David Demanse

Phase I, Dose-Escalation Study of BKM120, an Oral Pan-Class I PI3K Inhibitor, in Patients With Advanced Solid Tumors

PURPOSE This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), safety, preliminary activity, pharmacokinetics (PK), and pharmacodynamics of BKM120, a potent and highly specific oral pan-Class I PI3K inhibitor. PATIENTS AND METHODS Thirty-five patients with advanced solid tumors received daily BKM120 12.5 to 150 mg. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Assessments included archival tumor molecular status, response by Response Evaluation Criteria in Solid Tumors (RECIST), positron emission tomography tracer uptake ([(18)F]fluorodeoxyglucose positron emission tomography [FDG-PET]), fasting plasma C-peptide, and phosphorylated ribosomal protein S6 (pS6) in skin biopsies. RESULTS Overall, treatment was well tolerated. Dose-limiting toxicities were grade 2 mood alteration (80 mg), grade 3 epigastralgia, grade 3 rash, grade 2 and grade 3 mood alteration (100 mg), and two grade 4 hyperglycemia (150 mg). The MTD was 100 mg/d. Frequent treatment-related adverse events included rash, hyperglycemia, diarrhea, anorexia, and mood alteration (37% each); nausea (31%); fatigue (26%); pruritus (23%); and mucositis (23%). BKM120 demonstrated rapid absorption, half-life of ∼40 hours, ∼three-fold steady-state accumulation, dose-proportional exposure, and moderate interpatient variability. One patient demonstrated a confirmed partial response (triple-negative breast cancer); seven patients (20%) were on study for ≥ 8 months. BKM120 demonstrated dose-dependent pharmacodynamic effects on [(18)F]FDG-PET, fasting C-peptide, fasting blood glucose, and pS6. No significant trends were seen to correlate tumor molecular alterations with clinical activity. CONCLUSION This study demonstrates feasibility and proof-of-concept of class I PI3K inhibition in patients with advanced cancers. BKM120, at the MTD of 100 mg/d, is safe and well tolerated, with a favorable PK profile, clear evidence of target inhibition, and preliminary antitumor activity.

A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors

Purpose: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. Experimental Design: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non–small cell lung, ovarian, or pancreatic cancer. Results: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non–small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. Conclusions: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. Clin Cancer Res; 21(4); 730–8. ©2014 AACR.

Abstract P6-10-07: Phase I study of BYL719, an alpha-specific PI3K inhibitor, in patients with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC)

Background: Deregulation of the PI3K pathway occurs in >50% of breast cancers. Mutations in PIK3CA, the gene encoding the p110alpha subunit of PI3K contributes to resistance to endocrine and anti-HER2 therapies. BYL719 is a potent, specific oral inhibitor of the alpha subunit of PI3K, which inhibits wild-type p110alpha and its most common somatic mutations (IC50=5 nM) much more potently than other PI3K isoforms. Methodology: BYL719 has been investigated in a phase I study in patients with PIK3CA mutant advanced solid tumors. BYL719 has a favorable safety and PK profile; the MTD was established at 400 mg once daily (Juric et al., AACR 2012). As of 5 September 2012, 79 patients have been enrolled in this phase I study, among them 20 patients with PIK3CA mutant ER+ MBC. 5 of these patients had ER+/HER2 positive (HER2+) MBC. Presence of PIK3CA mutations was determined by either local or central assessment. Results: 20 patients with ER+ PIK3CA mutant MBC were treated once daily with BYL719 at doses of 30 mg (n = 1), 180 mg (n = 1), 270 mg (n = 1), 400 mg (n = 14) and 450 mg (n = 3). Median age was 55 years (range 40–78). 15/20 patients with ER+ PIK3CA mutant MBC had HER2 negative and 5/20 had HER2+ MBC. Patients had received a median of 5 previous treatment regimens (range 1–11). Most patients had received multiple prior lines of endocrine therapy including tamoxifen and aromatase inhibitors; 9 patients also received fulvestrant and 16 patients received prior chemotherapy. HER2+ patients have been previously treated with trastuzumab and/or lapatinib. Based on a recent analysis of 19 patients (data cut-off 5 July 2012), the safety of BYL719 in patients with ER+ MBC was comparable to the overall study population. Most frequent adverse events (AEs; ≥10%) suspected to be related to BYL719 were hyperglycemia, diarrhea, nausea, fatigue, decreased appetite, vomiting, rash and erythematous rash, dysgeusia, dry mouth, and stomatitis. The majority of AEs were CTCAE grade 1/2 and were clinically well manageable. Most frequent CTCAE grade 3/4 events were hyperglycemia and erythematous rash. 18/20 PIK3CA mutant ER+ MBC patients were treated at potentially effective doses of ≥270 mg/day. 6/18 patients (33%) achieved tumor shrinkage > 20%, among them 2 patients achieved partial responses (PR) by RECIST. Median progression free survival (PFS) analyzed in 17 patients treated at ≥270 mg/day in the ER+ BC patients was 7.3 months (CI [4.6,9.5]), compared to 3.7 months (CI [1.8,5.5]) in 38 patients with other PIK3CA mutant solid tumors (data cut-off 5 July 2012) Conclusion: BYL719 has a favorable safety profile with manageable side effects, which were mainly related to its mechanism of action. BYL719 shows promising preliminary clinical activity as single agent in patients with PIK3CA mutant ER+ MBC, warranting further clinical development. The investigation of BYL719 continues in patients with ER+ MBC as single agent, and in combination with endocrine therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-07.

