It has been nearly 18 years since the first molecularly targeted therapy, rituximab (Rituxan), was approved for the treatment of patients with B-cell non-Hodgkin lymphoma, a development that helped launch a new era in cancer care.
Today, as scientific advances propel the oncology field forward with novel strategies aimed at genomic aberrations and biological processes, the first generation of targeted agents continues to form the backbone of treatment for the tumor types in which they were initially approved and to fulfill expanded roles in other malignancies.
As the year opens on a fresh season of discovery, OncologyLive asked experts in lymphoma, chronic myeloid leukemia, breast cancer, and non–small cell lung cancer to discuss the impact that the first targeted agents have had on these malignancies and the prospects for new therapeutic approaches that might improve upon the impressive gains made during the past two decades.Lymphomas: Tactics for Improving Rituximab Regimens Vary With Subtype
Andy Chen, MD, PhD
The introduction of rituximab to the treatment of patients with non-Hodgkin lymphoma (NHL) in 1997 has doubled median survival to 10 years for individuals newly diagnosed with high-risk, low-grade follicular lymphoma and also has made a significant, although not as dramatic, impact in aggressive lymphomas, according to Andy Chen, MD, PhD. Rituximab is a genetically engineered murine/human monoclonal antibody directed against the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes.
Chen, who leads the lymphoma research group for the Knight Cancer Institute at Oregon Health & Science University (OHSU) in Portland, said approaches to improve upon established rituximab-containing regimens vary according to lymphoma subtype— with different degrees of success thus far. For B-cell NHL, the standard regimen had been R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) until recent years.
In 2012, German researchers demonstrated that pairing bendamustine (Treanda) with rituximab significantly improved progression-free survival (PFS) over R-CHOP (69.5 months vs 31.2 months, respectively) as first-line therapy among patients with indolent NHL subtypes, including follicular and mantle cell lymphoma (MCL).1
And in October 2014, the FDA approved bortezomib (Velcade) as part of a regimen that includes rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) for patients with previously untreated MCL, the first such treatment specifically indicated for this setting, based on a phase III clinical trial demonstrating a 59% relative improvement in PFS over R-CHOP.2
“But this has all been progression-free survival so far,” said Chen. “There has been no overall survival benefit yet. It’s hard to show an overall survival (OS) benefit these days in low-grade lymphoma because the average survival of the high-risk patient in the rituximab era is over 10 years.”
In chronic lymphocytic leukemia (CLL), the emergence of the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) and other targeted therapies has prompted efforts to combine a new agent with rituximab. Ibrutinib is approved for the treatment of patients with MCL or chronic lymphocytic leukemia (CLL) in relapse settings. Last year, the FDA also approved idelalisib (Zydelig), a PI3K-delta inhibitor, in CLL in combination with rituximab, and in relapsed follicular and small lymphocytic lymphoma.
“Low-grade lymphoid malignancies, particularly CLL, are further along in terms of novel and targeted therapies. A lot of those drugs that have worked well in low-grade lymphoma and CLL have not worked as effectively in aggressive lymphoma,” said Chen.
For aggressive lymphomas, researchers have had a more difficult time improving upon R-CHOP. Diffuse large B-cell lymphoma (DLBCL) is now divided molecularly into germinal center (GC) versus activated B-cell (ABC) subtypes, with significantly worse outcomes among patients with the ABC type who receive the standard R-CHOP therapy, Chen noted. He said researchers are experimenting with adding agents to the R-CHOP regimen such as ibrutinib, bortezomib, and lenalidomide (Revlimid) for ABC subtype DLBCL. Another approach involves seeking improvements to the chemotherapy component of the regimen, most notably dose-adjusted R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin).
Chen said there are indications that R-EPOCH may be more effective for some types of aggressive lymphomas than R-CHOP; a phase III clinical trial testing this hypothesis in DLBCL is currently under way.3
However, he said R-EPOCH is more cumbersome to administer in terms of dosing schedules and monitoring of blood counts, and therefore might not translate well into community settings. “We use it ourselves, but only for highly aggressive lymphomas like MYC-positive or double-hit lymphomas,” said Chen.