Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies.

PURPOSE: Data from two large phase III studies were analyzed to characterize the correlation between the occurrence of rash during treatment with the epidermal growth factor receptor inhibitor erlotinib and improved clinical outcomes. EXPERIMENTAL DESIGN: Overall survival, progression-free survival (PFS), and tumor response were compared between patients in a rash-evaluable subset who did or did not develop rash in National Cancer Institute of Canada Clinical Trials Group Studies BR.21 (single agent in non-small-cell lung cancer, n = 444 in erlotinib group and n = 229 in placebo group) and PA.3 (combination with gemcitabine in pancreatic cancer, n = 254 in erlotinib plus gemcitabine group and n = 245 in placebo plus gemcitabine group). RESULTS: Presence of rash strongly correlated with overall survival in both studies. In Study BR.21, these correlations increased with rash severity grade: grade 1 versus no rash [hazard ratio (HR), 0.41, P < 0.001] and grade >or=2 versus no rash (HR, 0.29, P < 0.001). Similar results were observed for PFS. Disease control (complete response + partial response + stable disease) seemed to increase with the presence and severity of rash. In Study PA.3, grade >or=2 rash (but not grade 1) strongly correlated with overall survival improvement: grade >or=2 versus no rash (HR, 0.47, P < 0.001). Similarly, grade >or=2 rash was strongly correlated with improvements in PFS and disease control. CONCLUSIONS: Physicians and patients should view rash development as a positive event indicative of greater likelihood of clinical benefit. Further studies are required to identify patients most likely to develop rash and to determine if dose escalation to induce rash can improve efficacy.

Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition.

Overexpression and enhanced activation of the epidermal growth factor receptor (EGFR) is frequently observed in human carcinomas. Inhibitors of EGFR signaling have shown clinical utility; however, understanding response at the molecular level is important to define patient subsets most likely to benefit, as well as to support the rational design of drug combinations. Pancreatic and colorectal tumor cell lines insensitive to EGFR inhibition were those that had lost or mutated the epithelial junction constituents E-cadherin and gamma-catenin, had lost homotypic adhesion, and often gained proteins associated with an epithelial to mesenchymal-like transition, such as vimentin, zeb1, or snail. In matched pairs of colorectal tumor cells, the epithelial lines showed an average 7-fold greater sensitivity than mesenchymal-like lines. In human pancreatic and colorectal tumor tissues, gain of mesenchymal characteristics and loss of epithelial characteristics correlated with advancing tumor stage. These data indicate an especially sensitive patient subset as well as a rationale for the combination of EGFR antagonists with agents that affect the epithelial to mesenchymal-like transition process as a mechanism to enhance sensitivity for more advanced mesenchymal-like tumors.

Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER-3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity.

Signaling through the receptor for epidermal growth factor receptor (EGFR) is frequently deregulated in solid tumors. Erlotinib (Tarceva, OSI-774, OSI Pharmaceuticals, Inc., Melville, NY) is a low molecular weight, orally bioavailable inhibitor of the EGFR that has been approved for both non-small cell lung cancer and pancreatic cancers. Previous studies have indicated that sensitivity to EGFR antagonists correlated with HER-3 signaling for non-small cell lung cancer. Herein, we have sought to understand the signaling pathways that mediate erlotinib sensitivity for pancreatic and colorectal cancers. In a panel of 12 pancreatic tumor cell lines, we find that EGFR is coexpressed with HER-3 in all cell lines sensitive to erlotinib but not in insensitive cell lines. Erlotinib can block HER-3 phosphorylation in these sensitive cell lines, suggesting that HER-3 is transactivated by EGFR. Knockdown of HER-3 in BxPC3, an erlotinib-sensitive pancreatic tumor cell line, results in inhibition of the phosphorylation for both Akt and S6 and is associated with a decrease in cell proliferation and reduced sensitivity to erlotinib. Therefore, EGFR transactivation of HER-3 mediates Akt signaling and can contribute to erlotinib sensitivity for pancreatic tumors. We extended our analysis to a panel of 13 colorectal tumor cell lines and find that, like pancreatic, HER-3 is coexpressed with EGFR in the most erlotinib-sensitive cell lines but not in erlotinib-insensitive cell lines. These studies suggest that HER-3 could be used as a biomarker to select patients who are most likely to respond to erlotinib therapy.

Effects of smoking on the pharmacokinetics of erlotinib.