Abstract PD5-5: Phase I study of the PI3Kα inhibitor BYL719 plus fulvestrant in patients with PIK3CA-altered and wild type ER+/HER2- locally advanced or metastatic breast cancer

Background: BYL719 selectively inhibits the α-isoform of Class I PI3K. PI3Kα is encoded by PIK3CA, a frequently altered gene in human cancers. Preclinical data indicate BYL719 may be more effective in patients (pts) with PIK3CA-altered tumors; however there are data to suggest that PIK3CA-wild-type (wt) tumors may also be sensitive to BYL719. Here, we present updated data from the Phase I study of BYL719 + fulvestrant in pts with PIK3CA-altered or -wt ER+/HER2– locally advanced/metastatic breast cancer (BC) (NCT01219699). Methods: Adult women with PIK3CA-altered (mutation or amplification) ER+/HER2– BC received continuous oral BYL719 (300–400 mg/day; 28-day cycles) + fixed-dose fulvestrant (500 mg every 4 weeks, plus an additional dose 2 weeks after first dose) during dose escalation and expansion. Pts with PIK3CA-wt ER+/HER2– BC were enrolled into the dose expansion to receive BYL719 400 mg/day + fulvestrant. A Bayesian logistic regression model with overdose control guided dose escalation. Primary objective: to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of BYL719 in combination with fulvestrant, which was declared previously as 400 mg/day. An expansion cohort at the MTD assessed safety (CTCAE v4.0), tolerability, pharmacokinetics (PK), and preliminary efficacy (RECIST v1.0). Results: As of May 2, 2014, 64 pts (PIK3CA-altered n=41; PIK3CA-wt n=16; PIK3CA status unknown/pending n=7) received BYL719 300–400 mg/day + fulvestrant. Median number of prior antineoplastic therapies: 5 (range: 1–12) for pts with PIK3CA-altered tumors and 5 (range: 4–16) for pts with PIK3CA-wt tumors. Prior fulvestrant treatment: 19 (46%) and 7 (44%) pts with PIK3CA-altered and -wt tumors, respectively. Overall, the most common (≥25%) adverse events (AEs; all grades/all doses) suspected to be study drug-related were hyperglycemia (41%), diarrhea (34%), nausea (30%), and vomiting (25%). The most common (>10%) study drug-related Grade 3/4 AEs (all doses) were maculopapular rash (14%) and hyperglycemia (13%). Preliminary antitumor activity was observed in this trial. At data cut-off, partial responses (PRs) were observed in 2 patients with PIK3CA-altered tumors evaluable for response (2/33, 6%), but no PRs were observed in the 15 evaluable patients with PIK3CA-wt tumors. Duration of exposure was >16 weeks in 24 (59%) patients with PIK3CA-altered tumors and in 5 (31%) patients with PIK3CA-wt tumors. PK and exposure of BYL719 + fulvestrant was similar to that observed with single-agent BYL719 at the same dose levels. At data cut-off, treatment was ongoing in 20 (49%) and 2 (13%) pts with PIK3CA-altered and -wt tumors, respectively. Conclusions: BYL719 + fulvestrant demonstrated a favorable safety profile in pts with PIK3CA-altered and -wt ER+/HER2– BC, with mostly on-target effects (i.e. hyperglycemia, rash). Preliminary clinical activity was seen in pts with PIK3CA-altered and -wt tumors, but confirmed PRs were only observed in pts with PIK3CA-altered tumors. The low number of pts with PIK3CA-wt tumors limits further conclusion. Citation Format: Filip Janku, Dejan Juric, Javier Cortes, Hope Rugo, Howard A Burris, Martin Schuler, Barbara Deschler-Baier, Mark R Middleton, Marta Gil-Martin, Jordan Berlin, Eric Winer, Douglas Bootle, Lars Blumenstein, David Demanse, Christina Coughlin, Cornelia Quadt, Jose Baselga. Phase I study of the PI3Kα inhibitor BYL719 plus fulvestrant in patients with PIK3CA-altered and wild type ER+/HER2- locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-5.

