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PDF file - 45K, Summary of adverse events suspected to be study-drug related by grade (safety set).

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PDF file - 40K, Figure S2: Biomarkers of in vivo response to inhibitors of PI3K/mTOR signaling. Reverse Phase Protein Analysis (RPPA) of KPL-1 tumor samples taken after 7 days treatment with the molecules indicated. Tumors taken 24 hours post final dose. A, pAKT Ser473. B, pS6 Ser235/236.

PDF file - 772K, Figure S1: Targeting the PI3K/mTOR pathway in HER2-amplified breast cancer cell lines. Effect of A, RAD001, B, BEZ235, C, BKM120 or D, BYL719 treatment on PI3K/mTOR signaling in two representative cell lines; SKBR3 and MDA453 (PIK3CA mutant H1047R). All lysates taken 24 hours post-treatment.

PDF file - 36K, Figure S3. Xenograft response data for 7-day tissue acquisition studies. A-C, SUM190, UACC812 and KPL-1 xenografts (6 mice per arm) were treated with BKM120 at 35 mg/kg, BYL719 at 50 mg/kg, RAD001 at 10 mg/kg and BEZ235 at 30 mg/kg, all daily PO. Trastuzumab was given at given at 10 mg/kg IP twice weekly. For SUM190 (A), tumors were collected 2.5 hours post final dose, for UACC812 (B) and KPL-1 (C), samples were collected 24 hours post final dose.

XLSX file - 213K, Table S2. Summary of in vivo activity of BKM120, BYL719, RAD001 and BEZ235 in breast cancer tumor models. T/C: Ratio of mean tumor volume of treated (T) to control (C) at final day of treatment. Final day was determined as the final day of treatment for the vehicle control arm for each study in Figure 5. Comparisons between groups were all made by Repeated Measures ANOVA (RMANOVA) followed by Dunnett test for multiple comparisons. BW: body weight; TR: treatment related; NTR: non-treatment related.

PDF file - 67K, Bayesian logistic regression model: dose-response curve and model inference results at the time of determination of the recommended Phase II dose.

PDF file - 65K, Criteria for defining dose-limiting toxicities.

Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2+) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2+ advanced/metastatic breast cancer resistant to trastuzumab-based therapy.Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2+ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control.Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways.Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935–45. ©2014 AACR.

PDF file - 38K, Patient disposition (full analysis set).

XLSX file - 14K, Table S1: Calculated IC50s for the PI3K/mTOR pathway inhibitors against the breast cancer cell line panel. ER: Estrogen Receptor. N/A: IC50 not achieved, N/D: IC50 not determined

PDF file - 48K, Exposure to buparlisib and trastuzumab (safety set).

PDF file - 62K, Summary of buparlisib pharmacokinetic parameters.

Background PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. The PI3Kα-sp...

BackgroundCombined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2− breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance.MethodsIn this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance.ResultsWe show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of bothPIK3CAmutant and wild-type ER+/HER2− breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2− breast cancer models.ConclusionsThese data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2− breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

Additional file 1: Figure S1. Activity of ribociclib (NVP-LEE011) in breast cancer cell lines. In vitro IC50s (generational inhibition) for each of the breast cell lines. Data represent mean IC50 +/- 95% confidence interval where available. Hormone receptor positive (ER+) cell lines highlighted in yellow. All experiments were repeated in at least duplicate.

Additional file 2: Figure S2. EFM19-PR cell line xenografts maintain resistance to palbociclib in vivo. Growth curves for EFM19 and EFM19-PR xenografts treated with 100 mg/kg palbociclib QD, 8 mice per arm (mean tumor volume ± SEM) and waterfall plot representing the change in tumor volume after 35 days of treatment.

Additional file 3: Figure S3. Regrowth of xenograft tumors post withdrawal of ER, CDK4/6 and PI3K/mTOR combined targeted therapy. Growth curves of the individual mice from the MCF7 xenograft study depicted in B) where treatment was withdrawn after 28 days and tumors were monitored for up to 9 weeks for progression. For all experiments the following dose schedule was used: Ribociclib 75mg/kg PO QD, alpelisib 35mg/kg PO QD, everolimus 10mg/kg PO QD, letrozole 2.5mg/kg PO QD, fulvestrant 5 mg/mouse QW by subcutaneous injection.

Background: In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer. Methods: This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18–59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients. Findings: Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigator's assessment, median progression-free survival was 23·8 months (95% CI 19·2–not reached) in the ribociclib group compared with 13·0 months (11·0–16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44–0·69; p

The treatment landscape for advanced breast cancer has changed radically over the last 30–40 years with the refinement of surgical and radiographic techniques, approval of a range of chemotherapy regimens in the adjuvant and metastatic settings, and improvements in screening procedures. A deeper understanding of the molecular pathways underpinning tumor growth has led to the identification and development of a number of targeted therapies with particularly high activity in breast cancer. As an example, the prognosis of women with human epidermal growth factor receptor 2-positive (HER2+) breast cancer has improved dramatically since the introduction of HER2-targeted therapies [1]. Meanwhile, in hormone receptor-positive (HR+) breast cancer, the mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to be effective in combination with exemestane [2]. Overall, these innovations have led to the earlier detection of breast cancers and better treatments, resulting in significant improvements in patient survival and quality of life. Finding future treatments for breast cancer will depend on gaining more insights into the pathways driving tumor growth and the mechanisms of acquired and de novo resistance. Investigational targeted agents currently in clinical development include the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib (BYL719) and the cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib (LEE011).

