ABSTRACT
BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).
Subject(s)
Carcinoma, Ovarian Epithelial , Maytansine , Ovarian Neoplasms , Female , Humans , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/genetics , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Immunoconjugates/therapeutic use , Maytansine/administration & dosage , Maytansine/adverse effects , Maytansine/analogs & derivatives , Maytansine/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Folate Receptor 1/antagonists & inhibitors , Folate Receptor 1/genetics , Drug Resistance, Neoplasm/genetics , Platinum Compounds/pharmacologyABSTRACT
AIMS: Mirvetuximab soravtansine is a first-in-class antibody-drug conjugate recently approved for the treatment of folate receptor-α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic model to describe the concentration-time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S-methyl-DM4). METHODS: Mirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum-resistant ovarian cancer in 3 clinical studies, and the plasma drug concentrations were analysed using a nonlinear mixed-effects modelling approach. Stepwise covariate modelling was performed to identify covariates. RESULTS: We developed a semi-mechanistic population pharmacokinetic model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumour cells. The clearance and volume of the central compartment were 0.0153 L/h and 2.63 L for mirvetuximab soravtansine, 8.83 L/h and 3.67 L for DM4, and 2.04 L/h and 6.3 L for S-methyl-DM4, respectively. Body weight, serum albumin and age were identified as statistically significant covariates. Exposures in patients with renal or hepatic impairment and who used concomitant cytochrome P450 (CYP) 3A4 inhibitors were estimated. CONCLUSION: There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. Dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.
Subject(s)
Antibodies, Monoclonal, Humanized , Immunoconjugates , Maytansine , Ovarian Neoplasms , Humans , Female , Drug Resistance, Neoplasm , Ovarian Neoplasms/drug therapy , Immunoconjugates/adverse effects , Folic Acid/pharmacology , Folic Acid/therapeutic use , Maytansine/analogs & derivativesABSTRACT
The concept of exploiting the specific binding properties of monoclonal antibodies as a mechanism for selective delivery of cytotoxic agents to tumor cells is an attractive solution to the challenge of increasing the therapeutic index of cell-killing agents for treating cancer. All three parts of an antibody-drug conjugate (ADC)-the antibody, the cytotoxic payload, and the linker chemistry that joins them together-as well as the biologic properties of the cell-surface target antigen are important in designing an effective anticancer agent. The approval of brentuximab vedotin in 2011 for treating relapsed Hodgkin's lymphoma and systemic anaplastic large cell lymphoma, and the approval of ado-trastuzumab emtansine in 2013 for treating HER2-positive metastatic breast cancer, have sparked vigorous research in the field, with >65 ADCs currently in clinical evaluation. This review highlights the ADCs that are approved for marketing, in pivotal clinical trials, or in at least phase II clinical development for treating both hematologic malignancies and solid tumors.
Subject(s)
Immunoconjugates/therapeutic use , Neoplasms/drug therapy , Ado-Trastuzumab Emtansine , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/secondary , Brentuximab Vedotin , Drug Development , Hodgkin Disease/drug therapy , Humans , Lymphoma, Large-Cell, Anaplastic/drug therapy , Maytansine/analogs & derivatives , Maytansine/therapeutic use , Trastuzumab/therapeutic useABSTRACT
PURPOSE: To characterize folate receptor alpha (FRα) expression in archival and fresh biopsy tumor samples from relapsed ovarian cancer patients. METHODS: Patients with ovarian tumors amenable to biopsy were eligible to enroll. Eligibility included a minimum requirement of FRα positivity in archival tumor samples (≥25% of cells with ≥2+ staining intensity). Patients received mirvetuximab soravtansine at 6mg/kg once every 3weeks. Core needle biopsies were collected before and after treatment and FRα levels assessed by immunohistochemistry. Descriptive statistics were used to summarize the association between receptor expression and response. RESULTS: Twenty-seven heavily pre-treated patients were enrolled. Six individuals (22%) did not have evaluable pre-treatment biopsies due to insufficient tumor cells. The concordance of FRα expression in archival and biopsy tissues was 71%, and no major shifts in receptor expression were seen in matched pre- and post-treatment biopsy samples. Adverse events were generally mild (≤grade 2) with keratopathy (48%), fatigue (44%), diarrhea, and blurred vision (each 37%) being the most common treatment-related toxicities. The confirmed objective response rate (ORR) was 22%, including two complete responses and four partial responses. Superior efficacy measures were observed in the subset of patients with the highest FRα levels (ORR, 31%; progression-free survival, 5.4months). CONCLUSION: Concordance of FRα expression in biopsy versus archival tumor samples suggests that archival tissue can reliably identify patients with receptor-positive tumors and is appropriate for patient selection in mirvetuximab soravtansine clinical trials. Regardless of the tissue source analyzed, higher FRα expression was associated with greater antitumor activity.