Search

Metastatic castration-resistant prostate cancer; Olaparib; Pembrolizumab Cáncer de próstata metastásico resistente a la castración; Olaparib; Pembrolizumab Càncer de pròstata metastàtic resistent a la castració; Olaparib; Pembrolizumab Background Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC). Objective To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC. Design, setting, and participants Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening. Intervention Pembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily. Outcome measurements and statistical analysis The primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS). Results and limitations Of 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range [IQR], 65–76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22–47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval [CI], 4.0–6.5) and median OS was 14 mo (95% CI, 10.4–18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3–5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design. Conclusions Pembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC.

The pertuzumab study in the neoadjuvant setting for HER2+ nonmetastatic breast cancer in Australia (PeRSIA-ML39622) is an analysis of safety and effectiveness data from the pertuzumab patient registry. Although the prognosis of patients with early stage HER2+ breast cancer has been greatly improved by advances in chemotherapy approximately 25% to 30% of patients develop recurrent disease. Our study aimed to examine the effectiveness of neoadjuvant pertuzumab on surgical outcomes, describe the medium-term effectiveness outcomes of patients treated with pertuzumab, and describe the planned and actual anticancer treatment regimens that patients received. Deidentified data were collected from the patients' medical records and entered into REDCap, between March 2018 and July 2019 (n = 95). The adverse events (AEs) reported most frequently were diarrhea (20; 21.1%), rash (4; 4.2%), and LVSD (4; 4.2%; two patients during neoadjuvant treatment and two patients during adjuvant treatment). AEs, ≥Grade 3 were diarrhea (2; 2.1%) and LVSD (1; 1.1%). Following surgery, a breast pathological complete response (bpCR) was achieved in 65 patients (70.7%; 95% CI: 60.2%-79.7%) and total pathological complete response (tpCR) in 59 patients (64.1%; 95% CI: 53.4%-73.9%). All patients who did not achieve a tpCR obtained a partial response (33/92, 35.9%). Our study is the first to capture real-world data on the use of pertuzumab in the neoadjuvant setting in Australia. The effectiveness and safety data are consistent with those reported in clinical trials of pertuzumab in patients with HER2+ breast cancer, with no new safety concerns.

