Doubled Progression-free Survival Research Articles

Capivasertib Doubles PFS in Some Breast Cancers.

In the phase III CAPItello-291 study, the combination of fulvestrant and capivasertib more than doubled progression-free survival compared with fulvestrant alone in patients with hormone receptor-positive, HER2-negative breast cancer who have developed resistance to aromatase inhibitors and CDK4/6 inhibitors. The AKT inhibitor could become a treatment option for these patients.

Efficacy, safety and toxicity management of adjuvant abemaciclib in early stage HR+/HER2- high-risk breast cancer

ABSTRACT Introduction The majority of the over 250,000 new cases of invasive breast cancer diagnosed in the United States are driven by hormone receptor signaling (HR+). Since 2015, cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard in combination with endocrine therapy (ET) for patients facing HR+ metastatic disease. Areas covered There are now three approved agents in the HR+ metastatic setting such as abemaciclib, ribociclib, and palbociclib. Due to the almost doubling of progression-free survival (PFS) and improvement in overall survival (OS) in the metastatic setting, studies were conducted to examine the benefit of adding CDK4/6i in the adjuvant setting for those patients at high risk for recurrence. Despite negative results of PALLAS (palbociclib) in this setting, monarchE (abemaciclib) showed an improvement in invasive disease-free survival (IDFS) and distant recurrence-free survival (DRFS) at the 3-year time point for patients with high-risk tumor characteristics leading to its approval. Herein, we discuss the data, the population studied and for which abemaciclib is approved as well as safety, tolerability, and dose reductions for practical management of these patients. Expert opinion Abemaciclib is appropriate and beneficial for those patients with high-risk, node-positive, hormonally driven, human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

DDEL-01. The role of key pharmacodynamic and pharmacokinetic parameters in drug response prediction of pediatric tumors in the precision oncology study INFORM

Abstract INTRODUCTION: The INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) study is a European pediatric precision oncology program. Using state of the art molecular assays, INFORM aims for identification of targetable genetic alterations, matching drugs and clinical trials. High evidence targets were associated with doubling of progression free survival when patients received a matching drug. However, the fraction of tumors with high evidence drug targets remains low requiring functional layers of information such as drug sensitivity profiling. The aim of this project is to identify and investigate the role of key pharmacodynamic and pharmacokinetic parameters to improve the predictivity of ex vivo drug response of pediatric tumors. METHODS: Positive control cell lines harboring specific mutations (n=7) and primary tumors (n=121) from INFORM, including 10% ependymomas, 7% high grade gliomas, 5% neuroblastomas and 4% medulloblastomas, were profiled ex vivo using a library of n=76 clinically relevant oncology drugs in a 384 well plate format. Metabolic activity was measured after 72h of treatment. Quality control (QC) was done using the robust z-factor, correlation of replicates and mean negative control. Hit selection was based on maximum percentage inhibition, normalized AUC metric (DSSasym) and maximum serum concentration (Cmax) of the drug. Clinical follow-up was collected using a questionnaire. RESULTS: A linear mixed model revealed the DSSasym to be the strongest pharmacodynamic parameter in drug prediction in cell lines. Drug screens of n=105 INFORM cases passed QC. Application of the filtering parameters resulted in prediction of n=1-16 drugs/case (min-max). A data base of published pediatric pharmacokinetic parameters of the drug library was generated. Analysis of predictive parameters and clinical follow-up of clinical samples is ongoing. CONCLUSION: Including pharmacodynamic as well as clinical pharmacokinetic parameters is paramount to identify potentially clinically active compounds from ex vivo drug screen data. Further algorithm development is warranted.

Early Switch to Fulvestrant Plus Palbociclib Improves Outcomes in ESR1-Mutated, Estrogen Receptor-Positive Metastatic Breast Cancer.

For patients with estrogen receptor-positive metastatic breast cancer who are treated with palbociclib plus an aromatase inhibitor, the strategy of switching to palbociclib plus fulvestrant upon detection of a resistance mutation more than doubled progression-free survival, according to results from the phase III PADA-1 trial.

Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors: A real-world perspective.

e21213 Background: Lung cancer is the leading cause of death in males and females in the United States. Approximately 85% of all cases are classified as non-small cell lung cancer (NSCLC) with majority diagnosed at an advanced stage. Unfortunately, response to traditional chemotherapy (ChT) has been poor with a five-year survival rate of 6% in metastatic NSCLC. Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape for advanced NSCLC and are being utilized alone or in combination with ChT as the standard first-line therapy. With widespread use of ICIs, immune-related adverse events (irAE) are commonly seen and in some studies their occurrence correlates with improved outcomes. The aim of our study was to evaluate whether development of irAEs has an impact on survival in NSCLC. Methods: We performed a retrospective analysis on stage IV NSCLC patients treated with ChT, ChT plus ICI, or ICI monotherapy from December 2016 to December 2019. Univariable and multivariable analyses identified characteristics predictive of progression-free survival (PFS) and overall survival (OS). OS was calculated using Kaplan Meier curves. Log-rank statistics were used to assess statistical significance between groups. Multivariable logistic regression was performed to identify predictors of survival. Results: 193 patients were evaluated out of which 92 (47.2%) received ChT plus pembrolizumab, 69 (35.4%) received pembrolizumab alone and 32 (16.4%) received ChT alone. 130 patients were found to have no irAEs compared to 57 patients who were noted to have any grade of irAE. The median PFS was 17.4 months (irAE group) vs. 8.5 months (non-irAE group) with hazard ratio (HR) of 0.58 (95% CI: 0.41 to 0.80, p = 0.001). The median OS was 29.4 months (irAE group) vs. 14.4 months (non-irAE group) with HR of 0.56 (95% CI: 0.39 to 0.82, p = 0.0026). A multivariate analysis was performed for age, gender, ECOG performance status, insurance status, BMI, PDL1 status and smoking history, amongst other variables. Worse survival outcomes were noted with an ECOG performance status ≥ 2, no history of smoking, and involvement of palliative care. Multivariable logistic regression analysis showed that PDL-1 expression > 50% was the only predictor of developing an irAE. Of note, receipt of ChT in combination with pembrolizumab compared to pembrolizumab alone did not predict for development of irAE. Conclusions: Development of irAEs was associated with doubling of PFS and OS, regardless of whether the ICI was administered alone or in combination with ChT. The differences were statistically significant regardless of age, gender, race, BMI, insurance status or performance status. Our study highlights the correlation between development of irAEs and improved survival outcomes in advanced NSCLC patients treated with ICIs.

Loss of 5'ALK leads to better response to crizotinib in sarcomas with ALK rearrangement.

e23554 Background: Crizotinib targets abnormal ALK activation, however, the clinical responses vary among patients with ALK rearrangement. A recent study showed that the NSCLC patients with 5'ALK loss have a favorable response to Crizotinib with doubled progression-free survival (PFS). We asked whether sarcoma patients with ALK rearrangement have a similar correlation between 5'ALK loss and clinical response to Crizotinib. Methods: The histopathologic diagnosis was made on H&E staining and IHC, including anti-ALK(D5F3). DNA isolated from FFPE materials was subjected to an NGS assay targeting 295 genes including ALK rearrangement. Results: 4 cases were detailed in Table. Case#1 is an inflammatory myofibroblastic tumor with a PLEKHH2-ALK rearrangement, which was previously reported in an NSCLC but not in sarcomas. Case #2 is an undifferentiated sarcoma with 2 ALK fusions, RANBP2-ALK and TMEM217-ALK, both in-frame fusions containing intact tyrosine kinase domains. The TMEM217-ALK is a novel fusion. Case#3 is a leiomyosarcoma with MYH9-ALK fusion, which was often seen in ALK-positive large B-cell lymphoma but not in sarcoma. Case #4 is an undifferentiated sarcoma with EML4-ALK fusion. All 4 cases had positive ALK IHC, consistent with the expression of ALK fusion proteins. Case#1 and #2 had a loss of 5' ALK, while case #3 and #4 retained the 5' ALK. All cases received and responded to Crizotinib therapy, with the Karnofsky Performance Status (KPS) improved from 30-60 score pre-therapy to 90-100 score after 3 months of Crizotinib. While Case#3 and #4, both retained the 5' ALK, relapsed at 9.4 m and 6.1 m, case#1 and #2, both lost 5' ALK, remain progression-free at 15m and 27m, respectively. The side effect was manageable with a grade II hepatic toxicity in only one patient. Conclusions: We report here 4 sarcomas with ALK rearrangement, including a novel fusion TMEM217-ALK. Two of these cases had a 5' ALK loss in addition to the 3' ALK rearrangement, and both had much longer PFS on Crizotinib therapy. The underlying mechanism deserved further investigation. Four fibrosarcomas with ALK rearrangements and their response to Crizotinib therapy.[Table: see text]

