progression-free survival

Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study.

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CLEOPATRA is a phase 3 study to compare the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive first-line metastatic breast cancer. The results of the primary analysis showed significantly longer median progression-free survival in the pertuzumab group than in the placebo group. Interim analysis of overall survival favoured the pertuzumab group but was not significant. Here, we report results for overall survival after an additional year of follow-up.

Methods

The study was a double-blind randomised trial undertaken at 204 centres in 25 countries. Patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy or biological treatment for their metastatic disease were randomly assigned to receive either pertuzumab, trastuzumab, and docetaxel (n=402) or the same regimen with a matching placebo replacing pertuzumab (n=406). Randomisation was in a 1:1 ratio, stratified by geographical region and previous treatment status. The primary endpoint was progression-free survival (assessed independently), which has been reported previously; no follow-up data were gathered for the primary endpoint. Secondary endpoints included overall survival, progression-free survival (assessed by investigator), objective response rate, and safety. Median follow-up was 30 months in both groups. Efficacy endpoints were analysed in the intention-to-treat population and safety was analysed by treatment received. The study is completed but safety and survival data continue to be followed up. This trial is registered with ClinicalTrials.gov, number NCT00567190.

Findings

In the intention-to-treat population, 267 patients died by data cutoff (May 14, 2012), 154 (38%) of 406 in the placebo group and 113 (28%) of 402 in the pertuzumab group. Median overall survival was 37·6 months (95% CI 34·3—NE [not estimable]) in the placebo group but had not been reached (95% CI 42·4—NE) in the pertuzumab group (hazard ratio 0·66, 95% CI 0·52—0·84; p=0·0008). Investigator-assessed median progression-free survival was 12·4 months (95% CI 10·4—13·5) in the placebo group and 18·7 months (16·6—21·6) in the pertuzumab group (hazard ratio 0·69, 95% CI 0·58—0·81). Serious adverse events were reported in 115 (29%) of 396 patients who received placebo, trastuzumab, and docetaxel and 148 (36%) of 408 who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhoea, pneumonia, and cellulitis. Overall, adverse events were similar to those reported at the primary analysis with respect to frequency, severity, and specificity.

Interpretation

Our analysis shows a significant improvement in overall survival with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel. Since this effect was not achieved at the expense of adverse events, this regimen represents a substantial improvement on the standard of care for this population of patients.

Source: Lancet

 

Maintenance Chemotherapy for Advanced Non–Small-Cell Lung Cancer: New Life for an Old Idea.

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Abstract

Although well established for the treatment of certain hematologic malignancies, maintenance therapy has only recently become a treatment paradigm for advanced non–small-cell lung cancer. Maintenance therapy, which is designed to prolong a clinically favorable state after completion of a predefined number of induction chemotherapy cycles, has two principal paradigms. Continuation maintenance therapy entails the ongoing administration of a component of the initial chemotherapy regimen, generally the nonplatinum cytotoxic drug or a molecular targeted agent. With switch maintenance (also known as sequential therapy), a new and potentially non–cross-resistant agent is introduced immediately on completion of first-line chemotherapy. Potential rationales for maintenance therapy include increased exposure to effective therapies, decreasing chemotherapy resistance, optimizing efficacy of chemotherapeutic agents, antiangiogenic effects, and altering antitumor immunity. To date, switch maintenance therapy strategies with pemetrexed and erlotinib have demonstrated improved overall survival, resulting in US Food and Drug Administration approval for this indication. Recently, continuation maintenance with pemetrexed was found to prolong overall survival as well. Factors predicting benefit from maintenance chemotherapy include the degree of response to first-line therapy, performance status, the likelihood of receiving further therapy at the time of progression, and tumor histology and molecular characteristics. Several aspects of maintenance therapy have raised considerable debate in the thoracic oncology community, including clinical trial end points, the prevalence of second-line chemotherapy administration, the role of treatment-free intervals, quality of life, economic considerations, and whether progression-free survival is a worthy therapeutic goal in this disease setting.

Source: JCO

 

Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.