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Folate Receptor 1/biosynthesis , Immunoconjugates/administration & dosage , Maytansine/analogs & derivatives , Neoplasms, Glandular and Epithelial/drug therapy , Neoplasms, Glandular and Epithelial/immunology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/immunology , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Carcinoma, Ovarian Epithelial , Female , Folate Receptor 1/immunology , Humans , Immunoconjugates/adverse effects , Maytansine/administration & dosage , Maytansine/adverse effects , Middle Aged , Molecular Targeted TherapyABSTRACT
The central role played by the class I(A) phosphatidylinositol-3-kinase (PI3K) signaling node in human cancer is highlighted in the multiple mechanisms by which these signals become dysregulated. Many studies suggest that constitutive PI3K activation in human cancer contributes to drug resistance, including targeted agents and standard cytotoxic therapy. The combination of activation mechanisms and the multiple downstream cascades that emanate from the PI3K node contributes to the difficulty in measuring PI3K activation as a biomarker. Although many agents suppress the pathway in models, the challenge remains to translate this biology into a patient selection strategy (i.e., identify patients with "PI3K activated" tumors) and subsequently link this biomarker definition to drug responses in patients. The various genetic and epigenetic lesions resulting in pathway activation necessitate combined approaches using genetic, genomic, and protein biomarkers to accurately characterize "PI3K activated" tumors. Such a combined approach to pathway status can be assessed using a statistical stratification of patients in a randomized trial into "pathway on" and "pathway off" subsets to compare the treatment effect in each arm. Instead of considering individual biomarkers for their predictive ability, this strategy proposes the use of a collection of biomarkers to identify a specific "pathway on" patient population predicted to have clinical benefit from a pathway inhibitor. Here, we review the current understanding of the mechanisms of PI3K activation in breast cancer and discuss a pathway-based approach using PI3K as a predictive biomarker in clinical development, which is currently in use in a global phase 3 setting.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/enzymology , Molecular Targeted Therapy , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction , Animals , Antineoplastic Agents/therapeutic use , Breast Neoplasms/diagnosis , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Enzyme Activation , Female , Humans , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphoinositide-3 Kinase Inhibitors , Prognosis , Protein Kinase Inhibitors/therapeutic use , Signal Transduction/drug effectsABSTRACT
An oral formulation of temsirolimus (Torisel), an inhibitor of the mammalian target of rapamycin, was evaluated on an intermittent schedule (once daily for 5 days every 2 weeks) in patients with advanced cancer. The maximum tolerated dose was determined to be 75 mg after dose-limiting toxicities of grade 3 elevated aminotransferases (1 patient) and grade 3 rash (1 patient) occurred with a 100-mg dose. The most common temsirolimus-related adverse events were mucositis, rash/maculopapular rash, and asthenia. Six of 12 patients who received the 75-mg dose required dose reductions due to temsirolimus-related adverse events. Two patients who received 75-mg temsirolimus and did not have dose reductions had minor tumor responses. Relative exposure from contributions of both temsirolimus and sirolimus, the principal metabolite, was 17.9% of the 75-mg dose. Thus, oral temsirolimus, 75 mg administered once daily for 5 days every 2 weeks, was further evaluated in patients with metastatic breast cancer.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Sirolimus/analogs & derivatives , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/pharmacokinetics , TOR Serine-Threonine Kinases , Treatment OutcomeABSTRACT
Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to assess the influence of tumor histology on outcome of patients treated with temsirolimus (Torisel) or interferon-alpha (IFN). Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN (3 million units [MU] subcutaneously three times weekly, escalating to 18 MU) or temsirolimus (25 mg intravenously weekly). Results Approximately 80% of patients had clear cell and 20% of patients had other histologies, the majority of which were papillary. Patients with clear cell and other RCC histologies, treated with temsirolimus, demonstrated comparable median overall and progression-free survival. In contrast, patients with other RCC histologies, treated with IFN, demonstrated shorter median overall and progression-free survival than patients with clear cell RCC. Hazard ratios for death for treatment with temsirolimus versus IFN were less than 1 for patients regardless of tumor histology. For patients treated with temsirolimus, 59% with clear cell and 68% with other RCC histologies experienced tumor reductions. For patients treated with IFN, 35% with clear cell and 14% with other RCC histologies had tumor reductions. However, temsirolimus did not appear to improve the objective response rate compared to IFN. Temsirolimus resulted in a superior clinical benefit rate compared with IFN, regardless of tumor histology. Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can, therefore, be used for the treatment of all types of RCC.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Interferon-alpha/therapeutic use , Kidney Neoplasms/drug therapy , Sirolimus/analogs & derivatives , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Female , Humans , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Male , Middle Aged , Sirolimus/therapeutic use , Treatment OutcomeABSTRACT
PURPOSE: STA-4783 is a new compound that markedly enhances the therapeutic index of paclitaxel against human tumor xenograft models. A phase I clinical trial was undertaken to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of STA-4783 in combination with paclitaxel. EXPERIMENTAL DESIGN: Adults with refractory solid tumors concurrently received STA-4783 and paclitaxel as a 3-h i.v. infusion at starting doses of 44 and 135 mg/m(2), respectively. After increasing paclitaxel to 175 mg/m(2), the STA-4783 dose was escalated as permitted by dose-limiting toxicity during the first 21-day cycle. RESULTS: Thirty-five patients were treated with eight dose levels of STA-4783/paclitaxel. In patients receiving 175 mg/m(2) paclitaxel, the incidence of severe toxicity increased with escalation of the STA-4783 dose above 263 mg/m(2), and 438 mg/m(2) was the maximum tolerated dose. All toxicities were typical of paclitaxel, with neutropenia, mucositis, and myalgia/arthralgia being dose limiting. Partial responses were achieved in one patient with Kaposi's sarcoma and another with ovarian cancer that progressed during prior treatment with paclitaxel. STA-4783 exhibited linear pharmacokinetics characterized by rapid elimination from plasma (biological half-life, 1.06 +/- 0.24 h) and a low steady-state apparent volume of distribution (25.1 +/- 8.1 L/m(2)). The total body clearance of paclitaxel decreased significantly with escalation of the STA-4783 dose. CONCLUSIONS: The STA-4783/paclitaxel combination was well tolerated with a toxicity profile similar to single-agent paclitaxel. Enhanced systemic exposure to paclitaxel resulting from a dose-dependent interaction with STA-4783 was associated with increased toxicity. Objective responses in two heavily pretreated patients, both with taxane exposure, have encouraged further clinical evaluation of this regimen.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Synergism , Hydrazines/administration & dosage , Neoplasms/drug therapy , Paclitaxel/administration & dosage , Adult , Aged , Dose-Response Relationship, Drug , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Models, Chemical , Time Factors , Treatment OutcomeABSTRACT
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in adult women. The most easily identifiable riskfactor is a strong family history of either ovarian or breast cancer; that may indicate the presence of an inherited germ-line mutation in either BRCA-1 or BRCA-2. Common symptoms, such as abdominal bloating and early satiety, indicate more advanced disease, involving the upper abdomen and present in approximately 70% of patients at the time of diagnosis. Physical examination often reveals the presence of a pelvic mass, which is best evaluated by transvaginal ultrasound (TVU) for confirmation. Exploratory laparotomy is required for histologic confirmation, staging and tumor debulking and should be performed by a surgeon trained in these aspects of ovarian cancer management. Patients with early-stage disease, limited to the ovary or pelvis (stages I and II, respectively), have survival in the 80-95% range, whereas the survival of patients with disease involving the upper abdomen or beyond (stages III and IV, respectively) is 10-30%. Because of the propensity of EOC to spread beyond the confines of the ovary, the majority of patients will require postoperative chemotherapy in an attempt to eradicate residual disease. For selected patients with early-stage disease, confined to the ovary, such as those with well-differentiated, completely encapsulated tumors (e.g., stage IA, grade 1), no further treatment is necessary in view of excellent survival after surgery alone. For patients with higher-risk early-stage disease (e.g., those with pelvic extension, capsular rupture or involvement, positive washings, ascites or high-grade lesions) and for patients with advanced-stage disease (stages III and IV), postoperative combination chemotherapy with a taxane and platinum combination is the standard of care. Such treatment is capable of inducing responses in > 70% of patients with residual EOC and is also capable of prolonging both disease-free and overall survival. Unfortunately, despite an initial response to chemotherapy in the majority of