Independent Radiological Committee Research Articles

445PD - Clinical Activity and Pharmacokinetics (PK) of Cabozantinib (XL184) in Patients with Progressive Medullary Thyroid Carcinoma (MTC)

ABSTRACT Background Cabozantinib (cabo) is a potent oral therapy that inhibits MET, VEGFR2, and RET. In a phase 1 study, cabo demonstrated anti-tumor activity in patients with MTC, and a long terminal half-life of 120 hours. We report clinical activity and PK analyses from a Phase 3 study of cabo versus placebo (P) in patients with progressive, unresectable, locally advanced or metastatic MTC. Methods Patients with MTC and documented RECIST progression within 14 months (mo) of screening were randomized 2:1 to receive cabo (140 mg freebase qd, n = 219) or placebo (n = 111). Blood samples for PK were collected on days 1 and 29. Baseline tumor and blood samples were evaluated for RET mutation status. Tumor assessments occurred every 12 weeks, and the primary efficacy measure was progression-free survival (PFS), assessed by an independent radiology committee using RECIST. Results Statistically significant PFS prolongation was observed, with median PFS for cabo of 11.2 mo versus 4.0 mo for P (HR 0.28, 95% CI 0.19-0.40, p Conclusions Cabo significantly prolonged PFS compared to placebo in a patient population with progressive MTC. PK analysis supports administration of cabo as a fixed dose without adjustment for patient covariates. Disclosure M.J. Schlumberger: MJ Schlumberger has been a compensated consultant for Exelixis. M. Brose: Dr. Brose has received research funding and honoraria from Exelixis. M. Shah: Dr. Shah has received research funding from Exelixis. D.R. Miles: D. Miles is an employee and stockholder of Exelixis. L.T. Nguyen: Linh Nguyen is an employee and stockholder in Exelixis. S. Sherman: Dr. Sherman is a compensated consultant to Exelixis. All other authors have declared no conflicts of interest.

Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up

BackgroundImatinib evaluated as a new treatment option in patients with recurrent or established progressive aggressive fibromatosis/desmoid tumor (AF/DT). Patients and methodsForty patients with unresectable and progressive symptomatic AF/DT were treated with imatinib (400 mg/day for 1 year) in a Simon's optimal two-stage phase II study (P0=10%, P1=30%, α=5%, β=10%). The primary end point was non-progressive at 3 months (RECIST). ResultsThe study population consisted of 28 women and 12 men, with a mean age of 41 (range 20–72 years). Most of the primary sites were extra-abdominal (24, 54.5%). Familial adenomatous polyposis was observed in six (15%) cases. The median follow-up was 34 months. Imatinib toxicity was similar to that previously reported in literature. Tumor assessment was validated by a central independent radiology committee for 35 patients At 3 months, one (3%) complete and three (9%) partial confirmed responses were observed. The non-progression rates at 3, 6 and 12 months were, respectively, 91%, 80% and 67%. The 2-year progression-free and overall survival rates were 55% and 95%, respectively. Two patients with mesenteric AF/DT died from progressive disease. ConclusionImatinib is active in the treatment of recurrent and progressive AF/DT, providing objective response and long-term stable disease in a large proportion of patients.

A Phase 3 Trial Comparing Bortezomib Plus Rituximab with Rituximab Alone In Patients with Relapsed, Rituximab-Naive or -Sensitive, Follicular Lymphoma

A Phase 3 Trial Comparing Bortezomib Plus Rituximab with Rituximab Alone In Patients with Relapsed, Rituximab-Naive or -Sensitive, Follicular Lymphoma

Updated outcome with long-term follow-up of imatinib for the treatment of progressive or recurrent aggressive fibromatosis (desmoid tumor): A FNCLCC/ French Sarcoma Group phase II trial

