An open label, randomized phase 2 trial assessing the impact of food on the tolerability of abemaciclib in patients with advanced breast cancer.

PURPOSE: Abemaciclib, a CDK4 & 6 inhibitor, is indicated for advanced breast cancer treatment. Diarrhea is a frequently associated adverse event of abemaciclib. The study objective was to investigate if food intake impacts local gastrointestinal toxicity. METHODS: This Phase 2 study (I3Y-MC-JPCP, NCT03703466) randomized 72 patients 1:1:1 to receive abemaciclib 200 mg monotherapy twice daily (1) with a meal, (2) in a modified fasting state or (3) without regard to food. Primary endpoints included: incidence of investigator assessed severe (≥ Grade 3), prolonged (> 7 days) Grade 2 diarrhea, treatment discontinuation, dose modifications, and loperamide utilization during the first 3 cycles of treatment. Patient outcomes were captured via a daily electronic diary. Pharmacokinetics (PK) are reported. RESULTS: Incidence of investigator assessed severe diarrhea (Grade ≥ 3) was 1.4% (1 patient in Arm 1). Median duration of Grade 3 diarrhea was 1 day by both investigator assessment (1 patient in Arm 1) and patient-reported assessment (1 patient each in Arms 1 and 3). Median duration of investigator-assessed Grade 2 diarrhea was 2 days overall. No patient discontinued treatment due to diarrhea. Nine patients (12.7%) had a dose reduction, and 7 patients (9.9%) had a dose omission due to diarrhea. Ninety-four percent of patients used loperamide at least once. Abemaciclib PK was comparable across the 3 arms. CONCLUSION: The results suggest that diarrhea incidence associated with abemaciclib was unrelated to timing of food intake, was predominantly low grade, of short duration and well managed with loperamide and dose modifications.

Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial.

BACKGROUND: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. METHODS: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. FINDINGS: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. INTERPRETATION: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. FUNDING: Eli Lilly and Company.

Health-Related Quality of Life in MONARCH 3: Abemaciclib plus an Aromatase Inhibitor as Initial Therapy in HR+, HER2- Advanced Breast Cancer.

BACKGROUND: MONARCH 3, a phase III trial (NCT02246621) of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), previously demonstrated significantly improved progression-free survival in patients receiving abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI). This study evaluated patient-reported outcomes, including global health-related quality of life (HRQoL), functioning, and symptoms. METHODS: Patients were randomly assigned 2:1 to receive abemaciclib (150 mg twice daily; n = 328) or placebo (n = 165), plus 1 mg anastrozole or 2.5 mg letrozole daily. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Breast Cancer-Specific Quality of Life Questionnaire HRQoL instruments were administered at baseline, every two cycles during cycles 2 through 19 (each cycle being 28 days), every three cycles thereafter, and once at a short-term posttherapy follow-up visit (approximately 30 days after discontinuation). Longitudinal mixed regression and Cox proportional hazards models evaluated postbaseline change and time to sustained deterioration (TTSD), respectively. RESULTS: Baseline scores were similar between treatment arms. Although select scores statistically favored the placebo arm, global HRQoL, most symptoms, and functioning scales did not meet the threshold for clinically meaningful differences between treatment arms. Only diarrhea favored the placebo arm with statistically and clinically meaningful differences. There were no TTSD differences between treatment arms for global HRQoL, most symptoms (except diarrhea), or functioning. CONCLUSION: Over a 2-year period, there were no clinically meaningful differences in global HRQoL, functioning, and most symptoms for patients receiving abemaciclib plus NSAI compared with NSAI alone. Only diarrhea favored the placebo arm, consistent with prior safety data, which has been shown to be manageable and reversible. Combined with clinical efficacy, results support treatment with abemaciclib plus NSAI for postmenopausal women with HR+, HER2- ABC. IMPLICATIONS FOR PRACTICE: The addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) was not associated with a clinically meaningful detriment in patient-reported global health-related quality of life, functioning, and most symptoms in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Prior studies have also demonstrated clinical efficacy of abemaciclib plus NSAI compared with NSAI alone, including improved progression-free survival and objective response rate. These results also complement previously reported toxicity data, as measured by investigator-assessed adverse events. Taken together, these results support treatment with abemaciclib plus NSAI for postmenopausal women with HR+, HER2- ABC.