patients, relapse is afrequent problem and is often detected by a rise in the serum tumor marker CA-125 in the absence of symptoms or signs of disease by physical examination or radiographic studies. In such cases, a hormonal maneuver is oftentimes considered in order to avoid the toxic effects of chemotherapy when the patient is asymptomatic and the goal of treatment is largely palliation, although eventually the development of clinical progression mandates the institution of second-line chemotherapy. If the treatment-free interval is > 6 months from the completion of first-line treatment, rechallenge with platinum-based chemotherapy is a reasonable first step. For those patients who develop resistance to second-line platinum or who have difficulty tolerating this agent, multiple other options are available for relapse management, including liposomal doxorubicin, topotecan, gemcitabine and etoposide per os. Eventually the disease becomes resistant to multiple chemotherapy agents, and reorienting management toward supportive care and pain control is necessary. Ongoing efforts to identify more effective multiagent first-line regimens, to develop more effective strategies for early detection and to incorporate agents with novel mechanisms of action, such as antiangiogenesis compounds, hold promise.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms, Glandular and Epithelial/therapy , Ovarian Neoplasms/therapy , Combined Modality Therapy , Disease-Free Survival , Female , Genetic Predisposition to Disease , Humans , Neoplasm Staging , Neoplasms, Glandular and Epithelial/genetics , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Risk Factors , Treatment OutcomeABSTRACT
PURPOSE: Human epidermal growth factor (HER) -mediated signaling is critical in many cancers, including subsets of breast and lung cancer. HER family members signal via the phosphatidylinositide 3-kinase (PI3K) -AKT/protein kinase B-mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion. On the basis of preclinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer models, we conducted a phase I combination study of neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, and temsirolimus, an mTOR inhibitor, in patients with advanced solid tumors. PATIENTS AND METHODS: This study enrolled patients to dosing combinations of neratinib and temsirolimus. The primary objective was to estimate the toxicity contour of the combination and establish recommended phase II doses. RESULTS: Sixty patients were treated on 12 of 16 possible dosing combinations. Diarrhea was the most common drug-related (93%) and dose-limiting toxicity (DLT), constituting four of 10 DLTs. Dose-limiting grade 3 metabolic abnormalities were also observed. Other frequent drug-related toxicities included nausea, stomatitis (both 53%), and anemia (48%). Two maximum-tolerated dose combinations were identified: 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 mg of temsirolimus. Responses were noted in patients with HER2-amplified breast cancer resistant to trastuzumab, HER2-mutant non-small-cell lung cancer, and tumor types without identified mutations in the HER-PI3K-mTOR pathway. CONCLUSION: The combination of neratinib and temsirolimus was tolerable and demonstrated antitumor activity in multiple tumor types, warranting further evaluation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Receptor, ErbB-2/genetics , Aged , Anemia/chemically induced , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Area Under Curve , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Female , Gene Amplification , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Male , Middle Aged , Mutation , Nausea/chemically induced , Neoplasms/genetics , Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Quinolines/administration & dosage , Quinolines/adverse effects , Quinolines/pharmacokinetics , Receptor, ErbB-2/metabolism , Signal Transduction/drug effects , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/analogs & derivatives , Sirolimus/pharmacokinetics , Stomatitis/chemically induced , TOR Serine-Threonine Kinases/metabolism , Treatment OutcomeABSTRACT
PURPOSE: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial targeted therapy in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review. RESULTS: A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio [HR], 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%). CONCLUSION: Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Neoadjuvant Therapy/methods , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Quinolines/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/surgery , Disease-Free Survival , Female , Health Status , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Male , Middle Aged , Molecular Targeted Therapy , Neoplasm Staging , Nephrectomy , Niacinamide/therapeutic use , Odds Ratio , Quality of Life , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sorafenib , Treatment OutcomeABSTRACT
