Exploratory Subgroup Analysis Research Articles

Learn to forget: Does post-exposure administration of d-cycloserine enhance fear extinction in agoraphobia?

The use of d-cycloserine (DCS) to augment exposure based therapy for anxiety disorders has shown mixed, although overall positive effects. Aim of the present study was to examine post-exposure administration of DCS in patients with agoraphobia with or without panic disorder. 73 patients with agoraphobia (with or without panic disorder) were treated with 12 sessions of cognitive behavioral therapy (CBT) including 3 exposures. Following successful exposure patients were given double blind either placebo or 50 mg of DCS. Primary outcome criterion was change in the Panic and Agoraphobia Scale (PAS) between CBT session t1, t4 (+∼2 months), t10 (+∼3 months) und t11 (+∼4 months). During the course of CBT the patients' symptomatology decreased significantly as measured by primary and secondary outcome criteria, however, without an additional benefit for DCS treated patients. Exploratory sub-group analyses for severely ill patients and patients with high anxiety and strong habituation during exposure showed that DCS administration was associated with increased improvement during the 1-month follow-up period (t10 - t11) with medium to large effect sizes (range in effect size η2p from .06 to .25). Our study results are consistent with recent research on DCS, indicating a beneficial augmentative effect for sub-groups of anxiety patients. The lack of an overall DCS effect for the whole patient sample might be explained by a dual mechanism in fear conditioning and extinction with different cognitive processes being involved during exposure depending on the degree of anxiety experienced by the patient.

Safety and clinical activity of atezolizumab monotherapy in metastatic non-small-cell lung cancer: final results from a phase I study

IntroductionAtezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody, inhibits PD-L1:PD-1 and PD-L1:B7.1 interactions, restoring anticancer immunity. Here, we report final analyses from the non-small-cell lung cancer (NSCLC) cohort of the first atezolizumab phase I study. MethodsPatients with NSCLC received atezolizumab 1–20 mg/kg or 1200 mg intravenously every 3 weeks. Baseline PD-L1 expression on tumour cells (TCs) and tumour-infiltrating immune cells (ICs) was assessed (VENTANA SP142 immunohistochemistry assay). Exploratory subgroup analyses investigated responses by baseline PD-L1 expression and oncogenic mutational status. ResultsEighty-nine patients, 98% of whom had received previous systemic therapy, were evaluable for safety and antitumour activity. Atezolizumab was well tolerated, with grade III/IV treatment-related adverse events (TRAEs) observed in 10 patients (11%). All-grade TRAEs occurring in >10% of patients were fatigue, nausea and decreased appetite; grade III/IV TRAEs occurring in >2% of patients were fatigue, dyspnoea, hyponatremia and hypoxia. One patient died from treatment-unrelated pneumonia. Objective response rate (ORR) was 50% (95% confidence interval [CI], 28%–72%), 33% (20%–48%), 29% (18%–41%) and 11% (1%–35%) for the TC3 or IC3, TC2/3 or IC2/3, TC1/2/3 or IC1/2/3 and TC0 and IC0 subgroups, respectively. All-patient ORR was 23% (95% CI, 14%–33%). Median duration of response was 16.4 months (range, 7.2–53.4+). One-, 2-, and 3-year survival rates were 63% (95% CI, 53%–73%), 37% (26%–47%) and 28% (18%–38%), respectively. ConclusionsSingle-agent atezolizumab was well tolerated with long-term clinical benefits, including durable responses and survival, in pretreated NSCLC. Improved responses and survival rates were seen with increasing baseline PD-L1 expression. ClinicalTrials.gov identifierNCT01375842.

Effect of resistance training on inflammatory markers of older adults: A meta-analysis.

Low-grade inflammation is associated with several deleterious health outcomes and may aggravate sarcopenia and dynapenia during aging. A strategy to alleviate these conditions is resistance training (RT). Thus, the aim was to critically examine the effects of regular RT on inflammatory markers of older adults from previous studies. The search was conducted on MEDLINE, July 2017. Only randomized controlled trials (RCTs) testing RT effects on C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and/or interleukin-6 (IL-6) of adults over 50 years-of-age were selected by two independent reviewers. The main meta-analyses showed RT reduced CRP in older adults (standard mean difference [SMD] = -0.61, 95%CI = -0.83; -0.31, p < 0.001), tended to reduce IL-6 (SMD = -0.19, 95%CI = -0.42; 0.02, p = 0.07) and did not change TNF-α. Further exploratory sub-group analyses showed a potential association of muscle mass for both CRP and TNF-α changes. Reductions in CRP and TNF-α only occurred in RCTs performing a higher number of exercises (>8), higher weekly frequency (3 times/week) and longer durations than 12 weeks. Anti-inflammatory effects of RT were significant only for CRP with a tendency for a decrease in IL-6 as well. The exploratory analyses suggested the reduction in inflammatory markers could be dependent on increases in muscle mass and higher volume of RT protocols. These potential mediators of RT anti-inflammatory effects should be addressed in future meta-analyses to clarify the effects of RT on inflammatory markers of older adults with very specific conditions and larger numbers of studies.