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Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas.
METHODS: We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335.
FINDINGS: 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p<0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved >/=3 cycles; p<0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0.0001), and stomatitis (16 [6%] vs 47 [19%]; p<0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024).
INTERPRETATION: In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects.

Source: Lancet.

T-DM1 Prolongs Survival in Advanced HER2-Positive Breast Cancer.

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The drug-antibody conjugate was more effective and less toxic than lapatinib plus capecitabine in patients previously treated with trastuzumab and a taxane.

We can expect that the next breast cancer drug soon to be approved by the FDA will be trastuzumab emtansine (T-DM1), an antibody-drug conjugate combining trastuzumab with a derivative of the cytotoxic maytansine via a stable linker molecule (JW Oncol Hematol Oct 2 2012). T-DM1 is more than just another new agent. It represents vindication for those who have worked on fusion molecules for the last 2 decades. Previous efforts with such molecules were often derailed because the linker was either unstable (resulting in systemic exposure to the toxin) or cytotoxic (resulting in prohibitive adverse effects). With T-DM1, intracellular drug delivery only to human epidermal growth factor receptor 2 (HER2)–overexpressing tumor cells has been observed.

Now, investigators report the results of the EMILIA study, an industry-sponsored, phase III, randomized, open-label trial involving 991 patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane. Patients received either T-DM1 or lapatinib plus capecitabine (LC) and were stratified by world region, number of prior chemotherapy regimens for advanced disease, and presence or absence of visceral disease. Primary endpoints were progression-free survival (PFS), overall survival (OS), and safety; secondary endpoints included objective response rate, duration of response, and time to symptom progression.

Median PFS was significantly longer with T-DM1 versus LC (9.6 vs. 6.4 months; hazard ratio, 0.65; P<0.001), as was median OS (30.9 vs. 25.1 months; HR, 0.68; P<0.001). Overall response rate was also superior with T-DM1 versus LC (43.6% vs. 30.8%; P<0.001), as were results for all secondary endpoints. Rates of grade 3 or 4 adverse events were 40.8% with T-DM1 and 57.0% with LC.

Comment: The excitement surrounding the anticipated FDA approval of T-DM1 is justified given that the drug successfully targets HER2-overexpressing disease with potent antitumor activity minus the full complement of adverse effects associated with typical chemotherapy partnered with trastuzumab. Of course, the stage is set for exploring T-DM1 in combination with other anti-HER2 agents, including pertuzumab (JW Oncol Hematol Jan 24 2012). Because the toxicity of T-DM1 is quite modest, adjuvant trials are under way to compare the use of this compound with standard trastuzumab-based regimens.

Source: Journal Watch Oncology and Hematology

 

The Next Big Thing for Metastatic Breast Cancer.

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The drug-antibody conjugate trastuzumab emtansine demonstrated single-agent activity in patients with previously treated HER2-positive disease.

Even with the recent approval of pertuzumab as a component (along with trastuzumab and docetaxel) of a first-line regimen for patients with human epidermal growth factor receptor 2 (HER2)–positive, metastatic breast cancer, the anticipated approval of trastuzumab emtansine (T-DM1) is eagerly awaited by oncologists as a treatment for patients with progressive HER2-positive breast cancer following treatment with trastuzumab. Indeed, clinical experience with T-DM1 — a fusion molecule combining trastuzumab with a cytotoxic (maytansine) utilizing a stable linker (see illustration) — has shown robust clinical activity following prior anti-HER2 therapy with relatively modest toxicity (J Clin Oncol 2011 Feb; 29:398).

Now, investigators have conducted an industry-supported, single-arm, phase II clinical trial to evaluate the effectiveness of T-DM1 (3.6 mg/kg intravenously, every 3 weeks) in 110 patients with metastatic HER-2-positive breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. Patients had previously received a median of seven prior nonendocrine agents.