Health-Related Quality of Life in MONARCH 2: Abemaciclib plus Fulvestrant in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer After Endocrine Therapy.

BACKGROUND: In the phase III MONARCH 2 study (NCT02107703), abemaciclib plus fulvestrant significantly improved progression-free survival (PFS) versus placebo plus fulvestrant in patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer (ABC). This study assessed patient-reported pain, global health-related quality of life (HRQoL), functioning, and symptoms. MATERIALS AND METHODS: Abemaciclib or placebo (150 p.o. mg twice daily) plus fulvestrant (500 mg, per label) were randomly assigned (2:1). The modified Brief Pain Inventory, Short Form (mBPI-sf); European Organization for Research and Treatment of Cancer (EORTC) QoL Core 30 (QLQ-C30); and Breast Cancer Questionnaire (QLQ-BR23) assessed outcomes. Data were collected at baseline, cycle 2, every two cycles 3-13, thereafter at every three cycles, and 30 days postdiscontinuation. Longitudinal mixed regression and Cox proportional hazards models assessed postbaseline change and time to sustained deterioration (TTSD) by study arm. RESULTS: On-treatment HRQoL scores were consistently maintained from baseline and similar between arms. Patients in the abemaciclib arm (n = 446) experienced a 4.9-month delay in pain deterioration (mBPI-sf), compared with the control arm (n = 223), and significantly greater TTSD on the mBPI-sf and analgesic use (hazard ratio, 0.76; 95% CI, 0.59-0.98) and QLQ-C30 pain item (hazard ratio, 0.62; 95% CI, 0.48-0.79). TTSD for functioning and most symptoms significantly favored the abemaciclib arm, including fatigue, nausea and vomiting, and cognitive and social functioning. Only diarrhea significantly favored the control arm (hazard ratio, 1.60; 95% CI, 1.20-2.10). CONCLUSION: HRQoL was maintained on abemaciclib plus fulvestrant. Alongside superior PFS and manageable safety profile, results support treatment with abemaciclib plus fulvestrant in a population of patients with endocrine-resistant HR+, HER2-negative ABC. IMPLICATIONS FOR PRACTICE: In MONARCH 2, abemaciclib plus fulvestrant demonstrated superior efficacy and a manageable safety profile for patients with in hormone receptor-positive (HR+), HER2-negative (-) advanced breast cancer (ABC). Impact on health-related quality of life (HRQoL) is important to consider, given the palliative nature of ABC treatment. In this study, abemaciclib plus fulvestrant, compared with placebo plus fulvestrant, significantly delayed sustained deterioration of pain and other patient-reported symptoms (including fatigue, nausea, vomiting), and social and cognitive functioning. Combined with demonstrated clinical benefit and tolerability, the stabilization of patient-reported symptoms and HRQoL further supports abemaciclib plus fulvestrant as a desirable treatment option in endocrine resistant, HR+, HER2- ABC.

Real-world patient-reported outcomes of women receiving initial endocrine-based therapy for HR+/HER2- advanced breast cancer in five European countries.