A facility-based study of women\u2019 satisfaction and perceived quality of reproductive and maternal health services in the Kenya output-based approach voucher program

BackgroundThis is a facility-based study designed to assess perceived quality of care and satisfaction of reproductive health services under the output-based approach (OBA) services in Kenya from clients’ perspective.MethodAn exit interview was conducted on 254 clients in public health facilities, non-governmental organizations, faith-based organizations and private facilities in Kitui, Kilifi, Kiambu, and Kisumu counties as well as in the Korogocho and Viwandani slums in Nairobi, Kenya using a 23-item scale questionnaire on quality of reproductive health services. Descriptive analysis, exploratory factor analysis, reliability test, and subgroup analysis using linear regression were performed.ResultsClients generally had a positive view on staff conduct and healthcare delivery but were neutral on hospital physical facilities, resources, and access to healthcare services. There was a high overall level of satisfaction among the clients with quick service, good handling of complications, and clean hospital stated as some of the reasons that enhanced satisfaction. The County of residence was shown to impact the perception of quality greatly with other social demographic characteristics showing low impact.ConclusionMajority of the women perceived the quality of OBA services to be high and were happy with the way healthcare providers were handling birth related complications. The conduct and practice of healthcare workers is an important determinant of client’s perception of quality of reproductive and maternal health services. Findings can be used by health care managers as a guide to evaluate different areas of healthcare delivery and to improve resources and physical facilities that are crucial in elevating clients’ level of satisfaction.

Symptom relief and anejaculation after aquablation or transurethral resection of the prostate: subgroup analysis from a blinded randomized trial.

To test the hypothesis that benign prostatic hyperplasia (BPH) robotic surgery with aquablation would have a more pronounced benefit in certain patient subgroups, such as men with more challenging anatomies (e.g. large prostates, large middle lobes) and men with moderate BPH. We conducted prespecified and post hoc exploratory subgroup analyses from a double-blind, multicentre prospective randomized controlled trial that compared transurethral resection of the prostate (TURP) using either standard electrocautery vs surgery using robotic waterjet (aquablation) to determine whether certain baseline factors predicted more marked responses after aquablation as compared with TURP. The primary efficacy endpoint was reduction in International Prostate Symptom Score (IPSS) at 6 months. The primary safety endpoint was the occurrence of Clavien-Dindo persistent grade 1 or grade ≥2 surgical complications. For men with larger prostates (50-80 g), the mean IPSS reduction was four points greater after aquablation than after TURP (P = 0.001), a larger difference than the overall result (1.8 points; P = 0.135). Similarly, the primary safety endpoint difference (20% vs 46% [26% difference]; P = 0.008) was greater for men with large prostate compared with the overall result (26% vs 42% [16% difference]; P = 0.015). Postoperative anejaculation was also less common after aquablation compared with TURP in sexually active men with large prostates (2% vs 41%; P < 0.001) vs the overall results (10% vs 36%; P < 0.001). Exploratory analysis showed larger IPSS changes after aquablation in men with enlarged middle lobes, men with severe middle lobe obstruction, men with a low baseline maximum urinary flow rate, and men with elevated (>100) post-void residual urine volume. In men with moderate-to-severe lower urinary tract symptoms attributable to BPH and larger, more complex prostates, aquablation was associated with both superior symptom score improvements and a superior safety profile, with a significantly lower rate of postoperative anejaculation. The standardized, robotically executed, surgical approach with aquablation may overcome the increased outcome variability in more complex anatomy, resulting in superior symptom score reduction.

Abstract CT099: The benefit of abemaciclib in prognostic subgroups: An update to the pooled analysis of MONARCH 2 and 3

