Patrick Urban

PI3K inhibitors as new cancer therapeutics: implications for clinical trial design

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.

Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial

BACKGROUND Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK-rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy. METHODS In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0-2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1-2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01828112, and is ongoing but no longer recruiting patients. FINDINGS Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5-21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1-6·9] for ceritinib vs 1·6 months [1·4-2·8] for chemotherapy; hazard ratio 0·49 [0·36-0·67]; p<0·0001). Serious adverse events were reported in 49 (43%) of 115 patients in the ceritinib group and 36 (32%) of 113 in the chemotherapy group. Treatment-related serious adverse events were similar between groups (13 [11%] in the ceritinib group vs 12 [11%] in the chemotherapy group). The most frequent grade 3-4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression. INTERPRETATION These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population. FUNDING Novartis Pharmaceuticals Corporation.

Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. METHODS The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. FINDINGS Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. INTERPRETATION The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. FUNDING Novartis Pharmaceuticals Corporation.

Increased level of phosphorylated akt measured by chemiluminescence-linked immunosorbent assay is a predictor of poor prognosis in primary breast cancer overexpressing ErbB-2

IntroductionAkt1, Akt2 and Akt3 kinases are downstream components of phosphoinositol 3-kinase derived signals from receptor tyrosine kinases, which influence cell growth, proliferation and survival. Akt2 overexpression and amplification have been described in breast, ovarian and pancreatic cancers. The present study was designed to investigate the prognostic significance of activated Akt in primary breast cancer and its association with other tumour biomarkers.MethodsUsing a two-site chemiluminescence-linked immunosorbent assay, we measured the quantitative expression levels of total phosphorylated (P-S473) Akt (Akt1/Akt2/Akt3) on cytosol fractions obtained from fresh frozen tissue samples of 156 primary breast cancer patients.ResultsAkt phosphorylation was not associated with nodal status or ErbB-2 protein expression levels. High levels of phosphorylated Akt correlated (P < 0.01) with poor prognosis, and the significance of this correlation increased (P < 0.001) in the subset of patients with ErbB-2 overexpressing tumours. In addition, phosphorylated Akt was found to be associated with mRNA expression levels of several proliferation markers (e.g. thymidylate synthase), measured using quantitative real-time RT-PCR.ConclusionOur findings demonstrate that, in breast cancer patients, Akt activation is associated with tumour proliferation and poor prognosis, particularly in the subset of patients with ErbB2-overexpressing tumours.

Increased Expression of Urokinase-Type Plasminogen Activator mRNA Determines Adverse Prognosis in ErbB2-Positive Primary Breast Cancer

PURPOSE To evaluate and validate mRNA expression markers capable of identifying patients with ErbB2-positive breast cancer associated with distant metastasis and reduced survival. PATIENTS AND METHODS Expression of 60 genes involved in breast cancer biology was assessed by quantitative real-time PCR (qrt-PCR) in 317 primary breast cancer patients and correlated with clinical outcome data. Results were validated subsequently using two previously published and publicly available microarray data sets with different patient populations comprising 295 and 286 breast cancer samples, respectively. RESULTS Of the 60 genes measured by qrt-PCR, urokinase-type plasminogen activator (uPA or PLAU) mRNA expression was the most significant marker associated with distant metastasis-free survival (MFS) by univariate Cox analysis in patients with ErbB2-positive tumors and an independent factor in multivariate analysis. Subsequent validation in two microarray data sets confirmed the prognostic value of uPA in ErbB2-positive tumors by both univariate and multivariate analysis. uPA mRNA expression was not significantly associated with MFS in ErbB2-negative tumors. Kaplan-Meier analysis showed in all three study populations that patients with ErbB2-positive/uPA-positive tumors exhibited significantly reduced MFS (hazard ratios [HR], 4.3; 95% CI, 1.6 to 11.8; HR, 2.7; 95% CI, 1.2 to 6.2; and, HR, 2.8; 95% CI, 1.1 to 7.1; all P < .02) as compared with the group with ErbB2-positive/uPA-negative tumors who exhibited similar outcome to those with ErbB2-negative tumors, irrespective of uPA status. CONCLUSION After evaluation of 898 breast cancer patients, uPA mRNA expression emerged as a powerful prognostic indicator in ErbB2-positive tumors. These results were consistent among three independent study populations assayed by different techniques, including qrt-PCR and two microarray platforms.

