Prospective phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy

Clinical development process of molecularly targeted agents for cancer and is similar to that of cytotoxic agents are pretty similar, targeting tumor location and histology [ 1– 3]. Irrespective of different tumor types and histology, Mmost molecular alterations exist irrespective of different tumor types and histologies, although the incidence can varyies [ 4]. This observation challenges existing drug development strategies for molecularly targeted agents and raises the possibility of a shift towards histology-agnostic molecularly-based treatment [ 5].

The mechanisms of cancer are marked by complex aberrations in active and critical cellular signaling pathways involved in tumorigenesis [ 6]. The phosphoinositide 3-kinase (PI3K)-v akt murine thymoma viral oncogene homolog (AKT)-mechanistic target of rapamycin (mTOR) signaling cascade is one of the most important intracellular pathways that is frequently activated in diverse cancers [ 7, 8]. In many types of tumors, the activation of the PI3K-AKT-mTOR pathway has been known as the relation to tumorigenesis, cancer progression and the acquired resistance to various anti-neoplastic agents [ 7, 9]. mTOR is an evolutionarily conserved serine/threonine kinase which acts downstream of the PI3K pathways. Thus, inhibition of the mTOR pathway represents a novel therapeutic strategy in the treatment of various cancers [ 10– 13]. Everolimus, an mTOR inhibitor, demonstrates antiproliferative activity through the inhibition of the PI3K-AKT-mTOR pathway and also has antiangiogenic effects [ 14, 15]. Everolimus has shown antitumor activity in various types of tumors, but, it activity has limited in only a subset of cancer patients [ 11, 12, 16, 17]. However, there have not been predictive biomarkers for everolimus, until now. Therefore, novel biomarkers are needed to identify patients who would receive the most benefit from everolimus treatment. Recently, in several studies, PIK3CA/PTEN genomic aberrations have been suggested to be strong predictors of everolimus sensitivity [ 18– 21]. PIK3CA amplifications and mutations have been implicated in pathway activation and sensitivity to mTOR inhibitors. Some preclinical models have further shown that PTEN-deficient tumors present an enhanced sensitivity to mTOR inhibitors because of the sustained activation of PI3K-AKT signaling [ 22, 23]. These findings have enabled researchers to apply mTOR inhibitors in many tumor-types with specific genomic aberrations irrespective of tumor histology and location.

We designed a single-arm, open-label phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy (#NCT02449538).

mTOR is a key down-stream protein kinase of the PI3K-AKT signaling pathway, and everolimus is a novel macrolide derivative of rapamycin that inhibits mTOR, thereby preventing phosphorylation of its down-stream molecules. Its promising antitumor effect has been reported in various tumor types such as renal cell carcinoma, biliary tract cancer, gastric cancer, and neuroendocrine tumor [ 10, 11, 13, 17]. PIK3CA/PTEN genomic aberrations have been suggested to be strong predictors of everolimus sensitivity. In the present study, we sought to investigate the anti-tumor activity of everolimus in solid tumors with specific genotypes such as PIK3CA amplification/mutation and/or PTEN loss. However, this study did not meet the primary end point of the first stage of Simon’s two stage design and was terminated without proceeding to the second stage. To proceed to the stage, at least one patient with CR or PR was needed at the end of the first stage of the study. Although there were four patients with SD among the 10 patients enrolled in the first stage, there was no CR or PR. Inconsistent findings among clinical trials for everolimus may be caused by heterogeneous patients’ population such as different tumor-types, different races and etc.

mTOR is composed of two distinct protein complexes, mTORC1 and mTORC2, that act on different levels of the pathway [ 24, 25]. Unlike the mTORC1 complex, mTORC2 positively regulates cell survival and proliferation on different signaling levels, mainly by phosphorylation as well as through a serum and glucocorticoid inducible kinase [ 26]. Everolimus usually acts as an allosteric inhibitor of the mTORC1 complex through interaction with FK-binding protein 12 [ 27]. Thus, everolimus is generally thought to have only weak activity against the mTORC2 complex, which can lead to AKT activation [ 28]. This might have affected the outcome of this study. Although this study selected its subpopulation using specific genotypes that are known as predictive markers for everolimus, mTOR signaling via the mTORC2 complex could not be blocked. Newly developed mTOR kinase blockades are expected to provide a more robust inhibition of mTOR signaling via suppression of both mTORC1 and mTORC2 complexes. These agents are now in preclinical and clinical trials and include TAK228/INK128, AZD8055, and AZD2014 [ 29– 31]. We have also conducted phase II trial using AZD2014 in gastric cancer (#NCT02449655).

Patients who achieved disease control with everolimus had GC ( n = 2), CRC ( n = 1), and chonlangiocarcinoma ( n = 1). All of these patients had tumors with PTEN loss and did not have other genomic aberrations such as HER2 amplification, RAS mutation, and BRAF mutation that might affect the PI3K-AKT-mTOR signaling. The mTOR signaling pathway is linked to multiple levels of feedbacks and diverse signal crosstalk. Although this study used biomarker-driven patient selection, PTEN loss and PIK3CA amplification/mutation alone were not sufficient for predicting the anti-tumor activity of everolimus. Janku et al. reported various molecular aberration including PIK3CA, PTEN, KRAS, NRAS, and BRAF in 1656 patients with PI3K/AKT/mTOR inhibitors [ 32]. Thus, more comprehensive molecular analysis will be helpful to fully realize the potential of personalized medicine using mTOR inhibitors including everolimus.

The study did not meet its primary objective of demonstrating the anti-tumor activity of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy. A greater understanding of the feedback mechanism and crosstalk linked to the mTOR signaling-pathway is needed. Further investigation using other potential genomic candidates and next-generation mTOR inhibitors is warranted in patients with refractory cancer.