Abstract Background: A recent exploratory subgroup analysis pooling data from over 1000 patients (pts) in MONARCH 2 (final analysis) and MONARCH 3 (interim analysis) demonstrated that pts with clinical characteristics that predict for worse outcome (e.g. liver metastases, progesterone receptor [PgR]-negative status, high-grade tumors) received the largest benefit from the addition of abemaciclib to endocrine therapy (ET). There is also interest in determining the extent to which abemaciclib improves progression-free survival (PFS) in pts with favorable prognostic factors (e.g. bone-only disease, long treatment-free interval [TFI]). Here we present an update of the subgroup analyses of the MONARCH 3 study using data from the preplanned final PFS analysis. Methods: Enrollment criteria and study designs were previously described (Sledge et al. J Clin Oncol. 2017; Goetz et al. J Clin Oncol. 2017). An exploratory pooled analysis was conducted using data from MONARCH 2 (NCT02107703) and the MONARCH 3 (NCT02246621) preplanned final PFS analysis to identify significant prognostic factors regardless of therapy received. Using the updated MONARCH 3 data, PFS and objective response rate (ORR) (in pts with measurable disease) were examined within the prognostic subgroups that had been previously identified as being statistically significant. Additionally, subpopulation treatment effect pattern plot (STEPP) methodology was used to evaluate the association between TFI following adjuvant ET and outcomes of NSAI alone or with abemaciclib. Results: Assessment of clinical factors from MONARCH 2 and MONARCH 3 (final PFS data) confirmed that the following factors remained significantly prognostic regardless of treatment received: bone-only disease, liver metastases, tumor grade, PgR status, and ECOG performance status. In MONARCH 3, prognosis was poor in pts with liver metastases, PgR-negative tumors, and high-grade tumors. While all subpopulations benefited from the addition of abemaciclib to ET regardless of prognosis, pts with these three poor prognostic factors received substantial benefit from abemaciclib, with PFS hazard ratios (HR) ranging from 0.4 to 0.5 and with differential improvement in ORR typically &amp;gt;30%. Furthermore, STEPP analysis of TFI (on the MONARCH 3 pts who had received adjuvant ET) demonstrated that pts who had a shorter TFI had a worse prognosis and received relatively greater benefit from abemaciclib plus NSAI than did pts with a longer TFI. Patients with bone-only disease or a long TFI also received benefit from abemaciclib, but to a relatively lesser extent (HR ranging from approximately 0.6 to 0.8). Conclusions: This exploratory analysis of the preplanned final PFS data from MONARCH 3 confirms previous findings that pts with poor prognostic factors may receive relatively greater benefit from the addition of abemaciclib to ET. Citation Format: Joyce O'Shaughnessy, Matthew P. Goetz, George W. Sledge, Miguel Martin, Yong Lin, Tammy Forrester, Ian C. Smith, Angelo Di Leo, Stephen Johnston. The benefit of abemaciclib in prognostic subgroups: An update to the pooled analysis of MONARCH 2 and 3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT099.

The impact of early outcome events on the effect of tranexamic acid in post-partum haemorrhage: an exploratory subgroup analysis of the WOMAN trial

BackgroundIn severe post-partum haemorrhage, death can occur within hours of bleeding onset so interventions to control the bleeding must be given immediately. In clinical trials of treatments for life-threatening bleeding, established treatments are given priority and the trial treatment is usually given last. However, enrolling patients in whom severe maternal morbidity or death is imminent or inevitable at the time of randomisation may dilute the effects of a trial treatment.MethodsWe conducted an exploratory analysis of data from the WOMAN trial, an international, randomised placebo-controlled trial of the effects of tranexamic acid on death and surgical intervention in 20,060 women with post-partum haemorrhage. We assessed the impact of early maternal death or hysterectomy due to exsanguination on the effect of tranexamic acid on each of these respective outcomes. We conducted repeated analyses excluding patients with these outcomes at increasing intervals from the time of randomisation. We quantified treatment effects using risk ratios (RR) and 99% confidence intervals (CI) and prepared cumulative failure plots.ResultsAmong 14,923 women randomised within 3 h of delivery (7518 tranexamic acid and 7405 placebo), there were 216 bleeding deaths (1.5%) and 383 hysterectomies due to bleeding (2.8%). After excluding deaths from exsanguination at increasing time intervals following randomization, there was a significant reduction in the risk of death due to bleeding with tranexamic acid (RR = 0.41; 99% CI 0.19–0.89). However, after excluding hysterectomies at increasing time intervals post-randomization, there was no reduction in the risk of hysterectomy due to bleeding with tranexamic acid (RR = 0.79; 99% CI 0.33–1.86).ConclusionsFindings from this analysis provide further evidence that tranexamic acid reduces the risk of death from exsanguination in women who experience postpartum haemorrhage. It is uncertain whether tranexamic acid reduces the risk of hysterectomy for bleeding after excluding early hysterectomies.Trial registrationISRCTN trial registration number ISRCTN76912190, 8 Dec 2008; ClinicalTrials.gov number NCT00872469, 30 March 2009; PACTR number PACTR201007000192283, 9 Feb 2010; EudraCT number 2008–008441-38, 8 Dec 2010 (retrospectively registered).

A randomized controlled trial on the effect of a silver carboxymethylcellulose dressing on surgical site infections after breast cancer surgery.