BACKGROUND Adding pertuzumab to trastuzumab in patients (pts) with HER2+ breast cancer improves pathological complete response (pCR) rates. Pertuzumab + trastuzumab + chemotherapy is approved in Australia as neoadjuvant therapy in early stage (>2 cm or node positive), locally advanced and inflammatory HER2+ breast cancer. This study captured real-world data on the safety and effectiveness of pertuzumab in the neoadjuvant setting. METHODS PeRSIA (ML39622) is a secondary data use non-interventional study of pts initiating neoadjuvant pertuzumab treatment for non-metastatic HER2+ breast cancer. The primary objective is to assess the effectiveness and safety of neoadjuvant pertuzumab when added to trastuzumab in the real-world setting. Deidentified data obtained from the pts’ medical notes were captured using REDCaP, hosted at the Walter and Eliza Hall Institute of Medical Research. This analysis reports the co-primary endpoints of breast pCR (bpCR) with or without in situ disease (ypT0/is or ypT0), total pCR (tpCR) with or without in situ disease (ypT0/is ypN0 or ypT0 ypN0), and the incidence of adverse events (AEs) related to pertuzumab. Secondary objectives include describing rates of breast and nodal surgery, relapse free survival (RFS) and overall survival (OS). RESULTS Ninety five pts receiving neoadjuvant pertuzumab were enrolled between March 2018 and July 2019, with data available for all pts. HER2-targeted neoadjuvant treatment was completed in 91 pts (95.8%) with a median number of 4 cycles [range 1-6] of pertuzumab and 5 cycles [range 1-6] of trastuzumab. Four pts did not complete the planned neoadjuvant therapy due to early CR (n=1), and pertuzumab-related AEs (n=3). The most common neoadjuvant chemotherapy regimens were sequential anthracyclines + taxanes (n=59, 62.1%) and single agent taxane (n=29, 30.5%). Surgery was performed in 92 pts (96.8%). Three pts did not proceed to surgery due to patient decision (n=1), physician decision (n=1), and development of a new non-breast cancer which resulted in death (n=1). Of those pts that underwent surgery, 65/92 (70.7%) had a bpCR and 59/92 (64.1%) had a tpCR. All pts who did not achieve a pCR obtained a partial response (33/92, 35.9%). Total pCR was seen in 27/34 (79.4%) pts with hormone receptor-negative and 32/58 (55.2%) pts with hormone receptor-positive cancers. 27/95 (28.4%) pts experienced an AE related to pertuzumab; diarrhea (21.1%) and rash (4.2%) were the most common AEs. Three pts (3.2%) discontinued pertuzumab due to an AE: cardiac toxicity, diarrhea and rash (n=1), cardiac toxicity (n=1), and diarrhea and sepsis (n=1). Following surgery, 93/95 (97.9%) patients received adjuvant HER2-directed therapy, and 4/95 (4.2%) received adjuvant chemotherapy. After a median follow-up from diagnosis of 21.2 [14.0-83.9] months, the RFS and OS were 92.6% and 99.0% respectively. Disease recurrence occurred in 6 pts (distant n=4, contralateral n=2). CONCLUSIONS This is the first multicenter, observational study of neoadjuvant therapy based on dual blockade with pertuzumab and trastuzumab for HER2+ non-metastatic breast cancer in Australia. The pCR rates achieved were numerically higher than previously reported in clinical trials. There were no significant safety findings outside of the expected safety profile for pertuzumab. Acknowledgments: Study sponsored by Roche Products, Pty. Limited. Theresa Wade (WriteSource Medical) provided medical writing. Table: Baseline Characteristics (n=95)CharacteristicNumber (%)Age, median (range)50.3 (24.4 -82.1)Charlson Comorbidity Index- 077 (81.1)- 19 (9.5)- 2 +9 (9.5)Tumour Size12 (12.6)- T156 (59.0)- T225 (26.3)- T3- Unreported2 (2.1)Tumour Grade- 10 (0)- 231 (32.6)- 362 (65.3)- Unreported2 (2.1)Nodal status- Positive63 (66.3)- Negative32 (33.7)Hormone Receptor Status- HR+60 (63.2)- HR-35 (36.8)Median baseline left ventricular ejection fraction (range)65.0% (35-79)Cardiac risk factors- 053 (55.8)- 122 (23.2)- 2+20 (21.1) Citation Format: Sheau Wen Lok, Richard De Boer, Sallt Baron-Hay, Peter Button, Bianca Devitt, Benjamin Forster, Peter Fox, Michael Harold, Sahisha Ketheeswaran, Ganessan Kichenadasse, Belinda E Kiely, Gavin Marx, Louise Nott, Laura Pellegrini, Ali Tafreshi, Peter GIbbs. Pertuzumab study for HER2-positive non-metastatic breast cancer in the neoadjuvant setting in Australia [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-38.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We report 5-year efficacy and safety outcomes from the phase III KEYNOTE-407 study (ClinicalTrials.gov identifier: NCT02775435 ). Eligible patients with previously untreated, metastatic squamous non–small-cell lung cancer (NSCLC) were randomly assigned 1:1 to pembrolizumab 200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3 weeks for four cycles, followed by pembrolizumab or placebo for up to 35 cycles. Primary end points were overall survival (OS) and progression-free survival (PFS) per RECIST version 1.1 by blinded independent central review (BICR). Five hundred fifty-nine patients were randomly assigned in the intention-to-treat population (pembrolizumab plus chemotherapy, n = 278; placebo plus chemotherapy, n = 281). The median time from random assignment to data cutoff was 56.9 (range, 49.9-66.2) months. OS and PFS were improved with pembrolizumab plus chemotherapy versus placebo plus chemotherapy (hazard ratio [95% CI], 0.71 [0.59 to 0.85] and 0.62 [0.52 to 0.74]), with 5-year OS rates of 18.4% versus 9.7%, respectively. Toxicity was manageable. Among 55 patients who completed 35 cycles of pembrolizumab, the objective response rate was 90.9% and the 3-year OS rate after completion of 35 cycles (approximately 5 years after random assignment) was 69.5%. Pembrolizumab plus chemotherapy maintained an OS and PFS benefit versus placebo plus chemotherapy in previously untreated, metastatic squamous NSCLC and is a standard-of-care first-line treatment option for metastatic squamous NSCLC regardless of programmed death ligand 1 expression.

PURPOSE We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non–small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738 ) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS). METHODS Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point. RESULTS Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti–PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure. CONCLUSION Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.