The role of PARP inhibitors in BRCA mutated pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) accounts for about 3% of all cancers in the United States and about 7% of all cancer deaths. Despite the lower prevalence relative to other solid tumors, it is one of the leading causes of cancer-related death in the US. PDAC is highly resistant to chemotherapy as well as radiation therapy. Current standard-of-care chemotherapeutic regimens provide transient disease control but eventually tumors develop chemoresistance. Tumors that are deficient in DNA damage repair mechanisms such as BRCA mutants respond better to platinum-based chemotherapies. However, these tumor cells can utilize the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) as a salvage DNA repair pathway to prolong survival. Hence, in the presence of BRCA mutations, the inhibition of the PARP pathway can lead to tumor cell death. This provides the rationale for using PARP inhibitors in patients with BRCA mutated PDAC. The phase III POLO trial showed a near doubling of progression-free survival (PFS) compared with placebo in advanced PDAC when a PARP inhibitor, olaparib, was used as maintenance therapy. As a result, the US Food and Drug Administration (FDA) approved olaparib as a maintenance treatment for germline BRCA mutated advanced PDAC that has not progressed on platinum-based chemotherapy. The success of olaparib in treating advanced PDAC opened the new field for utilizing PARP inhibitors in patients with DNA damage repair (DDR) gene defects. Currently, many clinical trials with various PARP inhibitors are ongoing either as monotherapy or in combination with other agents. In addition to germline/somatic BRCA mutations, some trials are enrolling patients with defects in other DDR genes such as ATM, PALB2, and CHEK2. With many ongoing PARP inhibitor trials, it is hopeful that the management of PDAC will continuously evolve and eventually lead to improved patient outcomes.

A Phase II Open Label Study of Everolimus in Combination With Endocrine Therapy in Resistant Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer

BackgroundTherapies targeting estrogen receptor signaling are standard for patients with hormone receptor (HR)-positive (HR+) metastatic breast cancer (MBC). Dysregulation of the phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is associated with treatment resistance. Addition of the mTOR inhibitor, everolimus, to exemestane doubled progression-free survival (PFS) in HR+/HER2− MBC patients whose disease had previously progressed during endocrine therapy. In this phase II study, we used everolimus in addition to the most recent endocrine therapy during which a patient's disease progressed, in an attempt to restore and extend the benefit of the antiestrogen therapy in patients with HR+/HER2− MBC. Patients and MethodsPatients with HR+ MBC who progressed on antiestrogen therapy received everolimus (10 mg orally daily) in combination with the antiestrogen therapy most recently administered. Treatment was administered in 4-week cycles and continued until disease progression or unacceptable toxicity. Blood and archival tumor specimens were collected for VeriStrat (Biodesix, Inc) and Foundation One (Foundation Medicine) assays, respectively. Accrual of 42 evaluable patients allowed detection of improvement in median PFS from 2.8 months (expected with hormonal treatment alone) to 5 months (power 80%, α = 5%). ResultsForty-seven patients were enrolled and treated. After a median follow-up of 22.2 months, median PFS was 6.6 months. Secondary efficacy end points included: overall response rate, 6%; clinical benefit rate, 40%; and median overall survival, 21.1 months. No unexpected toxicity was observed. Efficacy could not be correlated with PI3K/AKT/mTOR alterations or VeriStrat (Biodesix, Inc) prognostic signatures. ConclusionAfter progression during antiestrogen therapy, the addition of everolimus, without changing the hormonal therapy, resulted in a median PFS of 6.6 months, suggesting efficacy in patients with HR+/HER2− MBC.

PARP Inhibitors in Pancreatic Cancer: From Phase I to Plenary Session.

