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Background Buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus fulvestrant in the BELLE-2 study significantly improved progression-free survival (PFS) in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Patients and methods In this phase III study, patients were randomised 1:1 to buparlisib (100 mg/day; continuously in 28-day cycles) or placebo, plus fulvestrant (500 mg on cycle 1 day 15, and day 1 of subsequent cycles). Overall survival (OS) was assessed in the overall population and patients with known PI3K pathway status (both had shown significant PFS improvements). OS by PIK3CA status in circulating tumour DNA (ctDNA) was an exploratory end-point. Results A total of 2025 patients were screened for eligibility between 7th September 2012 and 10th September 2014, and 1178 received fulvestrant (500 mg) during a run-in phase; 31 discontinued. Of 1147 patients (median age 62 years), 98% had the Eastern Cooperative Oncology Group performance status ≤1, and 59% had visceral disease. Median follow-up from randomisation to data cut-off (23rd December 2016) was 37.6 months. Median OS trended in favour of the buparlisib arm in the overall population (33.2 versus 30.4 months; P = 0.045) and among patients with known PI3K pathway status (30.9 versus 28.9 months; P = 0.144); neither outcome was statistically significant. Median OS also trended in favour of buparlisib among patients with PIK3CA-mutant ctDNA (26.0 versus 24.8 months). Grade III/IV adverse events with ≥10% difference between the buparlisib versus placebo arms were elevated alanine aminotransferase (26% versus 1%), elevated aspartate aminotransferase (18% versus 3%) and hyperglycemia (15% versus Conclusions OS results were in favour of buparlisib plus fulvestrant versus placebo plus fulvestrant; however, there is no statistical significance and more frequent grade III/IV adverse events were reported. Use of more selective PI3K inhibitors might provide the greatest clinical benefit and tolerable safety profile in this setting. Further evaluation of the predictive benefit of PIK3CA-mutant ctDNA is warranted. Trial registration number NCT01610284 .

We report the results from a phase I study of buparlisib, an oral pan-class I phosphotidyinositol-3-kinase inhibitor, combined with capecitabine in patients with metastatic breast cancer. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m(2) twice daily. A complete response was seen in 1 patient with a basal-like tumor. Pharmacokinetic analysis suggested that a pharmacokinetic interaction might exist between the 2 agents. BACKGROUND: Buparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients received buparlisib once daily (range, 50 to 100 mg) for 3 weeks with capecitabine twice daily (range, 1000 to 1250 mg/m(2)) for 2 weeks with a 1-week break. Dose escalation used a traditional “3 + 3” design with standard definitions of dose-limiting toxicity (DLT) and maximum tolerated dose. RESULTS: Of the 25 patients enrolled, 23 were evaluable for DLT and 17 were evaluable for response. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m(2) twice daily. DLTs included grade 3 hyperglycemia and grade 3 confusion. The most common grade 3 toxicities were diarrhea and elevation of aspartate aminotransferase and alanine transaminase. One patient exhibited a complete response to treatment and four had a confirmed partial response. In cohorts 3 and 4, in which the buparlisib dose remained constant but the capecitabine dose was increased, significant increases in the buparlisib plasma concentration were noted. CONCLUSION: The combination of buparlisib with capecitabine in patients with metastatic breast cancer was generally well-tolerated, with several patients demonstrating prolonged responses. Unexpectedly low rates of PIK3CA mutations (3 of 17) were seen, and only 2 of 7 tumors with subtyping were luminal, making exploration of these putative predictive markers impossible. Further study of the combination is not unreasonable, with expanded pharmacokinetics and sequencing analysis to better elucidate potential drug–drug interactions and more accurate predictive biomarkers of response.

PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of molecules simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design. Several compounds displayed excellent antiproliferative activities against several breast cancer cell lines, including triple-negative breast cancer (TNBC) MDA-MB-231 cell. Further mechanistic studies demonstrated that the representative compound 9i could inhibit both PI3K/Akt/mTOR and hedgehog (Hh) signalings by inhibiting the phosphorylation of S6K and Akt as well as decreasing the SAG elevated expression of Gli1. Compound 9i could also induce apoptosis remarkably in T47D and MDA-MB-231 cells. In the transwell assay, 9i showed significant inhibition on the migration of MDA-MB-231.

