PHARMACEUTICAL NEWS

Biologic Granted Full Approval for treatment of CTCL

On October 15, 2008 the United States FDA approved Eisai Medical Research’s denileukin diftitox (Ontak^®) intravenous solution for the treatment of patients with persistent or recurrent CD-25 positive cutaneous T-cell lymphoma (CTCL). The decision by the FDA for the full approval followed confirmation of an improvement in progression-free survival (PFS) and overall response rate (ORR). This action was based on positive efficacy data from a phase III placebo-controlled, randomized trial of 144 patients with stages Ia-III CTCL who received either an IV infusion of denileukin diftitox at 18 or 9 mcg/kg days 1-5 of a 21 day cycle (max. 8 cycles) or placebo (saline). Results: The primary endpoint, ORR, was met; ORR was 46% for the 18 mcg/kg dose (p=0.002 vs. placebo) and 37% for the 9 mcg/kg dose (p=0.03 vs. placebo) vs. 15% for saline placebo. Significant improvements in PFS were achieved at both doses: 18 mcg/kg group HR=0.27, p=0.0002, 73% reduction in risk of progression; 9 mcg/kg group HR=0.42, p=0.02, 58% reduction in risk of disease progression compared to placebo.

Novel Agent Approved to Treat Indolent B-cell NHL

On October 31, 2008 the United States FDA approved Cephalon, Inc.’s bendamustine hydrochloride (Treanda^®), an intravenously administered cytotoxic compound that acts primarily as an alkylating agent inducing extensive and durable DNA breaks, for the treatment of patients with indolent B-cell NHL that progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. The approval was based on the data from a single-arm trial of 100 patients who received bendamustine HCl monotherapy intravenously at a dose of 120 mg/m2 infused over 60 minutes on days 1 and 2 of a 21-day cycle for up to 8 cycles. Efficacy endpoints were overall response rate (ORR) and duration of response (dR). Results: ORR 74% (CR 13%, CR unconfirmed 4%, PR in 57%) and median dR 9.2 months. Safety evaluation reported grade 3 or 4 adverse events (A/E) in 71% of patients; most frequently reported non-heme A/Es fatigue (11%), febrile neutropenia (6%); most frequent heme lab abnormalities lymphocytopenia (94%), neutropenia (60%), thrombocytopenia (25%).

On March 20, 2008 this agent was approved for the first-line treatment of chronic lymphocytic leukemia (CLL), however the DOSE, INFUSION DURATION, and CYCLE LENGTH are DIFFERENT for the CLL treatment regimen: dose is 100 mg/m2, 30 minute IV infusion on days 1 and 2 of a 28-day cycle for up to 6 cycles.

FROM THE LITERATURE

Advanced Thyroid Cancer: Is the Targeted Therapy Era
About to Begin?

Thyroid cancer, the most common endocrine malignancy, is the 17th most common cancer worldwide. The vast majority are differentiated thyroid cancers (DTC), including papillary and follicular subtypes, which account for 90% of thyroid malignancies. For these DTCs, standard treatment with primary surgery and thyroid-stimulating hormone (TSH) suppression with thyroid hormone administration is effective. Depending on disease stage, tumor size, and patient age, ablation of the thyroid remnant with radioactive iodine 131I (RAI) is added. This collective treatment strategy is associated with a good prognosis and an overall survival rate of 90% or better at 20 years. Anaplastic thyroid cancer, although rare (2% of thyroid cancers), is usually unresectable at presentation, highly resistant to therapy, uniformly RAI resistant, and associated with a very poor prognosis (median survival less than 1 year). Medullary thyroid cancer originates from parafollicular, calcitonin-producing cells and accounts for 3% to 5% of thyroid cancers but has a worse prognosis and high mortality.

Once, thyroid cancer metastasizes to distant sites, becomes iodine-nonavid, and is no longer amenable to RAI or surgery, the only viable option for treatment is chemotherapy. The only FDA approved agent is doxorubicin which has low response rates (10% to 37%), short duration of responses, and myelo- and cardiotoxicity rendering it a poor option. Fortunately for patients, targeted therapy appears to be a promising option based on data reported from two phase II trials of targeted agents in advanced thyroid cancer.

