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The Lancet. Oncology Oct 2017Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet... (Comparative Study)
Comparative Study
BACKGROUND
Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.
METHODS
In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479.
FINDINGS
Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5-22·1) in the rindopepimut group versus 20·0 months (18·1-21·9) in the control group (HR 1·01, 95% CI 0·79-1·30; p=0·93). The most common grade 3-4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one-a pulmonary embolism in a 64-year-old male patient after 11 months of treatment-was assessed as potentially related to rindopepimut.
INTERPRETATION
Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma.
FUNDING
Celldex Therapeutics, Inc.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cancer Vaccines; Dacarbazine; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; ErbB Receptors; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Internationality; Kaplan-Meier Estimate; Male; Middle Aged; Patient Selection; Proportional Hazards Models; Survival Analysis; Temozolomide; Time Factors; Treatment Outcome; Vaccines, Subunit; Young Adult
PubMed: 28844499
DOI: 10.1016/S1470-2045(17)30517-X -
The Lancet. Oncology May 2020We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1...
BACKGROUND
We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort.
METHODS
This was an open-label, phase 2 study of patients from the Yale Cancer Center (CT, USA). Eligible patients were at least 18 years of age with stage IV NSCLC with at least one brain metastasis 5-20 mm in size, not previously treated or progressing after previous radiotherapy, no neurological symptoms or corticosteroid requirement, and Eastern Cooperative Oncology Group performance status less than two. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease; systemic disease was not required for participation. Patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks. Patients were in two cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was patients with PD-L1 less than 1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response (partial response or complete response, according to mRECIST). All treated patients were analysed for response and safety endpoints. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT02085070.
FINDINGS
Between March 31, 2014, and May 21, 2018, 42 patients were treated. Median follow-up was 8·3 months (IQR 4·5-26·2). 11 (29·7% [95% CI 15·9-47·0]) of 37 patients in cohort 1 had a brain metastasis response. There were no responses in cohort 2. Grade 3-4 adverse events related to treatment included two patients with pneumonitis, and one each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycaemia, and hypokalaemia. Treatment-related serious adverse events occurred in six (14%) of 42 patients and were pneumonitis (n=2), acute kidney injury, colitis, hypokalaemia, and adrenal insufficiency (n=1 each). There were no treatment-related deaths.
INTERPRETATION
Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression at least 1% and is safe in selected patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted.
FUNDING
Merck and the Yale Cancer Center.
Topics: Aged; Antibodies, Monoclonal, Humanized; B7-H1 Antigen; Biomarkers, Tumor; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Neoplasm Metastasis
PubMed: 32251621
DOI: 10.1016/S1470-2045(20)30111-X -
Journal of Clinical Oncology : Official... Nov 2021I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium.
PURPOSE
I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate.
PATIENTS AND METHODS
Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected.
RESULTS
One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%.
CONCLUSION
Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.
Topics: 3-Iodobenzylguanidine; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Infant; Irinotecan; Male; Neoplasm Recurrence, Local; Neuroblastoma; Prognosis; Prospective Studies; Salvage Therapy; Survival Rate; Vincristine; Vorinostat; Young Adult
PubMed: 34270348
DOI: 10.1200/JCO.21.00703 -
Clinical Cancer Research : An Official... Sep 2021PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges.
A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non-Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1.
PURPOSE
PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges.
PATIENTS AND METHODS
We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with or without nivolumab using a 3+3 dose-escalation design (NCT03502330). Patients were enrolled from June 2018 to April 2019. Eligibility included patients with biopsy-proven advanced melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) who progressed on anti-PD-1/PD-L1. APX005M was dose escalated (0.03, 0.1, or 0.3 mg/kg i.v.) with a fixed dose of cabiralizumab with or without nivolumab every 2 weeks until disease progression or intolerable toxicity.