Background Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms. Patients and methods PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments. Results A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug–drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57–92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12–51%]). Conclusion Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population. Trial registration ID NCT01589861 .

BackgroundPhosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit.MethodsThe BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants.FindingsBetween Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [

Background The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signalling axis and androgen receptor (AR) pathways exhibit reciprocal feedback regulation in phosphatase and tensin homologue (PTEN)-deficient metastatic castration-resistant prostate cancer (CRPC) in preclinical models. This phase Ib study evaluated the pan-PI3K inhibitor buparlisib (BKM120) and the dual pan-PI3K/ mammalian target of rapamycin (mTOR) inhibitor dactolisib (BEZ235) in combination with abiraterone acetate (AA) in patients with CRPC. Materials and methods Patients with CRPC who had progressed on AA therapy received escalating doses of either buparlisib or dactolisib, along with fixed doses of AA (1000 mg once daily (qd)) and prednisone (5 mg twice daily (bid)). The primary objective was to define the maximum tolerated dose (MTD) and/or the recommended dose for expansion (RDE) of either buparlisib or dactolisib in combination with AA. Secondary objectives included safety, antitumour activity (Prostate Cancer Working Group 2 (PCWG2) criteria; 30% of prostate-specific antigen (PSA) decline at ≥week 12) and pharmacokinetic (PK) profile. Results In buparlisib + AA arm, 25 patients received buparlisib + AA (median age, 67 years; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1/2 for 7/17/1 patients, respectively). At 100 mg qd; two patients experienced dose-limiting toxicities (DLTs) (grade 3 hyperglycaemia; grade 2 asthenia), and this was the maximum buparlisib dose explored. Buparlisib + AA showed a 26% lower median area under the curve from time zero to 24°h (AUC0–24) and 48% lower median maximum serum concentration (Cmax) versus the single-agent buparlisib assessed in first-in-human study. No objective response and few PSA decreases were reported. In dactolisib + AA arm, 18 patients (median age, 71 years; ECOG PS of 0/1 for 6/12 patients, respectively) received dactolisib + AA at the first dose level (200 mg bid). Five patients had 9 DLTs (grades 2&3 stomatitis; grade 3 hyperglycaemia; grades 2& 3 diarrhoea; grades 1& 2 pyrexia, grade 2 vomiting, and grade 2 chills). Conclusions Based on the assessment of available pharmacokinetics, safety, and efficacy data, no further study is planned for either buparlisib or dactolisib in combination with AA in CRPC.

Background Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germlineBRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.

Background Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. Results As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Conclusions Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.

High expression of the immune checkpoint receptor PD-L1 is associated with worse patient outcome in a variety of human cancers, including head and neck squamous cell carcinoma (HNSCC). Binding of PD-L1 with its partner PD-1 generates an inhibitory signal that dampens the immune system. Immunotherapy, that is blocking the PD-1/PD-L1 checkpoint, has proven to be an effective tool in cancer therapy. However, not all patients are able to benefit from this immune checkpoint inhibition. Therefore, evidence is growing of intrinsic PD-L1 signaling in cancer cells. For example, intrinsic PD-L1 expression was associated with PI3K/Akt/mTOR signaling, which is part of diverse oncogenic processes including cell proliferation, growth and survival. In this study we demonstrate the effects of PI3K/Akt/mTOR pathway inhibition by buparlisib on PD-L1 expression in HNSCC cell lines. After buparlisib treatment for 72 h, PD-L1 was downregulated in total cell lysates of HNSCC cells. Moreover, flow cytometry revealed a downregulation of PD-L1 membrane expression. Interestingly, the buparlisib mediated effects on PD-L1 expression were reduced by additional irradiation. In PD-L1 overexpressing cells, the buparlisib induced inhibition of proliferation was neutralized. In summary, our findings imply that blocking the PI3K/Akt/mTOR pathway could be a good additional therapy for patients who show poor response to immune checkpoint therapy.