Background: Around 15,000 US patients per year are diagnosed with de novo ABC. Due to the absence of prior systemic treatment for breast cancer, tumors of patients with de novo ABC may exhibit a different disease biology, which could result in different tumor responses compared with patients who have relapsed breast cancer. Ribociclib is an orally bioavailable cyclin-dependent kinase (CDK) 4/6 inhibitor. Results from MONALEESA-2, a double-blind, placebo-controlled, randomized Phase 3 trial (NCT01958021), demonstrated that first-line therapy with ribociclib + letrozole significantly improved progression-free survival (PFS) vs placebo + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC. Many patients with de novo ABC receive endocrine therapy in the first line and in subsequent lines; here we present results from the MONALEESA-2 study in a subpopulation of patients with de novo ABC. Methods: Postmenopausal women (N=668) with HR+, HER2– ABC who had no prior systemic therapy for ABC were randomized 1:1 (stratified by liver and/or lung metastases) to receive ribociclib (600 mg/day; 3-weeks-on/1-week-off) + letrozole (2.5 mg/day; continuous) or placebo + letrozole. Patients with de novo ABC were eligible. Additional eligibility criteria included measurable disease or ≥1 predominantly lytic bone lesion, Eastern Cooperative Oncology Group performance status ≤1, and adequate bone marrow/organ function. Prior CDK4/6 inhibitors or systemic therapy for ABC were prohibited. Patients may have received ≤14 days of letrozole or anastrozole for ABC. The primary endpoint was locally assessed PFS; a predefined subgroup analysis evaluated PFS in patients with de novo ABC. Results: In total, 227 patients with de novo ABC were enrolled. Patients with de novo ABC were equally distributed with 114 (34%) and 113 (34%) in the ribociclib + letrozole and placebo + letrozole arms, respectively. Median duration of exposure to study treatment in the ribociclib + letrozole vs placebo + letrozole arms was 14.1 vs 12.8 months. Treatment was discontinued in 84 (37%) patients with de novo ABC (ribociclib + letrozole vs placebo + letrozole, n [%]; 34 [30%] vs 50 [44%]). Reasons for treatment discontinuation (ribociclib + letrozole vs placebo + letrozole, n [%]) included disease progression (21 [18%] vs 41 [36%]), patient/physician decision (5 [4%] vs 6 [5%]), and adverse events (6 [5%] vs 3 [3%]). PFS was increased in patients with de novo ABC who received ribociclib + letrozole vs placebo + letrozole (hazard ratio=0.448 [95% confidence interval: 0.267–0.750]). The 12-month PFS event-free probability in patients with de novo ABC was 82% in the ribociclib + letrozole arm vs 66% in the placebo + letrozole arm. Conclusions: The combination of ribociclib + letrozole significantly improved PFS compared with placebo + letrozole in postmenopausal women with HR+, HER2– de novo ABC at diagnosis and therefore may become an important treatment option in the de novo ABC setting. Keywords: Advanced breast cancer; CDK4/6 inhibitor; Letrozole; Ribociclib Citation Format: O'Shaughnessy J, Petrakova K, Sonke GS, André F, Conte P, Arteaga CL, Cameron DA, Hart LL, Villanueva C, Jakobsen EH, Lindquist D, Souami F, Li X, Germa C, Hirawat S, Hortobagyi GN. First-line ribociclib plus letrozole in patients with de novo HR+, HER2– advanced breast cancer (ABC): A subgroup analysis of the MONALEESA-2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-05.

