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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. [ABSTRACT FROM AUTHOR]

Why does a beneficial treatment effect on a longitudinal biomarker not translate into overall treatment benefit on survival, when the biomarker is in fact a prognostic factor of survival? In a recent exploratory data analysis in oncology, we were faced with this seemingly paradoxical result. To address this problem, we applied a theoretically principled methodology called dynamic path analysis, which allows us to perform mediation analysis with a longitudinal mediator and survival outcome. The aim of the analysis is to decompose the total treatment effect into a direct treatment effect and an indirect treatment effect mediated through a carefully constructed mediation path. The dynamic nature of the underlying methodology enables us to describe how these effects evolve over time, which can add to the mechanistic understanding of the underlying processes. In this paper, we present a detailed description of the dynamic path analysis framework and illustrate its application to survival mediation analysis using simulated and real data. The use case analysis provides clarity on the specific exploratory question of interest while the methodology generalizes to a wide range of applications in drug development where time-to-event is the primary clinical outcome of interest., (© 2024 John Wiley & Sons Ltd.)

Background: Defining hidradenitis suppurativa (HS) subtypes was previously limited by small sample sizes and poor interrater reliability; no study has investigated subtype treatment responses. The objective of this analysis was to characterize HS clusters in adult patients with moderate to severe HS and evaluate secukinumab treatment responses between clusters., Methods: Clusters were identified via an unsupervised machine learning clustering analysis using baseline data from the randomized, placebo-controlled SUNSHINE (NCT03713619) and SUNRISE (NCT03713632) phase 3 trials. To assess treatment responses, patients received secukinumab every 2 (SECQ2W) or 4 weeks (SECQ4W) or placebo, for 16 weeks, after which, placebo patients randomly switched to SECQ2W/SECQ4W, and SECQ2W/SECQ4W patients maintained their original treatment, until week 52. Baseline outcomes included patient characteristics, disease characteristics and severity, HS-associated comorbidities and previous treatment exposures. Treatment response was assessed via the HS clinical response (HiSCR), abscess and inflammatory nodule (AN) count, flares and NRS30 (skin pain)., Results: Based on baseline data, three clusters were identified from 1084 patients (Cluster 1: 54.1%, Cluster 2: 17.8%, Cluster 3: 28.1%). Cluster 1 was predominantly female (65.4%) and was characterized by milder HS. Cluster 2 had more patients from the Asia Pacific, Middle East and Africa region (58.5%) and was characterized by moderate HS. Cluster 3 had the highest rates of previous exposure to biologics (45.9%) and prior HS-related surgeries (47.5%) and was characterized by severe HS. SECQ2W and SECQ4W demonstrated efficacy versus placebo in all clusters at week 16; SECQ2W and SECQ4W efficacy was maintained to week 52. SECQ2W treatment showed a trend for greater efficacy versus SECQ4W in Cluster 3 through week 52., Conclusions: Three HS clusters were identified. Secukinumab demonstrated benefit over placebo in all clusters. However, patients with more severe disease may take longer to respond and more frequent secukinumab dosing may be required for these patients., Trial Registration: SUNSHINE (NCT03713619) and SUNRISE (NCT03713632)., (© 2024 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Hyperglycemia is an on-target effect of PI3Kα inhibitors. Early identification and intervention of treatment-induced hyperglycemia is important for improving management of patients receiving a PI3Kα inhibitor like alpelisib. Here, we characterize incidence of grade 3/4 alpelisib-related hyperglycemia, along with time to event, management, and outcomes using a machine learning model., Methods: Data for the risk model were pooled from patients receiving alpelisib ± fulvestrant in the open-label, phase 1 X2101 trial and the randomized, double-blind, phase 3 SOLAR-1 trial. The pooled population (n = 505) included patients with advanced solid tumors (X2101, n = 221) or HR+/HER2- advanced breast cancer (SOLAR-1, n = 284). External validation was performed using BYLieve trial patient data (n = 340). Hyperglycemia incidence and management were analyzed for SOLAR-1., Results: A random