PURPOSE: Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients. PATIENTS AND METHODS: This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor-positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events). RESULTS: Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003). CONCLUSION: Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Disease-Free Survival , Double-Blind Method , Female , Humans , Letrozole , Middle Aged , Neoplasm Metastasis , Nitriles/administration & dosage , Nitriles/adverse effects , Placebos , Postmenopause , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/analogs & derivatives , Treatment Outcome , Triazoles/administration & dosage , Triazoles/adverse effectsABSTRACT
PURPOSE: A phase II study of temsirolimus was conducted in children and adolescents with high-grade glioma, neuroblastoma or rhabdomyosarcoma. PATIENTS AND METHODS: Temsirolimus 75 mg/m(2) was administered once weekly until disease progression or intolerance. Using the Simon 2-stage design, further enrolment in each disease cohort required ≥ 2 objective responses within the first 12 weeks for the first 12 evaluable patients (those who received ≥ 3 temsirolimus doses). RESULTS: Fifty-two heavily pretreated patients with relapsed (12%) or refractory (88%) disease, median age 8 years (range 1-21 years), were enroled and treated. One patient with neuroblastoma achieved confirmed partial response within the first 12 weeks; thus, none of the 3 cohorts met the criterion for continued enrolment. Disease stabilisation at week 12 was observed in 7 of 17 patients (41%) with high-grade glioma (5 diffuse pontine gliomas, 1 glioblastoma multiforme and 1 anaplastic astrocytoma), 6 of 19 (32%) with neuroblastoma and 1 of 16 (6%) with rhabdomyosarcoma (partial response confirmed at week 18). In the three cohorts, median duration of stable disease or better was 128, 663 and 75 d, respectively. The most common treatment-related adverse events were thrombocytopaenia, hyperlipidaemia and aesthenia. Pharmacokinetic findings were similar to those observed in adults. CONCLUSIONS: Temsirolimus administered weekly at the dose of 75 mg/m(2) did not meet the primary objective efficacy threshold in children with high-grade glioma, neuroblastoma or rhabdomyosarcoma; however, meaningful prolonged stable disease merits further evaluation in combination therapy.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Glioma/drug therapy , Neuroblastoma/drug therapy , Rhabdomyosarcoma/drug therapy , Sirolimus/analogs & derivatives , Adolescent , Adult , Antineoplastic Agents/pharmacokinetics , Child , Child, Preschool , Cohort Studies , Disease Progression , Female , Humans , Infusions, Intravenous , Male , Sirolimus/pharmacokinetics , Sirolimus/therapeutic useABSTRACT
PURPOSE: Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize temsirolimus-related pneumonitis. PATIENTS AND METHODS: Patients were treated with intravenous temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method. RESULTS: Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the temsirolimus arm than on the interferon arm (log-rank P < .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed temsirolimus-related pneumonitis in 16 (31%) of 52 patients. CONCLUSION: Patients with ARCC receiving temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.
Subject(s)
Antineoplastic Agents/adverse effects , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Pneumonia/epidemiology , Sirolimus/analogs & derivatives , Carcinoma, Renal Cell/complications , Carcinoma, Renal Cell/mortality , Humans , Incidence , Interferon-alpha/therapeutic use , Kidney Neoplasms/complications , Kidney Neoplasms/mortality , Pneumonia/diagnostic imaging , Randomized Controlled Trials as Topic , Sirolimus/adverse effects , TOR Serine-Threonine Kinases/antagonists & inhibitors , Tomography, X-Ray ComputedABSTRACT
PURPOSE: To determine dose-limiting toxicities, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of weekly intravenous temsirolimus, a mammalian target of rapamycin (mTOR) signaling pathway inhibitor, in pediatric patients with recurrent or refractory solid tumors. PATIENTS AND METHODS: Cohorts of three to six patients 1 to 21 years of age with recurrent or refractory solid tumors were treated with a 1-hour intravenous infusion of temsirolimus weekly for 3 weeks per course at one of four dose levels: 10, 25, 75, or 150 mg/m(2). During the first two courses, pharmacokinetic and pharmacodynamic evaluations (phosphorylation of S6, AKT, and 4EBP1 in peripheral-blood mononuclear cells) were performed. RESULTS: Dose-limiting toxicity (grade 3 anorexia) occurred in one of 18 evaluable patients at the 150 mg/m(2) level, which was determined to be tolerable, and an MTD was not identified. In 13 patients evaluable for response after two courses of therapy, one had complete response (CR; neuroblastoma) and five had stable disease (SD). Four patients (three SDs + one CR) remained on treatment for more than 4 months. The sum of temsirolimus and sirolimus areas under the concentration-time curve was comparable to values in adults. AKT and 4EBP1 phosphorylation were inhibited at all dose levels, particularly after two courses. CONCLUSION: Weekly intravenous temsirolimus is well tolerated in children with recurrent solid tumors, demonstrates antitumor activity, has pharmacokinetics similar to those in adults, and inhibits the mTOR signaling pathway