Background: Aromatase inhibitors are the standard first-line treatment for patients (pts) with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC). However, resistance via disruption of the cyclin D–cyclin-dependent kinase (CDK)4/6–inhibitor of CDK4–retinoblastoma pathway is common. The oral, selective CDK4/6 inhibitor ribociclib has demonstrated synergistic activity with letrozole in preclinical models of ER+ breast cancer. This Phase Ib study investigated ribociclib plus letrozole in ER+, HER2– aBC (NCT01872260). Methods: Postmenopausal pts with ER+, HER2− aBC received ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg; continuous). The primary objective of the expansion phase was to evaluate safety and tolerability. Secondary and exploratory objectives included efficacy, pharmacokinetics (PK), and biomarkers. Results: As of October 30, 2015, 47 pts received ribociclib plus letrozole: 19 pts in the initial enrollment and 28 pts in the expansion phase. In the initial enrollment, 17/19 pts (89%) were previously treated for aBC (PT group); in the expansion phase, 27/28 pts (96%) were treatment-naïve for aBC (first-line group). All 19 PT pts and 10 first-line pts (62% of all pts) have discontinued treatment. Common (>5% of pts) treatment-related Grade 3/4 adverse events included neutropenia (43%), neutrophil count decreased (11%), and white blood cell count decreased (6%). Complete response (CR) was observed in 1 pt (4%) in the first-line group. In the PT and first-line groups, 1 pt (5%) and 10 pts (36%) had a partial response (PR), 7 pts (37%) and 4 pts (14%) had neither CR nor progressive disease (PD), 7 pts (37%) and 10 pts (36%) had stable disease (SD), and 4 pts (21%) and 3 pts (11%) had PD, respectively. Among pts with measurable disease, overall response rate (ORR; CR + PR) was 9% (95% confidence interval [CI]: 0–41%) for 11 PT pts and 46% (95% CI: 26–67%) for 24 first-line pts, and clinical benefit rate (CBR; CR + PR + SD ≥24 weeks) was 18% (95% CI: 2–52%) for 11 PT pts and 79% (95% CI: 58–93%) for 24 first-line pts. Ribociclib PK data were consistent with single-agent data and indicated no drug–drug interaction with letrozole. Notable genetic alterations detected by next-generation sequencing included PIK3CA mutations (4/10 PT pts [40%]; 14/22 first-line pts [64%]) and ESR1 mutations (2/10 PT pts [20%]). Responses were observed in pts harboring PIK3CA mutations (1 CR [first-line pt], 1 unconfirmed CR [first-line pt], 3 PR [1 PT pt, 2 first-line pts], and 3 unconfirmed PR [first-line pts]). Progression-free survival data for ribociclib plus letrozole, in addition to updated ORR and CBR, will be presented at the symposium. Conclusions: The combination of ribociclib plus letrozole demonstrated encouraging clinical activity, particularly in pts treatment-naïve for aBC, with an acceptable safety profile that is in line with CDK4/6 inhibition. These results, which are consistent with the positive results of the MONALEESA-2 study (NCT01958021), provide additional safety and efficacy evidence for the use of ribociclib plus letrozole for the first-line treatment of postmenopausal aBC. Citation Format: Munster P, Ismail-Khan R, Garcia-Estevez L, Mayer IA, Becerra C, Hamilton E, De Boer R, Wardley AM, Im S-A, Teixeira L, Wang Y, Su F, Germa C, Hirawat S, Juric D. Phase Ib safety, efficacy, and molecular analysis of ribociclib (LEE011) plus letrozole for the treatment of ER+, HER2– advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-18.

Background: Patients with ABC who present with visceral metastases have a worse outcome than patients with non-visceral disease, while patients with bone-only disease tend to have a better prognosis. Ribociclib (LEE011) is an oral, selective inhibitor of cyclin-dependent kinase (CDK) 4/6. In a Phase 3, placebo-controlled, randomized trial (MONALEESA-2; NCT01958021), first-line ribociclib (R) + letrozole (L) significantly prolonged progression-free survival (PFS) vs placebo (P) + L in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC, with a hazard ratio of 0.556 (95% confidence interval [CI]: 0.429–0.720; p=0.00000329) at the interim analysis cut-off date (Jan 29, 2016). Here, we present subgroup analyses in patients with visceral metastases, and those with bone-only disease. Methods: Postmenopausal women with HR+, HER2– ABC were randomized 1:1 to receive R (600 mg/day; 3-weeks-on/1-week-off) + L (2.5 mg/day; continuous) or P+L, stratified by the presence of liver and/or lung metastases. No prior CDK4/6 inhibitors or systemic therapy for ABC were allowed. Eligible patients had Eastern Cooperative Oncology Group performance status ≤1, baseline alanine/aspartate aminotransferase levels Results: Overall, 668 patients were randomized; 393 had visceral metastases and 147 had bone-only disease. Visceral metastasesBone-only disease n=393n=147 R+LP+LR+LP+L n=197n=196n=69n=78Median age, years (range)63 (23–91)63 (29–88)65 (37–85)63 (37–84)De novo metastatic disease, n (%)53 (27)55 (28)28 (41)24 (31)Non-de novo disease-free interval, n (%)≤24 months12 (6)15 (8)5 (7)6 (8)>24 months132 (67)126 (64)36 (52)48 (62)Discontinued treatment, n (%)83 (42)111 (57)29 (42)40 (51)Reason for discontinuation, n (%)Disease progression56 (28)93 (47)17 (25)31 (40)Patient/physician decision10 (5)15 (8)7 (10)6 (8)Adverse events16 (8)3 (2)4 (6)2 (3)Protocol deviation001 (1)1 (1)Death1 ( In patients with visceral metastases: Median PFS was not reached in the R+L arm (95% CI: 19.3–not estimable [NE]) vs 13.0 months (95% CI: 12.6 –16.5) in the P+L arm, with hazard ratio 0.535 (95% CI: 0.385–0.742). Median duration of exposure was 12.0 and 13.0 months (R and L, respectively) in the R+L arm, and 12.1 and 12.2 months (P and L, respectively) in the P+L arm. In patients with bone-only disease: Median PFS was not reached in the R+L arm (95% CI: NE–NE) vs 15.3 months (95% CI: 13.8–NE) in the P+L arm, with hazard ratio 0.690 (95% CI: 0.381–1.249). Median duration of exposure was 12.1 and 12.6 months (R and L, respectively) in the R+L arm, and 12.7 and 12.9 months (P and L, respectively) in the P+L arm. Conclusions: First-line R+L was well tolerated and significantly prolonged PFS vs P+L in postmenopausal women with HR+, HER2– ABC, both in patients with visceral metastases and those with bone-only disease. Keywords: Advanced breast cancer; CDK4/6 inhibitor; Letrozole; Ribociclib Citation Format: Burris HA, Chan A, Campone M, Blackwell KL, Winer EP, Janni W, Verma S, Burdaeva O, Alba E, Favret AM, Mondal S, Miller M, Germa C, Hirawat S, Yap YS. First-line ribociclib + letrozole in patients with HR+, HER2– advanced breast cancer (ABC) presenting with visceral metastases or bone-only disease: A subgroup analysis of the MONALEESA-2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-16.

