

Purpose: This phase I study examined the toxicity and tolerability of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies. Experimental Design: Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, Zubrod performance status 0–2, and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5 to 36 mg/m2 and up to 10 doses of docetaxel (75 mg/m2) every 3 weeks. Primary endpoints were safety, toxicity, and a recommended phase II dose. Circulating arginine levels were measured before each cycle. Tumor response was measured as a secondary endpoint every 6 weeks on study. Results: Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single dose-limiting toxicity (grade 3 urticarial rash) was observed at the 1st dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3 to 4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with 10 patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including 2 patients with PSA response) were documented, and 7 patients had stable disease. Conclusions: ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted, and expansion cohorts are now accruing for both castrate-resistant prostate cancer and non–small cell lung cancer at a recommended phase II dose of 36 mg/m2. Clin Cancer Res; 21(11); 2480–6. ©2015 AACR.

Fibroblast growth factor signaling in non-small-cell lung cancer.

Despite recent progress in the treatment on non-small cell lung cancer (NSCLC), outcomes remain suboptimal. Treatment advances that target the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signaling pathways highlight the need to understand the multiple convergent growth factor signaling pathways involved in the pathogenesis of NSCLC. Signaling through fibroblast growth factors (FGF), long recognized for its pro-angiogenic activity, has recently emerged as a contributing factor in the pathogenesis and progression of NSCLC through an autocrine signaling loop. In addition, this pathway may function as a mechanism of resistance to anti-EGFR and anti-VEGF treatment. Clinical experience with FGF receptor (FGFR) inhibitors is mounting, and more specific inhibitors of this signaling pathway are in development. This review describes the structure of the FGF signaling pathway, delineates its dual roles in angiogenesis and proliferation in NSCLC, evaluates FGF ligand and receptor expression as prognostic biomarkers in NSCLC, and discusses the development of FGF pathway inhibitors for the treatment of lung malignancies.

Phase I study of the combination of temsirolimus and pazopanib in advanced solid tumors

Inhibition of either vascular endothelial growth factor receptor or mammalian target of rapamycin (mTOR) signaling improves outcomes in patients with several advanced solid tumors. We conducted a phase I trial of temsirolimus with pazopanib to investigate the feasibility of simultaneous ‘vertical inhibition’ of vascular endothelial growth factor receptor and mTOR pathways. Patients with advanced solid tumors, no previous pazopanib or mTOR inhibitor, good performance status, and acceptable end-organ function were eligible. In a typical 3+3 escalation design starting at temsirolimus 15 mg by an intravenous infusion weekly and pazopanib 400 mg orally daily, we defined dose-limiting toxicity (DLT) as attributable grade 3 or higher nonhematologic adverse events in the first 28-day cycle and the maximum tolerable dose as the maximum dose level at which less than two patients experienced DLT. At the initial dose level, two patients had four DLTs (anorexia, fatigue, hyponatremia, and hypophosphatemia). After reduction to temsirolimus 10 mg intravenous infusion weekly and pazopanib 200 mg orally daily, one of three patients had DLT (fatigue) and the first patient in the subsequent expansion had dose-limiting hypophosphatemia. Attributable grade 3 or higher adverse events in more than one patient included leukopenia, neutropenia, fatigue, and hypophosphatemia. Tumor reduction not fulfilling the RECIST criteria for partial response was the best response in four of seven evaluable patients. The combination of temsirolimus and pazopanib was not feasible at clinically meaningful doses in this population because of constitutional and electrolyte disturbances.

Enhancing the clinical activity of sorafenib through dose escalation: rationale and current experience.

Sorafenib is an oral multitargeted tyrosine and serine/threonine kinase inhibitor approved for the treatment of advanced renal cell and hepatocellular carcinoma. An understanding of its dose–toxicity relationship has paved the way for trials seeking to enhance its clinical activity through the exploration of alternative dosing strategies. In this article, we review the dose–toxicity relationship of sorafenib observed during its phase I and early phase II testing, explore its toxicity profile at the recommended dose and schedule, discuss the evidence for dose escalation to higher levels, and examine the preliminary evidence for clinical activity of this strategy. Owing to a temporal relationship between toxicity and dose, it may be possible in select patients to escalate sorafenib to doses beyond those currently employed. However, because of the potential for increased toxicity, sorafenib dose escalation should currently be performed only in the context of a clinical trial.