Phosphatidylinositol 3-Kinase α–Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study

Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.

Abstract P2-16-14: Preliminary safety, pharmacokinetics and anti-tumor activity of BYL719, an alpha-specific PI3K inhibitor in combination with fulvestrant: Results from a phase I study

Background: Phosphatidylinositol-3-kinase (PI3K) pathway activation has been associated with resistance to anti-estrogen receptor (ER) therapy and PIK3CA mutated ER+ breast cancer (BC) cells are sensitive to inhibition of PI3K under estrogen deprivation. In an in vitro study, the combination of BYL719 and fulvestrant was synergistic in PIK3CA mutated BC cell lines. In the BYL719 single agent part of this study out of 21 ER+ BC patients (pts), 3 partial responses were observed and 5 pts remained on the study with stable disease for over 26 weeks. Median PFS in pts with ER+ PIK3CA mutated BC was 5.5 months (Gonzalez-Angulo, 2013). Methods: This phase I study was amended to determine the Maximum Tolerated Dose (MTD) of BYL719 in combination with the ER antagonist fulvestrant in PIK3CA mutated ER+ breast cancer pts. Dose escalation of BYL719 in combination with fixed dose fulvestrant used an adaptive Bayesian logistic regression model with overdose control. The starting dose of BYL719 was 300 mg once daily, 25% below the MTD of single agent BYL719. All pts received the standard dose of 500 mg fulvestrant every 4 weeks. No dose escalation of fulvestrant was permitted. Following the MTD declaration, a dose expansion cohort will open. Results: At the data cut-off (27 March 2013), 4 pts were enrolled in the initial cohort of 300 mg/q.d. BYL719 plus 500 mg/qmonth (with an additional dose at week 2) fulvestrant, followed by 8 pts into the subsequent 400 mg/q.d. BYL719 plus fulvestrant dose combination. No pts experienced dose limiting toxicity (DLT) in the 300 mg cohort, and 1 pt experienced a DLT of CTCAE grade 3 diarrhea, vomiting, fatigue, anorexia and bloating in the 400 mg cohort. The MTD of BYL719 in combination with fulvestrant has been declared as 400 mg/q.d. The most frequent BYL719 related toxicities (>15% pts), regardless of grade and treatment group, are diarrhea (42%), hyperglycemia (33%), decreased appetite (25%), nausea (25%), and fatigue (17%). Systemic drug exposure of oral BYL719 when given in combination with fulvestrant was found to be similar to the single agent data. The patients were typically pre-treated with numerous chemotherapy, hormonal or targeted therapies. One pt in the 300 mg/q.d. cohort had a confirmed partial response, and 2 pts in the 400 mg/q.d. cohort had a partial response (one confirmed and one only occurring after the data cut-off). From the 12 breast cancer pts treated, 2 (17%) discontinued treatment due to progressive disease, and the median exposure of all pts at the time of data cut-off was 9 weeks. Conclusions: This combination displays a favorable safety and PK profile, both comparable to the single agent BYL719 experience. BYL719 in combination with fulvestrant shows encouraging preliminary anti-tumor activity, which supports further investigation of this combination. Recruitment within the dose expansion is continuing to obtain a sample size of 20 patients carrying the PIK3CA mutation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-14.

P3-16-01: Safety Profile and Clinical Activity of Single-Agent BKM120, a Pan-Class I PI3K Inhibitor, for the Treatment of Patients with Metastatic Breast Carcinoma.

