Dr Thomas on the Safety Profile of Frontline Ipatasertib Plus Pembrolizumab in HNSCC

“Ipatasertib causes diarrhea, which was one of the concerns with the design of the study, because checkpoint inhibitor–induced diarrhea or colitis can be a serious condition, so we wanted to make sure we could tell the difference between colitis vs diarrhea from ipatasertib.”

Jacob Stephen Thomas, MD, an assistant professor of clinical medicine and the service chief of LAC+USC Oncology at the Keck School of Medicine of the University of Southern California, discussed safety data from a phase 2 trial (NCT05172258) of first-line ipatasertib in combination with pembrolizumab (Keytruda) in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

Safety findings from the study demonstrated that ipatasertib was associated with a predictable and manageable adverse effect profile, with diarrhea representing the most notable treatment-related toxicity, Thomas began. Because the regimen combined ipatasertib with immune checkpoint inhibition, investigators paid particular attention to distinguishing diarrhea caused by the targeted therapy from immune-mediated colitis, a potentially serious complication associated with checkpoint inhibitors, he noted.

Investigators found that the dosing schedule of ipatasertib helped make this distinction relatively straightforward, Thomas explained. The drug was administered intermittently, with treatment given on days 1 through 14 of each cycle, he said. As a result, episodes of diarrhea typically occurred during the period of active ipatasertib administration and improved once the medication was held, he added. This predictable temporal pattern differed from immune-mediated colitis, allowing investigators to distinguish between the two conditions based on both timing and clinical presentation, he noted.

Importantly, the study did not identify an increased incidence of checkpoint inhibitor–associated colitis despite the additional therapy, Thomas said. This finding suggests that adding ipatasertib to an immunotherapy regimen did not appear to exacerbate immune-related gastrointestinal toxicity, addressing one of the primary safety concerns associated with the study design, he concluded.