10518 Background: We present updated results from a previously reported phase II trial assessing clinical efficacy of imatinib in progressive or recurrent aggressive fibromatosis (Fayette et al. ASCO 2007) Methods: Patients with aggressive fibromatosis not amenable to radiotherapy or non-mutilating surgery were eligible and received imatinib 400mg daily (increased to 800mg daily in case of progression) up to 1 year then stopped. The primary end point was non-progressive disease rate at 3 months. Independent radiological committee reviewed responses. The number of patients was calculated according to a optimal 2-stages design. Results: Forty patients were included between September 2004 and October 2005 in 15 centers. The median follow up is 33 months [95% CI: 32–35]. Toxicity of imatinib is similar to that previously reported. At 3 months, the nonprogression rate was 91% [95% CI: 77–96] with 1 (2%) complete and 3 (8%) partial confirmed responses observed. The non progression rates at 6, 9, and 12 months were 80%, 69% and 66% respectively. The median time to progression was 9.5 months. The 2-year progression-free survival (PFS) was 55%. No plateau was observed. The 2-year-overall survival was 95%. Two patients with mesenteric aggressive fibromatosis died from progressive disease. In multivariate analysis including clinical factors, only previous radiotherapy was associated with reduced progression free survival. None of the biological factors tested using IHC on TMA (PDGFR α, PDGFR β, β catenin, c-kit, E cadherine, MCSFR, cycline D1 and Erk) were found correlated to response, progression free or overall survival. Conclusions: With a 2.8 years median follow up, this is the largest study which confirms the high efficacy of imatinib (400 mg daily) in patients presenting with aggressive fibromatosis failing local treatment and with documented evidence of progressive disease before imatinib treatment. [Table: see text]

Decrease in serum extracellular domain of HER2 at 4 and 8 weeks is associated with prolonged progression-free survival on lapatinib monotherapy.

Abstract Abstract #3140 Background: The extracellular domain of the HER2 oncoprotein (ECD HER2) is shed into the serum and can be detected by ELISA. This study investigated whether baseline serum ECD HER2 level is associated with prolonged progression-free survival (PFS) on lapatinib monotherapy. Additionally, we analyzed whether change in serum ECD HER2 at week 4 and 8 after start of lapatinib therapy is associated with prolonged PFS.
 Methods: Study EGF20009 investigated lapatinib monotherapy in 138 HER2-positive patients with metastatic breast cancer who had not previously received chemotherapy or trastuzumab. Serum was collected at baseline and every 4 weeks after initiation of oral lapatinib (1,500 mg daily or 500 mg twice daily). Disease assessment was performed at week 8, 12 and every 12 weeks thereafter. Disease status was assessed by an independent radiology committee, and response was measured using RECIST. Serum ECD HER2 was measured using the ELISA from Siemens HealthCare DX/Oncogene Science. A serum ECD HER2 decrease or increase ≥ 20% from baseline was defined as a significant change.
 Results: Baseline ECD HER2 was not associated with PFS; however, a ≥ 20% decrease from baseline serum ECD HER2 was associated with prolonged PFS, and a ≥ 20% increase from baseline was associated with shorter PFS. Patients who experienced a ≥ 20% decrease from baseline serum ECD HER2 at week 4 had a median PFS of 199 days (95% confidence interval [CI] = 145, 253) compared with 135 days (95% CI = 104, 171) for patients who did not (p = 0.016). Similarly, patients who experienced a ≥ 20% increase from baseline serum ECD HER2 at week 4 had a median PFS of 113 days (95% CI = 59, 135) compared with 199 days (95% CI = 142, 253) for patients who did not (p < 0.001). Similar associations were observed for the week-8 changes in serum ECD HER2 levels.
 Conclusions: Baseline ECD HER2 was not associated with PFS, whereas a ≥ 20% decrease from baseline serum ECD HER2 at week 4 and 8 was associated with prolonged PFS on lapatinib monotherapy. Single-agent lapatinib could be considered for the subset of patients whose ECD HER2 declines in the first 8 weeks of therapy, whereas a combination of chemotherapy with anti-HER2 therapy may be more appropriate for the patients whose ECD increases by ≥ 20%. Identification of a subgroup of patients who may be able to avoid cytotoxic chemotherapy in the MBC setting is an attractive prospect in our quest to find suitable therapies for appropriate patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3140.