BACKGROUND: Endocrine therapy (ET)-based regimens are the mainstay of treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer. With the introduction of new treatment classes, it is important to examine patient symptoms and health-related quality of life (HRQoL) at the start of this changing therapeutic landscape. This real-world study describes the patient-reported outcomes (PROs) of women with HR+/HER2- advanced breast cancer receiving ET-based regimens who were naïve to systemic treatment in the advanced setting across five European countries (EU5). METHODS: Data were collected between March and July 2017 from surveyed oncologists and their patients at a single time point using the multinational Adelphi Advanced Breast Cancer Disease Specific Programme™. Patients completed PRO questionnaires on HRQoL (EORTC QLQ-C30), pain severity and interference, and work and activity impairment. A multiple linear regression model explored factors associated with HRQoL. RESULTS: Across EU5, 226 physicians provided data on 781 women with HR+/HER2- advanced breast cancer taking their first ET-based regimen for advanced disease, of whom 252 provided PRO data. This subset had a mean age of 67.1 years, 94% were postmenopausal, 89% were diagnosed with advanced breast cancer at initial presentation, 79% had stage IV disease (66% of these patients had bone metastases and 38% had visceral metastases, including 18% with liver metastases) and 77% were on endocrine-only therapy as their initial treatment for advanced disease. The mean EORTC QLQ-C30 global health score (50.9) was worse than the reference value for patients with advanced breast cancer (60.2). Fatigue, pain, and insomnia were the most severe symptoms, and mean functioning scores were also worse than reference values. "Worst pain" and "pain interference" were moderate/severe for 42 and 80% of patients. Mean activity impairment was 44%, and greater activity impairment was associated with poorer HRQoL. CONCLUSIONS: Despite receiving first-line ET-based regimens for advanced disease, these women had a poor HRQoL and high levels of symptoms, pain, pain interference and activity impairment. New treatments that maintain a stable disease state and reduce activity impairment may have a positive effect on the HRQoL of those living with advanced breast cancer.

Comparison of demographics, treatment patterns, health care utilization, and costs among elderly patients with extensive-stage small cell and metastatic non-small cell lung cancers.

BACKGROUND: Limited data exist regarding real-world treatment patterns, resource utilization, and costs of extensive-stage small cell lung cancer (esSCLC) among elderly patients in the United States. While abundant data are available on treatment patterns in metastatic non-small cell lung cancer (mNSCLC), to our knowledge no data exist comparing costs and resource use between patients with esSCLC or mNSCLC. METHODS: We retrospectively analyzed administrative claims data (2000-2008) of patients aged ≥65 years from the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database. Patients were selected on the basis of having newly diagnosed esSCLC (n=5,855) or mNSCLC (n=24,090) during 1/1/2000-12/31/2005, and were required to have received cancer-directed therapy. Survival and other measures were compared between esSCLC and mNSCLC patients using Kaplan-Meier log-rank and univariate chi-square and t-tests. Study measures were followed from first diagnosis date of either esSCLC or mNSCLC until the earlier of death or end of the database. RESULTS: Survival between the cohorts did not differ significantly: mean of 10.4 months for esSCLC patients versus 11.1 months for mNSCLC; median survival was 7.4 months versus 5.9 months. A higher percentage of mNSCLC patients (vs. esSCLC) received radiation therapy (75.6% vs. 65.4%; P < 0.001) and surgery (13.6% vs. 7.8%; P < 0.001) during the metastatic disease period. Conversely, a higher percentage of esSCLC patients than mNSCLC patients received chemotherapy (85.5% vs. 60.3%; P < 0.001), red blood-cell transfusion (20.7% vs. 10.9%; P < 0.001), platelet transfusion (5.6% vs. 1.8%; P < 0.001), and growth-factor support (59.0% vs. 39.5%; P < 0.001). esSCLC patients incurred higher lifetime disease-related costs ($44,167 vs. $37,932; P < 0.001) and all-cause costs ($70,549 vs. $67,176; P < 0.001) than mNSCLC patients. CONCLUSIONS: Lifetime total and disease-related costs per patient were high. Increased use of chemotherapy, supportive care therapies (including growth factors), and disease-related hospitalizations were observed in esSCLC patients as compared with mNSCLC patients. Disease-related and all-cause costs for esSCLC also exceeded those of mNSCLC, except for hospice and skilled nursing services. Survival and per-patient costs for both groups underscore the unmet medical need for more effective therapies in patients with esSCLC or mNSCLC.

Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting.