At median follow-up of 17.4 months, the objective response rate (the primary objective) was 34.5%, the clinical benefit rate (inclusive of stable disease) was 48.2%, and median progression-free survival (PFS) was 6.9 months. T-DM1 was well tolerated. Most adverse events were grade 1 or 2. The most common events of any grade were fatigue, nausea, and thrombocytopenia. Grade 3 or 4 thrombocytopenia occurred in 9.1% of patients, and grade 3 fatigue occurred in 4.5%.

Comment: T-DM1 was recently shown to be superior to combination capecitabine and lapatinib in metastatic breast cancer patients who were not as heavily pretreated as those in the current study (JW Oncol Hematol Jul 3 2012). T-DM1 will be rapidly embraced by clinical oncologists once it is approved, and the future development of this agent will likely move to earlier-stage breast cancer and be used in combination with other HER2-targeted agents such as pertuzumab.

Source:Journal Watch Oncology and Hematology

 

Vandetanib Improves Progression-Free Survival in Differentiated Thyroid Cancer.

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Compared with placebo, this multikinase inhibitor nearly doubled PFS in patients with locally advanced, radioiodine-refractory differentiated disease in a phase II trial.

Effective treatments have been lacking for patients with radioiodine-resistant, locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated). Over the past five years, numerous phase II studies of multitargeted kinase inhibitors such as sorafenib and vascular endothelial growth factor (VEGF) inhibitors such as axitinib have demonstrated clinical efficacy (JW Oncol Hematol Dec 2 2008). However, toxicity has been substantial with these agents, and data is limited because most of these reports are single-arm studies without a control group for comparison. More recently, vandetanib — an inhibitor of VEGF receptor, endothelial growth factor receptor, and RET proto-oncogene kinases — was shown in a phase III trial to significantly prolong progression-free survival (PFS) in patients with unresectable, locally advanced or metastatic medullary thyroid cancer (J Clin Oncol 2012 Jan 10; 30:134).

Now, investigators in Europe have conducted an industry-supported, multicenter, randomized, double-blind, placebo-controlled, phase II study to test the effectiveness and safety of vandetanib in patients with nonmedullary thyroid cancer. A total of 145 patients (age range, 23–87; performance status 2) with unresectable or metastatic undifferentiated thyroid cancer (papillary, follicular, or poorly differentiated without anaplastic features) who were deemed unsuitable for radioiodine therapy received either oral vandetanib (300 mg daily) or placebo until they experienced disease progression, death, or stable disease for 12 months.

PFS (the primary endpoint) was superior with vandetanib versus placebo (11.1 vs. 5.9 months; hazard ratio, 0.63; P=0.017). At 6 months, the disease control rate (including rates of complete response, partial response, and stable disease at 6 months) was also superior with vandetanib. However, overall survival (OS) was not improved. Of note, the PFS benefit was greater for patients with papillary thyroid cancer (16.2 months vs. 7.7 months), but when compared to other histologies, the difference was not statically significant. Grade 3 or greater toxicity was substantially higher in patients treated with vandetanib when compared to placebo. Of note, 74% of patients treated with vandetanib reported diarrhea, and 14% had QTc prolongation. Two treatment-related deaths occurred in the vandetanib group (from pneumonia and skin metastases hemorrhage) and one occurred in the placebo group (from pneumonia).

Comment: The data from this study bring up the ongoing debate regarding the use of pharmaceutical agents that demonstrate a benefit in PFS but fail to demonstrate an improvement in OS. The investigators state that phase III trials are needed to further define the clinical benefits of this agent in differentiated thyroid carcinoma. However, a cautionary note should be sounded. Given the toxicity of vandetanib, off-protocol use of this agent in differentiated thyroid carcinomas should be discouraged.

Source: Journal Watch Oncology and Hematology

 

Neuronal immunoexpression and a distinct subtype of adult primary supratentorial glioblastoma with a better prognosis.

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In this study, the authors address whether neurofilament protein (NFP) expression can be used as an independent prognostic factor in primary glioblastoma multiformes (GBMs).

