Pfizer Discontinues Late-Stage Trial of Inotuzumab Ozogamicin

Mace Rothenberg, MD

A late-stage trial investigating inotuzumab ozogamicin as a treatment for patients with aggressive non-Hodgkin lymphoma has been halted after interim data showed the agent was unlikely to improve survival, announced Pfizer, the manufacturer of the drug.

Inotuzumab ozogamicin is in the relatively new class of drugs known as antibody-drug conjugates (ADC). In this case, the monoclonal antibody inotuzumab targets the CD22 cell surface antigen, which is expressed on approximately 90% of B-cell malignancies, and the drug is linked to the cytotoxic agent ozogamicin.

“We are working to better understand the findings from this review to determine if there are any patterns of outcome that may help us gain greater understanding of the potential effect of inotuzumab ozogamicin in specific patient subsets within the heterogeneous patient population enrolled in this trial,” said Mace Rothenberg, MD senior vice president of Clinical Development and Medical Affairs for Pfizer’s Oncology Business Unit, said in a statement.

The phase III study explored inotuzumab ozogamicin plus rituximab specifically as a treatment for patients with relapsed or refractory CD22-positive, aggressive non-Hodgkin lymphoma (NHL) who were not candidates for high-dose chemotherapy, this included patients with diffuse large B-cell lymphoma (DLBCL), transformed indolent lymphoma with DLBCL, and primary mediastinal large B-cell lymphomas. The comparator arm included an investigator’s choice of bendamustine plus rituximab or gemcitabine plus rituximab.

The preliminary efficacy of the combination of inotuzumab ozogamicin and rituximab was reported in the results of a phase I/II clinical trial, which were published earlier this year in the Journal of Clinical Oncology.

In that study, 118 patients with relapsed follicular lymphoma, relapsed DLBCL, or refractory aggressive NHL received a median of four cycles of the inotuzumab ozogamicin plus rituximab. At the maximum tolerated dose, the response rate was 87% in follicular lymphoma, 74% in DLBCL, and 20% in aggressive NHL. The study showed that the combination had a manageable safety profile, suggesting that it could be a promising treatment option for these patients.

The decision to stop the trial followed a scheduled interim analysis, which suggested that continuing to explore the drug was futile, since it was unlikely to show an improvement in overall survival when compared with the control arm. However, this analysis did not reveal any new or unexpected safety issues, Pfizer reported. As such, the agent will continue to be evaluated in adult acute lymphoblastic leukemia.

Pfizer's commitment to the ADC technology comes with a long track record of experience with these agents. In 2000 the FDA granted accelerated approval to the first ADC on the market, gemtuzumab ozogamicin (Mylotarg, Pfizer), for the treatment of relapsed CD33-positive acute myelogenous leukemia in older patients. However, in 2010, this agent was voluntarily withdrawn from the market, following a post approval trial that reported a lack of clinical benefit and higher than expected mortality rates.

Despite this first round of disappointing results, interest in ADCs continues to thrive. In 2011, brentuximab vedotin (Adcetris, Seattle Genetics) was granted accelerated approval to treat patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Additionally, earlier this year trastuzumab emtansine (Kadcyla, Genentech) was approved for the treatment of late-stage, HER2-positive breast cancer.

“Hematologic cancers are a complex group of diseases, with more than 70 different types of lymphomas, leukemias or myelomas that require unique treatment options,” Rothenberg said. “We remain committed to evaluating inotuzumab ozogamicin in patients with hematologic malignancies.”

Fayad L, Offner F, Smith MR, et al. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol. 2013 Feb;31(5):573-83.