Background Phosphatidylinositol 3-kinase (PI3K) is critical to cancer cell growth, survival, and metabolism. BKM120 is an oral pan-class I (α, β, γ, δ) PI3K inhibitor that has demonstrated in vitro and in vivo tumor cell growth inhibition in a range of cancer types including breast cancer. Materials and methods: The Phase I study CBKM120X2101 investigating single-agent daily BKM120 in patients (pts) with advanced solid tumors has been recently completed with the maximum tolerated dose established at 100 mg/day. Here, we report the analysis of metastatic breast carcinoma (MBC) pts enrolled in this study. Results: Overall, 83 pts have enrolled, 21 of whom have MBC. At the cut-off date of 25th February 2011, 20 MBC pts were evaluable: 1 pt at 80 mg, 1 pt at 150 mg and 18 pts at 100 mg. Patient characteristics were as follows: median age 55 years (range 37–71); performance status ECOG 0/1/2 for 7/12/1 pts, respectively; visceral disease was reported in 16 pts, including liver, 10 pts (50%); lung, 9 pts (45%); and pleura, 5 pts (25%); all pts had >3 lines of systemic therapy (3-12). The median time from last treatment and study entry was 46 days (29-235). The median duration of BKM120 treatment administered was 7.5 weeks (1.0−96.4). The most frequent grade 3 drug-related adverse events (AEs) were: transaminases increase, 4 pts; psychiatric disorders, 3 pts, consisting of anxiety, affective disorder, and mood alteration (1 pt each); diarrhea, 2 pts; fatigue, 2 pts; and hyperglycemia, 1 pt. The only grade 4 drug-related AE was hyperglycemia, reported in 1 pt at 150 mg. Most AEs were manageable with treatment interruption and dose reductions. Eighteen pts were evaluable for objective tumor response by RECIST. Two pts (11%) exhibited partial responses, which were confirmed in a triple-negative MBC pt, and unconfirmed in an ER+ HER2− MBC pt. For these 2 pts, the treatment duration was 29+ (ongoing) and 6 months, respectively. An additional 9 pts (50%) had stable disease, lasting >4 months in 7 pts (35%). Conclusions: This preliminary analysis showed that BKM120 has single-agent activity in heavily pretreated pts with MBC, and an acceptable safety profile. Molecular profiling and updated pharmacokinetic results will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-01.

Association of Somatic Driver Alterations With Prognosis in Postmenopausal, Hormone Receptor–Positive, HER2-Negative Early Breast Cancer: A Secondary Analysis of the BIG 1-98 Randomized Clinical Trial

Importance A range of somatic driver alterations has been described in estrogen receptor–positive, HER2-negative (ER+/HER2−) early breast cancer (BC); however, the clinical relevance is unknown. Objective To investigate associations of driver alterations with prognosis and the role of PIK3CA mutations in prediction of benefit associated with endocrine therapy in postmenopausal patients with ER+/HER2− early BC treated with tamoxifen or letrozole. Design, Setting, and Participants The Breast International Group (BIG) 1-98 trial randomized 8010 postmenopausal patients with hormone receptor–positive, operable, invasive BC to monotherapy with letrozole, tamoxifen, or a sequential strategy for 5 years. Driver alterations were characterized using next-generation sequencing in primary tumors from a subset of 764 patients from 7329 eligible patients with ER+/HER2− BC, with 841 distant recurrences after a median of 8.1 years of follow-up. To correct for the oversampling of distant recurrences, weighted analysis methods were used. This analysis was conducted from April 4, 2016, to November 30, 2016. Main Outcomes and Measures The prevalence of driver alterations, associations with clinicopathologic factors, distant recurrence-free interval, and treatment interactions were analyzed. Multivariable analyses were performed to adjust for clinicopathologic factors. Results Of 764 samples, 538 (70.4%), including 140 distant recurrence events, were successfully sequenced. Nineteen driver alterations were observed with 5% or greater frequency, with a mean of 4 alterations (range, 0-15) per tumor. PIK3CA mutations were the most common (49%) and were significantly associated with reduction in the risk for distant recurrence (hazard ratio [HR], 0.57; 95% CI, 0.38-0.85; P = .006). TP53 mutations (HR, 1.92; 95% CI, 1.21-3.04; P = .006), amplifications on 11q13 (HR, 2.14; 95% CI, 1.36-3.37; P = .001) and 8p11 (HR, 3.02; 95% CI, 1.88-4.84; P < .001), and increasing number of driver alterations (HR per additional alteration, 1.18; 95% CI, 1.11-1.25; P < .001) were associated with significantly greater risk. Amplifications on 11q13 and 8p11 remained significant predictors in multivariable analysis, but not PIK3CA and TP53 mutations. Patients with tumors harboring kinase or helical domain PIK3CA mutations derived significantly greater benefit from letrozole over tamoxifen than patients whose tumors did not (P interaction = .002). Conclusions and Relevance In ER+/HER2− postmenopausal, early-stage BC, amplifications on 11q13 and 8p11 were significantly associated with increased risk for distant recurrence and PIK3CA mutations were predictive of greater magnitude of benefit from letrozole. With these findings, DNA-based classification may aid adjuvant treatment decision making in this setting. Trial Registration ClinicalTrials.gov Identifier: NCT00004205