Background: Altered PI3K/mTOR signaling, through activating mutations in PIK3CA and/or PTEN loss, has been implicated in resistance to both hormonal and HER2-directed therapeutics for breast cancer. Recent data from the BOLERO-1 phase III clinical trials demonstrate an improvement in progression free survival (PFS) of 7.2 months in patients with HER2+/estrogen receptor negative (HER2+/ER-) advanced breast cancer when treated with trastuzumab and paclitaxel plus the mTORC1 inhibitor, everolimus (Afinitor ®). However, improvement in PFS was not observed in patients with HER2+/ER+ positive disease. These data suggest that hormone receptor levels may influence the response of HER2-amplifed cells to both HER2 and PI3K/mTOR directed therapies in the absence of hormonally directed therapies. In this study, we investigated the role of ER in HER2+ breast cancer by screening a large panel of HER2+/ER- and HER2+/ER+ breast cancer cell lines for responses to single agent and combined treatment with PI3K, mTOR, HER2 and ER-directed therapeutics. Materials and Methods: The anti-proliferative activity of BKM120 (pan-PI3K inhibitor), BYL719 (p110α-specific) and everolimus were assessed as single agents or in combination with trastuzumab and/or tamoxifen in a panel of six HER2+/ER+ versus six HER2+/ER- breast cancer cell lines in two-dimensional culture. Drug response IC50s were generated from actual cell counts as measured by Z2-particle counting. Biomarker analyses were conducted using baseline mRNA microarray (Agilent) and reverse phase protein array (RPPA) profiling of each of the cell lines to determine associations with response or resistance data. Results: RPPA analysis confirmed the presence of higher levels of ER protein in the cell lines designated as ER+ and significantly higher levels of PTEN protein were detected in those cell lines. Interestingly, each of the PI3K/mTOR pathway inhibitors tended to have increased single agent activity in the ER+ relative to the ER- lines. Combined activity with trastuzumab and either BKM120 or BYL719 was observed in 6 of the 12 cell lines tested and occurred independent of ER status. Similarly, combined activity of everolimus and trastuzumab was also observed in both HER2+/ER+ and HER2+/ER- cell lines. In 3/6 HER2+/ER+ cell lines the addition of tamoxifen provided no benefit to the combination of trastuzumab and PI3K/mTOR pathway inhibitor, whereas in two cell lines mild antagonism was observed with the triple combination. Finally, one cell line did show significant potentiation from the addition of endocrine therapy on top of HER2/PI3K/mTOR targeting. Discussion: These data confirm levels of estrogen receptor are likely playing a role in response to single agent PI3K/mTOR pathway inhibition and highlight the potential utility of combining endocrine therapy with HER2/PI3K/mTOR-directed therapeutics in a sub-group of HER2-amplified breast cancers. Further in depth biomarker analyses may reveal additional molecular alterations responsible for this differential sensitivity to the double and triple combinations and is underway. Citation Format: O'Brien NA, Nichols CM, Thomas J, Conklin D, Kalous O, Linnartz R, Di Tomasso E, Hurvitz SA, Hirawat S, Slamon DJ. Single agent and combined targeting of PI3K, mTOR, HER2 and ER signaling in a panel of HER2+/ER+ versus HER2+/ER- breast cancer cell lines. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-25.

PTC299 is a novel small molecule that specifically blocks the production of protein from selected mRNAs that under certain conditions use noncanonical ribosomal translational pathways. Hypoxia, oncogenic transformation, and viral infections limit normal translation and turn on these noncanonical translation pathways that are sensitive to PTC299. Vascular endothelial cell growth factor (VEGF) is an example of a transcript that is posttranscriptionally regulated. Single doses of PTC299 (0.03 to 3 mg/kg) were administered orally to healthy volunteers in a phase 1 single ascending‐dose study. In a subsequent multiple ascending‐dose study in healthy volunteers, multiple‐dose regimens (0.3 to 1.2 mg/kg twice a day or 1.6 mg/kg 3 times a day for 7 days) were evaluated. PTC299 was well tolerated in these studies. As expected in healthy volunteers, mean plasma VEGF levels did not change. Increases in Cmax and AUC of PTC299 were dose‐proportional. The target trough plasma concentration associated with preclinical efficacy was achieved within 7 days at doses of 0.6 mg/kg twice daily and above. These data demonstrate that PTC299 is orally bioavailable and well tolerated and support clinical evaluation of PTC299 in cancer, certain viral infections, or other diseases in which deregulation of translational control is a causal factor.