Introduction The phosphatidylinositol 3-kinase (PI3K) pathway promotes tumor growth and treatment resistance in non-small cell lung cancer (NSCLC). The aim of the open-label, two-stage, Phase II study BASALT-1 (NCT01820325) was to investigate the pan-PI3K inhibitor buparlisib (BKM120) in patients with PI3K pathway-activated, relapsed NSCLC. Methods After prescreening for PI3K pathway activation, patients with PI3K pathway-activated, metastatic, squamous or nonsquamous NSCLC, who had relapsed after prior systemic antineoplastic therapy, were enrolled. In Stage 1, patients received single-agent buparlisib (100 mg/day). A futility analysis was performed independently in each histology group, based on the 12-week progression-free survival rate for the first 30 patients treated in each group being less than 50%. Exploratory biomarker analyses were performed in archival tissue samples and circulating tumor DNA (ctDNA). Results Of 1242 prescreened patients, 13.5% exhibited PI3K pathway activation. As of June 5, 2014, 63 patients (30 squamous and 33 nonsquamous) were treated in Stage 1. The 12-week progression-free survival rates were 23.3% (95% confidence interval: 9.9–42.3) and 20.0% (95% confidence interval: 7.7–38.6) in the squamous and nonsquamous groups, respectively. Stage 2 was therefore not initiated in either group. PI3K pathway mutations in ctDNA were more concordant with metastatic tissue than with primary biopsies. Conclusions Despite preselecting patients for targeted treatment, BASALT-1 did not meet its primary objective during Stage 1. PI3K pathway activation can be detected using ctDNA, but may not be the main oncogenic driver in NSCLC. Combinations of PI3K inhibitors with other agents may demonstrate greater efficacy than monotherapy.

The plasma cell malignancy multiple myeloma (MM) is unique amongst haematological malignancies in its capacity to cause osteoclast-mediated skeletal destruction. The PI3K/Akt pathway mediates proliferation, survival and drug resistance in MM plasma cells and is also involved in regulating the formation and activity of bone-forming osteoblasts and bone-resorbing osteoclasts.NVP-BKM120 (Buparlisib, Novartis) is a PI3K inhibitor that is currently undergoing clinical evaluation in several tumour settings. In this study, we have examined the anti-tumorigenic effects of BKM120in an immuno competent mouse model of MM and its effects on osteoblast and osteoclast formation and function. BKM120 treatment (40 mg/kg) resulted in a significant decrease in serum paraprotein and tumour burden, and CT analysis of the proximal tibia revealed a significant reduction in the number of osteolytic bone lesions in BKM120-treated animals. BKM120 also mediated a significant increase in serum levels of the osteoblast marker P1NP, and a significant decrease in serum levels of the osteoclast markerTRAcP5. In vitro, BKM120 decreased MM plasma cell proliferation, osteoclast formation and function, and promoted osteoblast formation and function. These findings suggest that, in addition to its anti-tumour properties, BKM120 could be used to treat osteolytic bone disease in MM patients. Refereed/Peer-reviewed

Background The PI3K/AKT pathway activation is an independent marker of poor outcome in head and neck squamous-cell carcinoma (HNSCC). It is involved in resistance to cetuximab and PI3KCA mutations (5% of HNSCC) may be a key event of this dysregulation. Buparlisib is an oral, pan-Class I PI3K inhibitor that inhibits tumor growth in HNSCC xenografts. Methods This phase II evaluated the efficacy of oral buparlisib (100mg/d) in 2 parallel cohorts of refractory HNSCC (progression after platinum and cetuximab) with (PIK3CAmutated, exons 9/20) or without (PIK3CAnon-mutated) PI3KCA activating mutation. The primary endpoint was 2-month Disease Control Rate (DCR2m) as per centrally reviewed RECIST 1.1. Secondary endpoints included ORR, PFS, OS, and safety. Buparlisib would be considered ineffective if DCR2m ≤ 10% and promising if ≥ 30% (Simon’s optimal two-stage design; α: 5% unilateral, power: 90%): 7 successes/35 evaluable patients per cohort were required. Results 58 HNSCC heavily pre-treated (78% at least 2 prior lines) received at least one dose of buparlisib (PIK3CAnon-mutated, n = 36 and PIK3CAmutated, n = 22) The PIK3CAmutated cohort was prematurely closed because of slow accrual). The DCR2m was 38.9% (95% CI [25.5; + ∞[) for PIK3CAnon-mutated and 36.4% (95% CI [19.5; + ∞[) for PIK3CAmutated. No objective response was observed. Median PFS was 1.8 m (95% CI [1.6; 3.5]) and 1.7 m (95% CI [1.1; 4.1]) for PIK3CAnon-mutated and PIK3CAmutated respectively. Median OS was 5.8 m (95% CI [3.7; 9.2]) and 3.4 m (95% CI [2.6; 7.9]) for PIK3CAnon-mutated and PIK3CAmutated. Most common related AEs (>25%) included hyperglycemia, asthenia, anxiety, depression, lymphopenia, anemia, leucocyte increase, hematocrite decrease, Na decrease, nausea and diarrhea. Most frequent related AE ≥ Grade 3 (>5%) were hyperglycemia, lymphopenia, asthenia, Na decrease, depression, dermatitis. 14 pts (24.1%) discontinued buparlisib due to an AE. Conclusions Buparlisib had limited antitumor activity in heavily pre-treated HNSCC patients independent of PI3KCA mutational status. Clinical trial identification NCT01737450. Legal entity responsible for the study Centre Leon Berard. Funding INCA et Fondation ARC. Disclosure J. Fayette: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Honoraria (self): Merck Serono; Advisory / Consultancy: innate pharma; Advisory / Consultancy: Biogen. A. Daste: Honoraria (self), Advisory / Consultancy: BMS. C. Even: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Merck Serono. F. Peyrade: Honoraria (self): BMS; Honoraria (self): Merck Serono. C. Le Tourneau: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca.

