The best route to improving preclinical toxicity in immunotherapies could lie in reverse translation, feeding clinical data back into the preclinical space to inform model development, rather than trying to guess a priori what the models need to represent.
That was the conclusion of an FDA workshop convened with the American Association for Cancer Research (AACR) in the wake of treatment-related deaths last year in clinical trials of Merck & Co. Inc.’s anti-PD-1 mAb Keytruda pembrolizumab.
The deaths occurred in Phase III trials of Keytruda in combination with steroids or thalidomide-related medicines to treat multiple myeloma. The drug was already approved for non-small cell lung cancer (NSCLC), melanoma and bladder cancers.
“At that time, Dr. Pazdur, who is the head of the Oncology Center of Excellence, turned to us in the nonclinical side and asked what models we could use to interrogate this toxicity, and we unfortunately had to tell him we didn’t think models would be all that informative, particularly for drugs given in combination,” said FDA’s John Leighton at the Sept. 6 meeting.
Leighton is director of the division of hematology oncology toxicology at FDA’s Center for Drug Evaluation and Research (CDER).
In a 2016 retrospective analysis, FDA scientists found adverse events were so rare in