The activity of raltitrexed (Tomudex®) in malignant pleural mesothelioma: an EORTC phase II study (08992)

We investigated the activity and toxicity of raltitrexed (Tomudex®) as a single agent treatment in patients with Malignant Pleural Mesothelioma (MPM) in a multicentre phase II European Organization for Research and Treatment of Cancer (EORTC) study. This study enrolled chemonaı̈ve patients with histologically-confirmed measurable MPM. Raltitrexed was administered at the dose of 3 mg/m 2 intravenous (i.v.) bolus on an outpatient basis every 3 weeks. A maximum of eight cycles was planned in cases with an absence of progression or unacceptable toxicity. 24 patients received a total of 104 courses. 5 patients (20.8%, 95% confidence interval (CI) 7.1–42.2%) had a partial response (PR), which was confirmed by an independent radiology committee. Toxicity was mild, with diarrhoea, nausea, vomiting, fatigue and neutropenia as the major side-effects, but not exceeding grade 3 toxicity. We conclude that raltitrexed has activity as a single agent in the treatment of MPM, and that further studies with this drug in MPM are warranted.

Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial

BackgroundThe combination of paclitaxel with cisplatin or carboplatin has significant activity in non-small-cell lung cancer (NSCLC). This phase III study of chemotherapy-naïve advanced NSCLC patients was designed to assess whether response rate in patients receiving a paclitaxel/carboplatin combination was similar to that in patients receiving a paclitaxel/cisplatin combination. Paclitaxel was given at a dose of 200 mg/m2 (3-h intravenous infusion) followed by either carboplatin at an AUC of6 or cisplatin at a dose of 80 mg/m2, all repeated every 3 weeks. Survival, toxicity and quality of life were also compared. Patients and methodsPatients were randomised to receive one of the two combinations, stratified according to centre, performance status, disease stage and histology. The primary analyses of response rate and survival were carried out on response-evaluable patients. Survival was also analysed for all randomised patients. Toxicity analyses were carried out on all treated patients. ResultsA total of 618 patients were randomised. The two treatment arms were well balanced with regard to gender (83% male), age (median 58 years), performance status (83% ECOG 0–1), stage (68% IV, 32% IIIB) and histology (38% squamous cell carcinoma). In the paclitaxel/carboplatin arm, 306 patients received a total of 1311 courses (median four courses, range 1–10 courses) while in the paclitaxel/cisplatin arm, 302 patients received a total of 1321 courses (median four courses, range 1–10 courses). In only 76% of courses, carboplatin was administered as planned at an AUC of 6, while in 96% of courses, cisplatin was given at the planned dose of 80 mg/m2. The response rate was 25% (70 of 279) in the paclitaxel/carboplatin arm and 28% (80 of 284) in the paclitaxel/cisplatin arm (P = 0.45). Responses were reviewed by an independent radiological committee. For all randomised patients, median survival was 8.5 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm [hazard ratio 1.20, 90% confidence interval (CI) 1.03–1.40]; the 1-year survival rates were 33% and 38%, respectively. On the same dataset, a survival update after 22 months of additional follow-up yielded a median survival of 8.2 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm (hazard ratio 1.22, 90% CI 1.06–1.40; P = 0.019); the 2-year survival rates were 9% and 15%, respectively. Excluding neutropenia and thrombocytopenia, which were more frequent in the paclitaxel/carboplatin arm, and nausea/vomiting and nephrotoxicity, which were more frequent in the paclitaxel/cisplatin arm, the rate of severe toxicities was generally low and comparable between the two arms. Overall quality of life (EORTC QLQ-C30 and LC-13) was also similar between the two arms. ConclusionsThis is the first trial comparing carboplatin and cisplatin in the treatment of advanced NSCLC. Although paclitaxel/carboplatin yielded a similar response rate, the significantly longer median survival obtained with paclitaxel/cisplatin indicates that cisplatin-based chemotherapy should be the first treatment option.