BackgroundThe incidence of surgical site infections (SSIs) after breast cancer surgery is relatively high; ranging from 3 to 19%. The role of wound dressings in the prevention of SSI after breast cancer surgery is unclear. This study compares a silver carboxymethylcellulose dressing (AQUACEL Ag Surgical (Aquacel) with standard wound dressing in SSI rate after breast cancer surgery.Patients and methodsA single-centre randomized controlled trial among women ≥18 years, diagnosed with breast cancer, undergoing breast conserving or ablative surgery, was conducted in a combined in and outpatient setting. The intervention was the use of Aquacel, compared with standard gauze dressing. Primary outcome measure was SSI following CDC criteria.ResultsA total of 230 patients were analysed: 106 in the Aquacel group and 124 controls. Seven patients (6.6%) developed SSI in the Aquacel group and 16 patients (12.9%) in the control group (RR 0.51 [95% Confidence Interval (CI): 0.22–1.20]; p = 0.112; adjusted OR 0.49 [0.19–1.25] p = 0.135)). Unplanned exploratory subgroup analysis of breast conserving surgery patients showed that SSI rate was 1/56 (1.8%) in the Aquacel group vs. 7/65 (10.8%) in controls; adjusted OR 0.15 [0.02–1.31] p = 0.087. The Aquacel group showed better patient satisfaction (median 8 vs. 7 on a Numerical Rating Scale, p = 0.006), fewer dressing changes within 48 hours(adjusted OR 0.12 [0.05–0.27] p<0.001), fewer re-operations (0% vs. 3.2%, p = 0.062), and lower mean wound-related treatment costs, both in a high (€265.42 (SD = 908) vs. €470.65 (SD = 1223) [p<0.001]) and low (€59.12 (SD = 129) vs. €67.55 (SD = 172) [p<0.001]) attributable costs of SSI model.ConclusionIn this randomized controlled trial in women undergoing surgery for breast cancer, the use of AQUACEL Ag Surgical wound dressing did not significantly reduce the occurrence of SSIs compared to standard gauze dressing. The use of Aquacel resulted in significantly improved patient satisfaction, reduced dressing changes and reduced wound-related costs.Trial registrationwww.trialregister.nl: NTR5840

Short, full-dose neoadjuvant chemotherapy in localized high-risk adult soft tissue sarcomas (STS): An exploratory subgroup analysis on responding patients in a randomized controlled trial comparing 3 neoadjuvant versus 3 neoadjuvant + 2 adjuvant cycles of full dose anthracycline and ifosfamide chemotherapy at a 10yr median FU.

11558Background: We already reported (Cancer 2012;118:5857) the correlation of Choi criteria (Choi) and RECIST with outcome of pts affected by high-risk STS entering a multicentric Italian/Spanish ...

Efficiency of anlotinib hydrochloride as 3rd line treatment in patients (pts) from a randomized, double-blind, placebo-controlled phase III trial, an exploratory subgroup analysis of ALTER0303 trial for the previous therapy strategy effect.

e21182Background: ALTER 0303 trial (NCT02388919) has demonstrated that anlotinib could significantly prolonged OS (primary point) and PFS in refractory advanced NSCLC pts as 3rd line treatment. Met...

815 - Long-Term Efficacy and Safety of CT-P13 after Switching from Originator Infliximab: Exploratory Subgroup Analyses in IBD in the Nor-Switch Extension Trial

815 - Long-Term Efficacy and Safety of CT-P13 after Switching from Originator Infliximab: Exploratory Subgroup Analyses in IBD in the Nor-Switch Extension Trial

Effects of a 12-Week Digital Care Program for Chronic Knee Pain on Pain, Mobility, and Surgery Risk: Randomized Controlled Trial.