PURPOSE: To compare the pharmacokinetic variables of erlotinib in current smokers with nonsmokers after receiving a single oral 150 or 300 mg dose of erlotinib. EXPERIMENTAL DESIGN: This was a single-center, open-label pharmacokinetic study in healthy male subjects. Subjects were enrolled into two treatment cohorts based on smoking status (current smokers and nonsmokers). The pharmacokinetic profile for erlotinib and its metabolite, OSI-420, was determined for each subject following each treatment. RESULTS: Current smokers achieved significantly less erlotinib exposure following a single 150 or 300 mg dose than nonsmokers. Following the 150 mg dose, the geometric mean erlotinib AUC(0-infinity) in smokers was 2.8-fold lower than in nonsmokers and similar to that of nonsmokers at the 300 mg dose. C(max) in smokers was two-thirds of that in nonsmokers, and C(24h) in smokers was 8.3-fold lower than in nonsmokers. The median C(24h) of smokers at the 300 mg dose was slightly less than the C(24h) of smokers at the 150 mg dose. The median C(max) was greater in smokers at the 300 mg dose than in nonsmokers at the 150 mg dose. CONCLUSION: This study confirms that the pharmacokinetics of erlotinib is different in current smokers and nonsmokers. The observation that AUC(0-infinity) and C(24h) were significantly decreased in smokers compared with nonsmokers, and a smaller decrease in C(max) was observed, is consistent with increased metabolic clearance of erlotinib in current smokers.

Whole-brain radiotherapy with or without efaproxiral for the treatment of brain metastases: Determinants of response and its prognostic value for subsequent survival.

PURPOSE: To determine the prognostic factors for radiographic response and its prognostic value for subsequent survival in patients undergoing whole-brain radiotherapy (WBRT) for brain metastases. METHODS AND MATERIALS: Five hundred fifteen eligible patients were randomized in a phase III trial evaluating WBRT and supplemental oxygen with or without efaproxiral, an allosteric modifier of hemoglobin that reduces hemoglobin oxygen-binding affinity and enhances tumor oxygenation, potentially increasing tumor radiosensitivity. Brain images were obtained at baseline and at scheduled follow-up visits after WBRT. Landmark analysis was used to assess the ability of response at selected time points to predict subsequent survival. Logistic regression was used to assess determinants of response at 3 months. RESULTS: Treatment arm, Karnofsky Performance Status, presence or absence of liver metastases, and primary site were all determinants of response at the 3-month follow-up visit, with patients in the efaproxiral arm experiencing a 67% greater odds of response at this visit (p = 0.02). Response at 3 and 6 months was a significant prognostic factor for longer subsequent survival. CONCLUSIONS: The 3-month scan is a valuable prognostic factor for subsequent survival in patients with brain metastases treated with WBRT. Patients in the efaproxiral arm had a higher response rate at 3 and 6 months than those in the control arm.

Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases.

PURPOSE: To determine whether efaproxiral, an allosteric modifier of hemoglobin, improves survival in patients with brain metastases when used as an adjunct to whole-brain radiation therapy (WBRT). PATIENTS AND METHODS: Patients with brain metastases from solid tumors and a Karnofsky performance score of > or = 70 were randomly assigned to receive WBRT with supplemental oxygen and either efaproxiral at 75 or 100 mg/kg (efaproxiral arm) or no efaproxiral (control arm). The primary end point was survival. RESULTS: The study consisted of 515 eligible patients (efaproxiral arm, n = 265; control arm, n = 250). The median survival time (MST) was 5.4 months for the efaproxiral arm versus 4.4 months for the control arm (hazard ratio [HR] = 0.87; P = .16). For the subgroup of patients with non-small-cell lung cancer (NSCLC) or breast cancer, the MST was 6.0 and 4.4 months, respectively (HR = 0.82; P = .07). Cox multiple regression analysis demonstrated a significant reduction in the risk of death for the efaproxiral arm in both primary populations. Further analysis indicated that the benefit may be restricted to the subgroup of patients with breast cancer. Response rates (radiographic complete response plus partial response) improved by 7% (P = .10) and 13% (P = .01) for all patients and for NSCLC and breast cancer patients in the efaproxiral arm, respectively. The most common severe adverse event in patients treated with efaproxiral was hypoxemia, which was reversible and effectively managed with supplemental oxygen in most patients. CONCLUSION: The addition of efaproxiral, a noncytotoxic radiation sensitizer, to WBRT may improve response rates and survival in patients with brain metastases, particularly metastases from breast cancer. A confirmatory trial for breast cancer patients has been initiated.

Phase II multicenter study of induction chemotherapy followed by concurrent efaproxiral (RSR13) and thoracic radiotherapy for patients with locally advanced non-small-cell lung cancer.