1237 Journal of Thoracic Oncology ® • Volume 10, Number 9, September 2015 Therapeutic strategies directed against defined molecular subsets of non-small cell lung cancer (NSCLC) has underscored the transformative potential of biomarker directed drug development in oncogene-driven solid tumors. Riding on the success of targeting epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, small molecule inhibitors of the phosphatidyl-inositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway have engendered much excitement due to its critical role as a central signaling axis downstream of several receptor tyrosine kinases implicated in NSCLC (e.g., EGFR and MET). Although published data of novel agents targeting the PI3K/AKT/mTOR pathway in NSCLC have only demonstrated modest clinical activity to date (Table 1), the majority of studies have been conducted in unselected patient populations. In this issue of the journal, Vansteenkiste et al report the final efficacy results from a phase II trial of buparlisib, a pan-class I PI3K inhibitor in selected “PI3K-activated” NSCLC patients. In a commendable effort, 1242 patient samples underwent molecular prescreening for PIK3CA mutations, PTEN mutations, or PTEN loss by immunohistochemistry, identifying 63 subjects (13.5%) that were enrolled into two cohorts (squamous and nonsquamous). In terms of efficacy analysis, this trial used a conservative futility criterion—defined as 12-week progression-free survival rate less than 50%—that was unfortunately met in the first stage, terminating the trial early. Despite being a negative study from an efficacy standpoint, this trial has provided unique insights into the current challenges with targeted therapies directed against genetic alterations. Underpinning the success of contemporary trials evaluating targeted therapeutics are patient enrichment strategies using high-precision predictive biomarkers. Are PTEN and PIK3CA alterations sufficiently specific to select for tumors most likely to respond to PI3K inhibitors? Preclinical data certainly support this hypothesis, where PIK3CA-mutant transgenic lung cancer mouse models clearly respond to PI3K/mTOR inhibitors, and conditional ablation of PIK3CA or PIK3CB (through which PTEN signals) in cell-based models result in a significant reduction in cell growth. Yet, despite selecting for the relevant alterations in this trial, tumor responses were disappointingly low at 3% in both nonsquamous and squamous cell carcinoma, and there was no difference in progressionfree survival regardless of whether patients’ tumors were PIK3CA mutant or wild type. Furthermore, a subgroup of 23 patients with sufficient archival tissue subjected to broader sequencing of 600 genes failed to yield any notable coalterations that may have limited the efficacy of PI3K inhibitors. Similarly, responders were not differentiated by a specific mutational profile, with one patient harboring PTEN loss in the squamous group while another patient in the nonsquamous group had a PIK3CA and a KRAS mutation. Thus, somatic alterations alone cannot explain response or resistance to buparlisib.