BackgroundChronic knee pain, most commonly caused by knee osteoarthritis, is a prevalent condition which in most cases can be effectively treated through conservative, non-surgical care involving exercise therapy, education, psychosocial support, and weight loss. However, most people living with chronic knee pain do not receive adequate care, leading to unnecessary use of opiates and surgical procedures.ObjectiveAssess the efficacy of a remotely delivered digital care program for chronic knee pain.MethodsWe enrolled 162 participants into a randomized controlled trial between January and March 2017. Participants were recruited from participating employers using questionnaires for self-assessment of their knee pain, and randomized into treatment (n=101) and control (n=61) groups. Participants in the treatment group were enrolled in the Hinge Health digital care program for chronic knee pain. This is a remotely delivered, home-based 12-week intervention that includes sensor-guided exercise therapy, education, cognitive behavioral therapy, weight loss, and psychosocial support through a personal coach and team-based interactions. The control group received three education pieces regarding self-care for chronic knee pain. Both groups had access to treatment-as-usual. The primary outcome was the Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain subscale and KOOS Physical Function Shortform (KOOS-PS). Secondary outcomes were visual analog scales (VAS) for pain and stiffness respectively, surgery intent, and self-reported understanding of the condition and treatment options. Outcome measures were analyzed by intention to treat (excluding 7 control participants who received the digital care program due to administrative error) and per protocol.ResultsIn an intent-to-treat analysis the digital care program group had a significantly greater reduction in KOOS Pain compared to the control group at the end of the program (greater reduction of 7.7, 95% CI 3.0 to 12.3, P=.002), as well as a significantly greater improvement in physical function (7.2, 95% CI 3.0 to 11.5, P=.001). This was also reflected in the secondary outcomes VAS pain (12.3, 95% CI 5.4 to 19.1, P<.001) and VAS stiffness (13.4, 95% CI 5.6 to 21.1, P=.001). Participants’ self-reported likelihood (from 0% to 100%) of having surgery also reduced more strongly in the digital care program group compared to the control group over the next 1 year (–9.4 percentage points, pp, 95% CI –16.6 to –2.2, P=.01), 2 years (–11.3 pp, 95% CI –20.1 to –2.5, P=.01), and 5 years (–14.6 pp, 95% CI –23.6 to –5.5, P=.002). Interest in surgery (from 0 to 10) also reduced more so in the digital care program compared to control group (–1.0, 95% CI –1.7 to –0.2, P=.01). Participants’ understanding of the condition and treatment options (on a scale from 0 to 4) increased more substantially for participants in the digital care program than those in the control group (0.9, 95% CI 0.6 to 1.3, P<.001). In an analysis on participants that completed the intervention (per protocol analysis) all primary and secondary outcomes remained significant at greater effect magnitudes compared to intention to treat, with those completing the program showing a 61% (95% CI 48 to 74) reduction in VAS pain compared to 21% (95% CI 5 to 38) in the control group (P<.001). Accounting for the cost of administering the program, we estimate net cost savings on surgery alone of US $4340 over 1 year and $7900 over 5 years for those participants completing the digital care program compared to those in the control group receiving treatment-as-usual. In an exploratory subgroup analysis including only participants exhibiting clinical symptoms of osteoarthritis the program proved equally effective.ConclusionsThis trial provides strong evidence that a comprehensive 12-week digital care program for chronic knee pain, including osteoarthritis, yields significantly improved outcomes for pain, physical function, stiffness, surgery risk, and understanding of the condition, compared to a control group.Trial RegistrationInternational Standard Randomized Controlled Trial Number (ISRCTN) 13307390; http://www.isrctn.com/ISRCTN13307390 (Archived by WebCite at http://www.webcitation.org/6ycwjGL73)

Effects of personal air pollution exposure on asthma symptoms, lung function and airway inflammation.

There is evidence that air pollution increases the risk of asthma hospitalizations and healthcare utilization, but the effects on day-to-day asthma control are not fully understood. We undertook a prospective single-centre panel study to test the hypothesis that personal air pollution exposure is associated with asthma symptoms, lung function and airway inflammation. Thirty-two patients with a clinical diagnosis of asthma were provided with a personal air pollution monitor (Cairclip NO2 /O3 ) which was kept on or around their person throughout the 12-week follow-up period. Ambient levels of NO2 and particulate matter were modelled based upon satellite imaging data. Directly measured ozone, NO2 and particulate matter levels were obtained from a monitoring station in central Leicester. Participants made daily electronic records of asthma symptoms, peak expiratory flow and exhaled nitric oxide. Spirometry and asthma symptom questionnaires were completed at fortnightly study visits. Data were analysed using linear mixed effects models and cross-correlation. Cairclip exposure data were of good quality with clear evidence of diurnal variability and a missing data rate of approximately 20%. We were unable to detect consistent relationships between personal air pollution exposure and clinical outcomes in the group as a whole. In an exploratory subgroup analysis, total oxidant exposure was associated with increased daytime symptoms in women but not men. We did not find compelling evidence that air pollution exposure impacts on day-to-day clinical control in an unselected asthma population, but further studies are required in larger populations with higher exposure levels. Women may be more susceptible than men to the effects of air pollution, an observation which requires confirmation in future studies.

Prognostic value of pathological lymph node status and primary tumour regression grading following neoadjuvant chemotherapy - results from the MRC OE02 oesophageal cancer trial.

AimsNeoadjuvant chemotherapy (NAC) remains an important therapeutic option for advanced oesophageal cancer (OC). Pathological tumour regression grade (TRG) may offer additional information by directing adjuvant treatment and/or follow‐up but its clinical value remains unclear. We analysed the prognostic value of TRG and associated pathological factors in OC patients enrolled in the Medical Research Council (MRC) OE02 trial.Methods and resultsHistopathology was reviewed in 497 resections from OE02 trial participants randomised to surgery (S group; n = 244) or NAC followed by surgery [chemotherapy plus surgery (CS) group; n = 253]. The association between TRG groups [responders (TRG1–3) versus non‐responders (TRG4–5)], pathological lymph node (LN) status and overall survival (OS) was analysed. One hundred and ninety‐five of 253 (77%) CS patients were classified as ‘non‐responders’, with a significantly higher mortality risk compared to responders [hazard ratio (HR) = 1.53, 95% confidence interval (CI) = 1.05–2.24, P = 0.026]. OS was significantly better in patients without LN metastases irrespective of TRG [non‐responders HR = 1.87, 95% CI = 1.33–2.63, P < 0.001 versus responders HR = 2.21, 95% CI = 1.11–4.10, P = 0.024]. In multivariate analyses, LN status was the only independent factor predictive of OS in CS patients (HR = 1.93, 95% CI = 1.42–2.62, P < 0.001). Exploratory subgroup analyses excluding radiotherapy‐exposed patients (n = 48) showed similar prognostic outcomes.ConclusionLymph node status post‐NAC is the most important prognostic factor in patients with resectable oesophageal cancer, irrespective of TRG. Potential clinical implications, e.g. adjuvant treatment or intensified follow‐up, reinforce the importance of LN dissection for staging and prognostication.