PURPOSE: Efaproxiral (RSR13) reduces hemoglobin oxygen-binding affinity, facilitates oxygen release, and increases tissue pO2. We conducted a phase II multicenter study that assessed the efficacy and safety of efaproxiral when administered with thoracic radiation therapy (TRT), following induction chemotherapy, for treatment of locally advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-one patients with locally advanced NSCLC were enrolled at 13 sites. Treatment comprised two cycles of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6), 3 weeks apart, followed by TRT (64 Gy/32 fractions) with concurrent efaproxiral (50 to 100 mg/kg). Survival results were compared with results of study Radiation Therapy Oncology Group (RTOG) 94-10. RESULTS: Overall response rate was 75% (37 of 49 patients). Complete and partial response rates were 6% (three of 49 patients) and 69% (34 of 49 patients), respectively. Median survival time (MST) was 20.6 months (95% CI, 14.0 to 24.2); overall survival rates at 1- and 2-years were 67% and 37%, respectively. Survival results were compared with the sequential (S-CRT) and concurrent (C-CRT) chemoradiotherapy arms of RTOG 94-10. MSTs for cases matched by stage, Karnofsky performance status, and age were: RT-010, 20.6 months; S-CRT, 15.1 months; and C-CRT, 17.9 months. Grade 3 to 4 toxicities related to efaproxiral that occurred in more than one patient included transient hypoxemia (19%), radiation pneumonitis (11%), and fatigue (4%). CONCLUSION: Addition of efaproxiral to S-CRT represents a promising approach in NSCLC treatment, and a randomized study should be pursued. The low incidence of grade 3 to 4 toxicities suggests that the use of efaproxiral instead of a cytotoxic agent, as a radiation sensitizer, may be advantageous.

Phase I and pharmacokinetic study of docetaxel combined with melphalan and carboplatin, with autologous hematopoietic progenitor cell support, in patients with advanced refractory malignancies.

The purpose of this study was to define the maximal tolerated dose (MTD), extramedullary toxicities, and pharmacokinetics of docetaxel combined with high-dose melphalan and carboplatin with autologous hematopoietic progenitor cell support. Fifty-nine patients with advanced refractory malignancy (32 breast cancer, 10 non-Hodgkin lymphoma, 6 germ cell tumors, 4 Hodgkin disease, 4 ovarian cancer, 2 sarcoma, and 1 unknown primary adenocarcinoma) with a median of 3 prior chemotherapy regimens and a median of 3 organs involved were enrolled. Treatment included docetaxel (150-550 mg/m2 infused over 2 hours on day -6), melphalan (150-165 mg/m2 infused over 15 minutes from day -5 to -3), and carboplatin (1000-1300 mg/m2 as a 72-hour continuous infusion from day -5). Five patients died from direct regimen-related organ toxicity (2 capillary leak syndrome, 2 enterocolitis, and 1 hepatic toxicity), and 1 additional patient died from pulmonary aspergillosis. The docetaxel MTD was defined as 400 mg/m 2 , combined with melphalan (150 mg/m2 ) and carboplatin (1000 mg/m2 ). The MTD cohort was expanded to enroll a total of 26 patients, 1 of whom died from toxic enterocolitis. The remaining 25 patients presented the following extramedullary toxicity profile, which was manageable and largely reversible: stomatitis, myoarthralgias, peripheral neuropathy, gastrointestinal and cutaneous toxicities, and syndrome of inappropriate antidiuretic hormone secretion. Docetaxel exhibited linear pharmacokinetics in the dose range tested (150-550 mg/m2 ). Pharmacodynamic correlations were noted between the docetaxel area under the curve and peripheral neuropathy or stomatitis. The response rate among 38 patients with measurable disease was 95%, with 47% complete responses. At a median follow-up of 26 months (range, 7-72 months), the 3-year event-free survival and overall survival were 26% and 36%, respectively. In conclusion, a 4-fold dose escalation of docetaxel, combined with melphalan and carboplatin, is feasible with autologous hematopoietic progenitor cell support. The notable activity of this regimen in treatment-refractory patients warrants its further evaluation.

Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality.