BACKGROUND: This open-label Phase III trial (NCT02264990) evaluated the PARP inhibitor, veliparib, combined with carboplatin/paclitaxel versus chemotherapy alone for first-line treatment of patients with advanced non-squamous non-small cell lung cancers (NSCLC). A 52-gene expression classifier (LP52) previously shown to identify patients more likely to respond to veliparib was evaluated as a planned correlative analysis.; MATERIALS AND METHODS: Adult current or former smokers with advanced non-squamous NSCLC were randomized 1:1 to veliparib (120 mg daily for 7 days/cycle) with carboplatin and paclitaxel or to investigators' choice of platinum doublet chemotherapy (up to 6, 21-day cycles), with optional pemetrexed maintenance. Prospective analysis of the LP52 signature was conducted using a clinical Qiagen/HTG assay. The primary endpoint was overall survival (OS) in LP52+ patients.; RESULTS: Overall, 595 patients received veliparib+carboplatin/paclitaxel (n=298) or chemotherapy alone (n=297); 13% (n=40) in each arm were LP52+. The primary endpoint was not met; median OS was 11.2 months with veliparib+carboplatin/paclitaxel versus 9.2 months with chemotherapy alone in the LP52+ subgroup (hazard ratio [HR] 0.644, 95% confidence interval [CI]: 0.396-1.048; P=.113). In the overall population, median OS was 12.1 months in both arms (HR 0.986, 95% CI: 0.827-1.176; P=.846). No new safety signals were observed.; CONCLUSION: In patients with non-squamous NSCLC, there was no significant improvement in OS with veliparib+carboplatin/paclitaxel versus chemotherapy alone, although a trend toward improved OS in the LP52+ population suggests this subgroup may benefit from veliparib. Statistical power was limited due to the small sample size. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

INTRODUCTION AND OBJECTIVE:The phase 1/2 KEYNOTE-365 study (NCT02861573) previously showed that pembro+olaparib was associated with antitumor activity and acceptable safety in molecularly unselecte...

Background: The addition of pertuzumab to trastuzumab for patients (pts) with HER2 +ve breast cancer results in higher rates of pathological complete response (pCR);although, it is not yet known if this translates into improved survival outcomes. In May 2016 pertuzumab was approved in Australia by the Therapeutic Goods Administration, in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of locally advanced and inflammatory HER2+ve breast cancer; and in September 2018, for early stage (>2cm diameter or node positive) disease. This study aims to capture real world data on the safety and effectiveness of pertuzumab in the neoadjuvant setting. Methods: PeRSIA (ML39622) is a secondary data use non-interventional study of pts initiating or considering pertuzumab treatment in the neoadjuvant setting for non-metastatic HER2+ breast cancer. The primary objective is to assess the incidence rates of all adverse events (AEs) related to pertuzumab and the effectiveness of neoadjuvant pertuzumab when added to trastuzumab, in the real world setting. De-identified data obtained from the pts’ medical notes by the treating physician, were deposited to a centralized data capture tool (REDCaP), hosted at the Walter and Eliza Hall Institute of Medical Research. This interim analysis reports the co-primary endpoints of breast pCR (bpCR) with or without in situ disease (ypT0/is or ypT0), total pCR with or without in situ disease (ypT0/is ypN0 or ypT0 ypN0), and the incidence of AEs related to pertuzumab. Secondary objectives include rates of breast or nodal surgery, relapse free survival (RFS) and overall survival (OS). Results: Ninety pts receiving neoadjuvant pertuzumab were enrolled for data capture between March 2018 and June 2019. Sixty-nine of these pts had data available for interim analysis by June 18th 2019 (Table). HER2-targeted neoadjuvant treatment was completed in 65/69 pts (94.2%) with a median [min-max] duration of 4 [1-6] cycles of pertuzumab and 5 [1-6] cycles of trastuzumab, and chemotherapy was administered in all 69 pts. The most common neoadjuvant chemotherapy regimens were taxanes + anthracyclines (n=30, 43.5%) and single agent taxane (n=26, 37.7%). Surgery was performed in 66/69 pts (95.7%). The bpCR was 71.2% and the total pCR rate was 66.7%. All pts who did not achieve a pCR obtained a partial response (28.8%). Total pCR was achieved by 20/26 (76.9%) hormone receptor-negative and 24/40 (60.0%) hormone receptor-positive pts. Three pts (4.3%) experienced at least one pertuzumab-related AE [cardiac toxicity (n=1, 1.4%), diarrhea (n=2, 2.9%), rash (n=1, 1.4%) and (sepsis n=1, 1.4%)] and all ceased pertuzumab. RFS and OS were 97.1% and 98.6% respectively, with a median follow up time from diagnosis of 16.1 [4-36.4] months. One patient did not undergo surgery due to a new non-breast cancer which resulted in death. Conclusion: This is the first multicenter, prospective, observational study to report pCR with pertuzumab in real world clinical practice in Australia. Neoadjuvant therapy based on dual blockade with pertuzumab and trastuzumab for HER2+ non metastatic breast cancer achieved a total pCR rate of 66.7% and bpCR rate of 71.2%, which was numerically higher than previously reported in clinical trials. There were no significant safety findings outside of the accepted safety profile for pertuzumab. Acknowledgment: Study sponsored by Roche Products, Pty. Limited Table: Patient and Tumor CharacteristicsCharacteristicNumber (%)Age51.8 (25.9-82.1)Charlson Comorbidity Index058 (84.1)18 (11.6)≥23 (4.4)Tumor Size (Clinical/Radiological staging)T1 (5 cm)14 (20.3)Unknown2 (2.9)Tumor Grade10 (0)220 (29.0)347 (68.1)Unknown2 (2.9)Nodal Status (Clinical/Radiological)Node positive46 (66.7)Node negative23 (33.3)Hormone Receptor StatusHR+42 (60.9)HR−27 (39.1)Median baseline left ventricular ejection fraction65%Patient cardiac risk factorsNo risk factor40 (58.0)1 risk factor14 (20.3)≥2 risk factors15 (21.7) Citation Format: Sheau Wen Lok, Richard De Boer, Sally Baron-Hay, Fran Boyle, Peter Button, Belinda Castles, Bianca Devitt, Peter Fox, Michael Harold, Ganessan Kichenadasse, Belinda E Kiely, Gavin Marx, Louise Nott, Laura Pellegrini, Ali Tafreshi, Peter Gibbs. Pertuzumab study for HER2-positive non-metastatic breast cancer in the neoadjuvant setting in Australia: Interim analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-15.