Subgroup effects of occupational therapy-based intervention for people with advanced cancer

Background: Many people with advanced cancer have decreased ability to perform activities of daily living (ADL). We recently performed a randomized, controlled trial (RCT) assessing the efficacy of an occupational therapy-based program, the ’Cancer Home-Life Intervention’ in people with advanced cancer (N = 242) and found no overall effects on ADL ability. However, heterogeneity of treatment effect may disguise subgroup differences.Objective: To investigate whether subgroups of people with advanced cancer gain positive effects from the ‘Cancer Home-Life Intervention’ on ADL ability.Material and method: An exploratory subgroup analysis including 191 participants from a RCT. The outcome was ADL motor ability measured by the Assessment of Motor and Process Skills (AMPS). Subgroups were defined by age, gender, years of education, type of primary tumor, functional level, and activity problems.Results: The ‘Cancer Home-Life Intervention’ had no statistically significant effect in the six subgroups. Modifying effects of age (0.30 [95% CI: −0.05 to 0.64]) and gender (0.23 [95% CI: −0.11 to 0.57]) were not found.Conclusion: There were no subgroup effects of the ‘Cancer Home-Life Intervention’on ADL motor ability. Some indications suggest greater effects for those aged below 69 years; however, this result should be interpreted with caution.

Abstract P6-12-01: Can exercise influence survival following breast cancer? Evidence from randomised, controlled trials

Abstract Background: The Exercise for Health (EfH) trials were randomized, controlled trials designed to evaluate an 8-month pragmatic, exercise intervention, commencing 6 weeks post-surgery for women with newly diagnosed breast cancer residing in urban- or rural/regional areas. Outcomes for these exploratory analyses were overall survival (OS), breast cancer-specific survival (BCS) and disease-free survival (DFS). Methods: Consenting urban-residing women (EfH 1, n=194) and rural/regional-residing women (EfH 2, n=143) were randomized to exercise or usual care. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for OS, BCS and DFS (exercise group, n=207, 65% urban women; usual care group, n=130, 46% urban women), with and without adjustment for prognostic factors including trial (urban/rural), age, body mass index, disease stage and presence of comorbidities. Further exploratory subgroup analyses were also conducted to assess whether effect on OS, BCS and DFS differed according to prognostic variables. Results: After a median follow-up of 8.3 years (IQR: 8.0-8.7 years) there were 11 (5.3%) deaths in the exercise group compared with 15 (11.5%) deaths in the usual care group (Table 1). Table 1 Overall, breast cancer-specific and disease-free survival events by group allocation. All patientsUsual careExercise n=337n = 130n = 207 n (%)n (%)n (%)Breast cancer-related deaths20 (5.9)10 (7.7)10 (4.8)Non-breast cancer-related deaths6 (1.8)5 (3.8)1 (0.5)Overall survival events26 (7.7)15 (11.5)11 (5.3)Recurrence of breast cancer20 (5.9)8 (6.2)12 (5.8)Alive at follow-up9 (2.7)3 (2.3)6 (4.6)Deceased by follow-up11 (3.3)5 (3.1)6 (4.6)New primary breast cancer13 (3.9)5 (3.8)8 (3.9)Alive at follow-up13 (3.9)5 (3.8)8 (6.2)Deceased by follow-up0 (0.0)0 (0.0)0 (0.0)Disease-free survival events*48 (14.2)23 (17.7)25 (12.1)* Disease-free survival events include recurrence of breast cancer, new primary breast cancers, and all-cause deaths. Note that women who had recurrence and died before follow-up only count once towards disease-free survival events. HRs for the exercise group were: OS: 0.45, 95% CI=0.20-0.96; p=0.04; BCS: 0.61, 95% CI=0.25-1.46, p=0.26; and DFS: 0.66, 95% CI=0.38-1.17; p=0.16 (adjusted analyses yielded similar results). With the exception of BCS for those with a body mass index &amp;gt;30, all HRs for subgroup analyses favored exercise, with effect on OS for women of younger age (&amp;lt;55), those with stage II+ disease, and those with 1+ comorbidity at baseline significant (p&amp;lt;0.05). Effect of exercise on DFS was also significant (p&amp;lt;0.05) for urban women. Conclusion: Findings suggest that an individually-prescribed and monitored exercise program integrated during and beyond treatment for breast cancer, and that was designed to cater for all women, irrespective of place of residence and access to health services, has clear potential to influence survival. Citation Format: Hayes SC, Steele M, Spence R, Gordon L, Battistutta D, Bashford J, Pyke C, Saunders C, Eakin E. Can exercise influence survival following breast cancer? Evidence from randomised, controlled trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-01.

