PTEN Mut Research Articles

Abstract CT231: Temsirolimus (T) in patients (pts) with solid tumors with PTEN mutation (mut): results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

Abstract Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with PTEN mut treated with T are reported. Methods: Eligible pts had no standard treatment (tx) options, measurable disease, ECOG performance status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. After antihistamine pre-tx, 25 mg T was infused over 30-60 minutes once weekly until disease progression. Low accruing histology-specific cohorts with PTEN mut were collapsed into 1 histology-pooled cohort for analysis. Primary end point was disease control (DC), defined as complete or partial response (PR) or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The primary end point was summarized as a proportion and the hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test with alpha 0.10. Other end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), duration of SD and safety. DOR is defined as time from pt’s first documented objective response (OR) until progressive disease (PD). Duration of SD is defined as time from tx start to PD. Results: 34 pts with solid tumors (10 tumor types; 20/34 pts had prostate, soft tissue sarcoma [STS] or lung) with PTEN mut were enrolled. 6 pts were unevaluable for efficacy, 1 was ineligible. Table shows demographics, outcomes and toxicity. 2 pts obtained PR (prostate and STS) and 5 had SD16+ (lung, head and neck, breast, uterine, and site unspecified) for DC rate of 26% (1-sided 90% CI: 15.1%, 100%) and OR rate of 7% (95% CI: 1%, 24%). The null DC rate was rejected. Median PFS was 10 wks and median OS was 32 wks. Conclusions: T met prespecified criteria to declare a signal of activity in pts with solid tumors with PTEN mut. Table: Baseline Characteristics (N=34); Efficacy Outcomes (n=27); Toxicity Outcomes (N=34) Median (Med) age, years (range) 65 (42, 84) Female, % 14 (41) ECOG PS, % 0 13 (38) 1 18 (53) 2 3 (9) Prior systemic regimens, % 1 3 (9) 2 5 (15) ≥3 26 (77) DC rate, % (OR and SD16+) (1-sided 90% CI) 26 (15.1, 100) OR rate, % (95% CI) 7 (1, 24) Med PFS, wks (95% CI) 10 (7, 17) Med OS, wks (95% CI) 32 (13, 42) DOR, wks (n=2) 11 and 55 Med duration SD, wks (n=5) 27 (24, 36) Number of pts1 with tx-related grade 3-4 AE or SAE AE2 12 (35) SAE3 6 (18) 1Pts may have experienced one or more events 2alkaline phosphatase increase, anemia, chronic kidney disease, diarrhea, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, lung infection, oral pain and all SAEs 3acute kidney injury, dyspnea, generalized muscle weakness, hypophosphatemia, lung infection, oral mucositis, pericardial effusion Citation Format: Kristopher Wentzel, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Li Ding, Evan Pisick, Mridula Krishnan, Deepti Behl, Olatunji B. Alese, Carmen J. Calfa, Kathrine A. Cooper, Herbert L. Duvivier, Raghava Reddy Induru, Janet C. Ruzich, Song Zhao, Gina N. Grantham, Abigail Gregory, Susan Halabi, Richard L. Schilsky. Temsirolimus (T) in patients (pts) with solid tumors with PTEN mutation (mut): results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT231.

Utility of liquid biopsy for identifying emerging mutations (mut) and novel treatment options in luminal metastatic breast cancer (LMBC).