Addition of CDK4/6 inhibitors such as palbociclib, ribociclib or abemaciclib to endocrine-based therapies significantly improves progression-free and in some subgroups, overall survival in patients with advanced estrogen receptor-positive (ER+) breast cancer. However, acquired resistance to CDK4/6 inhibitors remains a significant unmet clinical need. It is critical to ascertain the mechanisms by which tumor cells evade CDK4/6 based therapy. In this study we screen multiple in vitro and in vivo models of acquired resistance to CDK4/6 inhibitors to identify potential resistance/escape pathways and targets for pharmaceutical intervention to overcome resistance. ER+ breast cancer cell lines of diverse molecular backgrounds were conditioned to acquire resistance to CDK4/6 inhibitors through either long-term culture in the presence of clinically relevant concentrations of inhibitors or as cell line xenografts treated through progression on a CDK4/6 inhibitor plus fulvestrant. Baseline and pharmacodynamic changes in cell signaling were measured using reverse phase protein array (RPPA) and RNAseq analysis. Acquired resistance to CDK4/6 inhibitors was associated with decreases in phosphorylated-Rb (pRb) and ER-alpha protein and increases in pAKT and pS6 relative to isogenic controls. The p110α-selective PI3K-inhibitor, alpelisib, in combination with fulvestrant or ribociclib/fulvestrant blocked pAKT signaling in xenografts progressing on palbociclib/fulvestrant and induced significant tumor regressions. Apelisib plus fulvestrant also produced robust anti-tumor responses in xenografts progressing on ribociclib/fulvestrant. Triple combination treatment with ribociclib/alpelisib/fulvestrant induced significant regressions in resistant tumors and in treatment naïve models, where complete tumor regressions occurred regardless of PIK3CA mutation status. Regressions were maintained for >9 weeks post withdrawal of treatment, indicating that therapeutic resistance may be prevented by this triple combination approach. RPPA analysis of responding tumors identified sustained inhibition of both PI3K- and CDK4/6:Rb-pathway signaling accompanied by activation of pro-apoptotic proteins. These data support clinical investigation of targeting PI3K with alpelisib in breast cancers progressing on CDK4/6 based therapies and investigation of upfront triple combination therapy prior to acquisition of resistance to CDK4/6. Citation Format: Neil A. O'Brien, Martina SJ McDermott, Dylan F. Conklin, Alex Gaither, Tong Luo, Raul Ayala, Suruchi Salgar, Emmanuelle DiTomaso, Naveen Babbar, Faye Su, Sara A. Hurvitz, Ronald Linnartz, Kristine Rose, Samit Hirawat, Dennis J. Slamon. Targeting activated PI3K/mTOR signaling overcomes resistance to CDK4/6-based therapies in preclinical ER+ breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3825.

The PI3K/Akt/mTOR pathway is one of the most frequently dysregulated signaling pathways in cancer and an important target for drug development. PI3K signaling plays a fundamental role in tumorigenesis, governing cell proliferation, survival, motility, and angiogenesis. Activation of the pathway is frequently observed in a variety of tumor types and can occur through several mechanisms. These mechanisms include (but are not limited to) upregulated signaling via the aberrant activation of receptors upstream of PI3K, amplification or gain-of-function mutations in the PIK3CA gene encoding the p110α catalytic subunit of PI3K, and inactivation of PTEN through mutation, deletion, or epigenetic silencing. PI3K pathway activation may occur as part of primary tumorigenesis, or as an adaptive response (via molecular alterations or increased phosphorylation of pathway components) that may lead to resistance to anticancer therapies. A range of PI3K inhibitors are being investigated for the treatment of different types of cancer; broad clinical development plans require a flexible yet well-structured approach to clinical trial design.

BACKGROUND: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2).METHODS: In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with PRESULTS: The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10−6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (PCONCLUSIONS: Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021. opens in new tab.)

Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation in squamous cell carcinoma of the head and neck contributes to treatment resistance and disease progression. Buparlisib, a pan-PI3K inhibitor, has shown preclinical antitumour activity and objective responses in patients with epithelial malignancies. We assessed whether the addition of buparlisib to paclitaxel improves clinical outcomes compared with paclitaxel and placebo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Methods In this multicentre, randomised, double-blind, placebo-controlled phase 2 study (BERIL-1), we recruited patients aged 18 years and older with histologically or cytologically confirmed recurrent and metastatic squamous cell carcinoma of the head and neck after disease progression on or after one previous platinum-based chemotherapy regimen in the metastatic setting. Eligible patients were enrolled from 58 centres across 18 countries and randomly assigned (1:1) to receive second-line oral buparlisib (100 mg once daily) or placebo, plus intravenous paclitaxel (80 mg/m 2 on days 1, 8, 15, and 22) in 28 day treatment cycles. Randomisation was done via a central patient screening and randomisation system with an interactive (voice and web) response system and stratification by number of previous lines of therapy in the recurrent and metastatic setting and study site. Patients and investigators (including local radiologists) were masked to treatment assignment from randomisation until the final overall survival analysis. The primary endpoint was progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in all randomly assigned patients. Efficacy analyses were done on the intention-to-treat population, whereas 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 NCT01852292, and is ongoing but no longer enrolling patients. Findings Between Nov 5, 2013, and May 5, 2015, 158 patients were enrolled and randomly assigned to receive either buparlisib plus paclitaxel (n=79) or placebo plus paclitaxel (n=79). Median progression-free survival was 4·6 months (95% CI 3·5–5·3) in the buparlisib group and 3·5 months (2·2–3·7) in the placebo group (hazard ratio 0·65 [95% CI 0·45–0·95], nominal one-sided p=0·011). Grade 3–4 adverse events were reported in 62 (82%) of 76 patients in the buparlisib group and 56 (72%) of 78 patients in the placebo group. The most common grade 3–4 adverse events (occurring in ≥10% of patients in the buparlisib group vs the placebo group) were hyperglycaemia (17 [22%] of 76 vs two [3%] of 78), anaemia (14 [18%] vs nine [12%]), neutropenia (13 [17%] vs four [5%]), and fatigue (six [8%] vs eight [10%]). Serious adverse events (regardless of relation to study treatment) were reported for 43 (57%) of 76 patients in the buparlisib group and 37 (47%) of 78 in the placebo group. On-treatment deaths occurred in 15 (20%) of 76 patients in the buparlisib group and 17 (22%) of 78 patients in the placebo group; most were caused by disease progression and none were judged to be related to study treatment. Interpretation On the basis of the improved clinical efficacy with a manageable safety profile, the results of this randomised phase 2 study suggest that buparlisib in combination with paclitaxel could be an effective second-line treatment for patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck. Further phase 3 studies are warranted to confirm this phase 2 finding. Funding Novartis Pharmaceuticals Corporation.

