JOSÉ BASELGA. Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA

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1 The Oncologist Targeting the Phosphoinositide-3 (PI3) Kinase Pathway in Breast Cancer JOSÉ BASELGA Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA Disclosures: José Baselga: Consultant/advisory role: Novartis, Merck, Exelixis. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers. ABSTRACT The phosphoinositide-3 kinase (PI3K) pathway has been identified as an important target in breast cancer research for a number of years, but is new to most clinicians responsible for the daily challenges of breast cancer management. In fact, the PI3K pathway is probably one of the most important pathways in cancer metabolism and growth. Mutations in the PI3K pathway are frequent in breast cancer, causing resistance to human epidermal growth factor receptor 2 targeted agents and, possibly, to hormonal agents as well. Available agents that affect the PI3K pathway include monoclonal antibodies and tyrosine kinase inhibitors, as well as PI3K inhibitors, Akt inhibitors, rapamycin analogs, and mammalian target of rapamycin (mtor) catalytic inhibitors. Multiple PI3K inhibitors are currently under development, including pure PI3K inhibitors, compounds that block both PI3K and mtor (dual inhibitors), pure catalytic mtor inhibitors, and inhibitors that block Akt. It is likely that these agents will have to be given in combination with other signal inhibitors because anti-mtor agents and PI3K inhibitors may result in the activation of compensatory feedback loops that would in turn result in decreased efficacy. This article reviews current data related to the PI3K pathway, its role in breast cancer, the frequency with which PI3K is aberrant in breast cancer, and the potential clinical implications of using agents that target the PI3K pathway. The Oncologist 2011;16(suppl 1):12 19 INTRODUCTION The phosphoinositide-3 kinase (PI3K) pathway has been identified as an important target in breast cancer research for a number of years, but could be unfamiliar to clinicians responsible for daily breast cancer management. This article reviews the current data related to the PI3K pathway, its role in breast cancer, how frequently PI3K is aberrant in breast cancer, and the potential clinical implications of these findings with the use of agents that target the PI3K pathway. AN OVERVIEW OF THE PI3K PATHWAY The PI3Ks are a family of lipid kinases whose primary biochemical function is to phosphorylate the 3-hydroxyl group of phosphoinositides [1]. Class IA PI3Ks, deregulated in cancer, are heterodimers comprised of a regulatory subunit (referred to as p85) and a catalytic subunit (p110). Activation of PI3Ks is initiated when a growth factor or ligand binds to its cognate receptor tyrosine kinase (RTK). These receptors include members of the human epidermal growth factor receptor (HER) family, and the insulin and insulin- Correspondence: José Baselga, M.D., Ph.D., Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Telephone: ; Fax: ; jbaselga@partners.org, AlphaMed Press /2011/$30.00/0 doi: /theoncologist.2011-S1-12 The Oncologist 2011;16(suppl 1):

2 Baselga 13 Figure 1. PI3K pathway mutations in cancer. Abbreviations: BAD, Bcl-2-associated death promoter; GRB2, growth factor receptor-bound protein 2; IRS1, insulin receptor substrate 1; MDM2, murine double minute 2; mtor, mammalian target of rapamycin; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol triphosphate; PTEN, phosphatase and tensin homologue deleted on chromosome ten; RAPTOR, regulatory associated protein of TOR; RICTOR, rapamycin-insensitive companion of mammalian target of rapamycin; TSC, tuberous sclerosis. like growth factor 1 receptor (IGF-1R), among others. Upon receptor activation, the PI3K heterodimer interacts with their intracellular portion via p85. Alternatively, an adaptor molecule may act as an intermediary between an RTK and p85, such as occurs with insulin receptor substrate 1 (IRS1) downstream of IGF-1R. Binding removes the inhibitory effect of p85 on p110, resulting in full activation of PI3K. The activated kinase catalyses the phosphorylation of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol triphosphate (PIP3). PIP3 acts as a docking site for Akt, a serine/threonine kinase that is the central mediator of the PI3K pathway, and phosphoinositide-dependent kinase 1. Once localized at the