Abstract S6-01: PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial

Background: PI3K pathway activation is a hallmark of hormone receptor-positive (HR+) BC cells resistant to endocrine therapy (ET). Preclinical and early clinical data suggest that combining the pan-PI3K inhibitor BUP (BKM120) with ET may provide clinical benefits in this setting. BELLE-2 (NCT01610284) is the first randomized Phase III trial to assess the efficacy and safety of a PI3K inhibitor combined with FULV in HR+ advanced BC, including a prospective analysis of whether PI3K pathway activation status measured in archival tumor tissue and ctDNA is predictive of clinical benefit. Methods: Postmenopausal women with HR+/HER2– locally advanced or metastatic BC refractory to aromatase inhibitor therapy were enrolled. After a 14-day run-in with FULV (500 mg), patients (pts) were randomized (1:1) to receive oral BUP (100 mg/day) or placebo (PBO) with FULV (500 mg per standard of care). Randomization of all pts was stratified by PI3K pathway status measured in archival tumor tissue (PIK3CA mutation or PTEN loss; activated, non-activated, unknown) and visceral disease status (present, absent). Baseline PIK3CA mutation status in ctDNA was assessed in a subset of 587 pts at trial entry. The primary endpoint was locally-assessed progression-free survival (PFS; RECIST v1.1) in the full population and PI3K pathway-activated group. Secondary endpoints included overall survival, safety, overall response rate (ORR), and clinical benefit rate (CBR). Results: 1147 pts received FULV with BUP or PBO, with 187 (16%) ongoing at data cut-off. Baseline characteristics were well balanced between the two arms: median age was 62 years, 98% had ECOG performance status of 0/1, 61% had visceral disease, 69% were sensitive to prior ET, 28% had received prior chemotherapy for metastatic BC. BELLE-2 met its primary endpoint in the full population (Table). In pts with PI3K pathway-activated tumor tissue, PFS increase for BUP+FULV vs PBO+FULV did not meet the planned endpoint. Among pts with PIK3CA status measured in ctDNA, median PFS, ORR, and CBR were significantly improved for BUP+FULV vs PBO+FULV in pts with PIK3CA-mutant tumors but not pts without. The most common Grade 3/4 adverse events (AEs; ≥5% of pts; BUP+FULV vs PBO+FULV) in all pts were increased alanine aminotransferase (26 vs 1%), increased aspartate aminotransferase (18 vs 3%), hyperglycemia (15 vs 0.2%), and rash (8 vs 0%). The most common reasons for treatment discontinuation were disease progression (54 vs 73%) and AEs (13 vs 2%). Conclusions: BELLE-2 met its primary endpoint in the full population. Prespecified analyses showed that characterizing PIK3CA mutation in ctDNA at trial entry identifies pts with endocrine- resistant HR+/HER2–advanced BC, for whom BUP+FULV results in meaningful clinical benefits. Citation Format: Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng L-M, Hurvitz S, Masuda N, Cortes J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Hachemi S, Le Mouhaer S, Di Tomaso E, Urban P, Massacesi C, Campone M. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial. [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 S6-01.

A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4).

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

Comparison of gene expression profiles in core biopsies and corresponding surgical breast cancer samples

IntroductionGene expression profiling has been successfully used to classify breast cancer into clinically distinct subtypes, and to predict the risk of recurrence and treatment response. The aim of this study was to investigate whether the gene expression profile (GEP) detected in a core biopsy (CB) is representative for the entire tumor, since CB is an important tool in breast cancer diagnosis. Moreover, we investigated whether performing CBs prior to the surgical excision could influence the GEP of the respective tumor.MethodsWe quantified the RNA expression of 60 relevant genes by quantitative real-time PCR in paired CBs and surgical specimens from 22 untreated primary breast cancer patients. Subsequently, expression data were compared with independent GEPs obtained from tumors of 317 patients without preceding CB.ResultsIn 82% of the cases the GEP detected in the CB correlated very well with the corresponding profile in the surgical sample (rs ≥ 0.95, p < 0.001). Gene-by-gene analysis revealed four genes significantly elevated in the surgical sample compared to the CB; these comprised genes mainly involved in inflammation and the wound repair process as well as in tumor invasion and metastasis.ConclusionA GEP detected in a CB are representative for the entire tumor and is, therefore, of clinical relevance. The observed alterations of individual genes after performance of CB deserve attention since they might impact the clinical interpretation with respect to prognosis and therapy prediction of the GEP as detected in the surgical specimen following CB performance.