BackgroundAlthough cough is a commonly reported symptom, objective quantitation of cough during normal activity has not been performed in patients with CF.MethodsAn ambulatory device was used to characterize cough over 24hours. Pulmonary function and subject-reported coughing were also assessed.ResultsPatients included 19 clinically stable adults with CF (males:females=10:9; median age [range]=26 [19-57] years; median %-predicted FEV1 [range]=65 [44-106]%). Median [range] cough rate was 27 [13-66] coughs/hour, with values while awake of 41 [20-102] and while asleep of 2 [0.1-7] (p

Walking abnormalities are prominent in Duchenne muscular dystrophy (DMD). We modified the 6-minute walk test (6MWT) for use as an outcome measure in patients with DMD and evaluated its performance in 21 ambulatory boys with DMD and 34 healthy boys, ages 4 to 12 years. Boys with DMD were tested twice, approximately 1 week apart; controls were tested once. The groups had similar age, height, and weight. All tests were completed. Boys who fell recovered rapidly from falls without injury. Mean +/- SD [range] 6-minute walk distance (6MWD) was lower in boys with DMD than in controls (366 +/- 83 [125-481] m vs. 621 +/- 68 [479-754] m; P < 0.0001; unpaired t-test). Test-retest correlation for boys with DMD was high (r = 0.91). Stride length (R(2) = 0.89; P < 0.0001) was the major determinant of 6MWD for both boys with DMD and controls. A modified 6MWT is feasible and safe, documents disease-related limitations on ambulation, is reproducible, and offers a new outcome measure for DMD natural history and therapeutic trials.

In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR.This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380.Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of -7.1 (SD 7.0) mV (p0.0001), and in the second, with a change of -3.7 (SD 7.3) mV (p=0.032). We recorded a response in total chloride transport (defined as a change in nasal PD of -5 mV or more) in 16 of the 23 patients in the first cycle's treatment phase (p0.0001) and in eight of the 21 patients in the second cycle (p0.0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle's treatment phase (p=0.0003) and for nine of 21 in the second cycle (p=0.02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded.In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction.

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from

Nonsense (premature stop codon) mutations are causative in 5% to 15% of patients with monogenetic inherited disorders. PTC124, a 284-Dalton 1,2,4-oxadiazole, promotes ribosomal readthrough of premature stop codons in mRNA and offers therapeutic potential for multiple genetic diseases. The authors conducted 2 phase I studies of PTC124 in 62 healthy adult volunteers. The initial, single-dose study evaluated doses of 3 to 200 mg/kg and assessed fed-fasting status on pharmacokinetics following a dose of 50 mg/kg. The subsequent multiple-dose study evaluated doses from 10 to 50 mg/kg/dose twice per day (bid) for up to 14 days. PTC124 administered orally as a liquid suspension was palatable and well tolerated through single doses of 100 mg/kg. At 150 and 200 mg/kg, PTC124 induced mild headache, dizziness, and gastrointestinal events. With repeated doses through 50 mg/kg/dose bid, reversible transaminase elevations

Androgens play a critical role not only in the physiological development of the prostate but also in the genesis of prostate cancer. The effects of androgen on the prostate gland and on the other tissues of the body are mediated by activation of the androgen receptor. The androgen receptor is a member of the superfamily of hormone receptors with a DNA-binding site, two zinc finger domains, and a hormone-binding site. Mutations in this receptor can be associated with loss of function or chronic endogeneous activation, depending upon the site of change. Androgens effect a conformal change in the structure of the androgen receptor associated with a change in protein phosphorylation. The androgen receptor can be activated by additional ligands affecting the hormone-binding site besides androgens. Activators and repressors of the androgen receptor modify this protein's function and are very delicately balanced such that disruptions of either function are associated with a disease state. Antiandrogens, which bind to the receptor and thus down-regulate the effects of endogeneous circulating androgens, remain the first line treatment for palliation of advanced prostate cancer. Mutations in the receptor are associated with a change in function of such compounds from antagonist to agonist in vitro. Newer evidence suggests there may be a role of intermittent androgen suppression rather than continuous suppression, perhaps by preventing overgrowth of hormone independent tumor cells. Future research focuses on the development of drugs directed at suppressing the androgen drive of the androgen sensitive clone of the tumor and making the nonsensitive subset more susceptible to cytotoxics.

