Combining Imaging and Molecular Markers in Oncology: The Pfizer Approach

By Malorye Allison

The overarching oncology biomarker strategy at Pfizer is fairly simple, according to Dominic Spinella, Ph.D., Senior Director in Translational Medicine, Global Oncology Lead, at Pfizer, Inc., who spoke at CHI’s recent Clinical Biomarkers meeting.

The group starts by looking for proof of mechanism. Selecting the patients for these studies is as important as selecting the markers. Certain types of tumors are clearly driven largely by specific molecular drivers, but finding those isn’t always easy. “Sometimes you can analyze archival biopsies, but you have to wonder if the biopsy reflects what’s going on in the patient’s tumor now,” Spinella said. “If you are looking at a causative mutation, it is very rarely back mutated. But wild type p53 in an archival biopsy doesn’t say anything about the tumor’s p53 status today.”

Whenever possible, Pfizer scientists like to start with molecular assays that act as surrogates for particular imaging tests. For example, a GLUT-1 test can be used to test the appropriateness of FDG-PET, or a thymidine-kinase assay for FLT-PET. As the lead compound nears nomination, the group starts using preclinical imaging.

“Our goal is to understand which imaging modality is most appropriate for which drug, and when is the optimal time to acquire images,” said Spinella. 

Once in the clinic, the oncology group will do a dose escalation trial in a standard “all-comers” Phase I design, to obtain safety and tolerability data. They are unlikely to do imaging studies at this point. But, “Once we have the maximum tolerated dose worked out, we will do an expanded cohort study with about 15 to 20 patients to look at the molecularly relevant markers,” he said

If they can’t see an effect on the target marker (or markers), “We terminate the project,” said Spinella. “If there is a significant effect, we employ a de-escalation dosing strategy with imaging, to establish the exposure/response relationship.” 

One of the advantages of using imaging is that “If the lower dose doesn’t work, you can tell right away.” If you can get the same effect below the maximally tolerated dose, “Then let’s do what we do in other disease,” he said. “Let’s take several doses into trials so we can use something less than the maximally tolerated dose in patients.”

The group looks for a statistically significant change in the imaging end-point across the entire treated cohort, but uses a somewhat less stringent p-value in these small, mechanism-oriented studies. “I’m looking for a trend,” Spinella said, “Such as a 20% reduction in Ktrans.” While the effect may seem muted and slight, “In the right patient population, even if you have a small responder subset, the whole cohort mean changes enough that you can see the effect.”

While the Pfizer group is leaning hard on biomarkers, and has dropped some projects due to negative biomarker data, “Objective tumor response always trumps negative biomarker data,” said Spinella.

4-12- 07 - Biomarker Breakthroughs