forest model identified 5 baseline characteristics most associated with risk of developing grade 3/4 hyperglycemia (fasting plasma glucose, body mass index, HbA 1c , monocytes, age). This model was used to derive a score to classify patients as high or low risk for developing grade 3/4 hyperglycemia. Applying the model to patients treated with alpelisib and fulvestrant in SOLAR-1 showed higher incidence of hyperglycemia (all grade and grade 3/4), increased use of antihyperglycemic medications, and more discontinuations due to hyperglycemia (16.7% vs. 2.6% of discontinuations) in the high- versus low-risk group. Among patients in SOLAR-1 (alpelisib + fulvestrant arm) with PIK3CA mutations, median progression-free survival was similar between the high- and low-risk groups (11.0 vs. 10.9 months). For external validation, the model was applied to the BYLieve trial, for which successful classification into high- and low-risk groups with shorter time to grade 3/4 hyperglycemia in the high-risk group was observed., Conclusions: A risk model using 5 clinically relevant baseline characteristics was able to identify patients at higher or lower probability for developing alpelisib-induced hyperglycemia. Early identification of patients who may be at higher risk for hyperglycemia may improve management (including monitoring and early intervention) and potentially lead to improved outcomes., Registration: ClinicalTrials.gov: NCT01219699 (registration date: October 13, 2010; retrospectively registered), ClinicalTrials.gov: NCT02437318 (registration date: May 7, 2015); ClinicalTrials.gov: NCT03056755 (registration date: February 17, 2017)., (© 2024. The Author(s).)

Objectives: Canakinumab, an interleukin-1 beta inhibitor, previously showed reduced lung cancer incidence and mortality (CANTOS). Here, we compare the efficacy/safety of canakinumab versus placebo in patients with advanced non-small cell lung cancer (NSCLC) who had progressed after platinum-based doublet chemotherapy (PDC) and immunotherapy., Materials and Methods: CANOPY-2, a randomized, double-blind, phase 3 trial, enrolled adult patients with stage IIIB/IV NSCLC, without EGFR or ALK alterations, who had received one prior PDC regimen and one prior programmed death-1/programmed death-ligand 1 inhibitor and experienced subsequent disease progression. Patients were randomized to canakinumab plus docetaxel or placebo plus docetaxel., Results: A total of 237 patients were randomly allocated: 120 (51 %) to canakinumab and 117 (49 %) to placebo, stratified by histology and prior lines of therapy. Three patients in the placebo arm did not receive study treatment. The trial did not meet its primary endpoint of overall survival: median 10.6 months (95 % confidence interval [CI], 8.2-12.4) for the canakinumab arm and 11.3 months (95 % CI, 8.5-13.8) for the placebo arm (hazard ratio, 1.06 [95 % CI, 0.76-1.48]; one-sided P-value = 0.633). AEs (any grade) were reported in 95 % of patients in the canakinumab group and in 98 % of patients in the placebo group. Grade 3-4 AEs were experienced by 62 % and 64 % of patients in the canakinumab and placebo groups, respectively, and grade 5 AEs were experienced by 8 % and 5 %. Prespecified, post-hoc subgroup analyses showed that patients with undetected circulating tumor DNA (ctDNA) and/or lower levels (< 10 mg/L) of C-reactive protein (CRP) achieved longer progression-free and overall survival than those with detected ctDNA or higher (≥ 10 mg/L) CRP levels. There was no association with treatment arm., Conclusion: Adding canakinumab to docetaxel did not provide additional benefit for patients with advanced NSCLC who had progressed after PDC and immunotherapy., Clinical Registration: NCT03626545., Competing Interests: Declaration of competing interest Luis Paz-Ares reports grants from AstraZeneca, Bristol Myers Squibb, Merck, and Pfizer; consulting fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Janssen, Lilly, Merck, Mirati, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, and Takeda; speaker honoraria from AstraZeneca, Janssen, Merck, and Mirati; leadership roles in Altum Sequencing and Genomica, all outside the submitted work. Yasushi Goto reports clinical trial grants from AZK and Pfizer; institutional grants from AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Kyorin, Novartis, Ono Pharmaceutical, and Pfizer; speaker honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, Merck, Novartis, Ono Pharmaceutical, Pfizer, and Taiho; leadership roles in Cancer Net Japan and JAMT, all outside the submitted work. Darren Lim reports