Aim: Buparlisib is an oral pan-class PI3K inhibitor. A phase I trial established the safety and recommended dose of single agent Buparlisib, and promising preliminary anti-tumor activity was seen. It is currently being studied in combinatorial trials in several different malignancies. The primary objective of this phase I trial was to identify the maximum tolerated dose (MTD) for Iri plus Buparlisib in patients with previously treated mCRC, with or without previous exposure to Iri. The secondary objectives were to determine the PK of each drug alone and in combination, to determine clinical response to the combination, and to correlate biomarkers of PI3K signaling with clinical response. Methods: A conventional 3 + 3 dose titration scheme was used. Iri was administered intravenously every 14 days and Buparlisib given orally daily. The first dose of Iri was administered on cycle1 day1, with Buparlisib starting 24 hours after the first dose of Iri. Pts were assessed for safety and toxicities every cycle (q14 days). Results: Twenty patients were enrolled: 14 were evaluable for DLT: 3 in cohort 0 (Iri 120 mg/m2 + Buparlisib 50 mg/d), 7 in cohort 1 (Iri 150 mg/m2 + Buparlisib 50 mg/d), 4 in cohort 2 (Iri 150 mg/m2 + Buparlisib 80 mg/d). The most common adverse events (all grades) were nausea, vomiting, diarrhea, fatigue, hyperglycemia, and transaminitis. The MTD was Iri 150 mg/m2 + Buparlisib 50 mg/d. One dose limiting toxicity (DLT), grade 2 genital mucositis, was observed in a male pt in cohort 1. In cohort 2, one pt had DLT of grade 3 diarrhea and another had DLT with asymptomatic grade 3 hyponatremia. One pt in cohort 1 experienced grade 2 delirium and a pt in cohort 2 had grade 3 psychosis. Of the 4 pts who received 4 cycles of therapy 2 had stable and 2 had progressive disease. No objective responses were observed. PK data and molecular correlates will be presented in the meeting. Conclusions: This first human trial established that Buparlisib (50 mg qd) and Iri (150 mg/m2 q14d) are tolerable in combination. The efficacy of this regimen will need to be tested in future studies. Disclosure: J.C. Baranda: Research Funding from Novartis. All other authors have declared no conflicts of interest.

Aim: Carboplatin and paclitaxel are mainstays of treatment for metastatic solid tumors, and the PI3K/mTOR pathway is one of the most commonly dysregulated in cancers. The combination of PI3K inhibition and platinum-based chemotherapy may enhance anti-cancer effect. Methods: Patients with metastatic solid tumors were treated with two regimens: Group 1 received carboplatin AUC 5 and paclitaxel 175mg/m2, on day 1 of a 21 day cycle with pegfilgrastim support; Group 2 received carboplatin AUC 5 (day 1) and paclitaxel 80mg/m2 (days 1, 8 and 15) on a 28-day cycle without growth factor support. In both groups, the pan-PI3K inhibitor buparlisib (BKM120) was administered daily with dose escalation of 50, 80 or 100mg/day, with optional continuation of BKM120 until progression, after cessation of chemotherapy following Cycle 6. The primary endpoint was Recommended Phase II Dose (RP2D). Results: Between 5 Apr 2011 and 28 Jan 2013, 30 subjects were enrolled. Median age was 53 (range 23-71). The most common tumor types were non-small cell lung cancer (N = 5) and ovarian cancer (N = 5). 16 patients were treated in Group 1 and 14 in Group 2. The median number of cycles was 4.5 (Group 1) or 6 (Group 2). Dose reductions and treatment delays during all cycles were more common in Group 2. The most common adverse events (AE) of any grade in Group 1 were fatigue, hyperglycemia, alopecia, arthralgias, alkaline phosphatase elevation and thrombocytopenia. In Group 2, the most common AEs were hyperglycemia, leucopenia, neutropenia, thrombocytopenia, fatigue and alopecia. The DLTs were elevated alkaline phosphatase (N = 1) and uncomplicated neutropenia (N = 2). The MTD for BKM120 was 100mg/d in Group 1 and 80mg/day in Group 2. Among 25 patients with measurable disease, the objective response rate was 28% (1CR, 4 PR, 2uPR). 5 patients with evaluable disease (not measurable by RECIST) experienced clinical benefit (clinical stability with no new radiographic lesions) for ≥ 10 cycles. Correlative studies in process include analysis of PIK3CA mutation status and PTEN expression status in pre-treatment tumor samples, and pharmacokinetic analysis of BKM120. Conclusions: BKM120 at 100 mg/d + carboplatin AUC 5 + paclitaxel 175mg/m2, both on day 1 of a 21 day cycle with growth factor support, is a well-tolerated regimen with promising activity in advanced solid tumors. Disclosure: M. Fury: MGF has served on an advisory board for Novartis within the last 12 months. All other authors have declared no conflicts of interest.

