Prognostic value of B-score for predicting joint replacement in the context of osteoarthritis phenotypes: Data from the osteoarthritis initiative

Objective Developing new therapies for knee osteoarthritis (KOA) requires improved prediction of disease progression. This study evaluated the prognostic value of clinical clusters and machine-learning derived quantitative 3D bone shape B-score for predicting total and partial knee replacement (KR). Design This retrospective study used longitudinal data from the Osteoarthritis Initiative. A previous study used patients' clinical profiles to delineate phenotypic clusters. For these clusters, the distribution of B-scores was assessed (employing Tukey's method). The value of both cluster allocation and B-score for KR-prediction was then evaluated using multivariable Cox regression models and Kaplan-Meier curves for time-to-event analyses. The impact of using B-score vs. cluster was evaluated using a likelihood ratio test for the multivariable Cox model; global performances were assessed by concordance statistics (Harrell's C-index) and time dependent receiver operating characteristic (ROC) curves. Results B-score differed significantly for the individual clinical clusters (p ​< ​0.001). Overall, 9.4% of participants had a KR over 9 years, with a shorter time to event in clusters with high B-score at baseline. Those clusters were characterized clinically by a high rate of comorbidities and potential signs of inflammation. Both phenotype and B-score independently predicted KR, with better prediction if combined (P ​< ​0.001). B-score added predictive value in groups with less pain and radiographic severity but limited physical activity. Conclusions B-scores correlated with phenotypes based on clinical patient profiles. B-score and phenotype independently predicted KR surgery, with higher predictive value if combined. This can be used for patient stratification in drug development and potentially risk prediction in clinical practice

Unsupervised machine-learning algorithms for the identification of clinical phenotypes in the osteoarthritis initiative database

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

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 ([F-18] 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 similar to 4 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

Alpelisib plus fulvestrant in PIK3CA-Altered and PIK3CA-wild-type estrogen receptor–positive advanced breast cancer: A phase 1b clinical trial

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.</p

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

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.status: publishe