grants from Bristol Myers Squibb; speaker honoraria from Boehringer Ingelheim, Merck, and Roche; and support for attending meetings from AstraZeneca and Taiho Pharmaceuticals, all outside the submitted work. Balazs Halmos reports research funding and honoraria for steering committee work from Novartis during the conduct of the study; reports grants from AbbVie, Advaxis, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Merck, and Pfizer; consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Genentech, Janssen, Merck, Pfizer, Takeda, and Veracyte; and participation in advisory board meetings for Apollomics and TPT, all outside the submitted work. Byoung Chul Cho reports research funding from AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, GI Innovation, Interpark Bio Convergence Corp., Janssen, MedPacto, Merck, MOGAN Institute, Novartis, Ono Pharmaceutical, and Yuhan; royalties from Champions Oncology; consulting fees from AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, MedPacto, Merck, Novartis, Ono Pharmaceutical, Pfizer, Roche, Takeda, and Yuhan; participation in advisory board meetings for Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Joseah BIO, and KANAPH Therapeutics Inc.; stock ownership of Bridgebio Therapeutics, Cyrus Therapeutics, Gencurix Inc., Interpark Bio Convergence Corp., KANAPH Therapeutics Inc., and TheraCanVac Inc.; is a board of director for Gencurix Inc. and Interpark Bio Convergence Corp.; and is a founder of DAAN Biotherapeutics, all outside the submitted work. José Luis González Larriba reports consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Janssen, and Merck; speaker honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, and Roche; and support for attending meetings from Bristol Myers Squibb, Janssen, Merck, Pfizer, Roche, and Takeda, all outside the submitted work. Caicun Zhou reports speaker honoraria from Amoy Diagnostics, Boehringer Ingelheim, C-stone, Eli Lilly, LUYE Pharma, Merck, Qilu, Roche, and Sanofi; and speaker and advisor fees from Hengrui, Innovent Biologics and TopAlliance Biosciences Inc., all outside the submitted work. Ingel Demedts reports consultancy and speaker honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck, and Roche, outside the submitted work. Jincheng Wu, David Demanse, and Bharani Dharan are Novartis employees. Bijoyesh Mookerjee, Socorro Portella, and Zewen Zhu were Novartis employees at the time the study was conducted. Martin Reck reports consulting fees, speaker honoraria and support for attending meetings from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Sanofi, and Roche; and participation in advisory board meetings for Sanofi, all outside of submitted work. Manuel Cobo, Akin Atmaca, and Sofia Baka declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Alpelisib in combination with cetuximab showed synergistic anti-tumour activity in head and neck squamous cell carcinoma (HNSCC) models., Objectives: The recommended phase 2 dose (RP2D) was determined in a phase 1b dose-escalation study. Phase 2 evaluated anti-tumour activity with a randomised part in cetuximab-naïve patients and a non-randomised part in cetuximab-resistant patients., Patients and Methods:  Alpelisib was administered in 28 d cycles as whole tablets, suspension from crushed tablets or suspension from dispersible tablets in patients with platinum-resistant, recurrent/metastatic HNSCC., Results: The RP2D determined for alpelisib was 300 mg/d. Alpelisib-cetuximab achieved an overall response rate of 25% and 9.9% and disease control rate of 75% and 43.7% in phase 1b and phase 2 studies, respectively. Median progression-free survival (PFS) per central review was 86 d for combination treatment and 87 d for cetuximab monotherapy (unadjusted HR 1.12; 95% CI 0.69-1.82; P > 0.05). When adjusted for baseline covariates [sum of longest diameters from central data, haemoglobin and white blood cell (WBC), the results favoured combination treatment (adjusted HR 0.54; 95% CI 0.30-0.97; P = 0.039). PFS per investigator assessment resulted in an unadjusted HR of 0.76 (95% CI 0.49-1.19; P > 0.05) favouring combination treatment. The median PFS in cetuximab-resistant patients was 3.9 months., Conclusions: The addition of alpelisib to cetuximab did not demonstrate a PFS benefit in cetuximab-naïve patients with advanced HNSCC. The alpelisib-cetuximab combination showed moderate activity in cetuximab-resistant patients, with a consistent safety profile., Clinical Trial Registration: ClinicalTrials.gov NCT01602315; EudraCT 2011-006017-34., (© 2023. The Author(s).)