Relevance of Platinum-Sensitivity Status in Relapsed/Refractory Extensive-Stage Small-Cell Lung Cancer in the Modern Era A Patient-Level Analysis of Southwest Oncology Group Trials

Background: Extensive-stage small-cell lung cancer (SCLC) patients who progress after platinum-based chemotherapy are traditionally categorized as platinum sensitive (progression ≥ 90 days from last platinum dose) or refractory (progression < 90 days), a practice arising from seminal observations of worse survival in refractory patients. Subsequent trials accounted for platinum sensitivity, resulting in higher sample sizes and increased resource use. Methods: To assess whether platinum-sensitivity status remains associated with outcomes, patient-level data from recent Southwest Oncology Group trials in second- and/or third-line extensive-stage SCLC were pooled. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) accounting for platinum sensitivity were calculated using unadjusted and adjusted Cox Proportional Hazard models. Recursive partitioning was performed to define prognostic risk groups. Results: Of 329 patients, 151 were platinum sensitive and 178 refractory. HRs from unadjusted Cox PFS and OS models for refractory versus sensitive disease were 1.0 (95% confidence interval, 0.81–1.25; p = 0.98) and 1.24 (0.99–1.57; p = 0.06), respectively. Adjusted Cox models showed that only elevated serum lactate dehydrogenase (HR, 2.04; p < 0.001), males (HR, 1.36; p = 0.04), performance status of 1 (HR, 1.25; p = 0.02), and weight loss greater than or equal to 5% (1.53, p = 0.01) were independently associated with OS. Platinum-sensitivity status was not associated with PFS (HR, 1.11; p = 0.49) or OS (HR, 1.25; p = 0.14), except in a model that excluded 36 patients who received more than one prior chemotherapy regimen (HR, 1.34; p = 0.049). Prognostic groups with differential OS outcomes (high, intermediate, and poor risk) were identified. Conclusions: Platinum-sensitivity status may no longer be strongly associated with PFS or OS in at least one multivariate model. Validation of prognostic risk groups identified here is warranted. These data have critical implications in the design of future SCLC trials.

Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): A randomised, phase 3 study

BACKGROUND EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive. METHODS We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712). FINDINGS Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9-39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75-1·12; p=0·40; median 5·4 months [95% CI 4·5-5·7] vs 4·8 months [3·9-5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83-1·04; p=0·22; median 10·9 months [95% CI 9·5-12·0] vs 9·2 months [8·7-10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36-0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46-1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78-1·40; p=0·77; and 1·02, 0·77-1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68-1·14; p=0·34; and 0·99, 0·78-1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85-1·17; p=0·97; and 1·03, 0·88-1·20; p=0·69; respectively). The most common grade 3-4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [<1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group. INTERPRETATION Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation. FUNDING National Cancer Institute and Eli Lilly and Company.

Abstract B75: A first in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0623 in patients with advanced solid tumors.