• Thyroid tumors are highly vascular and overexpress VEGF, and inhibition of VEGF receptor (VEGFR) signaling has been shown to block the growth of these thyroid tumors in vitro. A phase II single-arm trial in 60 patients with advanced, incurable thyroid cancer of all histologic subtypes resistant or not appropriate for RAI was conducted to assess the activity and safety of axitinib (orally 5mg BID), a potent and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3. Primary endpoint was objective response rate (ORR). Results: Partial response (PR) in 18/60 patients, yielding an ORR of 30% and stable disease (SD) lasting ≥16 weeks in another 38%. Objective responses were seen in all histologic subtypes. Median follow-up is 16.6 months. (Median PFS is 18.1 months, 70% of patients are still alive, and median OS has not yet been reached). Axitinib selectively decreased plasma levels of soluble (s) VEGFR2 and sVEGFR3, demonstrating effective targeting of VEGFR. Together with a generally favorable safety profile, the data suggest that axitinib would be a useful option in patients with advanced thyroid cancer.
  
  J Clin Oncol 26: 4708-4713, 2008
  
  
• Early reports of trials with multi-kinase inhibitors have shown promise in patients with metastatic thyroid cancer. The B-type Raf kinase (BRAF) in the mitogen-activated protein (MAP) kinase signaling pathway plays a key role in thyroid cancer (BRAF has been found in 29% to 69% of papillary cancers), therefore RAF signaling is a logical target in thyroid cancer. Sorafenib(Nexavar^®) is an orally active multi-tyrosine kinase inhibitor with multiple targets, including BRAF, VEGFR1, and VEGFR2.
  
  Based on these facts, a phase II, single-arm trial was conducted to determine the efficacy of sorafenib in patients with iodine-refractory metastatic thyroid cancer. A report of a planned analysis after treatment of the first 30 patients was recently published. Patients received sorafenib 400mg orally twice daily. Study endpoints were ORR, PFS, and best response by RECIST criteria. Results: PR rate was 23% and stable disease rate was 53% with an overall clinical benefit rate of 77%. Median overall PFS time was 79 weeks and for the subset differentiated cancers the median PFS time was 84 weeks. In 17 of 19 (95%) patients for whom serial thyroglobulin levels were available, a marked and rapid response in thyroglobulin levels was noted, with a mean decrease of 70% within 4 months of starting treatment. These results represent a significant advance over chemotherapy and suggest that sorafenib warrants further investigation in advanced thyroid cancer.
  
  J Clin Oncol 26: 4714-4719, 2008.
  
  

A New Treatment Option for Relapsed or Refractory
Aggressive NHL

The major cause of death in patients with aggressive histology NHL is relapse or nonresponse to initial therapy. These patients are heavily-pretreated with chemoimmunotherapy, stem-cell transplantation, and/or radioimmunotherapy that leaves them with very little bone marrow reserves. Consequently, they are left with few or no further treatment options. Lenalidomide(Revlimid^®) has activity in a variety of hematologic malignancies, including NHL. The results of a phase II, single-arm, safety/efficacy trial of lenalidomide oral monotherapy (25mg once daily on days 1 to 21, every 28 days for 52 weeks) in this patient population were recently published. The 49 patients had aggressive histology NHL as follows: diffuse large B-cell in 53% of them, follicular center lymphoma, grade 3 (10%), mantle-cell (31%), and transformed low-grade (6%). For the primary endpoint of response, the overall response rate (ORR) of the entire group of 49 patients was 35%, including a 12% rate of CR/CRu. The ORR of the 4 different histology groups were: diffuse B-cell 19%, follicular center grade 3 was 60%, mantle-cell (MCL) 53%, and transformed low-grade 33%. The 53% ORR in MCL along with a manageable toxicity profile suggests that lenalidomide is a potential treatment option for these patients. Estimates for median duration of response and PFS were 6.2 and 4.0 months, respectively. Lenalidomide, an immunomodulatory agent, may control aggressive NHL by enhancing the immune system. It has been reported that when used in combination, lenalidomide and rituximab produce a robust response rate in relapsed or refractory MCL.