Background: Fatigue is a subjective, complex and multi-faceted phenomenon, commonly experienced as tiredness. However, pathological fatigue is a major debilitating symptom associated with overwhelming feelings of physical and mental exhaustion. It is a well-recognized manifestation in chronic inflammatory rheumatic diseases, such as Sjögren's Syndrome and Systemic Lupus Erythematosus and an important predictor of patient's health-related quality of life (HRQoL). Patient reported outcome questions are the key instruments to assess fatigue. To date, there is no consensus about reliable quantitative assessments of fatigue., Method: Observational data for a period of one month were collected from 296 participants in the United States. Data comprised continuous multimodal digital data from Fitbit, including heart rate, physical activity and sleep features, and app-based daily and weekly questions covering various HRQoL factors including pain, mood, general physical activity and fatigue. Descriptive statistics and hierarchical clustering of digital data were used to describe behavioural phenotypes. Gradient boosting classifiers were trained to classify participant-reported weekly fatigue and daily tiredness from multi-sensor and other participant-reported data, and extract a set of key predictive features., Results: Cluster analysis of Fitbit parameters highlighted multiple digital phenotypes, including sleep-affected, fatigued and healthy phenotypes. Features from participant-reported data and Fitbit data both contributed as key predictive features of weekly physical and mental fatigue and daily tiredness. Participant answers to pain and depressed mood-related daily questions contributed the most as top features for predicting physical and mental fatigue, respectively. To classify daily tiredness, participant answers to questions on pain, mood and ability to perform daily activities contributed the most. Features related to daily resting heart rate and step counts and bouts were overall the most important Fitbit features for the classification models., Conclusion: These results demonstrate that multimodal digital data can be used to quantitatively and more frequently augment pathological and non-pathological participant-reported fatigue., Competing Interests: CR and ED were employees of Novartis. DD, MS, and VD are employees of Novartis. NM is employee of Evidation Health, Inc., (© 2023 Rao, Di Lascio, Demanse, Marshall, Sopala and De Luca.)