in peripheral-blood mononuclear cells. Further studies are needed to define the optimal dose for use in combination with other antineoplastic agents in pediatric patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Sirolimus/analogs & derivatives , Adaptor Proteins, Signal Transducing/metabolism , Adolescent , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Cell Cycle Proteins , Child , Child, Preschool , Drug Administration Schedule , Female , Humans , Infant , Infusions, Intravenous , Male , Maximum Tolerated Dose , Neoplasms/enzymology , Neoplasms/pathology , Phosphoproteins/metabolism , Phosphorylation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins c-akt/metabolism , Ribosomal Protein S6/metabolism , Signal Transduction/drug effects , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/pharmacokinetics , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Treatment Outcome , United States , Young AdultABSTRACT
BACKGROUND AND OBJECTIVES: For patients with advanced cancers, it is important that treatment improves the quality as well as the quantity of survival. This quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) analysis provides a combined measure of both the overall survival interval and the quality of survival for patients with advanced renal cell carcinoma (RCC) receiving temsirolimus, interferon (IFN)-alpha or the combination of these agents, using data from a phase III clinical trial. METHODS: Overall survival was partitioned into three distinct health states: time with serious toxicity (TOX), time after progression (REL) and time without symptoms of progression or toxicity (TWiST). Health states were quality weighted by patient-reported EQ-5D measures collected while receiving treatment. RESULTS: All 626 patients from the trial were included in computation of health-state durations. EQ-5D questionnaires were obtained from 260 patients upon progression and from 230 after a grade 3 or 4 adverse event, and from 278 patients in the TWiST state. Patients receiving temsirolimus had 38% longer TWiST than those receiving IFNalpha (6.5 vs 4.7 months, respectively; p = 0.0005). Patients receiving temsirolimus had 25% longer quality-adjusted survival in terms of Q-TWiST than those receiving IFNalpha (7.0 vs 5.6 months, respectively; p = 0.0015). Differences between the combination (temsirolimus + IFNalpha) and IFNalpha groups were not statistically significant. Threshold utility analysis indicated that temsirolimus was the preferred alternative for all possible utility weights for REL and TOX health states. CONCLUSION: Temsirolimus resulted in significantly longer Q-TWiST (quality-adjusted survival) in patients with advanced RCC than IFNalpha therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Renal Cell/mortality , Disease-Free Survival , Female , Humans , Interferon Type I/administration & dosage , Interferon Type I/adverse effects , Interferon Type I/therapeutic use , Kidney Neoplasms/mortality , Male , Middle Aged , Quality-Adjusted Life Years , Recombinant Proteins , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/analogs & derivatives , Sirolimus/therapeutic use , Surveys and Questionnaires , Young AdultABSTRACT
Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), has anti-tumor activity in patients with relapsed or refractory mantle cell lymphoma (MCL) and other mature lymphoid neoplasms. mTOR is an intracellular kinase that controls the mRNA translation of many proteins (eg, cyclin D1) that can act as oncogenes and contribute to lymphomagenesis. Characterized by overexpression of cyclin D1, MCL was identified as a disease that might be susceptible to mTOR inhibition. When single-agent temsirolimus was explored in two phase II studies for treatment of patients with relapsed or refractory MCL, it demonstrated anti-tumor activity, with overall response rates of 38% and 41%. Subsequently, a three-arm, randomized phase III trial was conducted to compare two dosing regimens of temsirolimus with investigator's choice of therapy for heavily pretreated patients with relapsed or refractory MCL (N = 162; randomized 1:1:1). Once-weekly intravenous temsirolimus 175 mg for 3 weeks followed by 75 mg once weekly (175/75) significantly improved progression-free survival (hazard ratio = 0.44; P = .0009) versus investigator's choice therapy. Median progression-free survival durations were 4.8 and 1.9 months, respectively. The objective response rates were 22% in the 175/75 group and 2% in the investigator's choice group (P = .0019). For patients receiving temsirolimus, the most frequent grade 3 or 4 adverse events were thrombocytopenia, anemia, neutropenia, and asthenia. The results of this trial established a recommended clinical dose for temsirolimus monotherapy in patients with relapsed or refractory MCL and validated the importance of mTOR in the pathogenesis of advanced MCL. Objective responses also have been reported for other mature B-cell neoplasms (eg, diffuse large B-cell lymphoma or follicular lymphoma) in the phase II setting. Temsirolimus as monotherapy or in combination with other active agents warrants further investigation for treatment of MCL and other non-Hodgkin lymphomas.