Methods

Three hundred and two consecutive adult patients with newly diagnosed supratentorial primary GBMs were analyzed (January 2000–August 2008). Detailed data regarding clinical, imaging, and pathological findings, oncological treatments, and outcomes were recorded. Neurofilament protein immunoexpression served to identify NFP-positive tumor cells (normal entrapped neurons and mature ganglion-like cells excluded).

Results

Neurofilament-positive cells were identified in 177 GBMs (58.6%). Patients with NFP-positive GBMs were younger (p < 0.0001), and their GBMs presented with more temporal lobe tumor localization (p = 0.029) and more cortical involvement (p = 0.0003). Neurofilament-negative GBMs presented with more ventricular contact (p < 0.0001) and more tumor midline crossing (p = 0.03). Median overall survival and progression-free survival (PFS) were 13.0 and 7.6 months, respectively, for NFP-positive GBMs, and 7.0 and 5.1 months, respectively, for NFP-negative GBMs. Multivariate analysis revealed NFP immunoexpression, tumor midline crossing, complete resection, and radiotherapy combined with chemotherapy as independent factors associated with overall survival. Neurofilament protein–positive immunoexpression was associated with longer overall survival (hazard ratio [HR] 0.54, 95% CI 0.40–0.74; p < 0.0001) and longer PFS (HR 0.71, 95% CI 0.53–0.96; p = 0.02).

Conclusions

Neurofilament protein–positive immunoexpression represents a strong, therapeutically independent prognostic factor for primary supratentorial GBM clinical outcome among adult patients. Neurofilament protein–GBM’s unique pathological features are not only associated with distinct clinical and anatomical behavior, but are also predictive of overall patient survival and PFS. Neurofilament protein immunoexpression may help identify a distinct subgroup of primary GBMs with a favorable prognosis, which should be considered in the design of future targeted therapies.

Source: Journal Of Neurosurgery.

 

 

 

Neuronal immunoexpression and a distinct subtype of adult primary supratentorial glioblastoma with a better prognosis.

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In this study, the authors address whether neurofilament protein (NFP) expression can be used as an independent prognostic factor in primary glioblastoma multiformes (GBMs).

Methods

Three hundred and two consecutive adult patients with newly diagnosed supratentorial primary GBMs were analyzed (January 2000–August 2008). Detailed data regarding clinical, imaging, and pathological findings, oncological treatments, and outcomes were recorded. Neurofilament protein immunoexpression served to identify NFP-positive tumor cells (normal entrapped neurons and mature ganglion-like cells excluded).

Results

Neurofilament-positive cells were identified in 177 GBMs (58.6%). Patients with NFP-positive GBMs were younger (p < 0.0001), and their GBMs presented with more temporal lobe tumor localization (p = 0.029) and more cortical involvement (p = 0.0003). Neurofilament-negative GBMs presented with more ventricular contact (p < 0.0001) and more tumor midline crossing (p = 0.03). Median overall survival and progression-free survival (PFS) were 13.0 and 7.6 months, respectively, for NFP-positive GBMs, and 7.0 and 5.1 months, respectively, for NFP-negative GBMs. Multivariate analysis revealed NFP immunoexpression, tumor midline crossing, complete resection, and radiotherapy combined with chemotherapy as independent factors associated with overall survival. Neurofilament protein–positive immunoexpression was associated with longer overall survival (hazard ratio [HR] 0.54, 95% CI 0.40–0.74; p < 0.0001) and longer PFS (HR 0.71, 95% CI 0.53–0.96; p = 0.02).

Conclusions

Neurofilament protein–positive immunoexpression represents a strong, therapeutically independent prognostic factor for primary supratentorial GBM clinical outcome among adult patients. Neurofilament protein–GBM’s unique pathological features are not only associated with distinct clinical and anatomical behavior, but are also predictive of overall patient survival and PFS. Neurofilament protein immunoexpression may help identify a distinct subgroup of primary GBMs with a favorable prognosis, which should be considered in the design of future targeted therapies.

Source: Journal Of Neurosurgery.

 

 

Radioimmunotherapy Consolidation for Mantle Cell Lymphoma.