1061 Background: Molecular characterization of LMBC for the choice of therapy and inclusion in clinical trials is frequently performed in archival biopsies procured several years before. Emerging mut secondary to therapeutic pressure are hence frequently missed but could be detected by real-time analysis of circulating tumor DNA. Aim: 1) To assess the emergence of ERBB2 and other mut upon therapeutic pressure; 2) To compare the concordance of mut in tumor and plasma samples between patients (pts) with metachronous and synchronous sample acquisition. Methods: Pts with LMBC and available tumor biopsy and plasma samples were identified and divided in two groups: 1) Cohort 1 (metachronous) if the time between tissue and plasma acquisition was > 3 months and systemic treatment was given between the sampling; 2) Cohort 2 (synchronous) if sampling occurred with < 3 months interval in the absence of systemic treatment. Tumor and plasma were analyzed using MiSeq Amplicon-based NGS (custom panel of 60 cancer-related genes). The emergent mut in plasma in Cohort 1 and the concordance of ESCAT Tier I and II mut ( PIK3CA, AKT1, ERBB2, ESR1, PTEN) in both Cohorts were determined and correlated with clinical features. Results: 176 pts were included, 112 in Cohort 1 and 64 in Cohort 2. In Cohort 1, emerging mut in PIK3CA were identified in 5 cases (14% of total cases with PIK3CA mut), ESR1 in 22 cases (85% of cases with ESR1 mut) and PTEN in 3 cases (43% of cases with PTEN mut). No emerging ERBB2 or AKT1 mut were seen in plasma. In Cohort 1 ERBB2 mut were identified in 10 pts (8.9%), 5 both in plasma and tissue and 5 only in tissue. Concordance between tumor and plasma was 53% in Cohort 1 and 66% in Cohort 2 (95% CI of the difference -2% to 38%, P =.09). In Cohort 1, concordance was not associated with (neo)adjuvant treatment, number of lines for MBC, presence of visceral metastasis, location of biopsy (primary tumor or metastasis), interval between sampling (range 3.6 – 288 months) or type of systemic treatment before plasma sampling. In Cohort 2, higher concordance associated with shorter interval between primary diagnosis and sampling (p = 0.02). PI3KCA and ESR1 were the two genes most frequently altered in both cohorts. PI3KCA mut had the highest degree of concordance in both groups (70% in Cohort 1 and 76% in Cohort 2). Concordance for ESR1 mut was low in both cohorts (20% and 48%, respectively). Conclusions: A significant number of ESR1 mut emerged upon therapeutic pressure in LMBC. Plasma analysis could also detect the emergence of PIK3CA and PTEN, but not ERBB2 mut. The trend towards lower concordance between metachronous and synchronous tumor and plasma sampling is probably due to increased tumor heterogeneity and clonal diversity secondary to systemic treatment. Our findings confirm that liquid biopsies provide complementary information respect to tumor tissue that may be potentially useful for clinical decisions.

Capicua (CIC) mutations in gliomas in association with MAPK activation for exposing a potential therapeutic target.

2056 Background: Capicua (CIC) Gene is a tumor suppressor, transcriptional repressor, and a member of the high mobility (HMG)-box protein family. CIC is a negative regulator of MAPK and RTK pathways; inactivating CIC mutations (mut) occur in approximately 40% of oligodendrogliomas (OLIG) and less frequently in other gliomas putatively activating downstream signaling. With a goal to identify potential novel treatment options for various gliomas, we explored key signaling pathways associated with CIC mut. Methods: Consecutive glioma tumors were analyzed using Next-Gen DNA sequencing (NextSeq, 592 genes or NovaSeq, whole-exome), RNA sequencing (NovaSeq, WTS ) and IHC (Caris Life Sciences, Phoenix, AZ). Immune cell fraction was calculated by QuantiSeq; MAPK activation score (MPAS) was evaluated using RNAseq data. A comparison was made using Chi2 or Fisher’s-exact test with correction for multiple-comparison (q) using Benjamini-Hochberg. Results: A total of 196 (3.7%) tumors with CIC mut were seen in 5266 gliomas tumors analyzed, with the highest prevalence seen in OLIG (143 of 285, 50.2%). There was no difference between grade 3 (73 of 142, 51.4%) and grade 2 OLIG (70 of 143, 49%). CIC mut were infrequent in astrocytomas (16 of 829, 1.9%; grade 3, 12/510 or 2.4%; grade 2, 4/261 or 1.5%; grade 1, 0/58). CIC mut were present in glioblastomas (24/2753 or 0.6%), gliosarcomas (1/128 or 0.8%), and other mixed subtypes (12/185 or 6.5%). CIC mut were associated with higher prevalence of IDH1/2 mut (92% in CIC-mut vs. 17% in wild type), MGMT promoter methylation (97% vs. 47%), FUBP1 mut (32% vs. 1%) but lower PTEN mut (1% vs. 25%) and TP53 mut (12% vs. 39%) (all q < 0.05). Significant mutual exclusivity for CIC mut and MAPK pathway drivers observed: EGFR amplification (1.5% vs. 27%) , EGFR mut (0.5% vs. 12.6%), NF1 mut (4% vs. 18%) (all q < 0.05). BRAF mut rate was similar in CIC-mut or wild-type (1% vs. 3%, p = ns). Although associated with a higher tumor mutation burden (cutoff > = 10 mut/MB, 13% vs. 3%), a lower prevalence of PDL1 expression (1% vs. 16%) and lower M1 macrophage infiltration were seen (all q < 0.05). Similar effects were seen when stratifying by oligodendroglial and astrocytic histology. CIC mut were associated with increased MPAS score in OLIG (p = 0.01), particularly when compared to tumors lacking additional MAPK drivers (p = 0.001). This effect was not seen in astrocytic tumors, although EGFR alterations (including CNA, EGFRvIII, EGFR fusion and mut) were independently associated with increased MPAS scores (p < 0.001). Conclusions: CIC mut were frequent in oligodendrogliomas but occurred rarely in other glioma tumors and are associated with favorable prognostic markers. RNA expression analysis suggests CIC mut is associated with MAPK activation in OLIG, as are EGFR alterations in astrocytomas. Targeted inhibition of this pathway in selected gliomas may be a promising therapeutic avenue and should be explored further.