Aim: In vitro, NSCLC cell lines with PIK3CA mutations have shown increased sensitivity to the oral pan-PI3K inhibitor buparlisib (BKM120). BASALT-1 is an open-label, two-stage, Phase II study to assess the safety and efficacy of buparlisib in patients (pts) with pre-treated metastatic NSCLC (squamous [sq] and non-squamous [non-sq] histology) and activated PI3K pathway (NCT01297491). Here we report results from the Stage 1 futility analysis (FA) for each histology. Methods: Pts (≥18 yrs) with previously treated, metastatic NSCLC (sq or non-sq histology) with activated PI3K pathway (defined as PIK3CA mutation and/or PTEN mutation and/or PTEN-negative staining [ Results: Thirty pts had been treated in each histologic group at the time of FA (>1200 pts screened). In the sq group, 21 pts were male (median age: 65.5 yrs); in the non-sq group, 19 pts were male (median age: 62.0 yrs). Median treatment exposure was 6.9 (sq group) and 7.2 (non-sq group) wks. Median PFS was 2.79 (95% CI: 1.38, 4.11) and 2.69 (95% CI: 1.41, 2.89) months for the sq and non-sq groups, respectively. PFS rate at 12 wks was 23.3% (95% CI: 9.9, 42.3) for the sq group and 20.0% (95% CI: 7.7, 38.6) for the non-sq group. Best overall responses (RECIST 1.1): partial response (1 pt [3.3%] in each group), stable disease (14 pts [46.7%] in each group), progressive disease (7 pts [23.3%] sq / 9 pts [30.0%] non-sq), unknown (8 pts [26.7%] sq / 6 pts [20.0%] non-sq). Most common (≥30%) AEs possibly related to study drug: hyperglycemia (36.7%), pruritus (33.3%), diarrhea (30%), and nausea (30%) for sq, and asthenia (30%) for non-sq. Conclusions: In this PI3K pathway-activated group of NSCLC pts, the futility criterion in Stage 1 was met in both histology groups. Thus, enrollment of Stage 2 was not initiated. Results of this study are in line with previous observations where single agents targeting the PI3K pathway have shown marginal activity. Studies of buparlisib in combination with docetaxel in pts with sq NSCLC are ongoing. Disclosure: J. Soria: - Research funds from Novartis (Instititution) - Compensated advisory board Novartis F. Grossi: Novartis advisory board; E. Felip: Advisory Board: BI, Novartis, Roche, BMS, Lilly; M. Thomas: AD-Board honoraria: Novartis, Roche, Lilly, BMS Speaker honoraria: BMS, Lilly; P. Roussou: - Novartis employee - Shares in Novartis; G. Atalla-Vidam: Novartis employee; P. Aimone: Novartis employee. All other authors have declared no conflicts of interest.