OBJECTIVE: To examine the real-world incidence and management of select adverse events (AEs) among female patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), receiving a cyclin-dependent kinase 4 and 6 (CDK4 and 6) inhibitor (palbociclib, abemaciclib, or ribociclib). METHODS: This retrospective study analyzed data from the US Oncology Network iKnowMed electronic health record database for 396 patients with an initial MBC diagnosis on/after 1 January 2014 and receipt of first CDK4 and 6 regimen between 1 January 2017 and 31 December 2018. In this descriptive study, the proportion of patients who experienced select AEs and associated dose modifications or discontinuations were reported. The occurrence of select healthcare resource utilization categories was also reported. RESULTS: Median follow-up time was 451, 262, and 355 days for patients in the palbociclib, abemaciclib, and ribociclib cohorts, respectively. The most common AEs were neutropenia (palbociclib, 44.8%; abemaciclib, 10.6%; ribociclib, 36.3%), diarrhea (palbociclib, 8.0%; abemaciclib, 43.0%; ribociclib, 8.8%), and fatigue (palbociclib, 12.9%; abemaciclib, 17.6%; ribociclib, 16.5%). AEs resulted in a treatment hold among 91 (23.0%), a dose reduction among 86 (21.7%), and permanent discontinuation among 48 (12.1%) patients overall. CONCLUSIONS: This real-world study provides insight into the occurrence of AEs which varied by CDK4 and 6 inhibitor. Compared to clinical trials, frequencies of AEs were numerically lower but dose reductions due to AEs were numerically higher. It is possible these differences reflect proactive management of AEs on the part of clinicians to help patients remain on therapy.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6 inhibitors) have changed the landscape for the treatment of metastatic breast cancer (MBC) among patients who are hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2−). An understanding of the real-world management of adverse events (AEs) will help optimize treatment strategies. Here, data from the US Oncology Network electronic health record database for 396 HR+, HER2−, MBC patients receiving a CDK4 and 6 inhibitor were examined to describe the proportion of patients who experienced select AEs and the associated outcomes of these AEs. Compared to clinical trials, frequencies of AEs were numerically lower but dose reductions due to AEs were numerically higher. It is possible that these differences reflect a proactive management of AEs on the part of clinicians to help patients remain on therapy.

Treatment Experiences with CDK4&6 Inhibitors Among Women with Metastatic Breast Cancer: A Qualitative Study.

PURPOSE: To describe patients' perspectives on the use of and potential challenges and barriers with adherence/persistence to cyclin-dependent kinase 4 and 6 inhibitors (CDK4&6i's) to treat metastatic breast cancer (MBC). METHODS: This qualitative study consisted of 60-minute semi-structured telephone interviews with patients with MBC in the US who were either current or recent CDK4&6i users, identified from administrative claims of survey-eligible commercial and Medicare Advantage patients in the HealthCore Integrated Research Database between November 1, 2018 and November 1, 2019. Patients were recruited by email and/or mailed letter. The 60-minute telephone interviews were conducted by a trained facilitator using a study-developed interview discussion guide that included topics impacting treatment choice and adherence/persistence. Interviews were audio-recorded, transcribed, and thematically analyzed. RESULTS: All 462 eligible patients were sent a recruitment email and/or letter to which 36 patients responded, consented to participate, and met study inclusion criteria; 25 patients scheduled interviews, and 24 completed them. Study participants were predominately white, non-Hispanic (96%) with a mean age of 59.5 years. Participants reported a largely positive experience and mentioned very few adherence/persistence issues. They further reported appreciating the ease and convenience of oral oncolytics, coped with side effects, had strong medical and social support, and experienced few cost issues. CONCLUSION: The few adherence/persistence issues reported by participants contrasts with other findings of suboptimal oral oncolytic use. Interview themes indicated several factors that likely contributed to the lack of adherence/persistence issues: trusted relationship with oncologist, belief in importance of medication, positive medication views, strong medical and social support, and minimal personal drug cost. Future research should focus on whether and how much these factors impact adherence/persistence in more diverse populations. If adherence/persistence issues are identified in these populations, then it would be appropriate to study the development of interventions that target factors associated with better adherence/persistence.