PB1648 THE CLINICAL RELEVANCE OF INDIRECT MYC INHIBITORS FOR PERSONALIZED T‐ALL TREATMENT

Background:Therapy refractory and relapsed T cell lymphoblastic leukemia (T‐ALL) is still one of the most common reasons for cancer related death in children. The current therapy option is stem cell transplantation, which is associated with many complications and therefore, targeted therapies with low toxicity profiles are urgently needed. The oncogenic transcription factor MYC is excellently suited as a therapeutic target as it has proven to be a potent driver for T‐ALL development. So far, direct inhibition of MYC is not possible due to its undruggable structure. Hence, inhibition of MYC can be achieved indirectly or by targeting synergistic pathways.Aims:The aim of our study is to identify major key regulators in MYC driven T‐ALL. Targeting synergistic pathways of MYC like the PI3K/AKT signalling pathway seems to be a promising strategy to precisely eliminate tumour cells without affecting healthy cells.Methods:We profiled several T‐ALL and a T cell lymphoma cell line model with a specific interest for genes implicated in MYC regulation on mRNA and protein level including major MYC regulator pathways like Notch‐signaling, Raf‐MEK‐ERK cascade, BRD4, protein folding and PI3K/AKT/mTOR pathway. In parallel, we designed a leukemia specific compound library (n = 180) of diverse phase I ‐ III inhibitors including clinically available chemotherapeutics, diverse kinase‐, HSP90‐, proteasome‐, HDAC‐ and BET inhibitors. Synergy studies were performed with preselected compounds in an 11 × 11 matrix.Results:Protein and mRNA profiling displayed a varying distribution of MYC expression, including its associated downstream and upstream signaling pathways. PTEN loss of function mutants (PTEN mut) are described to have an increased pAKT level due to PI3K dysregulation which has a stabilising effect on MYC, and besides that it has also been associated with a poor outcome in T‐ALL patients. Interestingly, PTEN mut expressing T‐ALL cell lines (MOLT4, HPBALL, JURKAT and SUPT1) shown a simultaneous hyper AKT phosphorylation (pAKT), whereas, PTEN wildtype (wt) cell lines (TALL1, HSB2, DND41 and PEER) exhibit remarkably low pAKT. However MYC expression did not strongly correlate with the PTEN/pAKT status. Therefore, we stratified high and low MYC expressing cell lines according to their PTEN mutational status. Thus, we screened the T‐ALL cell lines on our compound library, which covered major MYC regulatory pathways. Remarkably, specific classes of drugs, including PI3K/AKT/mTOR and Aurora kinase A inhibitors exhibited a promising drug profile in PTEN mut models, while MEK and ERK1/2 inhibitors were particularly potent in PTEN wt. These results were corroborated in a (PTEN wt) low MYC expressing T‐ALL1 cell line model, which showed an increased sensitivity toward Aurora Kinase A inhibitors when MYC was overexpressed. Furthermore, combination studies of PI3K inhibitors with the established indirect MYC inhibitors, e.g. BRD4 or Aurora kinase A inhibitors revealed an synergistic effect in PTEN mut when compared to PTEN wt expressing cell lines.Summary/Conclusion:The source of MYC overexpression is very heterogeneous because its maintenance is highly dependent upon many regulatory pathways. Knocking down the oncogenic transcription factor MYC via synergistic pathways is a promising strategy for targeted therapies in the future.

