December 2012, Vol 1, No 6
Ibrutinib: Proof of Concept Pays OffUncategorized
Ibrutinib as a single agent and in combination with rituximab achieved unprecedented response rates in studies of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) presented at the 54th Annual Meeting of the American Society of Hematology (ASH). The drug is being studied in several B-cell malignancies, including CLL/small lymphocytic leukemia (SLL), relapsed/refractory MCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and multiple myeloma. The drug is under development by Pharmacyclics and Janssen Biotech, Inc.
Ibrutinib is an investigational Bruton’s tyrosine kinase (BTK) inhibitor. BTK is a key mediator of at least 3 critical B-cell prosurvival mechanisms: regulating B-cell apoptosis, cell adhesion, and lymphocyte migration and homing.
“Ibrutinib is the molecule of the year. This agent represents a revolution in the treatment of lymphomas,” stated Martin Dreyling, professor at the University of Munich in Germany and a lymphoma expert. He cited 2 studies of ibrutinib at ASH as potentially practice changing. One was a study in relapsed/refractory MCL (Abstract 904), and the other was a study in DLBCL (Abstract 686).
The first study was a phase 2 trial in 115 patients (65 bortezomib naive and 50 bortezomib exposed) with relapsed/refractory MCL. Median number of previous treatments was 3. In these difficult-to-treat patients, ibrutinib achieved an overall response rate (ORR) of 70% and a complete response rate of 20%, which increased to 50% at 14 months. Lead author of the study was Michael Wang, MD, from MD Anderson Cancer Center in Houston, TX. A pivotal study of relapsed and refractory MCL following bortezomib treatment has been initiated. At next year’s ASH, Wang is expected to present results of a study of ibrutinib as first-line therapy for MCL.
Moving on to the study of 70 patients with relapsed DLBCL presented by Wyndham Wilson, MD, National Cancer Institute in Bethesda, MD, treatment with ibrutinib achieved an ORR of about 28%. However, when patients were stratified according to genetic expression, response rates in activated B-cell–like (ABC) DLBCL were 40% (this group has the worst prognosis), and in germinal center B-cell–like DLBCL, 5.3%.
These results in the ABC subgroup of relapsed DLBCL patients are considered unprecedented. Wilson and colleagues concluded that future clinical trials of ibrutinib in DLBCL should be confined to the ABC subtype.
CLL/SLL Phase 2 Studies
Two phase 2 trials were reported with ibrutinib in CLL/SLL. The first was with single-agent ibrutinib (Abstract 189), and the second with ibrutinib plus rituximab (Abstract 187).
The first phase 2 trial included 116 CLL/SLL patients in 2 groups: elderly naive, relapsed/refractory patients,
and high-risk relapsed/refractory patients. Ibrutinib monotherapy achieved excellent progression-free survival (PFS) at 26 months for both elderly, treatment-naive patients (estimated PFS, 96%) and relapsed/refractory high-risk CLL/SLL patients (estimated PFS, 75%).
“These results with ibrutinib continue to support the possibility that we can address some of the critical unmet needs in CLL/SLL. Rarely does a drug come along that helps patients this much. This drug is highly effective and very well tolerated,” said lead author John R. Byrd, MD, D. Warren Brown Chair of Leukemia Research and director of the Division of Hematology at Ohio State University Comprehensive Cancer Center in Columbus.
ORRs were 68% in the treatment-naive, relapsed/refractory patients at a median follow-up of 20.3 months and 71% in the high-risk relapsed/refractory group at a median follow-up of 15.7 months. At 26 months, estimated overall survival is 96% and 83%, respectively.
In the second phase 2 study, the combination of ibrutinib plus rituximab achieved an ORR of 83% in 40 patients with high-risk CLL, and 38 of the 40 patients have no evidence of disease progression and are continuing on treatment.
“High-risk CLL patients typically have inferior outcomes compared with low- and intermediate-risk patients. This study shows profound activity for this combination in high-risk patients with CLL. The overall response rate is favorable compared with standard treatment, and the toxicity compares favorably to other treatment options,” stated Jan Burger, MD, lead author of this phase 2 trial. Burger is associate professor at the University of Texas MD Anderson Cancer Center.
High risk was defined as having 1 of the following characteristics: deletion of 17p, TP53 mutation, deletion of 11q, or <3 years of remission after first-line chemoimmunotherapy.
No disease progression was observed in 95% of the entire group and in 90% of those with 17p deletions. Ibrutinib achieved rapid reduction in the size of lymph nodes and spleen; 84% experienced >50% decrease in lymph node size.
In both phase 2 trials in CLL, treatment was well tolerated, with transient and infrequent grade 3 and 4 toxicities associated with ibrutinib.
Memantine Delays Cognitive Decline in Patients With Brain Metastases Treated With Whole-Brain Radiation
Memantine delayed cognitive decline in patients treated with whole-brain radiation therapy (WBRT) for brain metastases, according to results of a randomized phase 3 trial presented at the 54th Annual Meeting of ASTRO. Cognitive decline is common with WBRT, occurring in 50% to 60% of patients 4 months following radiation treatment. [ Read More ]
Key Points Although RAS mutations at glycine-12 and glycine-13 are adjacent, identical substitutions at these positions (eg, G12S vs G13S) lead to very different levels of RAS activation The central clinical question remains unanswered: will a patient with metastatic colorectal cancer harboring a KRAS G13D mutation benefit from anti-EGFR therapy? [ Read More ]