Development of a Prognostic Factor Index Among Women With HR+/HER2- Metastatic Breast Cancer in a Community Oncology Setting.

BACKGROUND: This study explored the impact of multiple prognostic factors on patient overall survival (OS) and real-world progression-free survival (rwPFS) for patients with hormone receptor-positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (MBC). MATERIALS AND METHODS: This retrospective study used electronic health record data of patients in the United States from community oncology practices from January 1, 2008 to April 30, 2017. Eligibility included HR+/HER2- MBC diagnosis in 2008 or later and prior systemic therapy for MBC. An index variable was created to assess the effect of multiple clinical prognostic factors collectively, including liver metastases (LM), primary endocrine resistance (PER), negative progesterone receptor (PR-) status, and high tumor grade (TG). Patients were grouped based on the number of prognostic factors present at MBC diagnosis: 0, 1, and 2+. Differences in rwPFS and OS from start of first-line therapy were evaluated by the Kaplan-Meier method and multivariable Cox proportional hazards regression. RESULTS: Approximately 29.1% of the 378 eligible patient sample had 0, 36.0% had 1, and 34.9% had 2+ prognostic factors. For the patients with 1 of the prognostic factors, 24.3% had high TG, 14.7% were LM+, 39.7% had PER, and 21.3% were PR-. Univariate and multivariate results showed that rwPFS and OS were significantly (P < .05) shorter in patients with 1 and 2+ prognostic factors compared with patients with 0. CONCLUSIONS: The individual prognostic factors and the prognostic factor index may enable early identification of patients with a less favorable prognosis across the HR+/HER2- MBC population and help inform treatment decisions in difficult-to-treat populations.

Treatment patterns, adverse events, and direct and indirect economic burden in a privately insured population of patients with HR+/HER2- metastatic breast cancer in the United States.

BACKGROUND: Real-world evidence specific to HR+/HER2- metastatic breast cancer (MBC) prior to introduction of CDK4/6 inhibitors is limited. In an effort to provide context for the introduction of new treatments, we assessed treatment patterns, adverse events, productivity loss, and direct/indirect economic burden in a privately insured population of patients with HR+/HER2- MBC. RESEARCH DESIGN AND METHODS: Using a retrospective cohort design, patients aged 18-64 years, selected from MarketScan databases (2007-2014), were analyzed using descriptive and multivariable methods. RESULTS: Among 5,563 eligible patients, endocrine therapy was the most common first-line (1L) therapy; its utilization trended downward from 63% (1L) to 23% (4L), with a simultaneous increase in chemotherapy use, 25% (1L) to 50% (4L). Two hundred and seventy-eight unique treatment regimens were used in the 1L setting. The average per patient monthly all-cause costs were $14,424. The 12-month indirect costs for short-term disability were substantially higher in MBC patients ($10,397) than in matched noncancer patients ($394). CONCLUSION: The increasing use of chemotherapy as patients progressed to second and later lines and the substantial direct/indirect economic burden underscore an unmet need. The high number of 1L regimens highlights significant heterogeneity and a lack of consensus related to the management of HR+/HER2- MBC in routine practice.

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study.

BACKGROUND: Cyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen. PATIENTS AND METHODS: Women ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0-1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1. RESULTS: Sixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease. CONCLUSIONS: Abemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier NCT02057133.

Treatment patterns, survival and economic outcomes in Medicare-enrolled, older patients with HR+/HER2- metastatic breast cancer.