Therapeutic and prognostic impacts of specific gene alterations for squamous cell lung cancer: A result of nationwide genome screening in Japan (LC-SCRUM-Japan).

9060 Background: Various gene alterations occur during the development of squamous cell lung cancer (SqLC), but specific gene alterations for SqLC and their clinical significance remain unknown. Methods: In a nationwide genome screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer patients for genetic alterations using a next-generation sequencing (NGS) system, Oncomine Comprehensive Assay, and have established a large-scale clinico-genomic database. Results: Since February 2013 to December 2018, a total of 6692 lung cancer patients (686 SqLCs, 5360 non-squamous non-small cell lung cancers [Non-sq] and 646 small cell lung cancers [SCLCs]) had been enrolled in the LC-SCRUM-Japan. The success rate of the NGS assay was 91%. Of 639 SqLCs analyzed, 274 (48%) had potentially targetable gene alterations, including 77 NFE2L2 (encoding NRF2) mut, 50 PIK3CA mut, 46 FGFR1 amp, 40 EGFRmut/amp, 36 PTEN mut, 23 KRAS mut, 6 AKT1 mut, 6 MET ex14skip, 5 ALK fusions, 2 FGFR3 fusions. Among the alterations detected, NFE2L2 mut and FGFR1 amp were significantly frequent in SqLC than Non-sq or SCLC (NFE2L2, 12.1% vs. 1.0% vs. 1.3%; p < 0.001, and FGFR1, 7.2% vs. 1.1% vs. 3.4%; p < 0.001). In advanced SqLC patients who received platinum-containing chemotherapies, the median progression-free survival (mPFS) was significantly shorter in NFE2L2-mutated patients (NRF2-type) than NFE2L2/FGFR1-negative patients (nonNF-type) (3.8 [95%CI, 2.9-5.1] vs. 4.5 [95%CI, 3.8-5.4] months, p = 0.03), and similarly, the mPFS of FGFR1-amplified patients (FGFR1-type) (3.5 months [95%CI, 1.5-4.9]) tended to be shorter than that of nonNF-type (p = 0.07), although the response rates were equivalent among the three types. NRF2-type also showed shorter overall survival (OS) than nonNF-type (median OS, 10.4 [95%CI, 6.9-22.3] vs. 16.6 [95%CI, 13.6-21.7] months, p = 0.10). Therapeutic efficacy of nivolumab or pembrolizumab was not different among these types in the current follow-up data. Conclusions: Our large scale genome screening identified specific gene alterations for SqLC and the alterations were associated with a less efficacy of chemotherapy and worse prognosis, suggesting the need for the development of genotype-directed therapeutic strategy for SqLC patients.

Impact of genomic heterogeneity on PI3K/AKT/mTOR inhibitors (PAMi) efficacy in gynecologic cancer (GYN) patients (pts).