Survival rates for pancreatic cancer remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops. Tumors deficient in deoxyribonucleic acid (DNA) damage repair mechanisms such as BRCA mutants show better responses to platinum based agents, however, such tumors can utilize the poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) pathway as a salvage mechanism. Therefore, inhibition of PARP pathway could lead to tumor destruction and synthetic lethality in presence of BRCA mutation. Various PARP inhibitors have been approved for treatment of patients with germline or somatic BRCA mutant breast and ovarian cancer. This provides basis of using PARP inhibitors in patients with pancreatic cancer that harbor BRCA mutation. A recent phase III Pancreas Cancer Olaparib Ongoing (POLO) study showed impressive results with near doubling of progression free survival compared to placebo (7.4 vs 3.8 months). These results highlight the importance of germline testing for all patients with pancreatic cancer and inclusion of additional deficiencies in homologous recombination repair (ATM and PALB2) including BRCA variants of uncertain significance should be further explored.

Hormone receptor positive breast cancer: state of the art.

Hormone receptor (HR) positive breast cancer represents the vast majority of breast cancer cases. Treatment for these patients has been 5 years of endocrine therapy in the localized setting and endocrine therapy alone in the metastatic setting until progression of disease and switch to chemotherapy until quite recently. The current article will review recent data on role of extended endocrine therapy with tamoxifen and aromatase inhibitors and adjuvant bisphosphonates in the localized disease setting. It will then review the role of targeted agents such as cyclin dependent kinases 4/6 inhibitors, two of which were FDA approved in 2017 in the metastatic setting and are now standard of care. Landscape of HR positive breast cancer is changing with doubling of progression-free survival with drugs approved in the last 2 years. Although antiestrogen therapy remains the backbone of therapy, we are continuing to improve outcome for patients by changes and additions to this therapy.

Alectinib Superior to Crizotinib for ALK+ NSCLC.

Findings from the global phase III ALEX trial unequivocally show that alectinib is superior to crizotinib as first-line therapy for ALK+ non-small cell lung cancer. Alectinib more than doubled progression-free survival, significantly reduced the incidence of brain and CNS metastases, and should be considered the new standard of care.

Crucial role of vascular endothelial growth factor in the immune system of patients with ovarian cancer

Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor A (VEGF-A) (1). Since the 2000s, several large phase III clinical trials, such as GOG218 and ICON7, have shown that bevacizumab has a drastic effect on ovarian cancer prognosis, in combination with standard chemotherapy (2,3). In patients who showed platinum-sensitive relapse, bevacizumab has also been shown to improve progression-free survival (PFS) (OCEANS) (4), although no overall survival (OS) benefit was found. Furthermore, in platinum-resistant relapse, a recent phase III trial (AURELIA) reported an increase in response rate and a doubling of PFS (6.7 vs . 3.4 months) in patients who received a single agent chemotherapy plus bevacizumab, compared to those who received chemotherapy alone (5). These clinical results show that angiogenesis via VEGF signaling is a crucial contributor to ovarian carcinogenesis and progression. Consequently, bevacizumab has great potential for ovarian cancer treatment. Indeed, it is well known that patients with high VEGF expression have significantly poorer survival rates than those with low VEGF expression (6), and that massive ascites contain aberrant high concentrations of VEGF with peritoneal dissemination in advanced or recurrent ovarian cancer (7). The clinical efficacy of bevacizumab is primarily due to its anti-angiogenic effects; however, recent reports have revealed that it has not only direct antitumor effects but also immunomodulatory effects (8).

A Second Anti-CD20 Drug for NHL

Abstract Data from the phase III GADOLIN study indicate that the anti-CD20 drug obinutuzumab is an effective treatment option for patients with indolent non-Hodgkin lymphoma who are refractory to standard rituximab. Compared to the chemotherapy bendamustine alone, adding obinutuzumab doubled progression-free survival.

Abstract OT2-6-09: 4EVER - A phase IIIb, multi-center, open label study for postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer (BC) treated with everolimus (EVE) in combination with exemestane (EXE)