The selective cyclin dependent kinases 4 and 6 (CDK-4/6) inhibitor, palbociclib, has recently been approved in combination with endocrine-based therapies for the treatment of advanced ER+/HER2- breast cancer (BC). Despite the improvements in progression-free and overall survivals, a significant number of patients on CDK-4/6 therapy will go on to develop progressive disease. As such, it is critical to identify the mechanisms by which tumor cells evade CDK-4/6 targeted therapy and to develop therapeutic strategies to overcome resistance. In this study, we evaluated the efficacy of a p110α-selective PI3K inhibitor, alpelisib (BYL719) and the mTORC1 specific inhibitor, everolimus (RAD001), in ER+/HER2- xenograft tumors conditioned in vitro and in vivo to acquire resistance to combined palbociclib + endocrine-based therapy. The EFM19 (ER+/HER2-, PIK3CA mt), MDA134 (ER+/HER2-, PIK3CA wt), and MDA361 (ER+/HER2+, PIK3CA mt) BC cell lines were conditioned to acquire palbociclib resistance through long-term culture in the presence of increasing concentrations of drug. Baseline total/phosphoprotein levels of over 280 cancer-associated analytes were measured in the parental and resistant cell lines by Reverse Phase Protein Array (RPPA). In vivo resistant models were developed from xenografts of the MCF7 and HCC1500 ER+ BC cell lines, treated until progression with palbociclib (75 mg/kg) + fulvestrant (5 mg/mse). EFM19-PR cells maintained palbociclib resistance in vivo and were included in the xenograft studies. Resistance to palbociclib was confirmed in vitro by a shift in growth inhibitory IC50 from an average of less 50nM to over 1 µM. Significantly reduced Rb and ER protein levels were detected in each of these palbociclib resistant cell lines by RPPA. Cross-resistance to an alternative CDK-4/6 inhibitor (ribociclib) was found in in vitro studies. In addition, switching treatment of the xenografts progressing on palbociclib + fulvestrant to ribociclib (75mg/kg) + fulvestrant did not impact tumor progression. However, when progressing tumors were switched to BYL719 (30mg/kg) + fulvestrant or RAD001 (10mg/kg) + fulvestrant, sustained tumor regression was observed for over 45 days of treatment in every model tested. The triplet combination of ribociclib + fulvestrant + BYL719 or RAD001 provided marginal additional benefit over the doublet combination of BYL719 or RAD001 + fulvestrant. RPPA analysis of xenograft tissue collected from these studies will help to identify additional molecular alterations involved in resistance to CDK-4/6 targeted therapy. These preclinical data indicate that acquired resistance to CDK-4/6 inhibition occurs through a loss of dependence on Rb-signaling. However, targeting an alternative pathway like PI3K/mTOR with molecules such as BYL719 or RAD001 may be a viable strategy for further clinical investigation. Citation Format: Neil A. O'Brien, Dylan Conklin, Tong Luo, Raul Ayala, Shawnt Issakhanian, Ondrej Kalous, Erika Von Euw, Sara A. Hurvitz, Emmanuelle DiTomaso, Faye Su, Ronald Linnartz, Stefan Scherer, Samit Hirawat, Dennis J. Slamon. Anti-tumor activity of the PI3K/mTOR pathway inhibitors alpelisib (BYL719) and everolimus (RAD001) in xenograft models of acquired resistance to CDK-4/6 targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4150. doi:10.1158/1538-7445.AM2017-4150

1038 Background: Endocrine therapy (ET) is the basis of first-line (1L) treatment for HR+ ABC. However, ET resistance are almost universal. At the first interim analysis (IA) of MONALEESA-2 (NCT01958021), ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + LET in patients (pts) with HR+, HER2– ABC.1 Here we report updated efficacy and safety data from MONALEESA-2 with a further ~11 months of follow-up. Methods: Postmenopausal women with no prior therapy for ABC were randomized 1:1 toRIB (600 mg/day, 3-weeks-on/1-week-off) + LET(2.5 mg/day, continuous) vs PBO + LET. The primary endpoint was locally assessed PFS. Secondary endpoints include overall survival (OS; key) and safety. OS significance was defined by a p-value threshold of 3.15 x 10-5. Tumor assessments were performed every 8 weeks for the first 18 months, and every 12 weeks, thereafter. Results: 668 pts were enrolled (334 in each arm). At the second IA for OS (data cut-off Jan 2, 2017), the median duration of follow-up was 26.4 months; 116 deaths and 345 PFS events had occurred. OS data remain immature, with 15.0% vs 19.8% of pt deaths in the RIB + LET vs PBO + LET arm (HR = 0.746; 95% CI: 0.517–1.078; p= 0.059). Updated PFS analyses confirmed continued treatment benefit in the RIB + LET vs PBO + LET arm. The 24-month PFS rates (RIB + LET vs PBO + LET) were 54.7% vs 35.9%. Treatment benefit was consistent across pt subgroups. The most common Grade 3/4 laboratory abnormalities (≥10% of pts; RIB + LET vs PBO + LET) were decreased neutrophils (62.6% vs 1.5%), decreased leukocytes (36.8% vs 1.5%), decreased lymphocytes (16.2% vs 3.9%), and elevated alanine aminotransferase (11.4% vs 1.2%). Conclusion: After 26+ months of follow-up, treatment benefit with 1LRIB + LET persists in postmenopausal women with HR+, HER2– ABC. The study remains immature for OS analysis. The safety profile of RIB + LET remains manageable. 1. Hortobagyi G, et al. N Engl J Med 2016;375:1738–48. Clinical trial information: NCT01958021.