Abstract OT2-6-08: Phase II, randomized, parallel-cohort study of neoadjuvant buparlisib (BKM120) in combination with trastuzumab and paclitaxel in women with HER2-positive, PIK3CA mutant and PIK3CA wild-type primary breast cancer – NeoPHOEBE

Background: The PI3K/Akt/mTOR pathway is frequently activated in breast cancer (BC) and is important for the oncogenic function of HER2. Buparlisib is an oral pan-PI3K inhibitor that targets all 4 isoforms of class I PI3K (α, β, γ, Δ). Preliminary clinical activity was observed with buparlisib in patients (pts) with advanced BC as a single agent, and in combination with paclitaxel (Dirix et al. ESMO 2012) or trastuzumab (Pistilli et al. ESMO 2012). Study design: NeoPHOEBE ([NCT01816594][1]) is a Phase II, randomized, double-blind, parallel-cohort study of neoadjuvant buparlisib or matched placebo plus trastuzumab and weekly paclitaxel. Upfront stratification of pts into 2 independent cohorts according to PIK3CA mutation status will determine whether pts with PIK3CA -mutant tumors may benefit more from this treatment combination. Adult women with newly diagnosed, HER2-positive, primary non-inflammatory BC who have not previously received systemic therapy for invasive disease are eligible. Other eligibility criteria: tumor size >2 cm; unilateral disease; available tumor tissue for central review of estrogen receptor (ER) and HER2 status, and PIK3CA genotype; known PIK3CA mutation status; and ECOG PS ≤1. Pts in each cohort ( PIK3CA mutant or wild-type [wt]) are randomized (1:1) to receive continuous daily buparlisib (100 mg) or placebo and weekly trastuzumab (4 mg/kg loading dose then 2 mg/kg) for 6 weeks, followed by continuous daily buparlisib (80 mg) or placebo with weekly trastuzumab (2 mg/kg) and weekly paclitaxel (80 mg/m2) for 12 weeks. Study treatment is followed by surgery within 4 weeks of last paclitaxel dose. Stratification at randomization is based on PIK3CA (mutant vs wt) and ER (positive vs negative) status. Endpoints: All endpoints will be measured in both PIK3CA -mutant and wt cohorts. The primary endpoint is rate of pathologic complete response (pCR; ypT0) at time of surgery. The key secondary endpoint is objective response rate (ORR) at the end of week 6. Other secondary endpoints include pCR by other definitions, ORR prior to surgery, pCR and objective response by ER status, percent of pts with node-negative disease at surgery, rate of breast conserving surgery, and safety. Exploratory objectives include change in standardized uptake value (SUV) at Day 15 by FDG-PET; and ORR and pCR by PTEN expression, Ki67 level, apoptosis rates, percentage of tumor infiltrating lymphocytes (TIL), and by phenotype of 50% TIL at baseline. Statistical methods: The sample size is based on a minimax 2-stage randomized Phase II design with a prospective control. This design allows for early stopping if the desired efficacy is not observed after stage 1. Both cohorts are powered (80%) to detect a clinically meaningful increase in pCR of 18% at a one-sided significance level (α = 0.15). Target accrual: Planned enrollment for NeoPHOEBE is up to 220 pts at 65 sites in 12 countries across South America, Europe, and Asia-Pacific. Contact: For further study information, contact BIG@bordet.be. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-08. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01816594&atom=%2Fcanres%2F73%2F24_Supplement%2FOT2-6-08.atom

Multicenter phase 2 study of patupilone for recurrent or progressive brain metastases from non-small cell lung cancer

Treatment options for patients with non–small cell lung cancer (NSCLC) with brain metastases are limited. Patupilone (EPO906), a blood‐brain barrier–penetrating, microtubule‐targeting, cytotoxic agent, has shown clinical activity in phase 1/2 studies in patients with NSCLC. This study evaluates the efficacy, pharmacokinetics, and safety of patupilone in NSCLC brain metastases.