RESULTS
Twenty-six patients (12 melanoma, 1 NSCLC, and 13 RCC) were enrolled in six cohorts, 17 on nivolumab-containing regimens. Median duration of follow-up was 21.3 months. The most common treatment-related adverse events were asymptomatic elevations of lactate dehydrogenase ( = 26), creatine kinase ( = 25), aspartate aminotransferase ( = 25), and alanine aminotransferase ( = 19); periorbital edema ( = 17); and fatigue ( = 13). One dose-limiting toxicity (acute respiratory distress syndrome) occurred in cohort 2. The recommended phase 2 dose was APX005M 0.3 mg/kg, cabiralizumab 4 mg/kg, and nivolumab 240 mg every 2 weeks. Median days on treatment were 66 (range, 23-443). Median cycles were 4.5 (range, 2-21). One patient had unconfirmed partial response (4%), 8 stable disease (31%), 16 disease progression (62%), and 1 unevaluable (4%). Pro-inflammatory cytokines were upregulated 4 hours post-infusion. CD40 and MCSF increased after therapy.
CONCLUSIONS
This first in-human study of patients with anti-PD-1/PD-L1-resistant tumors treated with dual macrophage-polarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Drug Combinations; Drug Resistance, Neoplasm; Immune Checkpoint Inhibitors; Kidney Neoplasms; Lung Neoplasms; Melanoma; Nivolumab
PubMed: 34140403
DOI: 10.1158/1078-0432.CCR-21-0903 -
Clinical Cancer Research : An Official... Feb 2023A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory...
PURPOSE
A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).
PATIENTS AND METHODS
In phase I, we tested sequentially two cell populations for CAR transduction: (i) central memory (Tcm) or (ii) naïve, stem, and central memory (Tn/mem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase II dose (RP2D), which was tested in phase II.
RESULTS
The Tcm cohort was closed early due to lack of activity. The 200 ×106 Tn/mem-derived CD19-CAR T-cell dose was found to be safe and active, and was declared the RP2D. At RP2D, 58 participants underwent leukapheresis and 46 received CD19-CAR T cells. Median age for treated participants was 38 years (range, 22-72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like (Ph-like) genotype, and 16 (35%) had extramedullary disease (EMD) at lymphodepletion (LD). Three (7%) participants had grade 3 cytokine release syndrome (CRS), and none had grade ≥ 4 CRS. Eight (17%) participants had grade ≥ 3 neurotoxicity, including one fatal cerebral edema. Forty (87%) patients achieved complete remission (CR)/CR with incomplete hematologic recovery, 2 (4%) progressed, and 4 (9%) were unevaluable for response. Among 42 response-evaluable participants, 16/17 with Ph-like ALL and 13/15 with EMD at LD responded. Twenty-one (53%) responders underwent alloHCT consolidation, which was associated with improved relapse-free survival (adjusted HR = 0.16; 95% confidence interval, 0.05-0.48; P = 0.001).
CONCLUSIONS
Tn/mem-derived CD19-CAR T cells were safe and active, including in Ph-like ALL and EMD. See related commentary by El Marabti and Abdel-Wahab, p. 694.
Topics: Humans; Adult; Young Adult; Middle Aged; Aged; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; T-Lymphocytes; Lymphoma, B-Cell; Antigens, CD19; Hematopoietic Stem Cell Transplantation
PubMed: 36255386
DOI: 10.1158/1078-0432.CCR-22-2038 -
Clinical Cancer Research : An Official... Apr 2023Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase II randomized trial to determine the activity and...
PURPOSE
Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase II randomized trial to determine the activity and tolerability of single-agent cediranib or sunitinib in patients with advanced metastatic ASPS.
PATIENTS AND METHODS
Patients 16 years of age and older were randomized to receive cediranib (30 mg) or sunitinib (37.5 mg) in 28-day cycles. Patients could cross over to the other treatment arm at disease progression. The primary endpoint was to measure the objective response rate (ORR) for each agent. Median progression-free survival (mPFS) for the two arms was also determined.
RESULTS
Twenty-nine of 34 enrolled patients were evaluable for response. One patient on each of the initial two treatment arms had a partial response (ORR: 6.7% and 7.1% for cediranib and sunitinib, respectively). Twenty-four patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). There were no significant differences in mPFS for the two treatment arms. Clinical benefit (i.e., objective response or stable disease for a minimum of four or six cycles of therapy) on the first-line tyrosine kinase inhibitor (TKI) therapy did not predict benefit on the second-line TKI. Both drugs were well tolerated. As of August 2021, 1 patient (unevaluable for ORR) remains on study.
CONCLUSIONS
The study did not meet its endpoints for ORR. Although both TKIs provided clinical benefit, the outcomes may have been attenuated in patients who had progressed ≤6 months before enrollment, potentially accounting for the low response rates. See related commentary by Wilky and Maleddu, p. 1163.