Purpose: Altered PI3K/mTOR signaling is implicated in the pathogenesis of a number of breast cancers, including those resistant to hormonal and HER2-targeted therapies. Experimental Design: The activity of four classes of PI3K/mTOR inhibitory molecules, including a pan-PI3K inhibitor (NVP-BKM120), a p110α isoform–specific PI3K inhibitor (NVP-BYL719), an mTORC1-specific inhibitor (NVP-RAD001), and a dual PI3K/mTORC1/2 inhibitor (NVP-BEZ235), was evaluated both in vitro and in vivo against a panel of 48 human breast cell lines. Results: Each agent showed significant antiproliferative activity in vitro, particularly in luminal estrogen receptor–positive and/or HER2+ cell lines harboring PI3K mutations. In addition, monotherapy with each of the four inhibitors led to significant inhibition of in vivo growth in HER2+ breast cancer models. The PI3K/mTOR pathway inhibitors were also effective in overcoming both de novo and acquired trastuzumab resistance in vitro and in vivo. Furthermore, combined targeting of HER2 and PI3K/mTOR leads to increased apoptosis in vitro and induction of tumor regression in trastuzumab-resistant xenograft models. Finally, as previously shown, targeting mTORC1 alone with RAD001 leads to consistent feedback activation of AKT both in vitro and in vivo, whereas the dual mTOR1–2/PI3K inhibitor BEZ235 eliminates this feedback loop. However, despite these important signaling differences, both molecules are equally effective in inhibiting tumor cell proliferation both in vitro and in vivo. Conclusion: These preclinical data support the findings of the BOLERO 3 trial that shows that targeting of the PI3K/mTOR pathway in combination with trastuzumab is beneficial in trastuzumab-resistant breast cancer. Clin Cancer Res; 20(13); 3507–20. ©2014 AACR.

Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2+) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2+ advanced/metastatic breast cancer resistant to trastuzumab-based therapy. Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2+ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways. Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935–45. ©2014 AACR.

6045Background: A phase II, placebo-controlled study of buparlisib (BUP) and paclitaxel (PAC) in patients (pts) with platinum-pretreated recurrent/metastatic HNSCC (NCT01852292) met its primary end...

The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described.

Myelodysplasia with refractory anemia is associated with transfusion dependence.

Two patients are reported with hemolytic anemia due to red blood cell fragmentation in association with prosthetic heart vales. They were treated with erythropoietin which eliminated the need for packed red blood cell transfusion.

Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein.To evaluate ataluren activity, safety, and pharmacokinetics in children with nonsense mutation CF.Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients took ataluren three times per day (morning, midday, and evening) with randomization to the order of receiving a lower dose (4, 4, and 8 mg/kg) and a higher dose (10, 10, and 20 mg/kg) in the two cycles.The study enrolled 30 patients (16 male and 14 female, ages 6 through 18 yr) with a nonsense mutation in at least one allele of the CFTR gene, a classical CF phenotype, and abnormal baseline nasal epithelial chloride transport. Ataluren induced a nasal chloride transport response (at least a -5-mV improvement) or hyperpolarization (value more electrically negative than -5 mV) in 50% and 47% of patients, respectively, with more hyperpolarizations at the higher dose. Improvements were seen in seven of nine nonsense mutation genotypes represented. Ataluren significantly increased the proportion of nasal epithelial cells expressing apical full-length CFTR protein. Adverse events and laboratory abnormalities were infrequent and usually mild. Ataluren pharmacokinetics were similar to those in adults.In children with nonsense mutation CF, ataluren can induce functional CFTR production and is well tolerated.

Walking abnormalities are prominent in Duchenne muscular dystrophy (DMD). We modified the 6-minute walk test (6MWT) for use as an outcome measure in patients with DMD and evaluated its performance in 21 ambulatory boys with DMD and 34 healthy boys, ages 4 to 12 years. Boys with DMD were tested twice, approximately 1 week apart; controls were tested once. The groups had similar age, height, and weight. All tests were completed. Boys who fell recovered rapidly from falls without injury. Mean +/- SD [range] 6-minute walk distance (6MWD) was lower in boys with DMD than in controls (366 +/- 83 [125-481] m vs. 621 +/- 68 [479-754] m; P0.0001; unpaired t-test). Test-retest correlation for boys with DMD was high (r = 0.91). Stride length (R(2) = 0.89; P0.0001) was the major determinant of 6MWD for both boys with DMD and controls. A modified 6MWT is feasible and safe, documents disease-related limitations on ambulation, is reproducible, and offers a new outcome measure for DMD natural history and therapeutic trials.