June 2012, Vol 1, No 2
ALK-Targeted Agent Has High Activity in Some Childhood CancersConference Correspondent
In a preliminary phase 1 study, the targeted drug crizotinib (Xalkori) stabilized disease progression and, in some children, eradicated cancer cells in relapsed, refractory, aggressive childhood cancers that are likely to harbor genetic abnormalities in the ALK gene: anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors (IMT), and aggressive neuroblastoma.
Crizotinib, which is targeted to abnormalities in the ALK gene, is FDA-approved for the treatment of ALKdriven non–small cell lung cancer (NSCLC), which accounts for about 5% of all NSCLC. ALK is also a potential target in childhood cancers, because ALK abnormalities are present in 80% to 95% of ALCL cases, 50% of IMT cases, and 10% to 15% of aggressive neuroblastomas.
If these promising early findings are borne out in larger, randomized trials, crizotinib will become the second effective molecularly targeted agent for pediatric cancers, explained lead author Yael Mosse, MD, assistant professor of pediatrics at the Children’s Hospital of Philadelphia and University of Pennsylvania.
“Crizotinib had a high degree of activity. Larger trials with this agent are in development for ALCL. This drug may also find a role in selected subsets of patients with IMTs and neuroblastomas,” she said.
The Children’s Oncology Group study included 70 children with progressive cancer despite standard treatment. Six different cohorts were treated with crizotinib doses ranging from 100 to 365 mg/m2. The drug was extremely well tolerated, Mosse said, and the dose chosen for studies going forward was 250 mg/m2, which is twice the dose used in adults with NSCLC.
Results were as follows: 7 of 8 patients (88%) with ALCL had a complete response (CR). These responses have been long-lasting, with all patients on treatment for up to 18 months, she said. Of the 7 patients with IMT (a rare sarcoma) enrolled in the trial, the majority have had a response, with some responses lasting for up to 2 years; all patients with IMT are still on the drug, and Mosse said it is too early to report results.
“There is no other treatment that is effective in IMT,” she said.
Of the 27 patients with aggressive neuroblastoma, 8 had known ALK mutations; 2 of these patients achieved a CR and have been on therapy from 9 months to more than 2 years with no sign of disease progression. Mosse pointed out that most heavily pretreated neuroblastoma patients, such as those in this preliminary trial, would progress within 1 to 2 months on other available therapies. Among the 19 patients with unknown ALK status, there was 1 CR and 6 with prolonged stable disease after 7 to 29 cycles of treatment.
Toxicity was acceptable and mostly low grade. At the highest dose level, elevations in liver enzymes were reported, and 1 patient had a drop in white blood cell count.
Mosse suggested that higher doses of crizotinib are more likely to achieve responses in neuroblastoma patients.
Summing up, Mosse said that the phase 1 study showed dramatic activity in ALCL, “all you would want in a phase 2 trial.”
“For neuroblastoma, we need more study to determine which patients will benefit from crizotinib. The drug has dramatic potential in other ALK-driven tumors,” she added.
ASCO President Michael P. Link, MD, said: “I am delighted to hear these findings, which provide a glimpse at a new paradigm. Histology and the affected organ are not sufficient [treatment targets]. We need to identify the particular molecular drivers of tumors. The study shows that an inhibitor of genetic abnormalities may work in different cancer types. The way forward is collaboration – in this case, experts in lung cancer, pediatric cancer, lymphoma, and brain cancer.”
Advocating for biomarker-driven “smart” trials, making the case for patient selection for specific drugs, and the concept of rational combinations as potential targeted therapies in order to improve the efficacy of clinical trials were topics of an insightful presentation delivered by Dr Aleksandar Sekulic on behalf of Dr Pat LoRusso [ Read More ]
To receive credit, complete the posttest at www.mlicme.org/P11077.html. Until recently, cancer treatment relied solely on histologic diagnosis for determining systemic therapy. Aside from considerations related to a patient’s underlying comorbidities and performance status, there was minimal deviation from an organ-of-origin–based treatment strategy. This relatively primitive understanding of malignancy failed [ Read More ]