Abstract BACKGROUND The double blind, placebo-controlled BOLERO-2 trial demonstrated a significant doubling of progression free survival (PFS) with EVE and EXE compared to EXE alone for postmenopausal women with hormone-receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) BC after recurrence/progression on non-steroidal aromatase inhibitors (NSAI) (Baselga J, et al. NEJM. 2012). The 4EVER study further evaluates the combination of EVE+EXE in a broader population to obtain greater insights and presents an extensive exploratory translational research program. SPECIFIC AIMS/TRIAL DESIGN 4EVER is a German multi-center, open-label, single-arm trial. 300 patients will receive EVE (10 mg/d)+EXE (25 mg/d) within clinical practice. The primary objective is to assess the overall response rate (ORR), the secondary objectives include PFS, overall survival, safety, quality of life (QoL), health utilities and health care resources. The exploratory biomarker objectives include pharmacogenetics, bone-turnover biomarkers, presence and molecular characteristics of circulating tumor cells, correlation of response to EVE+EXE with proteomics, and the influence of age, performance status, cancer activity and inflammation on anxiety and depression. Exploratory biomarkers are assessed at baseline and after 4, 12, and 24 weeks of treatment. ELIGIBILITY CRITERIA: Main inclusion criteria are postmenopausal women with metastatic or locally advanced ER+, HER2- BC, not amenable to curative treatment by surgery or radiotherapy, refractory to NSAI and with at least one lesion that can be accurately measured or bone lesions lytic or mixed (lytic+sclerotic) in the absence of measurable disease. STATISTICAL METHODS/TARGET ACCRUAL: The study is designed as an open-label, single-arm, phase IIIB trial to assess the efficacy and safety of EVE plus EXE in postmenopausal women with hormone receptor positive breast cancer progressing following prior therapy with NSAI. The primary objective is to estimate the ORR. Therefore, no statistical hypothesis or model is underlying the analysis. The ORR, i.e. best overall response of complete response (CR) or partial response (PR), as well as individual response categories CR, PR, stable disease (SD), progressive disease (PD) or unknown will be summarized using frequency tables together with their associated two-sided exact 95% confidence intervals (Clopper-Pearson method). The full analysis set will be used for the primary efficacy analysis. The primary efficacy and safety analysis will be conducted on all patient data at the time all patients who are still receiving study drug will have completed at least 24 weeks of treatment (or discontinued prematurely). The study plans to randomize 300 patients over a 1-year accrual period. The expected trial duration from activation to reporting of ORR is about 2 years. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-09.

Patient-reported physical, emotional, and social functioning in advanced breast cancer: Insights from BOLERO-2.

155 Background: The phase III BOLERO-2 study at 18 months’ median follow-up showed that everolimus (EVE) + exemestane (EXE) significantly improved progression-free survival (PFS) vs EXE alone in 724 patients with hormone receptor–positive (HR+) advanced breast cancer (ABC) with recurrence/progression during/after nonsteroidal aromatase inhibitor (NSAI) therapy. A higher rate of grade 3/4 adverse events was noted with EVE + EXE but was not associated with deterioration in quality of life (QOL) based on the EORTC QLQ-C30 Global Health Status scale. Additional patient-reported post hoc analyses of QOL are reported herein. Methods: During BOLERO-2, QOL (EORTC QLQ-C30 and QLQ-BR23) was assessed at baseline and q 6 wk thereafter until progression or discontinuation. Physical, emotional, and social functioning subscales of QLQ-C30 were analyzed. Time to definitive deterioration (TTD) was defined based on either a 5% (protocol-specified) or a 10-point (more stringent) decrease from baseline for each subscale and analyzed by Kaplan-Meier methods. The difference between treatments was assessed by a log-rank test stratified by randomization factors. Results: QLQ-C30 compliance was >80% at week 48. Among the 3 protocol-specified QLQ-C30 subscales, analyses based on a 5% decrease in QOL showed a longer TTD for both physical and emotional functioning in the EVE + EXE group vs EXE alone (log-rank p = 0.0120 and p = 0.0277, respectively). The TTDs for social functioning were similar in both treatment arms (log-rank p = 0.3374). Analyses based on a 10-point decrease indicated a longer TTD for physical functioning in the EVE + EXE group (15.2 mo) vs EXE alone (9.7 mo; log-rank p = 0.0211). The TTDs for emotional and social functioning were similar between EVE + EXE and EXE alone: 13.9 vs 13.8, respectively (log-rank p = 0.4023), and 11.5 vs 9.5, respectively (log-rank p = 0.2507). Conclusions: The treatment goal for ABC is to maximize clinical benefit with minimal negative effects on QOL. These additional BOLERO-2 QOL analyses confirmed that the more than doubling of PFS with EVE + EXE was accompanied by maintained physical, emotional, and social functioning compared with EXE alone in patients with HR+ ABC progressing after NSAI. Clinical trial information: NCT00863655.

