Dr Mattes on the Mechanism of Action of Ipatasertib in HNSCC

Malcolm Mattes, MD, associate professor, Section of Radiation Oncology, Rutgers Robert Wood Johnson Medical School; radiation oncologist, Rutgers Cancer Institute of New Jersey, discusses the mechanism of action of ipatasertib (RG7440), as well as the rationale for investigating the addition of this agent to chemoradiotherapy in the phase 1 CTEP 10492 trial (NCT05172245) of patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Ipatasertib is an AKT inhibitor that blocks AKT activity in the PI3K/AKT/mTOR pathway, which is one of the most commonly dysregulated signaling pathways in human malignancies, Mattes says. AKT inhibitors are hypothesized to induce fewer adverse effects than PI3K inhibitors, Mattes explains. Furthermore, unlike mTOR inhibitors, AKT inhibitors are highly selective for their target and do not activate AKT, Mattes notes.

The primary objective of the CTEP 10492 trial is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose of ipatasertib plus chemoradiation based on dose-limiting toxicities. Secondary end points include the assessment of acute and late toxicities; completion rates of chemotherapy and radiotherapy; swallowing function at 6 and 12 months; and preliminary efficacy assessments based on overall response rate, recurrence-free survival, and overall survival.

CTEP 10492 includes both a dose-escalation and dose-expansion phase. Across both phases, patients with HNSCC will receive a standard 70 Gy dose of radiation therapy for 7 weeks concurrent with weekly cisplatin, according to Mattes. Patients will also receive ipatasertib for 2 28-day cycles.

The dose-escalation portion of the trial includes 5 dose-escalation levels. Investigators are currently evaluating the agent at dose level 3, which is 300 mg of ipatasertib, and 11 patients have been enrolled onto the study thus far, Mattes says. The dose-expansion portion of the study will further evaluate the safety of the MTD of ipatasertib plus chemoradiation, Mattes explains. Moreover, pharmacodynamic assessments of the combination will reveal whether ipatasertib is acting as hypothesized to radiosensitize cells and block the AKT pathway, Mattes concludes.