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).