Background: Endocrine therapy (ET) remains a foundation of systemic therapy for HR+/ HER2- metastatic breast cancer (MBC), although chemotherapy (CT) is used in select patients. In this "real-world" study, we explored treatment patterns, health care resource use (HCRU), costs, adverse events (AEs) and overall survival (OS) in Medicare-enrolled, older patients with HR+/HER2- MBC. Methods: Patients with HR+/HER2- MBC (2007-2011) and aged >66 years were retrospectively analyzed using the SEER-Medicare data. Treatment patterns, HCRU, costs, AEs and OS after MBC diagnosis through end of study period (31 December 2013) were examined using descriptive and multivariable analyses. Results: Among 3622 eligible patients, ET was the most common treatment (77%), followed by CT (50%), radiation (48%) and surgery (19%). The proportion of patients treated with ET monotherapy decreased across therapy lines, from 74% in first line (1 L) to 35% in 4 L. The total number of unique therapy regimens used was 181 in 1 L, 171 in 2 L, 128 in 3 L, and 95 in 4 L. The median OS from MBC diagnosis was 25.3 months (95% CI, 24.0-26.7). In multivariable analyses, receipt of CT and combination CT + ET (versus ET monotherapy) in 1 L, metastatic disease at initial diagnosis, larger tumor size, and presence of visceral and brain metastases at MBC diagnosis significantly predicted receipt of 2 L therapy. Conclusions: ET was the most common first-line treatment for study patients, but its use decreased gradually in the subsequent lines. The heterogeneity in the treatment selection highlights a lack of consensus for the management of HR+/HER2- MBC in routine practice.

Systematic Review of Brain Metastases in Patients With Non-Small-Cell Lung Cancer in the United States, European Union, and Japan.

Brain metastases (BRM) occur frequently in non-small-cell lung cancer (NSCLC) and present a substantial unmet medical need. Previous literature on global BRM prevalence, treatment patterns, costs, and outcomes typically has described a subset of these factors. The primary objective of this systematic literature review was to summarize BRM-related epidemiology, treatment patterns, costs, and survival of patients with NSCLC in the United States, European Union, and Japan. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. Literature searches were conducted in PubMed, Ovid MedLine, and Embase to identify studies published between 2003 and 2014. Peer-reviewed, English language, and human observational studies of patients with NSCLC and BRM were identified. Demographic characteristics, treatment patterns, histology subtype, costs, and survival data were extracted into Microsoft Excel and descriptively analyzed using SAS version 9.2 (SAS Institute, Inc). Of 8257 studies, 243 were eligible. Data from 46,422 patients with NSCLC and 27,907 patients with BRM were summarized. Radiation therapy was used by 70.7% (n = 19,736) of the total BRM population, followed by systemic therapy (8.9%, n = 2497), and surgery (6.1%, n = 1690). Reported median survival was 9.78 months ranging from 2.5 to 38 months. Radiation therapy had the best outcome at 10.0 months with 41.6% (n = 101) of the studies reporting the use of stereotactic radiosurgery. Highly variable median survival and treatment patterns were reported between countries. Costs and histology subtype data were not reported for most countries, highlighting the need for additional research to describe the economic burden of BRM and improve the diagnosis, prognosis, and prescription of effective therapies.

A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia.

Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2V617F mutation. The study had a standard 3+3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2V617F-positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4h after single and multiple doses, and mean half-life on day 1 was approximately 6h. Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients. A ≥50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥50% reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52%) and 6/14 patients (43%) receiving ≥120mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120.

Survival patterns in United States (US) medicare enrollees with non-CML myeloproliferative neoplasms (MPN).

PURPOSE: Non-CML myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Reported median overall survival (OS) ranges from a few to several years for MF, a decade or more for ET and PV. The study objective was to compare US survival rates of ET, PV, and MF patients with matched non-MPN/non-cancer controls in a nationally representative database. PATIENTS AND METHODS: Data were taken retrospectively from the Survey, Epidemiology, and End Results (SEER)-Medicare linked database. Medicare enrollees with a new SEER MPN diagnosis between Jan 1, 2001 and Dec 31, 2007 were eligible. First MPN diagnosis was required at or after Medicare enrollment to allow for continuous follow-up. Non-MPN/non-cancer control groups were selected from Medicare separately for each MPN subtype and demographically matched to cases at a ratio of 5:1. Survival was determined starting from the case diagnosis date using the Kaplan-Meier method. RESULTS: A total of 3,364 MPN patients (n = 1,217 ET; 1,625 PV; 522 MF) met the inclusion criteria and were matched to controls. Mean age was 78.4, 76.1, and 77.4 years for ET, PV, and MF, respectively, and percent female was 63, 50, and 41. Median OS was significantly (p<0.05) lower for MPN cases vs. controls (ET: 68 vs. 101 months; PV: 65 vs. 104; MF: 24 vs. 106). CONCLUSIONS: In the US Medicare population, survival in MF patients was worse than that of patients with ET or PV and significantly worse than matched controls. Survival of patients with ET or PV was substantially inferior to matched controls. These findings have implications for the clinical management of MPN patients and underscore the need for effective therapies in all MPN subtypes.