5569 Background: Aberrant PI3K/AKT/mTOR activation is common in GYN. Predictive biomarkers to PAMi in GYN have yet to be identified. Methods: Advanced GYN pts with available genomic data, treated with PAMi in phase I/II clinical trials were selected. Mutation (mut) allele fractions (MAFs) were corrected for tumor purity and defined as clonal (cl) (≥ 0.4) or subclonal (scl) ( < 0.4). PAMi efficacy: (i) time to progression (TTP); (ii) clinical benefit rate (CBR: complete/partial response or stable disease > 4 months [m]); and (iii) ratio TTP on PAMi/ TTP on non-standard chemotherapy pre- or post-PAMi (PAMi/nsChemo TTP). Results: From 2010 to 2016, 264 GYN pts (152 ovarian(OC); 75 endometrial(EC); 37 cervical(CC)) had genomic analysis; 50 pts (24 OC [11 PIK3CA mut, 5 KRAS mut], 15 EC [6 PIK3CA mut, 5 PTEN mut, 4 KRAS mut], and 11 CC [9 PIK3CA mut, 3 KRAS mut]) received PAMi (17 pan-PI3K/mTOR or AKT inh, 17 α-PI3K inh, 16 PAMi targeted combos). PAMi therapy was matched (MA) to PIK3CA/PTEN mut in 30 pts (60%). Median age was 57 years (30-70); median number of prior lines was 2 (1-6) and 34 pts (68%) received nsChemo. Efficacy of PAMi: (i) median TTP (3.27 m [95% CI 2.1-4.4] with trend for longer TTP in OC compared to others [3.93 vs. 2.1 m, HR 0.57; p = 0.08], without differences according to MA status [p = 0.26] or regimen [p = 0.5]); (ii) CBR (42% [95% CI 27-58%], without differences according to tumor type [p = 0.47], MA status [p = 1] or regimen [p = 0.86]); and (iii) TTP PAMi/nsChemo ≥ 1.3 (42% [95% CI 24-63%], without differences according to tumor type [p = 0.53], MA status [p = 0.23] or regimen [p = 0.41]). Partial responses were seen in 5 pts (4 PIK3CA mut on single agent PAMi; 1 KRAS mut on PI3K + MEK inh). Of 4 KRAS mut pts, none had CBR with single agent PAMi. PIK3CA mut were cl in 63% of OC, 17% of EC and 40% of CC. Clonal exon 20 PIK3CA mut were more frequent in OC (p = 0.03). We found longer TTP for cl PIK3CA events (4.0 vs. 1.5 m in scl, HR 5.1, p = 0.006) and a trend for exon 20 events (4.4 vs. 1.4 m in exon 9, HR 1.7, p = 0.25). Conclusions: Regardless of PIK3CA/PTEN mut status, PAMi confer CBR in almost 40% of GYN pts. Functionality and clonality of PIK3CA mut impact on TTP and interact with tumor type. Coexisting KRAS mut may drive resistance to single agent PAMi.

Impact of early trials in molecularly-characterized patients (pts) with head and neck cancer (HNC).

6031 Background: Multiple genomic alterations were described in HNC, including squamous cell carcinomas (SCC), salivary gland (SG) and nasopharyngeal (NF) tumors. Tumor molecular profiling (TMP) may increase therapeutic alternatives in early trials for pts with refractory metastatic (met) HNC. We evaluate the impact of matched/unmatched therapy (mT/uT) in HNC with potentially targetable alterations. Methods: From 2010-16, 47 met HNC pts were treated in 57 early trials after TMP. Clinical benefit was measured by: time to progression (TTP); clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] > 4months [m]); progression-free survival [PFS] ratio≥1.3 (PFS under molecular therapeutics/PFS upon last prior chemotherapy [pT]). Results: Median age was 51 years; median number of pT lines was 1 (0-5). In total, 26 SCC, 11 SG, 8 NF and 2 nasosinusal pts (mostly with lymph nodes and lung met) were treated with small kinases (SK) inhibitors (inh) (50%; main targets PI3K/HER/FGFR), immune-oncology (IO) drugs (40%, PD-1/PD-L1), angiogenesis inh (5%) or chaperone, cytidine analog, RNA polymerase (5%). 14/57 trials were mT including CDKinh (1 CDKN2A mutation [mut]), PI3Kinh (5 PIK3CA mut, 2 PTEN mut), PI3K/MEKinh (1 NRAS mut), HERinh (1 ERBB3mut), FGFRinh (2 FGFR1mRNA high, 1 FGF3/4/19 ligand amplified) and porcupine inh (1 ZNFR3mut). Distribution by tumor: IO (16 SCC/5 NF), SKmT (8SG/4SCC/2NF) and SKuT (9SCC/4SG). Responses: 1CR in SCC (IO), 5 PR in SCC (4 IO, 1 FGFRinh), 3 PR in NF (1 cytidin analog, 1 IO, 1 PI3K/MEKinh). Benefit: median TTP 9.33m (CI95% 7-20) with upward trend in NF and SG vs SCC (HR 0.6;p = 0.28), without differences according to target therapies (HR 0.8; p = 0.9); CBR of 58%, without differences by tumor type (p = 0.42) or therapy (SKmT, SKuT, IO; p = 0.5); 60% with PFS ratio≥1.3, significantly higher in SCC and SG (p = 0.016), particularly with IO drug and SKmT, respectively. Conclusions: Considering our preselected fit population as bias selection, individualized treatment selection with novel therapeutics based on TMP, especially in NF and SG irrespective of targets (SKmT, SKuT, IO), and in SCC with IO drugs, seems to confer substantial clinical benefit.

Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities.

High invasiveness and resistance to chemo- and radiotherapy of glioblastoma multiforme (GBM) make it the most lethal brain tumor. Therefore, new treatment strategies for preventing migration and invasion of GBM cells are needed. Using two different migration assays, Western blotting, conventional and super-resolution (dSTORM) fluorescence microscopy we examine the effects of the dual PI3K/mTOR-inhibitor PI-103 alone and in combination with the Hsp90 inhibitor NVP-AUY922 and/or irradiation on the migration, expression of marker proteins, focal adhesions and F-actin cytoskeleton in two GBM cell lines (DK-MG and SNB19) markedly differing in their invasive capacity. Both lines were found to be strikingly different in morphology and migration behavior. The less invasive DK-MG cells maintained a polarized morphology and migrated in a directionally persistent manner, whereas the highly invasive SNB19 cells showed a multipolar morphology and migrated randomly. Interestingly, a single dose of 2 Gy accelerated wound closure in both cell lines without affecting their migration measured by single-cell tracking. PI-103 inhibited migration of DK-MG (p53 wt, PTEN wt) but not of SNB19 (p53 mut, PTEN mut) cells probably due to aberrant reactivation of the PI3K pathway in SNB19 cells treated with PI-103. In contrast, NVP-AUY922 exerted strong anti-migratory effects in both cell lines. Inhibition of cell migration was associated with massive morphological changes and reorganization of the actin cytoskeleton. Our results showed a cell line-specific response to PI3K/mTOR inhibition in terms of GBM cell motility. We conclude that anti-migratory agents warrant further preclinical investigation as potential therapeutics for treatment of GBM.

Abstract OT2-3-08: Phase III randomized study of the oral pan-PI3K inhibitor BKM120 with fulvestrant in postmenopausal women with HR+/HER2– locally advanced or metastatic breast cancer, treated with aromatase inhibitor, and progressed on or after mTOR inhibitor-based treatment – BELLE-3

Abstract Background: The PI3K/AKT/mTOR pathway is frequently activated in breast cancer (BC), and has been implicated in resistance to endocrine therapies and mTOR inhibitors (mTORi). BKM120 is an oral inhibitor of all 4 isoforms of class I PI3K (α, β, γ, δ). In combination with fulvestrant, BKM120 has demonstrated pro-apoptotic effects in vitro and anti-tumor activity in vivo. Preliminary clinical activity was observed with BKM120 in pts with BC, both as a single agent and in combination with letrozole (Mayer, et al. ASCO 2012: #510), or trastuzumab (Saura, et al. SABCS 2011: #PD09-03). Use of the pan-PI3K inhibitor BKM120 may overcome resistance to mTORi in BC by targeting the PI3K pathway upstream; this will be explored in the current study. Stratification of pts according to PI3K activation status will definitively conclude whether this biomarker is predictive of response. Study design: This is a Phase III randomized, double-blind, placebo-controlled trial of BKM120 or placebo in combination with fulvestrant (BELLE-3; CBKM120F2303). Postmenopausal women with HR+/HER2– locally advanced or metastatic BC whose disease has been treated with aromatase inhibitor (AI), and is refractory to endocrine and mTORi combination therapy (progression while on mTORi and endocrine therapy or within 30 days of end of treatment) are eligible for enrollment. Other eligibility criteria include: ≤1 previous line of chemotherapy for advanced disease; and available archival tumor tissue for analysis of PI3K-related biomarkers. Pts are randomized (2:1) to receive continuous BKM120 (100 mg) or placebo daily, and fulvestrant (500 mg). Randomization is stratified according to PI3K pathway activation (PIK3CA mut and/or PTEN mut and/or loss of PTEN protein expression by immunohistochemistry), and visceral disease status. Study treatment is given until disease progression or until study discontinuation for any reason. Co-primary endpoints are progression-free survival (PFS) in both full and PI3K pathway-activated populations based on local investigator assessment (RECIST 1.1). Key secondary endpoints are overall survival (OS) in both full and PI3K pathway-activated populations. Other secondary endpoints are PFS and OS (PI3K non-activated/unknown population), overall response rate and clinical benefit rate, safety (CTCAE 4.03), pharmacokinetics of BKM120, and patient-reported quality of life (EORTC QLQ-C30 and QLQ-BR23). Statistical methods: PFS and OS will be estimated using the Kaplan–Meier method for full and PI3K pathway-activated populations. Both primary and key secondary endpoints will be tested using a stratified log-rank test at levels α governed by a graphical gate-keeping procedure. A stratified Cox regression will be used to estimate the hazard ratio, along with two-sided 95% CI. Target accrual: Estimated enrollment for BELLE-3 is 615 pts. Recruitment in this Global study is ongoing with planned enrollment of patients in North America, South America, Europe and Asia. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-08.