Hepatic venoocclusive disease (HVOD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) and is a well-recognized dose-limiting toxicity of oral busulfan (Bu)-based preparative regimens. The unpredictable absorption of oral Bu from the gastrointestinal (GI) tract and hepatic first-pass effects have led to the development of an intravenous Bu preparation (i.v. Bu). The purpose of this retrospective comparison was to evaluate the incidence rate of HVOD and the 100-day mortality rate in patients treated with a busulfan/cyclophosphamide (BuCy2) regimen in which either oral Bu or i.v. Bu was administered. Data from 2 similar groups of patients treated between March 1995 and December 1997 were analyzed. Thirty patients were treated with oral Bu (1 mg/kg x 16 doses) at City of Hope and 61 patients were treated with i.v. Bu (0.8 mg/kg x 16 doses) in a multicenter trial involving 7 sites. Bu was followed by Cy (60 mg/kg x 2 days) and a histocompatible-sibling-donor HSCT. In the i.v. Bu treatment group, 48% of the patients were classified as heavily pretreated (> or = 3 prior chemotherapy regimens, prior radiation, or prior HSCT) with 13% having had a prior HSCT and 75% having active disease at the time of transplantation. According to the same classification criteria, 33% of the patients in the oral-Bu treatment group were considered heavily pretreated, with 23% having had a prior HSCT and 80% having active disease at the time of transplantation. The incidence rates of clinically diagnosed HVOD were 5/61 (8%) and 10/30 (33%) after i.v. and oral Bu, respectively. HVOD-related mortality occurred in 2 (3.3%) of 61 i.v. and 6 (20%) of 30 oral Bu patients. The (standardized) Jones criteria for HVOD were met by 4.9% of i.v. and 20% of oral Bu patients. Univariate logistic regression analysis identified oral versus i.v. Bu (P = .001) and a diagnosis of myelodysplastic syndrome (P = .04) as statistically significant factors in the development of HVOD, with prior extensive treatment identified as marginally significant (P = .25). No other demographic parameter was found to be significant. After adjustment for prior treatment, multivariate analyses showed that the use of oral versus i.v. Bu was the strongest predictor for development of HVOD (odds ratio, 7.5; 95% confidence interval, 2.1-27.2; P = .002). This study showed that the incidence rate of HVOD is significantly lower (P = .002) and the 100-day survival rate significantly higher (P = .002) in patients treated with i.v. Bu than in patients treated with oral Bu when Bu is used as part of a BuCy2 preparative regimen for allogeneic HSCT.

Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study.

Busulfan (Bu) is commonly used as a component of conditioning regimens for hematopoietic stem cell transplantation. Precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption. An IV Bu formulation was developed to provide dose assurance and complete bioavailability. In a phase I study, the plasma bioequivalence of IV Bu was established at approximately 80% of the oral dose. We now report the findings of the first phase II study, in which 61 adults with hematologic cancers were treated with a Bu-cyclophosphamide (BuCy) regimen consisting of IV Bu (0.8 mg/kg every 6 hours x 16) followed by Cy (60 mg/kg qd x 2) and transplantation of stem cells from an HLA-matched sibling donor. The median age of study participants was 37 years; 75% of patients had active disease; 48% were heavily pretreated, and 13% had undergone a prior transplantation. Median follow-up was 2.3 years; median time to engraftment (absolute neutrophil count, >0.5 x 10(9)/L) was 13 days; 100% of patients with cytogenetic and/or molecular markers had documented chimerism; and there were no engraftment failures. Two-year overall and disease-free survival were 67% and 42%, respectively. There were no unexpected toxic reactions. Fatal veno-occlusive disease occurred in 2 patients, 1 of whom had undergone a prior transplantation. Treatment-related mortality at 100 days was 9.8% (6/61). Bu pharmacokinetics after IV drug administration demonstrated high inter- and intrapatient consistency; 86% of patients maintained an area under the curve between 800 and 1500 microMol-min. In conclusion, the IV Bu in this regimen was very well tolerated and demonstrated excellent antitumor efficacy, most likely because of dose assurance with predictable pharmacokinetics.

Biokinetics of yttrium-90--labeled huBrE-3 monoclonal antibody.