Aim: Aberrant hedgehog (Hh) signaling has been observed in tumors with dysregulated PI3K signaling. Sonidegib (LDE225; smoothened inhibitor that blocks Hh activity) and buparlisib (BKM120; pan class I PI3K inhibitor) show antitumor activity in ph I studies and combined, enhanced activity in xenograft models. In this ph Ib study (NCT01576666), the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), pharmacokinetic (PK) interaction, and preliminary antitumor activity of LDE225 + BKM120 were assessed in pts with metastatic breast cancer (mBC), pancreatic adenocarcinoma (PANC), metastatic colorectal cancer (mCRC), or recurrent glioblastoma (GBM). Methods: Adult pts received different daily doses (followed by Bayesian logistic regression model) of LDE225 and BKM120, starting at 400 and 60 mg, respectively. Safety, tolerability, PK, antitumor activity, and biomarkers (PIK3CA/PTEN) were assessed. Safety and PK are reported. Results: Pts (N = 46; 7 mBC, 9 PANC, 19 mCRC, 11 GBM) were enrolled into 5 cohorts (Table). As of Dec 12, 2013, 44 pts (95.7%) discontinued, primarily due to disease progression (n = 29) and adverse events (AEs; n = 7). G 3/4 AEs (> 5%) regardless of study drug included increased alanine and aspartate aminotransferase (21.7% each), increased blood creatine phosphokinase (17.4%), hyperglycemia (8.7%), and increased blood alkaline phosphatase, aphasia, nausea, fatigue (6.5% each). See Table for dose-limiting toxicities (DLTs); MTD was not reached. At the RDE (LDE225 400 mg/BKM120 80 mg), no drug-drug interaction was observed, the interindividual variability of LDE225 and BKM120 PK (cycle 1 D 1) was ≈ 67% and ≈ 30%, respectively, and trough levels over time aligned with single-agent exposure. Summary of Dose-Limiting Toxicities Observed in the Dose-Escalation Phase Cohort Dose Level (once daily) DLTs Occurring Within 6 Weeks of First Dose (n = 1 for each) No. of Pts Enrolled No. of Pts With DLTsa/ No. of Evaluable Ptsb 1 LDE225 400 mg + BKM120 60 mg None 6 0/4 2 LDE225 800 mg + BKM120 60 mg - Grade 3 aspartate aminotransferase elevation - Grade 3 anorexia - Grade 3 creatine phosphokinase elevation - Grade 4 creatine phosphokinase elevation 7 2/5 3 LDE225 400 mg + BKM120 80 mg Grade 3 creatine phosphokinase elevation 15 1/7 4 LDE225 400 mg + BKM120 100 mg - Grade 2 photosensitivity - Grade 3 rash - Grade 3 alanine aminotransferase elevation - Grade 3 aspartate aminotransferase elevation 9 3/9 5 LDE225 200 mg + BKM120 100 mg Grade 3 alanine aminotransferase elevation 9 1/4 a Pts w/multiple occurrences of a DLT at 1 dose level were each counted once. b Pts who met the minimum exposure criteria to be included in the dose-determining set. Conclusions: LDE225 + BKM120 is tolerable, with expected DLTs, consistent with ph I studies. PKs of each agent in combination appear similar to PKs observed in single-agent studies. Based on these data, further study of the combination is warranted. Disclosure: M. Schuler: participated in advisory boards (compensated) for AstraZeneca, Boehringer Ingelheim (BI), Novartis (NVS), Pfizer; received research funding from BI, NVS; received honoraria for CME lectures from Alexion, BI, Celgene, GSK, Lilly, NVS, Pfizer; A. Rampersad: is employed by Novartis Pharmaceuticals Corporation; J. Zhou: is employed by Novartis Pharmaceuticals Corporation; Y. Wu: is employed by Novartis Pharmaceuticals Corporation and owns stock; S. Kalambakas: is employed by Novartis Pharmaceuticals Corporation and owns stock; P.Y. Wen: participated in an advisory board for Novartis and received research funding from Novartis.All other authors have declared no conflicts of interest.

Aim: Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (a, b, γ, and d). This study evaluated the effects of the inhibitor on breast cancer normal cell lines (MDA-MB-231, MCF-7, SK-BR-3) and the BCSCs in vitro. Methods: The BCSCs were typically enriched via mammosphere culture. The inhibition of drugs on cancer cells were tested by MTT assay. The tumorigenicities and invasion abilities were detected by wound-healing assay and plate clone formation assay. The mammosphere-forming efficiency of breast cancer cells treated with different concentrations of the BKM120, an operational surrogate of BCSCs, were also performed. The nature of the drug interaction of was evaluated by using the combination index (CI) according to the method of Chou and Talalay. The impact of BKM120 and combined with docetaxel on PI3K/AKT/mTOR pathway was assessed by Western blotting. Results: All three kinds of BCSCs were appeared resistant to BKM120 in vitro, compared with the non-tumorigenic cancer cells. In addition, when three cancer cells treated with the IC50 dose of BKM120, the invasion abilities of cancer cells significantly decreased (P Conclusions: BKM120 can inhibit the growth of normal cancer cells and BCSCs, by inhibiting cell proliferation, descenting the invasion abilities, and reducing the expression of pAKT and pS6 indicating that treatment with BKM120 and docetaxel may be an efficient therapy for normal cancer cells and BCSCs. Disclosure: All authors have declared no conflicts of interest.