Abstract P5-21-02: Efficacy and safety of abemaciclib in patients with liver metastases in the MONARCH 1, 2, and 3 studies

Abstract Background: Abemaciclib is an oral, selective inhibitor of cyclin-dependent kinases 4 &amp; 6 that is dosed on a twice daily continuous schedule. In patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), abemaciclib has demonstrated clinical efficacy with a tolerable safety profile when administered as monotherapy in MONARCH 1 (NCT02102490), in combination with fulvestrant in MONARCH 2 (NCT02107703), and in combination with non-steroidal aromatase inhibitors (NSAI) in MONARCH 3 (NCT02246621). Inducing tumor response and delaying disease progression is of critical need in pts with liver metastases (mets). Methods: An exploratory subgroup analysis was conducted in pts with liver mets at baseline across the MONARCH 1, 2, and 3 studies. All pts had HR+, HER2- ABC. The primary endpoint of MONARCH 1 was objective response rate (ORR), and the primary endpoint of MONARCH 2 and 3 was investigator-assessed progression-free survival (PFS). Analysis methods for these endpoints were previously described. Key enrollment criteria and dosing information are listed in Table 1. Table 1. Eligibility criteria and dosing information for the MONARCH 1, 2, and 3 studiesKey enrollment criteriaMONARCH 1MONARCH 2MONARCH 3Prior endocrine therapyProgressed on or after ETProgressed while receiving adjuvant or first-line ET, or ≤ 12 months from the end of adjuvant ETET naïve or disease relapse &amp;gt;12 months after (neo)adjuvant ETChemotherapy regimens in advanced setting1 or 200Visceral crisisNo restrictionNot permittedNot permittedDose and Schedule abemaciclib200 mg, twice daily, continuous150 mg1, twice daily, continuous150 mg, twice daily, continuousfulvestrant-500 mg, per label-anastrozole2--1 mg, dailyletrozole2--2.5 mg, daily1post-amendment; 2physician's choice of NSAI (anastrozole or letrozole); ET: endocrine therapy Results: Efficacy results of pts with liver mets are described in Table 2. The most frequent adverse events observed in pts with liver mets in MONARCH 1 were diarrhea, nausea, and fatigue and in the abemaciclib arms of MONARCH 2 and 3 were diarrhea, neutropenia, and nausea. Table 2. PFS and response rates of pts with liver mets in MONARCH 1, 2, and 3 MONARCH 1MONARCH 2 abemaciclib armMONARCH 2 placebo armMONARCH 3 abemaciclib armMONARCH 3 placebo armPts with liver mets, n93115594830PFS, HR (95% CI)N/A.45 (.31, .64).47 (.25, .87)Median PFS, months5.611.63.115.07.2ORR, n (%)20 (21.5)54 (47.0)9 (15.3)26 (54.2)6 (20.0)CBR, n (%)39 (41.9)77 (67.0)21 (35.6)32 (66.7)12 (40.0)CBR: clinical benefit rate (complete response [CR] + partial response [PR] + stable disease ≥6 months); HR: hazard ratio; ORR: objective response rate (CR+PR); PFS: progression-free survival; pts: patients Conclusions: The results suggest that the combination of abemaciclib and endocrine therapy was an effective treatment option in pts with liver metastases, a population deriving modest benefit from single-agent endocrine therapy. Tolerability results were generally consistent with the safety populations previously reported for each study. Citation Format: Di Leo A, Dickler M, Sledge GW, Toi M, Forrester T, Nanda S, Koustenis A, Bourayou N, Johnston S. Efficacy and safety of abemaciclib in patients with liver metastases in the MONARCH 1, 2, and 3 studies [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-02.

Comprehensive analyses of the clinical benefits of immune checkpoint inhibitors in advanced non-small cell lung cancer.