Correlation of molecular alterations with efficacy of everolimus in hormone-receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2.

142 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 in EVE + EXE arm and 70 in EXE arm) whose baseline characteristics and clinical outcome were comparable to the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE + EXE over EXE was maintained in the subgroups defined by each of the 9 genes with a mutation rate >10% (e.g., PIK3CA, FGFR1, CCND1) or when less frequently mutated genes (e.g., PTEN, AKT1) were included in their respective pathways. Patients with 0 or 1 genetic alteration in PI3K or FGFR pathways or CCND1 had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity to EVE in this setting. Conclusions: This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. The preliminary results suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2– BC will be further investigated. Clinical trial information: NCT00863655.

Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2.

LBA509 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone-receptor positive (HR+), HER2-negative (HER2-) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using both univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 and 70 in EVE+EXE and EXE arms, respectively) whose baseline characteristics and clinical outcome were comparable with the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE+EXE over EXE is maintained in the subgroups defined by each of the nine genes with a mutation rate >10% (eg, PIK3CA, FGFR1, and CCND1), or when less frequently mutated genes (eg, PTEN, AKT1) were included in their respective pathways. Patients with no or only 1 genetic alteration in PI3K or FGFR pathways, or CCND1, had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity/resistance to EVE in this setting. Conclusions: This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. It demonstrated the feasibility of applying large-scale NGS and subsequent correlative analysis to such trials. The observations suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways, or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2- BC will be further investigated. Clinical trial information: NCT00863655.

Patient-reported physical, emotional, and social functioning in advanced breast cancer: Insights from BOLERO-2.

553 Background: The phase 3 BOLERO-2 study at 18 months’ median follow-up showed that everolimus (EVE) + exemestane (EXE) significantly improved progression-free survival (PFS) vs EXE alone in 724 hormone-receptor–positive (HR+) advanced breast cancer (ABC) patients with recurrence/progression during/after nonsteroidal aromatase inhibitor (NSAI) therapy. A higher rate of grade 3/4 adverse events was noted with EVE + EXE, but was not associated with deterioration in quality of life (QOL) based on the EORTC QLQ-C30 Global Health Status scale. Additional patient-reported post hoc analyses of QOL are reported herein. Methods: During BOLERO-2, QOL (EORTC QLQ-C30 and QLQ-BR23) was assessed at baseline and q 6 wk thereafter until progression or discontinuation. Physical, emotional, and social functioning subscales of QLQ-C30 were analyzed. Time to definitive deterioration (TTD) was defined based on either a 5% (protocol specified) or 10-point (more stringent) decrease from baseline for each subscale and analyzed by Kaplan-Meier methods. The difference between treatments was assessed by a log-rank test stratified by randomization factors. Results: QLQ-C30 compliance was > 80% at week 48. Among the 3 protocol-specified QLQ-C30 subscales, analyses based on a 5% decrease in QOL showed a longer TTD for both physical and emotional functioning in the EVE + EXE group vs EXE alone (log-rank P = .0120 and P = .0277, respectively). The TTD for social functioning was similar in both treatment arms (log-rank P = .3374). Analyses based on a 10-point decrease indicated a longer TTD for physical functioning in the EVE + EXE group (15.2 mo) vs EXE alone (9.7 mo; log-rank P = .0211). The TTDs for emotional and social functioning were similar between EVE + EXE and EXE alone: 13.9 vs 13.8, respectively (log-rank P = .4023), and 11.5 vs 9.5, respectively (log-rank P = .2507). Conclusions: The treatment goal for ABC is to maximize clinical benefit with minimal negative effects on QOL. These additional BOLERO-2 QOL analyses confirmed that the more than doubling of PFS with EVE + EXE was accompanied by maintained physical, emotional, and social functioning compared with EXE alone in patients with HR+ ABC progressing after NSAI. Clinical trial information: NCT00863655.

Incidence, management, and resolution of noninfectious pneumonitis in BOLERO-2.