Abstract S1-10: Clinical implications of somatic mutations in post-menopausal early-stage estrogen receptor (ER)-positive HER2-negative breast cancer (BC): Results from the BIG 1-98 study

Background Next generation sequencing (NGS) has revealed that ER+/HER2- BCs have diverse somatic copy number and mutation profiles but thus far the clinical relevance of such findings is unknown. We characterized the molecular alterations in post-menopausal primary BC patients treated in the BIG 1-98 adjuvant letrozole and tamoxifen study and evaluated their associations with prognosis. Materials and Methods NGS was used to genotype DNA from archival primary tumor blocks for 286 cancer-related genes. From 2706 available eligible samples (confirmed ER+, excluding HER2-positivity or neoadjuvant treatment, adequate DNA quality/quantity), a case-cohort design selected 764 samples: all distant relapses and a stratified sampling of non-relapses after 8yr median follow-up. Mutation prevalence and associations with clinicopathological factors (CP) as well as distant recurrence-free interval (DRFS) were analyzed using weighted tests and Cox regression models, with sampling weights to represent the ER+/HER2-negative trial population. Multivariable analyses were adjusted for tumor size, nodal status, grade and age. Results NGS data was available from 538/764 samples (70%), there were 140 (26%) distant relapses. Median sequencing depth was 483x. There was a mean of 11 mutations (1-46) per sample, with 25% having 13 or more mutations and no tumors without a mutation. Overall 28 genes were altered at a frequency of >10%. The most commonly mutated genes were PIK3CA (49.3%), NCOR1 (27.2%), MAP3K1 (23.8%) TP53 (16.6%), CCND1 (17.8%) and GATA3 (17.1%). Alterations that were significantly associated with both Luminal B (Ki67 >14%) and grade 3 included TP53 mutations (p Gene alterations that were significantly associated with shorter DRFS included TP53 (HR:2.16), ARID1A (HR:2.43), CHEK2 (HR:2.54), BRCA2 (HR:1.93), PTEN (HR:2.03), CCND1 (HR:1.82) and FGFR1 (HR:1.78). PIK3CA was significantly associated with lower risk of distant relapse (HR:0.64; 0.43-0.97). Increasing number of total mutations was significantly associated with shorter DRFS (HR:1.04; 95% CI 1.01-1.07; p=0.006). In the multivariable model adjusted for CP factors, ARID1A, BRCA2, CCND1, CHEK2 and PTEN remained independent for shorter DRFS. Greater than 90% of PIK3CA mutations co-existed with another alteration, most common being NCOR1 (29%), MAP3K1 (24%), CDH1 (16%), GATA3 (16%), TP53 (14%) and CCND1 (13%). Patients with a PIK3CA mutation had greater benefit with letrozole over tamoxifen monotherapy (HR 0.32; 0.13-0.8) than those without (HR:0.70; 0.33-1.48) (Pint=0.06). This effect was strongest in the subgroup of PIK3CA mutant patients who were CCND1 and TP53 wild-type (HR:0.24, 0.12-0.48; Pint=0.02) with only 1% relapsing at 5 years. Conclusion: For the first time, we report the prognostic relevance of oncogenic mutations in ER+/HER2- postmenopausal early-stage BCs from a clinical trial. Tumors with PIK3CA mutations derived greater benefit from letrozole over tamoxifen monotherapy, especially if wild-type for CCND1 and TP53. These findings could significantly improve prognostic risk classification and guide future clinical trials of targeted therapies in ER+/HER2- BCs. Citation Format: Loi S, Asher R, Lee CK, Luen S, Savas P, Kammler R, Dell9Orto P, Blasi OM, Demanse D, JeBailley L, Dolan S, Hackl W, Thuerlimann B, Viale G, Regan M, Colleoni MA. Clinical implications of somatic mutations in post-menopausal early-stage estrogen receptor (ER)-positive HER2-negative breast cancer (BC): Results from the BIG 1-98 study [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 S1-10.