168 Background: Treatment with immune checkpoint inhibitors is becoming the standard of care for patients and it was approved for the treatment of non-small-cell lung cancer (NSCLC) growing at a rapid pace. However, selecting patients who are appropriate for therapy and which therapeutic strategies to use can be challenging. Methods: We searched for randomized clinical trials (RCTs) investigating immune checkpoint inhibitors versus observation in patients with advanced NSCLC until September 2017. Overall survival (OS) and progression-free survival (PFS) were pooled by meta-analysis. The GRADE system was used to describe the quality of evidence. Results: The analysis included 11 trials with 5,538 unique patients. High- to moderate-quality evidence indicated that immune checkpoint inhibitors extended NSCLC survival and PFS, expressed as hazard ratios (HRs) (OS: 0.79, P = 0.000; PFS: 0.78, P = 0.000). High- to moderate-quality evidence revealed prolonged OS and PFS were similar across preplanned subgroups in patients with squamous (0.77, P = 0.000 and 0.74, P = 0.001) or nonsquamous disease (0.76, P = 0.003 and 0.73, P = 0.041), EGFR wild-type positive status (0.67, P = 0.000 and 0.59, P = 0.010), current or former smokers (OS: 0.83, P = 0.009), and male (0.79, P = 0.000 and 0.67, P = 0.023). Increasing improvement in OS was associated with increasing PD-L1 expression (TC3 or IC3 HR 0.54, P = 0.000; TC2/3 or IC2/3 HR 0.62, P = 0.007; TC1/2/3 or IC1/2/3 HR 0.64, P = 0.000; TC0 and IC0 HR 0.72, P = 0.017; high- to moderate-quality evidence). In exploratory subgroup analysis suggest that there was advantageous of immune checkpoint inhibitors in previous definitive chemotherapy compared with chemoradiotherapy, with concurrent administration of chemotherapy (OS as HR: P = 0.001, P = 0.006, respectively). Conclusions: This large and comprehensive analysis produced firm evidence that immune checkpoint inhibitors extended advanced NSCLC survival and PFS, while in some patients with EGFR wild-type positive status, current or former smokers, male and higher PD-L1 expression had substantial benefit. The benefits from therapy appear to be influenced by preceding definitive therapy and concurrent chemotherapy.

Age does not influence efficacy of ramucirumab in advanced gastric cancer: Subgroup analyses of REGARD and RAINBOW.

REGARD and RAINBOW were global, phase 3, randomized, double-blind trials of second-line ramucirumab for metastatic gastric or gastroesophageal junction adenocarcinoma. Exploratory subgroup analyses were described to assess the efficacy and safety of ramucirumab in REGARD and RAINBOW in young (≤45 and <65years) and elderly (≥65, ≥70, and ≥75years) patients. Patients were randomized 2:1 to receive ramucirumab plus best supportive care or placebo plus best supportive care (REGARD) or 1:1 to ramucirumab plus paclitaxel or placebo plus paclitaxel (RAINBOW). Subpopulation Treatment Effect Pattern Plots assessed efficacy and adverse events by age groups for ramucirumab versus placebo. The hazard ratios (HRs) for overall survival favored treatment with ramucirumab: REGARD ≤45years (HR: 0.59, 95% confidence interval: 0.27-1.26), <65years (0.80, 0.59-1.10), ≥65years (0.72, 0.48-1.08), ≥70years (0.73, 0.44-1.23), and ≥75years (0.59, 0.25-1.37); and RAINBOW ≤45 years (0.56, 0.33-0.93), <65years (0.78, 0.63-0.97), ≥65years (0.88, 0.66-1.18), and ≥70years (0.88, 0.60-1.28). The exception was elderly patients aged ≥75years in RAINBOW (0.97, 0.47-2.01); however, patient numbers were low in this subgroup (n=36). Similar findings were observed for progression-free survival, for which HRs numerically favored ramucirumab-treated patients. Adverse events (including grade ≥3) were not associated with age. In comparison with placebo, ramucirumab conferred improvements in efficacy across age groups with a tolerable safety profile. Despite some limitations, these exploratory analyses support the use of ramucirumab in advanced gastric cancer, irrespective of age.

Efficacy outcomes with bevacizumab added to chemotherapy (bev+CT) compared with chemotherapy alone (CT) in left- and right-sided tumors in metastatic colorectal cancer (mCRC).

726 Background: Primary tumor location is an important prognostic factor in mCRC. Efficacy differences with EGFR antibodies by tumor location show a predictive effect (Arnold et al. Ann Oncol 2017). Two first-line (1L) pivotal bev trials showed the prognostic value of sidedness (Loupakis et al. J Natl Cancer Inst 2015). In this exploratory study, further analysis of the predictive effect of bev is presented. Methods: Data from two randomized phase III studies (NO16966 [NCT00069095], AVF2107g [NCT00109070]) of bev+CT vs CT-alone as 1L treatment for mCRC were analyzed retrospectively. Patients (pts) with sidedness information available were included; pts from NO16966 (part 1) randomized to CT only were excluded. Sidedness was identified by case report forms. Results: Sidedness was determined in 1590 pts (27% Right and 73% Left) out of 2214 pts total (Table). In the pooled analysis, PFS improved with bev+CT compared to CT only in both right-sided (HR=0.75; 95% CI 0.61, 0.93) and left-sided (HR=0.76; 95% CI 0.67, 0.86) mCRC with similar magnitude of benefit in both sides. OS also improved with bev+CT in right-sided (HR=0.82; 95% CI 0.65, 1.03) and left-sided (HR=0.85; 95% CI 0.74, 0.98) pts. Conclusions: This exploratory subgroup analysis of two pivotal studies indicates that the effect of bev is independent of tumor location in mCRC patients. Survival outcomes. Clinical trial information: NCT00069095 and NCT00109070. [Table: see text]