Subject(s)
Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Sirolimus/analogs & derivatives , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic/methods , Humans , Lymphoma, Non-Hodgkin/classification , Models, Biological , Protein Kinases/metabolism , Protein Kinases/physiology , Sirolimus/administration & dosage , Sirolimus/therapeutic use , TOR Serine-Threonine KinasesABSTRACT
Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a therapeutic target in patients with advanced renal cell carcinoma (RCC). The TORC1 complex controls translation of key proteins involved in cell proliferation and regulates the expression and stability of hypoxia-inducible factor (HIF)-1alpha. Temsirolimus, the first mTOR inhibitor approved for treatment of advanced RCC, has demonstrated significantly longer overall survival (hazard ratio for death, 0.73; 95% confidence interval, 0.58-0.92, P = .008) and progression-free survival (P <.001) compared with interferon alfa (IFN) for patients with poor prognostic features. Median progression-free survival durations were 3.8 and 1.9 months, respectively, for patients treated with temsirolimus or IFN, and median overall survivals were 10.9 and 7.3 months, respectively. Exploratory analyses indicate that temsirolimus benefits those patients with metastatic RCC and multiple adverse prognostic factors regardless of tumor histology or nephrectomy status. Most adverse events that occur in patients receiving temsirolimus can be managed medically (eg, hyperglycemia, hyperlipidemia) or addressed by supportive measures (eg, stomatitis, rash). Although development of symptomatic pneumonitis is rare, monitoring is recommended. Temsirolimus is now considered an important first-line treatment option for patients with advanced RCC and multiple factors predictive of short survival. Current trials are investigating the use of temsirolimus in sequence or in combination with other targeted agents to further improve outcomes.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Clinical Trials as Topic/methods , Kidney Neoplasms/drug therapy , Sirolimus/analogs & derivatives , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic/trends , Disease Progression , Humans , Models, Biological , Protein Kinases/metabolism , Protein Kinases/physiology , Signal Transduction/drug effects , Signal Transduction/physiology , Sirolimus/adverse effects , Sirolimus/therapeutic use , TOR Serine-Threonine KinasesABSTRACT
BACKGROUND: Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 alpha correlated with efficacy in patients treated with temsirolimus (Torisel) versus interferon-alpha (IFN). METHODS: Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 alpha baseline levels were measured in archived tumor specimens by immunohistochemistry. RESULTS: There was no correlation between baseline PTEN and HIF1 alpha levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors. CONCLUSIONS: The baseline status of the molecular markers PTEN and HIF1 alpha did not correlate with efficacy in renal cell carcinoma patients treated with temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with temsirolimus regardless of PTEN and HIF1 alpha status. Thus, baseline PTEN and HIF-1 levels may not predict response to temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to temsirolimus in patients with advanced renal cell carcinoma.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Interferon-alpha/therapeutic use , Kidney Neoplasms/drug therapy , PTEN Phosphohydrolase/metabolism , Sirolimus/analogs & derivatives , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/mortality , Female , Humans , Interferon-alpha/administration & dosage , Kidney Neoplasms/metabolism , Kidney Neoplasms/mortality , Male , Middle Aged , Signal Transduction , Sirolimus/administration & dosage , Sirolimus/therapeutic useABSTRACT
PURPOSE: Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease. PATIENTS AND METHODS: In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment. RESULTS: Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia. CONCLUSION: Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.