cell plasma membrane, Akt is phosphorylated and stimulates protein synthesis and cell growth by activating mammalian target of rapamycin (mtor) through effects on the intermediary tuberous sclerosis 1/2 complex. The PI3K pathway is integral to diverse cellular functions, including cellular metabolism and proliferation, differentiation, and survival (Fig. 1). Additional evidence of the importance of this pathway is the high frequency with which and the multiple sites where this pathway is aberrantly hyperactivated in cancer, as illustrated in Figure 1, which shows locations in the pathway where activating mutations and deletions have been identified. In addition to the activating components of the pathway, some of the components of the pathway have an intrinsic inhibitory effect, such as phosphatase and tensin homologue deleted on chromosome ten (PTEN), for example [2]. PTEN loss activates the pathway, because PTEN has been charged with the reconversion of PIP3 into PIP2. Mutations also occur at the level of RTK receptors, mutations in PTEN itself, Akt, and Ras, among others. THE PI3K PATHWAY IN BREAST CANCER The PI3K pathway is frequently aberrantly activated in breast cancer with mutations occurring in up to one quarter of breast cancers. The majority of mutations are in PIK3CA, encoding the catalytic p110 subunit, and are nonrandomly localized in three hot spots, resulting in single amino acid

3 14 Targeting PI3K in Breast Cancer Table 1. Frequency of mutations in the PIK3CA and PTEN genes in 547 human breast cancers Mutation Breast cancer subtype PIK3CA catalytic domain * PIK3CA other PIK3CA total PTEN All breast tumors 73/547 (13.3%) 44/547 (8.0%) 117/547 (21.4%) 2/88 (2.3%) HR 48/232 (20.7%) 32/232 (13.8%) 80/232 (34.5%) 2/58 (3.4%) ER PR 39/186 (21%) 22/186 (11.8%) 61/186 (32.8%) 1/48 (2.1%) ER PR 9/41 (22%) 10/41 (24.4%) 19/41 (46.3%) 1/8 (12.5%) ER PR 0/5 (0%) 0/5 (0%) 0/5 (0%) 0/2 (0%) HER2 13/75 (17.3%) 4/75 (5.3%) 17/75 (22.7%) 0/10 (0%) Triple negative 12/240 (5.0%) 8/240 (3.3%) 20/240 (8.3%) 0/20 (0%) From Stemke-Hale K, Gonzalez-Angulo AM, Lluch A et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008;68: , with permission. substitutions: E545K and E542K in the helical domain (exon 9) and H1047R in the kinase domain (exon 20). These mutations increase enzymatic function, enhance downstream signaling elements including Akt, and promote oncogenic transformation. Overall, the proportion of breast tumors exhibiting these mutations is in the range of 20% 25%, depending on the breast cancer subtype. For example, in hormone receptor positive tumors, these mutations occur in 30% of cases. Also, in HER2 disease, mutations are evident in about one quarter of tumors. Meanwhile, it seems that mutations in triple-negative breast cancer may be less frequent [3] (Table 1). It is important to note that, as more data series are gathered, these numbers could change, but these data trends offer an initial picture on the distribution of these mutations in the different subtypes of breast cancer. As shown in Table 1, PTEN alterations have been described as well, but may be less common. Mutations or amplifications in oncogenes are frequently associated with adverse outcomes, the classical example of which has been HER2 amplification. The relationship between PI3K mutation status and clinical outcome is now being studied. In an initial study, investigators at Memorial Sloan Kettering Cancer Center identified that PI3KCA mutations are associated with favorable clinicopathologic features and better clinical outcomes, including survival benefits [4]. Consequently, clinical data with PI3K inhibitors and with mtor inhibitors need to be evaluated carefully with respect to historical series, because patients with these tumors could have a better outcome. The corollary of this, though, is that if these patients intrinsically have a less aggressive form of the disease, it could well be that a less aggressive therapy, including PI3K inhibitors and hormonal therapies, should be considered. On the other hand, PI3K mutations may also play a role in resistance to some of the therapies that block upstream tyrosine kinase receptors. For example, PI3K mutations have been implicated as a mechanism of resistance to anti- HER2 agents. One study looked at PTEN status and PI3K mutation status in patients who had been treated with trastuzumab. Tumors with the PTEN deletion of PI3K mutations