Powerful downmodulation of Akt signaling with ipatasertib proves effective and tolerable in subgroup of patients who have developed resistance to standard therapies
Results from a first-in-human Phase I study reported in the November issue of Cancer Discovery*, evidence both the efficacy and tolerability of the experimental Akt inhibitor ipatasertib (GDC-0068). This research, led by Josep Tabernero, Director of the Vall d´Hebron Institute of Oncology (VHIO) and Principal Investigator of the Gastrointestinal & Endocrine Tumors Group at VHIO, was carried out in partnership with VHIO´s Breast Cancer & Melanoma and Genitourinary, CNS Tumors, Sarcoma & Cancer of Unknown Primary Site Groups, as well as colleagues at the Biomedical Research Institute of Valencia (INCLIVA – Spain), and Genentech, Inc. (CA, USA).
Ipatasertib is a potent small molecule inhibitor that blocks activity of the AKT protein, resulting in the inhibition of the Akt signaling pathway and tumor cell proliferation. Importantly, this pathway is found dysregulated in a wide variety of cancers since it plays a pivotal role in the survival of tumor cells.
“Up until now the blocking of AKT has represented a major challenge for the scientific community due to the toxicity of current inhibitors that target the inactive conformation of Akt and affects both healthy as well as cancerous cells. Ipatasertib however, preferentially targets active phosphorylated Akt and thus only strikes against tumor cells,” explains Cristina Saura, Principal Investigator of VHIO´s Breast Cancer & Melanoma Group, and first co-author of the study.
A total of 52 patients were enrolled in the Phase I study with diverse solid tumors – including metastatic prostate, breast, and colorectal cancer. They received varying doses of ipatasertib during 21-day treatment cycles followed by 7 days´ rest. Despite the fact that 92% of patients reported at least one adverse event related to the therapy, the majority of these symptoms were both well tolerated and managed through conventional treatment or adjustment to dose, and these patients continued with the therapy. The most frequently experienced adverse events were diarrhea, nausea, asthenia, hyperglycemia, decreased appetite, rash, and vomiting.
This first-in-human study to assess tolerability and safety of this novel agent was initiated in response to the promising preclinical findings reported by teams led by Josep Tabernero demonstrating the anti-tumoral effect of ipatasertib in patient-derived xenograft cancer models. “This early phase trial has shown that the dose of ipatasertib that proved effective in our preclinical studies correlates with that in humans,” observes Josep Tabernero, senior author of the study. “In addition, preclinical findings showed alterations on the AKT pathway in patients that derived more benefit from treatment which may help us to gauge individual tumor sensitivity to treatment with ipatasertib,” he concludes.
81% of patients enrolled presented activation of the Akt pathway due to loss of PTEN function or PIK3CA or AKT mutations. The researchers designed an exhaustive pharmacodynamic study of patient biopsies and showed expression of multiple Akt pathway target genes is decreased in a dose-dependent manner and as a consequence of the active binding of ipatasertib to AKT. Patients with activated Akt pathway responded better to treatment with ipatasertib.
Upon post-treatment assessment, 30% of cases showed a best overall response of stable disease, demonstrating the anti-tumoral effect of ipatasertib in these patients. In addition to favorable results regarding safety and tolerable side effects, this experimental agent is already showing promise at clinical level in this subgroup of patients. Based on these preliminary clinical data, ipatasertib is now being evaluated in Phase Ib/II clinical trials in metastatic prostate, gastric, and breast cancers, and may be a promising co-performer in combination with chemotherapy as well as other approved anti-cancer targeted therapies and approaches.
*A First-in-Human Phase I Study of the ATP-Competitive Akt Inhibitor Ipatasertib (GDC-0068) Demonstrates Robust and Safe Targeting of Akt in Patients with Solid Tumors. Cristina Saura, Desamparados Roda, Susana Roselló, Mafalda Oliveira, Teresa Macarulla, José Alejandro Pérez-Fidalgo, Rafael Morales-Barrera, Juan Manuel Sanchis-García, Luna Musib, Nageshwar Budha, Jin Zhu, Michelle Nannini, Wai Y. Chan, Sandra M. Sanabria Bohórquez, Raymond D. Meng, Kui Lin, Yibing Yan, Premal Patel, José Baselga, Josep Tabernero and Andres Cervantes. Cancer Discov. DOI: 10.1158/2159-8290.CD-16-0512. 21 November 2016.