BACKGROUND: This study reports summary biokinetics for 17 patients treated with huBrE-3 antibody labeled with indium-111 ((111)In) and yttrium-90 ((90)Y) in a Phase I dose escalation trial. METHODS: Patients were infused with huBrE-3 antibody conjugated to 1-p-isothiocyanatobenzyl 3-methyl- and 1-p-isothiocyanatobenzyl 4-methyl-diethylenetriamine pentaacetic acid (MX-DTPA). The huBrE-3 was labeled with increasing amounts of (90)Y radioactivity according to the following activity regimen: 10 mCi/m(2), 20 mCi/m(2), 33 mCi/m(2), 50 mCi/m(2), and 70 mCi/m(2). In addition to the (90)Y activity, 3--5 mCi of (111)In was labeled to huBrE-3 to serve as an imaging agent. In characterizing the biokinetics of huBrE-3, serial urine and blood samples were acquired. Additionally, whole-body imaging using a scintillation camera was performed at four time points postinfusion. RESULTS: Cumulative urine data yielded a plot of total-body biologic excretion that was relatively flat. Total body regions of interest derived from nuclear medicine scintigrams decreased according to a monoexponential function with a slope slightly greater than the rate of physical decay. When physical decay was combined with the urine biologic excretion rate, the calculated rate of activity decrease was indistinguishable from the scintigraphic rate of decrease in total-body activity. CONCLUSIONS: The authors concluded from these observations that the radioactivity remains essentially inside the patient, that biologic excretion of activity from the total body is not appreciable, and that the path for biologic excretion of activity that does occur is via the urine. The half-time associated with the beta (slow) phase for extraction from the blood averages 40.5 hours. Since large amounts of radioactivity do not appear in the urine, and total-body activity is decreased approximately according to physical decay (64.1 hours), activity must pool elsewhere after leaving the blood. The logical place is the skeleton, with possible selective binding to the bone marrow. Bone marrow biopsies from 4 of 7 patients who consented to serial biopsies were supportive of this conclusion.

Prognostic model for relapse after high-dose chemotherapy with autologous stem-cell transplantation for stage IV oligometastatic breast cancer.

PURPOSE: To study prognostic factors after high-dose chemotherapy (HDC) for patients with stage IV oligometastatic breast cancer. PATIENTS AND METHODS: Sixty patients with minimal metastatic disease amenable to local therapy enrolled onto a prospective HDC trial were analyzed for potential prognostic factors. Tumor blocks were retrospectively collected from referring institutions. RESULTS: Median follow-up was 62 months (range, 4 to 120 months). Median relapse-free survival (RFS) and overall survival (OS) times were 52 and 80 months, respectively. Five-year RFS and OS rates were 52% (95% confidence interval [CI], 39% to 64%) and 62% (95% CI, 49% to 74%), respectively. HER-2 expression, number of tumor sites, primary axillary nodal ratio (number of positive nodes divided by number of sampled nodes), number of positive axillary nodes, and delivery or omission of radiotherapy to metastases correlated with RFS. HER-2 overexpression and more than one site were independent adverse risk factors for RFS. HER-2 and the axillary nodal ratio were independent predictors of OS. The following prognostic categories for RFS were established (RFS rate, median RFS): good risk, no factors (77%, 80 months); intermediate risk, one factor (41%, 28 months); and poor risk, both factors (10%, 10 months). CONCLUSION: Long-term results in patients with oligometastatic breast cancer are encouraging but need validation in prospective randomized studies. HER-2 expression, number of sites, and primary nodal ratio are independent outcome predictors. Confirmation of these observations in this selected population would imply the need for reevaluation of the current tenet that early detection of metastatic breast cancer recurrence is of no benefit.

Liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients.

Liposomal amphotercin B was compared with conventional amphotericin B for empirical antifungal therapy in febrile neutropenic patients in a randomized, double-blind, multicentre trial. Using a composite end-point, the two drugs were equivalent in overall efficacy. However, the liposomal amphotericin B treatment group had fewer proven fungal infections, fewer infusion-related side effects and less nephrotoxicity. Patient data from that study were analysed to compare the pharmacoeconomics of liposomal versus conventional amphotericin B therapy. Itemized billing data from 414 patients were collected and analysed. Hospital costs from first dose were significantly higher for all patients who received liposomal amphotericin B ($48,962 versus $43,183, P = 0.02). However, hospital costs were very sensitive to the cost of the study medication ($39,648 versus $43,048, when acquisition costs are not included, P = 0.4). Using decision analysis models and sensitivity analyses to vary the cost of study medications and risk of nephrotoxicity, the break-even points for the cost of liposomal therapy were calculated to range from $72 to $87 per 50 mg for all patients, and $83 to $112 per 50 mg in allogeneic bone marrow transplant patients. Therefore, the drug acquisition costs and the risk of nephrotoxicity are important factors in determining the cost-effectiveness of liposomal amphotericin B as empirical therapy in persistently febrile neutropenic patients. In a recent randomized double-blind study comparing liposomal amphotericin B at 3 or 5 mg/kg/day with amphotericin B lipid complex (ABLC) 5 mg/kg/day as empirical antifungal treatment in patients with febrile neutropenia, liposomal amphotericin B was associated with less toxicity than ABLC, both in terms of infusion-related reactions and nephrotoxicity. The incidence of study drug discontinuation due to toxicity was: liposomal amphotericin B 3 mg/kg/day, 14%; liposomal amphotericin B 5 mg/kg/day, 15%; and ABLC, 42% (P < 0.001).