responded less efficiently to trastuzumab, which suggests a mechanism of trastuzumab resistance in HER2 breast cancer [5]. This finding is not surprising, because trastuzumab blocks the signaling pathway upstream from PI3K. If a downstream mutation exists, it would override upstream inhibition. In laboratory experiments, a genomewide small hairpin RNA screen was used to determine potential mediators of resistance to lapatinib, a small tyrosine kinase receptor of HER2. In these assays, PTEN deletion resulted in lapatinib resistance. One experiment was conducted in cells with different levels of PTEN and PI3K expression, as well as control cells with wild-type PTEN and wild-type PI3K. The bottom of Figure 2 illustrates cells with p110 overexpression and cells with the two frequent PI3K hotspot mutations. All cells were treated with either trastuzumab, lapatinib, or a combination of the two. As evidenced in the figure, cells harboring PI3K mutations or the PTEN deletion were clearly resistant to both trastuzumab and lapatinib [6] (Fig. 2). Evidence also exists to suggest that PI3K mutations may confer resistance to hormonal therapy. In support of this, hyperactivation of receptors that signal via the PI3K pathway, such as HER1, HER2, and insulin like growth factor receptor (IGFR) also result in resistance to antiestrogen therapy [7]. The proposed mechanism of resistance is via direct induction of estrogen receptor (ER) transcription (Fig. 3). Additional studies have demonstrated that PI3K

4 Baselga 15 Figure 2. Hyperactivation of the PI3K pathway regulates trastuzumab and lapatinib sensitivity in HER2 breast cancer cells. Abbreviations: HER2, human epidermal growth factor receptor 2; PI3K, phosphoinositide-3 kinase; PTEN, phosphatase and tensin homologue deleted on chromosome ten. From Eichhorn PJ, Gili M, Scaltriti M et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mtor/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008;68: , with permission. mutations could also mediate resistance to downstream mtor inhibitors. AGENTS TARGETING PI3K The first agents against the pathway that were studied in the clinic were rapamycin analogs. These agents work by interfering with mtorc1, which is the complex formed by mtor and regulatory associated protein of TOR. Clinical data are now available to suggest that mtor inhibition may play a role in the therapy of breast cancer. In a neoadjuvant randomized phase II study in patients with newly diagnosed, primary ER breast tumors 2 cm, patients were randomized to receive either letrozole plus placebo for 16 weeks or letrozole plus daily everolimus (RAD001), a rapamycin analog. The primary endpoint of the trial was response to the combination therapy [8]. Patients who received the rapamycin analog had a better response rate, which provided a clear indication that the mtor inhibitor may be a potential novel addition to the therapy of breast cancer. Because a decrease in the proliferation marker Ki67 has been proposed as a valid surrogate marker of clinical benefit to antihormonal agents in the neoadjuvant setting, investigators also analyzed changes in Ki67 in the two therapy groups. Baseline distributions of Ki67 values were similar in the treatment arms. Using the definition that patients with a ln(ki67) 1 at day 15 had an antiproliferative response, 57% of everolimus-treated patients were responders, compared with 30% of placebo-treated patients (p.01) (Fig. 4). This finding suggested that the combination is more efficient at blocking proliferation and correlates with the observed greater clinical benefit of the combination treatment. Based on these data, a number of ongoing phase III studies are exploring the efficacy of everolimus in patients with metastatic ER breast cancer. Although fewer data are available with trastuzumab and mtor blockade, a phase I study was conducted in patients who were largely resistant to paclitaxel and had prior exposure to trastuzumab. With the addition of everolimus, the activity demonstrated was quite remarkable [9]. Based on these findings, additional studies are being conducted in the HER2 metastatic setting. Meanwhile, an important pharmacodynamic finding in the initial metastatic and neoadjuvant studies was the observation that, upon mtor blockade with everolimus, there was an increase in the activated phosphorylated form of Akt (pakt). Figure 5 shows Akt phosphorylation status prior to and