Background: Deregulation of the RAS/RAF/MEK/ERK signaling pathway has been implicated in diverse human tumors. GDC-0623 is an orally bioavailable inhibitor of MEK1/2 which has shown antitumor activity in preclinical models (Hatzivassiliou et al. 2013). Methods: An open-label Phase I dose-escalation study using a 3 + 3 design was initiated in patients with advanced solid tumors to evaluate the safety and pharmacokinetic (PK) characteristics of GDC-0623. Patients were administered oral GDC-0623 as a QD or BID regimen on a 21-day on/7-day off dosing schedule in the fasted state (minimum 2 hour fast). In addition, two cohorts were enrolled to examine the effect of food (4 pts) and acidic beverage (3 pts) on GDC-0623 PK. Serial plasma samples for GDC-0623 PK analysis were collected over 24 hours following first dose and after 15 days of continuous dosing. Results: On the QD regimen, 45 pts enrolled in eight successive cohorts (7-160 mg). Dose-limiting toxicities (DLTs) were Grade 4 (G4) creatine phosphokinase (CPK) elevation (90 mg), transient G3 visual disturbance and the serious adverse event (SAE) of G3 dehydration both occurring in the same patient (120 mg), and G3 thrombocytopenia and G3 hyponatremia (160 mg). The maximum tolerated dose was 120 mg (QD cohort). Eight patients enrolled in a single cohort dosing at 45 mg BID. One patient had a DLT of G2 retinal pigment epithelial detachment. Further BID cohorts were not enrolled since the AE profiles between on 90 mg QD and 45 mg BID were comparable. The most frequent adverse events (AE) attributed by the investigator to be GDC-0623-related were rash, visual disturbance - including impaired or blurred vision - which was often associated with sub-retinal fluid, diarrhea, nausea and vomiting, fatigue, elevated CPK, peripheral edema, decreased appetite, headache and dizziness. Preliminarily, GDC-0623 showed dose-proportional PK over the dose range administered. GDC-0623 was rapidly absorbed and distributed, with a terminal half-life of 4-6 hours. Due to its short half-life, GDC-0623 had no accumulation at steady-state following daily oral dosing. Effect of food or acidic beverage on GDC-0623 PK was inconclusive given the inter-patient and intra-patient variability in GDC-0623 PK and very small sample size. One confirmed partial response was observed in a patient with KRAS wild type squamous cell vaginal carcinoma at the QD MTD. Six patients had stable disease ≥ 5 months. Conclusion: GDC-0623 is well-tolerated and showed dose-proportional and time-independent PK. Classic MEK-related AEs, including rash, gastrointestinal symptoms and visual disturbance occurred with similar frequency for QD and BID dosing regimens at the same total daily dose, suggesting comparable intensity of MEK target effect. Updated data will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B75. Citation Format: Anthony El-Khoueiry, Carla Kurkjian, Thomas Semrad, Luna Musib, Mary Gates, Steve Eppler, Ilsung Chang, Iris Chan, Isabelle Rooney, Johanna Bendell. A first in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0623 in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B75.

Phase II study of dovitinib in patients progressing on anti-vascular endothelial growth factor therapy

BACKGROUND Prior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-vascular endothelial growth factor (VEGF) therapy. We tested dovitinib, an inhibitor of both FGF and VEGF receptors, in patients progressing on anti-VEGF treatment. METHODS Patients with measurable advanced colorectal or non-small cell lung cancer with progression despite anti-VEGF treatment within 56 days, good performance status and adequate organ function were eligible. A research tumor biopsy was followed by treatment with dovitinib 500 mg on a 5-day on/2-day off schedule for 28-day cycles. The primary endpoint of tumor response was evaluated every 2 cycles. Secondary endpoints included toxicity and 8-week disease control rate. Intratumor mRNA expression of angiogenic mediators was analyzed using a next generation sequencing based expression array. RESULTS Ten patients treated previously with bevacizumab or ziv-aflibercept enrolled. The study closed with termination of dovitinib development. No responses were observed in 7 evaluable patients. The best response was stable disease in 1 patient. Common toxicities included gastrointestinal, metabolic, and biochemical derangements. All patients experienced at least one grade ≥ 3 treatment-related adverse event, most commonly fatigue, elevated GGT, and lymphopenia. Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA. CONCLUSIONS We found no evidence for the activity of dovitinib in patients who had recently progressed on anti-VEGF therapy and toxicities were significant. In tumors progressing despite anti-VEGF therapy, a multitude of pro-angiogenic mediators are expressed, including members of the FGF pathway.

Molecular testing to optimize therapeutic decision making in advanced colorectal cancer

Colorectal cancer (CRC) is a leading cause of cancer death in the United States. In recent years, therapeutic advances have prolonged the survival of patients with advanced disease. Along with the addition of new treatments, an increasing body of literature explores the potential benefit of using molecular testing to define tumor, circulating, or host biomarkers of benefit to specific treatment strategies. At present, testing for specific mutations in exons 2, 3, and 4 of KRAS and NRAS has become accepted practice to select patients for treatment with epidermal growth factor receptor (EGFR)-targeted agents. Additionally, testing for the BRAF V600E mutation is used to refine decisions based on patient prognosis. The presence of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) *28 polymorphism is associated with toxicity from irinotecan, although it has not been universally applied. Nonetheless, molecular markers to predict response and toxicity of cytotoxic therapy are evolving. While the development of selection biomarkers for anti-angiogenic treatments has not proved fruitful to date, improved development strategies and novel targeted agents are anticipated to revolutionize the approach to treatment of advanced CRC in the near future. This review summarizes currently available data to select treatment strategies in patients with advanced CRC.