Topics: Humans; Sunitinib; Sarcoma, Alveolar Soft Part; Indoles; Quinazolines; Protein Kinase Inhibitors
PubMed: 36302173
DOI: 10.1158/1078-0432.CCR-22-2145 -
Molecular and Clinical Oncology Aug 2022The present study investigated the associations of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels with clinicopathological variables...
The present study investigated the associations of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels with clinicopathological variables and survival outcomes in Libyan patients with pancreatic ductal adenocarcinoma (PDAC). The clinicopathological variables of 123 patients with PDAC registered at the National Cancer Institute in Misurata, Libya, between 2010 and 2018 were retrospectively analyzed. Blood samples from these patients were analyzed for serum CEA and CA19-9 levels before treatment by electrochemiluminescence immunoassay (double antibody sandwich ELISA) on a Roche cobas e 602 modules. The relationships between CA19-9 and CEA serum levels with clinicopathologic variables and survival outcomes were analyzed using the Kaplan-Meier method, log-rank test and Cox regression analyzes. Cut-off values for serum CEA and CA19-9 levels were 5 ng/ml and 400 U/ml, respectively. The median serum levels of all patients with PDAC for CEA and CA19-9 were 8 ng/ml (1.1-377 ng/ml) and 389 U/ml (1-10,050 U/ml), respectively. Tumors with higher serum CEA and CA19-9 levels were found in 63 and 48% of patients, respectively. Higher CEA and CA19-9 serum levels were significantly associated with more indicators of a malignant phenotype, including a surgically unresectable tumor, unevaluable lymph nodes, advanced stages and distant metastases. Regarding survival, patients with higher serum levels of the biomarkers CEA and CA19-9 had shorter overall survival rates (P<0.016 and (P<0.014, log-rank, respectively) and lower disease-free survival rates (P<0.002 and P<0.0001, log-rank, respectively) The present study demonstrated significant clinical and prognostic value of serum levels of biomarkers CEA and CA19-9 for Libyan patients with PDAC. Moreover, patients with PDAC with higher serum CEA and CA19-9 levels had more aggressive tumors, higher rates of disease recurrence and shorter overall survival rates and thus required more vigilant follow-up. Further multinational studies with larger PDAC cohorts are warranted to confirm these findings in terms of improved clinical decision making, more effective management and improved survival.
PubMed: 35832472
DOI: 10.3892/mco.2022.2559 -
JAMA Network Open May 2020Rates of chlamydial and gonococcal infection continue to increase in the United States, as do the associated costs of untreated infections. Improved diagnostic...
IMPORTANCE
Rates of chlamydial and gonococcal infection continue to increase in the United States, as do the associated costs of untreated infections. Improved diagnostic technologies that support testing and treating in 1 clinical visit are critical to advancing efforts to control the rates of chlamydial and gonococcal infection.
OBJECTIVE
To evaluate the clinical performance of a point-of-care (POC) molecular diagnostic assay for the detection of chlamydia and gonorrhea.
DESIGN, SETTING, AND PARTICIPANTS
A noninterventional, cross-sectional clinical study was conducted from September 18, 2018, through March 13, 2019, at sexually transmitted infection (STI), HIV, family planning, and obstetrics and gynecology clinics where STI screening is routine, using a convenience sample and comparing commercially available assays with a new 30-minute POC assay. Patients included were those eligible for STI screening or diagnostic testing who had not taken antibiotics effective against chlamydia or gonorrhea within the previous 28 days. Four vaginal swab samples were collected from women and a first-catch urine sample was obtained from men.
MAIN OUTCOMES AND MEASURES
A composite infection status was used to classify participants as infected if 2 or more comparator results were positive, as not infected if 2 or more comparator samples were negative, and as unevaluable if 1 result was invalid and the other 2 results did not agree with each other.