during therapy, demonstrating an increase in pakt in everolimus-treated patients [10] (Fig. 5). We had identified a potential explanation for what was at first a counterintuitive finding: S6, a molecule that is immediately downstream from and activated by mtor, suppresses signaling of IGF-1R via suppression of IRS1. The blockade of mtor and the resulting inhibition of S6 causes a negative feedback loop effect, and IGF-1R becomes activated, which in turns results in increased PI3K signaling and activation of Akt (Fig. 6). The activation of this compensatory pathway (Fig. 7) could be, in part, responsible for the limited activity that this class of agents has shown against breast cancer to date [11]. In preclinical models, the activation of this compensatory pathway is totally prevented by anti-igf-1r monoclonal antibodies and there is strong evidence that combining anti IGF-1R monoclonal antibodies and mtor inhibitors results in synergism [12]. This combination is currently being explored in a phase I clinical trial, and remarkable activity has been observed in patients with ER luminal B breast cancer [13]. Another equally appealing approach would be the use of PI3K inhibitors in combination with mtor inhibitors. PI3K INHIBITORS UNDER CLINICAL DEVELOPMENT Current PI3K inhibitors under development are grouped by their specificity, ranging from pure PI3K inhibitors, to compounds that block both PI3K and mtor (dual inhibitors), to pure catalytic mtor inhibitors, and to inhibitors that block Akt. Two agents that are discussed in further detail here are the compounds being developed by Exelixis and sanofi-aventis: XL147 and XL765. The XL147 agent is a selective PI3K inhibitor. This compound is a potent inhibitor of the Class I PI3K family.

5 16 Targeting PI3K in Breast Cancer Figure 3. Strategies to overcome resistance in hormone receptor positive breast cancer. Abbreviations: CBP, CREB binding protein; ER, estrogen receptor; ERE, estrogen-responsive element; HER2, human epidermal growth factor receptor 2; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase/extracellular signal related kinase kinase; mtor, mammalian target of rapamycin; PI3K, phosphoinositide-3 kinase; SOS, son of sevenless. From Di Cosimo S, Baselga J. Management of breast cancer with targeted agents: Importance of heterogenicity. Nat Rev Clin Oncol 2010;7: , with permission. Figure 4. Phase 2 neoadjuvant everolimus (RAD001) breast cancer study: Change in Ki67. The agent, which can be administered orally, does not inhibit mtor or the mitogen-activated protein kinase/extracellular signal related kinase kinase pathway, and has demonstrated preclinical efficacy in PI3K, PTEN, and KRAS mutant xenografts. Initial phase I studies have demonstrated an adequate safety profile. In a single-agent dose-escalation study, two XL147 dosing schedules were investigated. These include 20 days on and 7 days off (21/7) and a continuous daily schedule. The first study also included a cohort expansion in patients with non-small cell lung cancer (NSCLC) and lymphoma [14]. A second study in NSCLC patients is being expanded, combining XL147 with erlotinib [15]. A third study is combining XL147 with paclitaxel and carboplatin, with cohort expansions in patients with endometrial cancer, ovarian cancer, and NSCLC [16]. In the first study, 48 patients were enrolled by the time

6 Baselga 17 Figure 5. The mtor inhibitor everolimus increases tumor pakt in breast cancer patients. From Tabernero J, Rojo F, Calvo E et al. Dose- and scheduledependent inhibition of the mammalian target of rapamycin pathway with everolimus: A phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008;26: Reprinted with permission American Society of Clinical Oncology. All rights reserved. Figure 6. mtor represses IRS1 under basal conditions. Abbreviations: IGF1-R, insulin-like growth factor 1 receptor; IRS1, insulin receptor substrate 1; mtor, mammalian target of rapamycin; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol triphosphate; PTEN, phosphatase and tensin homologue deleted on chromosome ten; RAPTOR, regulatory associated protein of TOR; RICTOR, rapamycin-insensitive companion of mammalian target of rapamycin; TSC, tuberous sclerosis. data were presented at the 2009 annual meeting of the American Society of Clinical Oncology (ASCO). A maximum-tolerated dose (MTD) of 600 mg was determined for Figure 7. Activation of IRS1 and Akt by mtor