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A high response rate was achieved with limited cycles of R-CHOP followed by a single dose of 90Yibritumomab tiuxetan.

High overall and complete response rates can be achieved with six to eight cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with mantle cell lymphoma (MCL), but median response duration is only 18 to 24 months.

Given the high activity of radioimmunotherapy (RIT) in patients with relapsed MCL (J Clin Oncol 2009; 27:5213), investigators conducted a multicenter phase II trial to test the efficacy and safety of four cycles of R-CHOP plus yttrium-90 (90Y)–ibritumomab tiuxetan RIT consolidation in patients with previously untreated MCL.

Of 56 treatment-naive adults (median age, 60; 73% men; 91% with stage III–IV disease; 48% with extranodal involvement), 52 received four cycles of R-CHOP followed by a single dose of standard 90Y-RIT. The overall response rate was 82%, and response improved to complete or partial remission in 22 patients after 90Y-RIT. At a median follow-up of 72 months, the median time to treatment failure was 34.2 months; median overall survival (OS) had not been reached. The estimated 5-year OS rate trended higher for patients aged 65 versus those >65 (79% vs. 62%; P=0.08). Toxicities were as expected with R-CHOP and were primarily transient neutropenia and thrombocytopenia for 90Y-RIT.

Comment: Given the typically short duration of progression-free survival after immunochemotherapy in MCL patients, postinduction strategies are under study to improve outcomes. In younger patients, high-dose chemotherapy and autologous stem-cell transplantation are often utilized, whereas older or infirm patients might benefit from maintenance rituximab (JW Oncol Hematol Aug 21 2012). The present study confirms 90Y-RIT as an active agent that increases response rate and duration following abbreviated induction cycles, although without an established survival benefit as yet. Confirmatory studies will be important, as will optimizing patient selection for 90Y-RIT versus alternative postinduction regimens.

Source: Journal Watch Oncology and Hematology

Neuronal immunoexpression and a distinct subtype of adult primary supratentorial glioblastoma with a better prognosis.

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In this study, the authors address whether neurofilament protein (NFP) expression can be used as an independent prognostic factor in primary glioblastoma multiformes (GBMs).

Methods

Three hundred and two consecutive adult patients with newly diagnosed supratentorial primary GBMs were analyzed (January 2000–August 2008). Detailed data regarding clinical, imaging, and pathological findings, oncological treatments, and outcomes were recorded. Neurofilament protein immunoexpression served to identify NFP-positive tumor cells (normal entrapped neurons and mature ganglion-like cells excluded).

Results

Neurofilament-positive cells were identified in 177 GBMs (58.6%). Patients with NFP-positive GBMs were younger (p < 0.0001), and their GBMs presented with more temporal lobe tumor localization (p = 0.029) and more cortical involvement (p = 0.0003). Neurofilament-negative GBMs presented with more ventricular contact (p < 0.0001) and more tumor midline crossing (p = 0.03). Median overall survival and progression-free survival (PFS) were 13.0 and 7.6 months, respectively, for NFP-positive GBMs, and 7.0 and 5.1 months, respectively, for NFP-negative GBMs. Multivariate analysis revealed NFP immunoexpression, tumor midline crossing, complete resection, and radiotherapy combined with chemotherapy as independent factors associated with overall survival. Neurofilament protein–positive immunoexpression was associated with longer overall survival (hazard ratio [HR] 0.54, 95% CI 0.40–0.74; p < 0.0001) and longer PFS (HR 0.71, 95% CI 0.53–0.96; p = 0.02).

Conclusions

Neurofilament protein–positive immunoexpression represents a strong, therapeutically independent prognostic factor for primary supratentorial GBM clinical outcome among adult patients. Neurofilament protein–GBM’s unique pathological features are not only associated with distinct clinical and anatomical behavior, but are also predictive of overall patient survival and PFS. Neurofilament protein immunoexpression may help identify a distinct subgroup of primary GBMs with a favorable prognosis, which should be considered in the design of future targeted therapie.

Source: Journal of neurosurgery.