Objectives: Osteoarthritis (OA) is a complex disease comprising diverse underlying patho-mechanisms. To enable the development of effective therapies, segmentation of the heterogenous patient population is critical. This study aimed at identifying such patient clusters using two different machine learning algorithms., Methods: Using the progression and incident cohorts of the Osteoarthritis Initiative (OAI) dataset, deep embedded clustering (DEC) and multiple factor analysis with clustering (MFAC) approaches, including 157 input-variables at baseline, were employed to differentiate specific patient profiles., Results: DEC resulted in 5 and MFAC in 3 distinct patient phenotypes. Both identified a "comorbid" cluster with higher body mass index (BMI), relevant burden of comorbidity and low levels of physical activity. Both methods also identified a younger and physically more active cluster and an elderly cluster with functional limitations, but low disease impact. The additional two clusters identified with DEC were subgroups of the young/physically active and the elderly/physically inactive clusters. Overall pain trajectories over 9 years were stable, only the numeric rating scale (NRS) for pain showed distinct increase, while physical activity decreased in all clusters. Clusters showed different (though non-significant) trajectories of joint space changes over the follow-up period of 8 years., Conclusion: Two different clustering approaches yielded similar patient allocations primarily separating complex "comorbid" patients from healthier subjects, the latter divided in young/physically active vs elderly/physically inactive subjects. The observed association to clinical (pain/physical activity) and structural progression could be helpful for early trial design as strategy to enrich for patients who may specifically benefit from disease-modifying treatments., Competing Interests: Declaration of Competing Interest David Demanse is employee and shareholder of Novartis. Franziska Saxer is employee and shareholder of Novartis, she is affiliated to the University Basel and member of the European Union Medical Devices - Expert Panel section Orthopaedics, traumatology, rehabilitation, rheumatology. Patrick Lustenberger is employee of IBM, Switzerland and shareholder of Novartis. László B. Tankó was employee of Novartis and held shares, he is current employee of Bayer Pharmaceuticals. Philipp Nikolaus was employee of IBM, Switzerland, he is current employee of MSCI Inc. Ilja Rasin is employee of IBM, Switzerland. Damian F. Brennan is a former employee of IBM, Switzerland and in this employment consultant to Novartis. He currently is employee of the Macquarie Group, Australia. Ronenn Roubenoff is employee and shareholder of Novartis. Sumehra Premji is a former employee of IBM Switzerland and in this employment, consultant and account partner to Novartis. She is current employee and shareholder of Novartis. Philip G Conaghan reports fees for speaker’s bureaus (AbbVie, Novartis) and consultancies (AstraZeneca, BMS, Eli Lilly, Galapagos, Genascence, GSK, Merck, Novartis, Pfizer, Regeneron, Stryker and UCB). Matthias Schieker is employee and shareholder of Novartis and owner LivImplant GmbH., (Copyright © 2022 Novartis Institutes of BioMedical Research. Published by Elsevier Inc. All rights reserved.)

Model-informed dose selection has been drawing increasing interest in oncology early clinical development. The current paper describes the example of FGF401, a selective fibroblast growth factor receptor 4 (FGFR4) inhibitor, in which a comprehensive modeling and simulation (M&S) framework, using both pharmacometrics and statistical methods, was established during its first-in-human clinical development using the totality of pharmacokinetics (PK), pharmacodynamic (PD) biomarkers, and safety and efficacy data in patients with cancer. These M&S results were used to inform FGF401 dose selection for future development. A two-compartment population PK (PopPK) model with a delayed 0-order absorption and linear elimination adequately described FGF401 PK. Indirect PopPK/PD models including a precursor compartment were independently established for two biomarkers: circulating FGF19 and 7α-hydroxy-4-cholesten-3-one (C4). Model simulations indicated a close-to-maximal PD effect achieved at the clinical exposure range. Time-to-progression was analyzed by Kaplan-Meier method which favored a trough concentration (C trough )-driven efficacy requiring C trough above a threshold close to the drug concentration producing 90% inhibition of phospho-FGFR4. Clinical tumor growth inhibition was described by a PopPK/PD model that reproduced the dose-dependent effect on tumor growth. Exposure-safety analyses on the expected on-target adverse events, including elevation of aspartate aminotransferase and diarrhea, indicated a lack of clinically relevant relationship with FGF401 exposure. Simulations from an indirect PopPK/PD model established for alanine aminotransferase, including a chain of three precursor compartments, further supported that maximal target inhibition was achieved and there was a lack of safety-exposure relationship. This M&S framework supported a dose selection of 120 mg once daily fasted or with a low-fat meal and provides a practical example that might be applied broadly in oncology early clinical development., (© 2022 Novartis. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Machine learning (ML) opens new perspectives in identifying predictive factors of efficacy among a large number of patients' characteristics in oncology studies. The objective of this work was to combine ML with population pharmacokinetic/pharmacodynamic (PK/PD) modeling of tumor growth inhibition to understand the sources of variability between patients and therefore improve model predictions to support drug development decisions. Data from 127 patients with hepatocellular carcinoma enrolled in a phase I/II study evaluating once-daily oral doses of the fibroblast growth factor receptor FGFR4 kinase inhibitor, Roblitinib (FGF401), were used. Roblitinib  PKs was best described by a two-compartment model with a delayed zero-order absorption and linear elimination. Clinical efficacy using the longitudinal sum of the longest lesion diameter data was described with a population PK/PD model of tumor growth inhibition including resistance to treatment. ML, applying elastic net modeling of time to progression data, was associated with cross-validation, and allowed to derive a composite predictive risk score from a set of 75 patients' baseline characteristics. The two approaches were combined by testing the inclusion of the continuous risk score as a covariate on PD model parameters. The score was found as a significant covariate on the resistance parameter and resulted in 19% reduction of its variability, and 32% variability reduction on the average dose for stasis. The final PK/PD model was used to simulate effect of patients' characteristics on tumor growth inhibition profiles. The proposed methodology can be used to support drug development decisions, especially when large interpatient variability is observed., (© 2022 Novartis AG. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Importance: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor-positive (ER+), endocrine therapy-resistant breast cancers., Objective: To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC)., Design, Setting, and Participants: An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries. Participants were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy. The study began enrolling patients October 5, 2010, and the data cutoff was March 22, 2017., Interventions: Escalating doses of alpelisib were administered once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase., Main Outcomes and Measures: The primary end point was determination of the MTD of once-daily alpelisib plus fulvestrant. Secondary end points included safety and preliminary activity., Results: From October 5, 2010, to March 22, 2017, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n = 9; 350 mg, n = 8; 400 mg, n = 70) plus fixed-dose fulvestrant (500 mg). During dose escalation, dose-limiting toxic effects were reported in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib when combined with fulvestrant was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily. Overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10% of patients), regardless of causality, were hyperglycemia (19 [22%]) and maculopapular rash (11 [13%]); 9 patients permanently discontinued therapy owing to adverse events. Median progression-free survival at the MTD was 5.4 months (95% CI, 4.6-9.0 months). Median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months). Overall response rate in the PIK3CA-altered group was 29% (95% CI, 17%-43%), with no objective tumor responses in the wild-type group., Conclusions and Relevance: Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and data suggest that this combination may have greater clinical activity in PIK3CA-altered vs wild-type tumors., Trial Registration: ClinicalTrials.gov identifier: NCT01219699.

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.

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.

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., (©2014 American Association for Cancer Research.)

Objective: To establish the predictive accuracy of the Kattan preoperative nomogram by comparing predictions at 5 years with actual progression in patients who had a radical prostatectomy (RP)., Materials and Methods: We reviewed the data for 928 patients treated by RP as a first-line treatment for localized prostate cancer, between 1994 and 2005. Recurrence was defined as one prostate-specific antigen (PSA) level of >0.4 ng/mL. The 5-year progression-free probability (PFP) rate was evaluated on censured data using the Kaplan-Meier method. Relationships between all predictor variables included in the Kattan nomogram (PSA level, biopsy Gleason scores and clinical stage) and survival were evaluated by Cox proportional-hazards regression analysis. The discriminating ability of the nomogram was assessed by the concordance index (c-index). Bootstrapping was used to assess confidence intervals (CIs), and then the calibration was assessed., Results: The median follow-up was 60 months. Overall, 177 (19%) patients had a recurrence; the 5-year PFP rate (95% CI) was 80.9 (78-83)%. Of the three variables included in the nomogram, all were associated with recurrence in a multivariate analysis (P < 0.001). The c-index (95% CI) was only 0.664 (0.584-0.744). In general, the nomogram was not well calibrated., Conclusions: There was a discrepancy between the predicted PFP as estimated by the Kattan nomogram and actual relapse in this group of patients. Clinicians should be aware that the nomogram is less accurate when used outside the population used to formulate the nomogram. Although more accurate tools are needed, the Kattan nomogram is still the best choice for urologists so far.