inhibitors is prevented by the co-administration of anti-igf-1r monoclonal antibodies. Abbreviations: IGF1-R, insulin-like growth factor 1 receptor; IRS1, insulin receptor substrate 1; mtor, mammalian target of rapamycin; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol triphosphate; PTEN, phosphatase and tensin homologue deleted on chromosome ten; RAPTOR, regulatory associated protein of TOR; RICTOR, rapamycin-insensitive companion of mammalian target of rapamycin; TSC, tuberous sclerosis. the 21/7 dosing schedule. The trial is still ongoing with continuous daily dosing. A dose-limiting toxicity of rash was reported. For the most part, however, the compound is well tolerated. There is excellent pharmacodynamic clinical evidence of inhibition of the pathway, in addition to evidence of clinical activity [14]. Clinical responses have been reported in a patient with NSCLC and also in a proportion of patients with longstanding, stable disease 12 weeks. Interestingly, the compound also inhibits extracellular signal related kinase (ERK) signaling, as seen by immunochemistry [14]. Inhibition of ERK signaling is not seen with mtor inhibitors, which actually activate the perk pathway, and likewise has not been reported with other PI3K inhibitors. Potential mechanisms leading to this lack of ERK activation are unknown. Another compound, XL765, is a dual mtor and PI3K in-

7 18 Targeting PI3K in Breast Cancer hibitor. In terms of mtor inhibition, this is a catalytic inhibitor of TORC1 and TORC2, as opposed to the rapamycin analogs described above that target solely TORC1. Like XL147, the agent is designed for oral administration and has demonstrated clinical efficacy in a variety of models. There are a number of phase I clinical trials currently under way with XL765. The first study is looking at different dosing schedules daily or twice a day [17]. Other studies are investigating XL765 in combination with temozolomide in glioblastoma multiforme patients [18], and in combination with erlotinib, with expansions in NSCLC patients [19]. At the time of the last report at the 2009 ASCO meeting, 51 patients had been enrolled. An MTD of 50 mg twice daily was identified, and the first study is still enrolling on a daily schedule. With XL765, dose-limiting toxicities have included transaminase elevations at higher dose levels. These were reversible and not seen at lower levels. Excellent pharmacodynamic activity has been observed in normal and tumor tissue, and some evidence of clinical antitumor activity has been observed as well, including in patients with KRAS-mutant colorectal cancer. Impressive inhibition of the pathway was seen by examining pakt and pebp1. Similar findings were also observed with respect to ERK inhibition. Based on these promising initial clinical data, phase II studies are now open or about to be open to enrollment for patients with ER /progesterone receptor (PR) breast cancer, and in those with HER2 disease. Although these trials will initially enroll a wide patient population, potential enrollees will eventually undergo real-time advanced tumor genotyping in order to select for patients with tumors with either PI3K mutations or PTEN deletions. Hence, it is anticipated that a number of patients in each cohort will have PI3K mutations, so that patients with a higher likelihood of benefiting may be included in the study. A phase I/II randomized study of letrozole and XL147 versus letrozole and XL765 is also planned. This interesting design will pose the question of whether it is better to inhibit PI3K alone or PI3K and mtor when given in combination with hormonal therapy. Although the study design was still under discussion at the time of this presentation, it is likely that the phase I study will be a classical 3 3 dose escalation, and then the phase II study will have 50 patients accrue to each arm. The key eligibility criteria will include postmenopausal patients with ER PR tumors with metastatic breast cancer. Eligible patients will also be refractory to a nonsteroidal aromatase inhibitor. The primary objective of the phase I study is to determine the MTD; the phase II objective will be the objective response rate and progressionfree survival rate at 3 months. Another phase I/II study is planned with XL147 in patients who have received trastuzumab and who have failed to respond to treatment. One treatment arm will consist of XL147 in combination with