Late Monday, Pfizer Inc. disclosed its decision to halt a Phase III trial (B1931008) of inotuzumab ozogamicin, an investigational antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting CD22, administered in combination with Rituxan (rituximab, Roche AG and Biogen Idec Inc.), in relapsed or refractory CD22-positive aggressive non-Hodgkin's lymphoma (NHL).
New York-based Pfizer said it would discontinue development of the drug in NHL after an independent data monitoring committee concluded during a scheduled interim analysis that the treatment would not meet the primary endpoint of improving overall survival compared with investigator's choice of bendamustine plus rituximab or gemcitabine plus rituximab. No new or unexpected safety issues were identified. Pfizer plans to publish the study findings at a future medical meeting, according to spokeswoman Victoria Davis.
Although Pfizer continues to evaluate the drug in the open-label, randomized, Phase III INO-VATE ALL Study (B1931022) in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL), the Phase III failure showed that the use of hot ADC technology doesn't guarantee success, especially in cancer.
The pharma said it is still examining data from the NHL trial to determine if certain outcome patterns may suggest potential benefit from inotuzumab ozogamicin in specific patient subsets within the trial population. Pfizer remains committed to evaluating inotuzumab ozogamicin in hematologic malignancies, Davis told BioWorld Today, adding that "Pfizer's Oncology Research Unit is focused on leadership in ADC-based therapies," with more than 10 investigational ADCs under development in solid and liquid tumors.
Pfizer also has a licensing deal with ADC developer Seattle Genetics Inc., of Bothell, Wash., for access to a single target, inked in 2011 for $8 million up front and $200 million in milestones. (See BioWorld Today, Jan. 7, 2011.)
Inotuzumab ozogamicin is a first-generation ADC that dates back to the early 2000s, when it was developed by Celltech Pharmaceuticals plc, now part of Brussels, Belgium-based UCB SA, in a collaboration with Wyeth Pharmaceuticals, now part of Pfizer. Celltech and Wyeth worked on the conjugate using technology derived from Mylotarg (gemtuzumab ozogamicin for injection, Pfizer), which became the first approved ADC but was voluntarily pulled from the market in 2010 due to toxicity issues blamed on an unstable linker. (See BioWorld Today, May 22, 2000, and Oct. 15, 2010.)
UCB is collaborating with Pfizer on the current trials. Pfizer also is working with the MD Anderson Cancer Center on a Phase I/II study of the drug prior to stem cell transplant in CD22-positive lymphoid malignancies. Pfizer has responsibility for the molecule's manufacturing and development activities.
Although any ADC failure in the clinic – especially in Phase III – is a major disappointment for the sponsor and patients, the result should not handicap ADC development, said Lawson Macartney, CEO of San Diego-based Ambrx Inc., which has inked a stunning strand of ADC deals with pharma partners. (See BioWorld Today, June 19, 2012, April 8, 2013, and May 6, 2013.)
While acknowledging that he had no detailed knowledge about the trial design and could only speculate on the suboptimal efficacy, Macartney posed a series of what-ifs, asking, "Is this the right antibody? Is this the right way to conjugate a payload? And is this the right payload?"
The conjugation techniques in the Pfizer drug were not terribly specific, he observed.
"Our mantra is that how you conjugate the antibody to the payload really, really matters," Macartney told BioWorld Today. "We've shown in experiments that if you conjugate to the wrong place, you can reduce activity. What we may be seeing here is a recapitulation of some of the older data with some of the older antibody-drug conjugates, where perhaps more rational design might have given a different outcome," he added.
Early stage ADCs using less stable linking technologies are inherently imprecise and less efficient, translating into smaller payloads of the targeted agent actually reaching a tumor cell, agreed Trevor Hallam, chief scientific officer of San Francisco-based Sutro Biopharma Inc., another developer of next-generation ADCs. (See BioWorld Today, Dec. 19, 2012.)
Site-specific conjugations result in more precise targeting and more homogenous products that are easier for regulators to review.
"The characterization of these molecules leaves nothing to chance," Hallam said. "You optimize for something that's precisely conjugated, you know exactly how it delivers into the tumor cell and you know the whole life story of that molecule as it gets metabolized and goes about its business to kill the tumor."
Beyond the ADC technology, cancer trials are notoriously difficult and many fail, Hallam observed, pointing to trial design, patient subsets and comparator arms as factors that Pfizer and other ADC developers will examine for clues.
A Phase III efficacy failure can result "from 1,001 reasons," Hallam added, but interest in ADCs remains high, particularly in the potential for targeted combination drugs in cancer.
"It would be interesting to think about something that's causing breaks in the tumor DNA combined with a drug that would stop that DNA repair in the tumor," he suggested.