Abstract OT2-3-09: Phase III randomized study of the oral pan-PI3K inhibitor BKM120 with fulvestrant in postmenopausal women with HR+/HER2– locally advanced or metastatic breast cancer resistant to aromatase inhibitor – BELLE-2

Abstract Background: The PI3K/AKT/mTOR pathway has been reported altered in up to 40% of hormone receptor-positive (HR+) breast cancers (BC). Furthermore, pathway activation has been implicated in resistance to endocrine therapy, including aromatase inhibitors (AI). BKM120 is an oral inhibitor of all 4 isoforms of class I PI3K (α, β, γ, δ). In combination with fulvestrant, BKM120 has demonstrated pro-apoptotic effects in vitro, and achieved near-complete tumor regression in HR+ PIK3CA-mutated estrogen-independent xenografts. Preliminary clinical activity was observed with BKM120 in patients with BC, both as a single agent and in combination with letrozole (Mayer, et al. ASCO 2012: #510) or trastuzumab (Saura, et al. SABCS 2011: #PD09-03). Study design: This is a Phase III randomized, double-blind, placebo-controlled trial of BKM120 or placebo in combination with fulvestrant in postmenopausal women with HR+/HER2– locally advanced or metastatic BC that progressed on or after AI treatment (BELLE-2; CBKM120F2302; NCT01610284). After a 14-day fulvestrant run-in phase to allow determination of tumor PI3K pathway activation status, patients are randomized (1:1) to receive continuous BKM120 (100 mg/d) or placebo, and fulvestrant 500 mg at C1D15, and D1 of all cycles thereafter; 1 cycle=28 days. Randomization is stratified according to PI3K pathway activation (PIK3CA mut and/or PTEN mut and/or loss of PTEN protein expression by IHC), and visceral disease status. Study treatment is given until disease progression or until study discontinuation for any reason. Eligibility criteria include: postmenopausal women with HR+/HER2– locally advanced or metastatic BC refractory to AI (progression while on AI, or within 4 wks [metastatic] or 12 mos [adjuvant] of last AI dose); no more than 1 previous line of chemotherapy for advanced disease; and available archival tumor tissue for analysis of PI3K-related biomarkers. Co-primary endpoints: PFS in the full and PI3K pathway-activated populations based on local investigator assessment (RECIST 1.1). Key secondary endpoints: overall survival (OS) in both full and PI3K pathway-activated populations. Other secondary endpoints: PFS and OS (PI3K non-activated/unknown population), overall response rate and clinical benefit rate (both in full, PI3K-activated, PI3K non-activated/unknown populations), safety (CTCAE 4.03), pharmacokinetics of BKM120 and fulvestrant, and patient-reported quality of life (EORTC QLQ-C30 and QLQ-BR23). Statistical methods: PFS and OS will be estimated using the Kaplan–Meier method for both full and PI3K pathway activated populations. Both primary and key secondary endpoints will be tested using a stratified log-rank test at levels α governed by a graphical gate-keeping procedure. A stratified Cox regression will be used to estimate the hazard ratio, along with two-sided 95% confidence interval. Target accrual: Estimated enrollment for BELLE-2 is 842 patients. Recruitment in this Global study is ongoing with planned enrollment of patients in North America, South America, Europe, Asia and Africa. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-09.