These results demonstrate the activity of lenalidomide in this relapsed/refractory patient population and warrant further investigation alone or as a component combination therapy.

J Clin Oncol 26: 4952-4957, 2008

Monoclonal Antibody Plus Interferon for Metastatic RCC

Bevacizumab(Avastin^®) plus interferon alfa (IFN) produces superior PFS and ORR in previously untreated patients with metastatic clear cell renal cell carcinoma (RCC) compared with IFN monotherapy according to results of a phase III trial of 732 patients. The prespecified stopping rule for OS, the primary endpoint, has not yet been reached. The median PFS was 8.5 months in patients treated with the combination vs. 5.2 months in those receiving IFN monotherapy (p<0.0001; HR=0.71). Bevacizumab plus IFN had a higher ORR of 25.5% compared to 13.1% with IFN monotherapy (p<0.0001). Overall toxicity was greater for the combination vs. IFN monotherapy, including significantly more grade 3 hypertension (9% vs. 0%), anorexia (17% vs. 8%), fatigue (35% vs. 28%), and proteinuria (13% vs. 0%). This trial validates antibody-mediated inhibition of the VEGF ligand as a clinically relevant strategy in RCC. The mechanism of these two agents may not be entirely independent, as IFN has demonstrated antiangiogenic effects.

JCO Early Release, published online ahead of print Oct. 20, 2008

Cardiac Toxicity of Second Generation TKIs in Patients
with Metastatic RCC

Sunitinib(Sutent^®) and sorafenib have considerable efficacy in metastatic RCC but TKI-associated cardiotoxicity has been reported in about 10% of the patients. Detailed cardiovascular monitoring during TKI treatment may reveal early signs of myocardial damage. Oncology health care providers need to recognize the signs and symptoms of cardiac damage in patients receiving these drugs. An observational study in Vienna, Austria analyzed all patients intended for TKI treatment for coronary artery disease (CAD) risk factors, history or evidence of CAD, hypertension, rhythm disturbances, and CHF. Monitoring included assessment of symptoms, ECGs, and biochemical markers (cardiac enzymes, troponin T). Echocardiograms were done at baseline and at time of a cardiac event (increased enzymes, symptomatic arrhythmia, new left ventricular dysfunction, or acute coronary syndrome). 86 patients received either sunitinib or sorafenib and among 74 eligible patients, 33.8% had a cardiac event, 40.5% had ECG changes, and 18% were symptomatic. Seven patients (9.4%) were seriously compromised and required intermediate care and/or ICU admission. All patients recovered after cardiovascular management and were considered eligible for TKI continuation. There was no significant survival difference between patients who experienced a cardiac event and those who did not have a cardiac event. The authors conclude that their observations indicate that cardiac damage from TKI treatment is a largely underestimated phenomenon, but is manageable if patients have careful cardiovascular monitoring and cardiac treatment at the first signs of myocardial damage.

JCO, Published Ahead of Print on October 6, 2008

Dual TKIs and HER-2 Negative Breast Cancer

Lapatinib(Tykerb^®/Tyverb^®), a dual tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2 positive locally advanced or metastatic breast cancer (MBC). But what about lapatinib activity in HER-2 negative and HER-2–uncharacterized (untested) MBC? A phase III randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for MBC evaluated the efficacy of lapatinib in HER-2 negative MBC. A preplanned retrospective evaluation of HER-2 status was performed. The primary endpoint was time to progression (TTP); secondary endpoints were ORR, clinical benefit rate (CBR), event-free survival (EFS), and OS. Results: In the ITT population (N=579) there were no significant differences in TTP, EFS, or OS between treatment arms. In 86 HER-2 (+) patients (15%), the paclitaxel-lapatanib arm resulted in statistically significant improvement in TTP, EFP, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any endpoint in HER-2 negative patients. Conclusion: Patients with HER-2 negative or HER-2 untested MBC did not benefit from the addition of lapatinib to paclitaxel, but the first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2 positive patients. Phase II and III studies of lapatinib plus taxanes are ongoing in patients with HER-2 positive MBC.

JCO Early Release, published online ahead of print on October 27, 2008.

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