trastuzumab, and the other treatment arm will consist of XL147 in combination with trastuzumab and paclitaxel. The phase I and phase II studies will each accrue 25 patients to each arm and are being conducted with the goal of answering important therapeutic questions. The primary endpoint of the phase I study is the MTD of XL147 in combination with each regimen (trastuzumab or trastuzumab plus paclitaxel). The phase II primary endpoint is the objective response rate. Eligible patients will have metastatic HER2 breast cancer, and will have progressed on at least one prior trastuzumab-containing regimen. Tumor biopsies will be requested in the phase II trial, when feasible. CONCLUSIONS Mutations in the PI3K pathway are frequent in breast cancer and result in resistance to HER2-targeted agents and, possibly, to hormonal agents as well. Anti-mTOR agents have clinical activity against breast cancer, but activation of feedback loops may result in decreased efficacy. In phase I studies, the PI3K inhibitors XL147 and XL765 have been shown to effectively block the PI3K and ERK pathways, and they have demonstrated signs of clinical activity. Phase II clinical trials with XL147 are under way in two settings in hormone-refractory disease and also in patients who have failed trastuzumab. Trial results are awaited to determine the role of these new agents in clinical practice. REFERENCES 1 Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296: Wellcome Trust Sanger Institute. Catalogue of Somatic Mutations in Cancer (COSMIC). Available at: cosmic/, accessed March 9, Stemke-Hale K, Gonzalez-Angulo AM, Lluch A et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008;68: Kalinsky K, Jacks LM, Heguy A et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res 2009;15: Berns K, Horlings HM, Hennessy BT et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007;12: Eichhorn PJ, Gili M, Scaltriti M et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mtor/ phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008; 68:

8 Baselga 19 7 Di Cosimo S, Baselga J. Management of breast cancer with targeted agents: Importance of heterogenicity. Nat Rev Clin Oncol 2010;7: Baselga J, Semiglazov V, van Dam P et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009;27: André F. Multicenter phase I clinical trial of daily and weekly RAD001 in combination with weekly paclitaxel and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab. J Clin Oncol 2008;26(suppl): Atzori F, Tabernero J, Cervantes A et al. A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly (qw) MK-0646, an insulinlike growth factor-1 receptor (IGF1R) monoclonal antibody (MAb) in patients (pts) with advanced solid tumors. J Clin Oncol 2008; 26(15 suppl): Tabernero J, Rojo F, Calvo E et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: A phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008;26: Di Cosimo S, Scaltriti M, Val D et al. The PI3-K/AKT/mTOR pathway as a target for breast cancer therapy. J Clin Oncol 2007;25(suppl 18): Di Cosimo S, Bendell JC, Cervantes-Ruiperez et al. A phase I study of the oral mtor inhibitor ridaforolimus (RIDA) in combination with the IGF-1R antibody dalotozumab (DALO) in patients (pts) with advanced solid tumors. J Clin Oncol 2010;28(15 suppl): Shapiro G, Kwak E, Baselga J et al. Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors. J Clin Oncol 2009;27(15 suppl): Faulkner N, LoRusso PM, Guthrie T et al. A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients with advanced solid tumors. Mol Cancer Ther 2009;8(suppl 1):C Wheler JJ, Traynor AM, Bailey HH et al. A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with paclitaxel (P) and carboplatin (C) in patients with advanced solid tumors. Mol Cancer Ther 2009;8(suppl 1):B LoRusso P. A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765, a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced solid tumors. J Clin Oncol 2009;27(15 suppl): Wen PY, Omuro AM, Batchelor TT et al. A Phase 1 safety and pharmacokinetic study of XL765 (SAR245409), a novel PI3K/TORC1/TORC2 inhibitor, in combination with temozolomide (TMZ) in patients (pts) with malignant glioma. Mol Cancer Ther 2009;8(suppl 1):B Janne PA, Felip E, Cedres S et al. A phase 1 safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor, XL765 (SAR245409), in combination with erlotinib in patients (pts) with advanced solid tumors. Mol Cancer Ther 2009;8(suppl 1):A254.