Targeted Therapies

Timely Information for Practicing Hematologists and Oncologists

www.tgt-therapies.com

OCTOBER 2005

 

NON-HODGKIN'S LYMPHOMA (NHL)

Fludarabine followed by radioimmunotherapy. Leonard and colleagues treated 35 patients with untreated follicular lymphoma with 3 cycles of fludarabine 25 mg/m2 for 5 days every 5 weeks followed, 6 to 8 weeks later, by tositumomab and I131 tositumomab. After the completion of fludarabine therapy, 31 patients (89%) responded (3 complete responses [CRs] and 28 partial responses [PRs]). After the completion of the total planned regimen including I131 tositumomab, all 35 patients had responded and 30 patients (86%) had achieved a CR. Molecular remission was observed in 10 of 13 evaluable patients. Median progression-free survival (PFS) had not been reached at a median follow-up of 58 months. Multivariate analysis identified the baseline Follicular Lymphoma International Prognostic Index score to be an independent predictor of PFS. Seventy-four percent and 46% of patients experienced grade 3 or 4 neutropenia and grade 3 or 4 thrombocytopenia, respectively. These toxicities were manageable and the combined therapy was generally well tolerated. Sequential fludarabine and I131 tositumomab therapy appears to be effective front-line treatment for patients with low- or intermediate-risk follicular lymphoma. (Leonard JP, et al. J Clin Oncol 2005;23:5696–5704.)

 

Rituximab plus epratuzumab. CD22 is expressed in a similar pattern and frequency as CD20 in B-cell NHL. This finding led Leonard and co-workers to study the use of anti-CD20 rituximab 375 mg/m2 plus anti-CD22 epratuzumab 360 mg/m2 once weekly for 4 doses each in 23 patients with recurrent B-cell lymphoma (all patients were rituximab naive). Among 15 patients with follicular lymphoma, 10 patients achieved a response (9 CRs). Four of 6 patients with diffuse large B-cell lymphoma (DLBCL) had a response (3 CRs). The median time to progression for all patients with indolent NHL was 17.8 months. Treatment was well tolerated. The authors concluded that the combination of rituximab and epratuzumab is active and safe and that further studies are warranted. (Leonard JP, et al. J Clin Oncol 2005;23:5044–5051.)

 

Impact of rituximab plus CHOP. Sehn and colleagues conducted a population-based analysis to assess the impact of the addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy on the outcomes of adult patients with DLBCL in British Columbia, Canada. Patients were identified through 3 independent databases. Outcomes of 142 pre–rituximab-era patients were compared with those of 152 post–rituximab-era patients. Progression-free and overall survival were improved in the post-rituximab group (P = 0.002 and P <0.0001, respectively). This benefit was seen regardless of age. These data confirm that the addition of rituximab to CHOP chemotherapy has improved clinical outcomes for DLBCL patients in British Columbia. (Sehn LH, et al. J Clin Oncol 2005;23:5027–5033.)

 

CETUXIMAB

Phase II studies in squamous cell carcinoma of the head and neck (SCCHN) and a report of hypomagnesemia. Early studies of this monoclonal antibody directed against epidermal growth factor receptor (EGFR) have revealed antitumor activity in SCCHN and an enhancement of the antitumor activity of cisplatin. These findings led to 2 multicenter phase II studies, by Herbst and associates and Baselga and colleagues, investigating the combination of cisplatin-based chemotherapy and cetuximab in patients with recurrent SCCHN. Both studies showed that the addition of cetuximab to cisplatin-based regimens can produce responses in patients with platinum-refractory recurrent or metastatic disease. Treatment was well tolerated and the most common adverse event associated with cetuximab was rash. In a third study, Schrag and coworkers reported that magnesium wasting occurred in 34 (22%) of 154 patients receiving cetuximab. This appears to be due to a cetuximab-induced impairment of magnesium resorption in the kidney. Thus, serum magnesium and electrolyte levels should be monitored during cetuximab therapy, especially when combined with other nephrotoxic agents, such as cisplatin. (Herbst RS, et al. J Clin Oncol 2005;23:5578–5587, Baselga J, et al. J Clin Oncol 2005;23:5568–5577, and Schrag D, et al. J Natl Cancer Inst 2005;97:1221–1224.)

 

NEW AGENTS

Phase I study of lapatinib. Lapatinib is an inhibitor of ErbB1 (EGFR) and ErbB2 tyrosine kinases, leading to the inhibition of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling. Prior phase I studies have demonstrated that lapatinib was well tolerated at doses of up to 1,800 mg once daily. Burris and associates conducted a phase I study in which 67 patients with metastatic ErbB1- and/or ErbB2-expressing solid tumors were randomized to 1 of 5 oral lapatinib cohorts to receive from 500 to 1,600 mg of the drug once daily. Lapatinib was well tolerated at all doses studied. Five grade 3 lapatinib-related adverse events were reported (gastrointestinal events and rash) in 4 patients. The most frequently reported lapatinib-related events were diarrhea (42%) and rash (31%). Four patients with trastuzumab-resistant breast cancer achieved a PR and 10 patients had stable disease. These data indicate that lapatinib is a potentially effective therapy against ErbB1- and/or ErbB2-expressing solid tumors. (Burris HA, et al. J Clin Oncol 2005;23:5305–5313.)

 

Phase II studies of temsirolus (CCI-779). Temsirolus causes G1 cell cycle arrest by forming a complex with immunophilin FK-506 binding protein–12 (FKBP-12) that blocks the activity of rapamycin kinase. Antitumor activity has been observed in phase I studies and recently demonstrated in phase II studies of single-agent temsirolus (250 mg weekly IV) in relapsed mantle cell lymphoma, glioblastoma multiforme, and breast cancer. Common toxicities included mucositis, maculopapular rash, and nausea. Hematologic adverse events were common in lymphoma patients (>80%), but occurred in <10% of patients with glioblastoma or breast cancer. Further study of temsirolus in hematologic and solid tumors is warranted. (Witzig TE, et al. J Clin Oncol 2005;23:5347–5356, Chan S, et al. J Clin Oncol 2005;23:5314–5322, and Galanis E, et al. J Clin Oncol 2005;23:5294–5304.)

 

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