Abstract A46: Inhibition of PIK3CA with BYL719 can overcome resistance to cetuximab in squamous cell carcinoma of the head and neck (SCCHN)

Background: Preclinical data suggest squamous cell tumors, such as SCCHN, are driven by epidermal growth factor receptor (EGFR) overexpression. However, many patients are refractory to anti-EGFR treatment due to intrinsic and acquired resistance. PI3K/AKT/mTOR pathway activation is a potential mechanism of resistance to EGFR-directed therapy. BYL719, a selective α-isoform PI3K inhibitor, enhances cetuximab (EGFR inhibitor) activity in SCCHN cell lines. A Phase Ib/II study combining BYL719 with cetuximab in patients with recurrent/metastatic SCCHN is testing this hypothesis (Razak et al, ASCO 2014, abst 6044; NCT01602315). Here, we outline the preclinical rationale for combining BYL719 with cetuximab in the setting of cetuximab-resistant squamous cell carcinoma, highlight Phase Ib safety and efficacy data in patients with SCCHN who have received prior cetuximab, and describe the design of the Phase II portion of the study, which is assessing both cetuximab-naive and -pretreated patients. Methods: The combination of BYL719 and cetuximab was tested in vivo in two xenograft models of esophageal squamous cell carcinoma: KYSE180 (cetuximab-sensitive model) and KYSE180_CR (cetuximab-resistant, induced by long-term in vivo treatment). In the Phase Ib study, BYL719 was administered once daily (QD) in 28-day cycles with standard weekly (QW) cetuximab (400 mg/m2 on Cycle 1 Day 1; 250 mg/m2 QW thereafter) to adults with histologically/cytologically confirmed recurrent/metastatic SCCHN resistant/intolerant to platinum-based chemotherapy (prior cetuximab therapy was allowed). Results: In the KYSE180 model, the addition of BYL719 to cetuximab demonstrated an additive effect leading to tumor regression; furthermore, in the KYSE180_CR model, adding BYL719 to cetuximab completely restored sensitivity and led to similar activity as seen in the cetuximab-sensitive model, suggesting that inhibiting PIK3CA signaling may overcome resistance to cetuximab. In the Phase Ib study, as of March 10, 2014, 37 patients were treated with BYL719 300 mg QD (n=32) or 400 mg QD (n=5) and cetuximab. Frequent adverse events (>30%; all-grade/Grade 3/4) were hyperglycemia (54/24), stomatitis (38/5), and dermatitis acneiform (35/3). Best overall response (BOR) per RECIST v1.1 in the full population (n=37) was 4 partial responses (PRs), 16 stable disease (SD; of which 5 were unconfirmed PRs), 10 unknown (UNK) responses, and 1 non-complete response/non-progressive disease (PD) at 300 mg or 400 mg. Six patients had PD as BOR. The overall response rate (ORR) in the full population was 4/37 (11%) and the disease control rate (DCR) was 20/37 (54%). Within this population, 7 patients had received prior cetuximab therapy (6 in the metastatic/recurrent setting and 1 curative; BOR: 4 SD, 1 PR, 1 PD, and 1 UNK). Of these 7 patients, 1 had a confirmed PR, 2 had unconfirmed PRs, 2 had SD, and 1 had PD with BYL719 and cetuximab. One patient with prior cetuximab therapy had an UNK response due to death from tumor lysis syndrome after 1 week in the study. The ORR among patients with prior cetuximab was 1/7 (14%) and DCR was 5/7 (71%). Phase II tests the combination of BYL719 at the recommended Phase II dose of 300 mg QD in two second-line SCCHN patient populations. Patients who are cetuximab-naive are randomized to cetuximab alone or to BYL719 in combination with cetuximab, while patients who have received cetuximab and platinum therapy in the first-line setting are enrolled in a single arm to receive BYL719 with cetuximab. Conclusion: Combined inhibition of PI3Kα and EGFR by BYL719 and cetuximab, respectively, overcame cetuximab resistance in the preclinical setting, was well tolerated, and demonstrated encouraging antitumor activity in both cetuximab-naive and -pretreated patients with SCCHN. The Phase II part of the study in both patient populations is ongoing. Citation Format: Pamela Munster, Moshe Elkabets, Jill Gilbert, Albiruni R Abdul Razak, Myung-Ju Ahn, Chia-Jui Yen, Se-Hoon Lee, Hung-Ming Wang, Carla van Herpen, Wan-Teck Lim, David Demanse, Rupam Ranjan Pal, Alan Huang, Qing Sheng, Chiara Lambertini, Malte Peters, Christina Coughlin, Maurizio Scaltriti, Jose Baselga, George Blumenschein. Inhibition of PIK3CA with BYL719 can overcome resistance to cetuximab in squamous cell carcinoma of the head and neck (SCCHN). [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A46.