RESULTS
Swab samples from 1523 women (median age, 27 years [interquartile range, 17-37 years]), 817 (53.6%) of whom presented with symptoms, and 922 men (median age, 29 years [interquartile range, 17-41 years]), 308 (33.4%) of whom were symptomatic, were tested. For chlamydia, sensitivity of the new POC assay was 96.1% (95% CI, 91.2%-98.3%) for women and 92.5% (95% CI, 86.4%-96.0%) for men. For gonorrhea, sensitivity estimates were 100.0% (95% CI, 92.1%-100.0%) for women and 97.3% (95% CI, 90.7%-99.3%) for men. For chlamydia, specificity of the new POC assay was 99.1% (95% CI, 98.4%-99.5%) for women and 99.3% (95% CI, 98.4%-99.7%) for men. For gonorrhea, specificity estimates were 99.9% (95% CI, 99.5%-100%) for women and 100% (95% CI, 95.5%-100%) for men. Non-laboratory-trained personnel performed 94.8% of all tests (2318 of 2445) during the study.
CONCLUSIONS AND RELEVANCE
This study suggests that self-obtained vaginal swab samples were associated with performance equivalent to laboratory-based molecular diagnostics, which can support use of this POC assay in many settings. The availability of an easy-to-use, rapid (30-minute) molecular test for accurate detection of chlamydia and gonorrhea has the power to facilitate testing and treatment in a single patient visit for these STIs.
Topics: Adolescent; Adult; Chlamydia Infections; Cross-Sectional Studies; Female; Gonorrhea; Humans; Male; Point-of-Care Systems; Sensitivity and Specificity
PubMed: 32407506
DOI: 10.1001/jamanetworkopen.2020.4819 -
Journal For Immunotherapy of Cancer Aug 2020Limited data exist on potential clinical benefit with anti-programmed cell death ligand-1 (PD-L1) retreatment in patients who stop initial therapy for reasons other than...
BACKGROUND
Limited data exist on potential clinical benefit with anti-programmed cell death ligand-1 (PD-L1) retreatment in patients who stop initial therapy for reasons other than disease progression or toxicity and develop disease progression while off treatment.
PATIENTS AND METHODS
NCT01693562 was a phase I/II study evaluating durvalumab monotherapy in advanced solid tumors. Patients benefiting from treatment were taken off durvalumab at 1 year per protocol and prospectively followed. At disease progression, they were eligible for durvalumab retreatment. Outcomes evaluated during retreatment included best overall response (BOR2), duration of response (DoR2), disease control rate (DCR2), and progression-free survival (PFS2).
RESULTS
Of 980 patients enrolled and treated with durvalumab 10 mg/kg every 2 weeks (Q2W) in the dose-expansion cohorts, 168 completed 1 year of initial durvalumab treatment with confirmed BOR1 of complete response in 20 (11.9%), partial response (PR) in 84 (50%), stable disease (SD) in 52 (31%), and disease progression in 12 (7.1%). All 168 patients stopped treatment and were eligible for retreatment at progression; 70 patients (41.7%) representing 14 primary tumor types were retreated and response evaluable. Confirmed BOR2 was PR in 8 patients (11.4%), SD in 42 (60.0%), disease progression in 16 (22.9%), and unevaluable in 4 (5.7%). Median DoR2 was 16.5 months. DCR2 ≥24 weeks (DCR2 24) was 47.1%. PFS2 rate at 12 months was 34.2%, and median PFS2 was 5.9 months. Median overall survival (OS2) was 23.8 months. Response rates, DCR2 24, and median DoR2 were generally greater in patients with high PD-L1 expression than those with low/negative expression. No new safety signals were observed during retreatment.
CONCLUSION
Retreatment restored antitumor activity, resulting in high rates of durable disease control with an acceptable safety profile. This evidence supports retreatment of patients who stop anti-PD-L1 therapy for reasons other than progression or toxicity, and supports further investigation.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Disease Progression; Female; Humans; Male; Middle Aged
PubMed: 32847985
DOI: 10.1136/jitc-2020-000650 -
British Journal of Cancer Sep 2006The effects of sorafenib--an oral multikinase inhibitor targeting the tumour and tumour vasculature--were evaluated in patients with advanced melanoma enrolled in a... (Randomized Controlled Trial)
Randomized Controlled Trial
The effects of sorafenib--an oral multikinase inhibitor targeting the tumour and tumour vasculature--were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with > or =25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with > or =25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had > or =25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had > or =25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.
Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Benzenesulfonates; DNA Primers; Female; Genes, ras; Humans; Male; Melanoma; Middle Aged; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Polymerase Chain Reaction; Proto-Oncogene Proteins B-raf; Pyridines; Safety; Sorafenib
PubMed: 16880785
DOI: 10.1038/sj.bjc.6603291