561 Background: The BOLERO-2 trial showed that adding everolimus (EVE) to exemestane (EXE) more than doubled progression-free survival (PFS) without reducing quality of life versus placebo (PBO) + EXE alone in postmenopausal women with hormone-receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC) progressing on/after nonsteroidal aromatase inhibitor (NSAI) therapy. Although generally well tolerated, mTOR inhibitors such as EVE have been associated with noninfectious pneumonitis (NIP). Methods: Patients (pts) were randomized 2:1 to receive EVE+EXE or PBO+EXE. Incidence and severity of NIP, consequent dose interruptions/adjustments, study drug discontinuations, and time to resolution were recorded. Results: Median duration of exposure to EVE was 24 weeks with median dose intensity of 8.6 mg/d. Pulmonary adverse events (AEs) of any grade (NIP, interstitial lung disease, lung infiltration, pneumonia, or pulmonary fibrosis) were recorded in 97 of 482 pts (20%) in the EVE+EXE arm versus 1 of 238 pts (<1%) in the PBO+EXE arm. Of these, 16% of pts (77 of 482) in the EVE+EXE arm versus 0 in the PBO+EXE arm had a diagnosis consistent with NIP. In the EVE+EXE arm, grade 1 (no symptoms), grade 2 and 3 NIP occurred in 7%, 6% and 3% of pts, respectively, and no grade 4 events were reported. Complete resolution of NIP to grade ≤1 was recorded for all but 4 pts for whom NIP was still observed at last follow-up before study discontinuation. Overall, in the EVE+EXE arm, NIP was recorded as the reason for dose interruption and treatment discontinuation in 7.5% and 5.6% of pts, respectively. Conclusions: Data from BOLERO-2 support the combination of EVE and EXE to significantly prolong PFS in postmenopausal women with HR+, HER2– ABC progressing on/after NSAI. The incidence of NIP in this study was generally consistent with reports from other oncology settings, was of mild to moderate severity, and was generally reversible with appropriate interventions and temporary dose modifications. Patient and healthcare provider education for early diagnosis and management of NIP are highly recommended. Clinical trial information: NCT00863655.

Clinical management and resolution of stomatitis in BOLERO-2.

558 Background: In BOLERO-2, adding everolimus (EVE) to exemestane (EXE) more than doubled progression-free survival without affecting quality of life vs EXE alone in postmenopausal women with hormone-receptor–positive advanced breast cancer who had recurrence or progression on/after nonsteroidal aromatase inhibitor therapy. Although mTOR inhibitors are generally well tolerated, stomatitis is one of their most clinically relevant and potentially dose-limiting toxicities (Sonis Cancer2010). The incidence, grade, and clinical course of stomatitis among patients (pts) participating in the BOLERO-2 study are described. Methods: Pts were randomized 2:1 to receive EVE+EXE or placebo (PBO)+EXE. Stomatitis incidence, severity, consequent dose interruptions/adjustments, study drug discontinuations, and time to resolution were recorded. Results: The median duration of EVE+EXE treatment exposure was 30 wk (range, 1-123 wk). Stomatitis (any grade) occurred more frequently with EVE+EXE than with PBO+EXE (59% vs 12%, respectively). Grade 3 stomatitis occurred in 8% vs 1% of pts receiving EVE+EXE vs PBO+EXE, respectively; no grade 4 was reported. Onset of grade ≥2 stomatitis after treatment initiation was earlier in the EVE+EXE arm vs the PBO+EXE arm: median time was 15d vs 24d, respectively. In the EVE+EXE arm, 97% of pts with grade 3 stomatitis (n=38) improved to ≤1 after a median of 13 d. Complete resolution was observed in 82% of these pts after a median of 38 d. In the PBO+EXE arm, all pts with grade 3 stomatitis (n=2) improved to ≤1 after a median of 18 d. Complete resolution was observed after a median of 29 d. Overall, 24% of pts in the EVE+EXE arm required dose interruptions/adjustments vs 1% of pts in the PBO+EXE arm, and 3% of pts (n=13) discontinued EVE+EXE vs <1% of pts (n=1) discontinuing PBO+EXE, all related to stomatitis. Conclusions: The BOLERO-2 data foster a new era of combining targeted and endocrine therapies. In the study, treatment-emergent stomatitis was of mild to moderate intensity, occurred shortly after treatment initiation, and was generally reversible. Most incidents were successfully managed with palliative interventions and temporary dose modifications. Oral hygiene and other preventive measures are recommended. Clinical trial information: NCT00863655.