Evaluating the utility of existing patient-reported outcome scales in novel patient populations with pancreatic cancer, lung cancer, and myeloproliferative neoplasms using medicare current beneficiary survey data.

BACKGROUND: While there are validated patient-reported outcomes (PRO) instruments for use in specific cancer populations, no validated general instruments exist for use in conditions common to multiple cancers, such as muscle wasting and consequent physical disability. The Medicare Current Beneficiary Survey (MCBS), a survey in a nationally representative sample of Medicare beneficiaries, includes items from three well known scales with general applicability to cancer patients: Katz activities of daily living (ADL), Rosow-Breslau instrumental ADL (IADL), and a subset of physical performance items from the Nagi scale. OBJECTIVE: This study evaluated properties of the Katz ADL, Rosow-Breslau IADL, and a subset of the Nagi scale in patients with pancreatic cancer, lung cancer, and myeloproliferative neoplasms (MPN) using data from MCBS linked with Medicare claims in order to understand the potential utility of the three scales in these populations; understanding patient-perceived significance was not in scope. METHODS: The study cohorts included Medicare beneficiaries aged ≥65 years as of 1 January of the year of their first cancer diagnosis with one or more health assessments in a community setting in the MCBS Access to Care data from 1991 to 2009. Beneficiaries had at least two diagnoses in de-identified Medicare claims data linked to the MCBS for one of the following cancers: pancreatic, lung, or MPN. The Katz ADL, Rosow-Breslau IADL, and Nagi scales were calculated to assess physical functioning over time from cancer diagnosis. Psychometric properties for each scale in each cohort were evaluated by testing for internal consistency, test-retest reliability, and responsiveness by comparing differences in mean scale scores over time as cancer progresses, and differences in mean scale scores before and after hospitalization (for lung cancer cohort). RESULTS: The study cohorts included 90 patients with pancreatic cancer, 863 with lung cancer, and 135 with MPN. Among each cancer cohort, the Katz ADL, Rosow-Breslau IADL, and Nagi scales had acceptable internal consistency (Cronbach's alpha generally between 0.70 and 0.90) and test-retest reliability for consecutive surveys before diagnosis and consecutive surveys after diagnosis (when patients' functioning was more stable). Compared with mean scale scores at the survey 1-2 years before cancer diagnosis (baseline), mean scale scores at the first survey after cancer diagnosis were significantly higher (P < 0.05), indicating worsening, for Katz ADL, Rosow-Breslau IADL, and Nagi scales (items scored 0-1) (0.54 vs. 1.45, 1.15 vs. 2.20, and 2.29 vs. 3.08, respectively, for pancreatic cancer; 0.73 vs. 1.24, 1.29 vs. 2.01, and 2.41 vs. 2.85 for lung cancer; and 0.44 vs. 0.86, 0.87 vs. 1.36, and 1.87 vs. 2.32 for MPN). Among lung cancer patients, scale scores increased significantly following a hospitalization, suggesting a worsening of functional status. CONCLUSIONS: The Katz ADL, Rosow-Breslau IADL, and Nagi scales collected in the MCBS demonstrate acceptable internal consistency and test-retest reliability among patients with pancreatic cancer, lung cancer, and MPN, and are consistent with clinical worsening following diagnosis or hospitalization. These results suggest that using retrospective data may allow researchers to conduct preliminary assessments of existing PRO instruments in new populations of interest and generate useful exploratory disease information before embarking on de novo PRO development.