Introduction This exploratory analysis retrospectively evaluated outcomes in patients with advanced NSCLC to determine whether baseline brain metastases influenced the efficacy of first-line pembrolizumab plus chemotherapy versus chemotherapy alone. Methods We pooled data for patients with advanced NSCLC in KEYNOTE-021 cohort G (nonsquamous), KEYNOTE-189 (nonsquamous), and KEYNOTE-407 (squamous). Patients were assigned to platinum-doublet chemotherapy with or without the addition of 35 cycles of pembrolizumab 200 mg every 3 weeks. All studies permitted enrollment of patients with previously treated or untreated (KEYNOTE-189 and KEYNOTE-407 only) stable brain metastases. Patients with previously treated brain metastases were clinically stable for 2 or more weeks (≥4 wk in KEYNOTE-021 cohort G), had no evidence of new or enlarging brain metastases, and had no steroid use at least 3 days before dosing. Patients with known untreated asymptomatic brain metastases required regular imaging of the brain. Results A total of 1298 patients were included, 171 with and 1127 without baseline brain metastases. Median (range) durations of follow-up at data cutoff were 10.9 (0.1‒35.1) and 11.0 (0.1‒34.9) months, respectively. Hazard ratios (pembrolizumab + chemotherapy/chemotherapy) were similar for patients with and without brain metastases for overall survival (0.48 [95% confidence interval (CI): 0.32‒0.70] and 0.63 [95% CI: 0.53‒0.75], respectively) and progression-free survival (0.44 [95% CI: 0.31‒0.62] and 0.55 [95% CI: 0.48‒0.63], respectively). In patients with brain metastases, median overall survival was 18.8 months with pembrolizumab plus chemotherapy and 7.6 months with chemotherapy, and median progression-free survival was 6.9 months and 4.1 months, respectively. Objective response rates were higher and duration of response longer with pembrolizumab plus chemotherapy versus chemotherapy regardless of brain metastasis status. Incidences of treatment-related adverse events with pembrolizumab plus chemotherapy versus chemotherapy were 88.2% versus 82.8% among patients with brain metastases and 94.5% versus 90.6% in those without. Conclusions With or without brain metastasis, pembrolizumab plus platinum-based histology-specific chemotherapy improved clinical outcomes versus chemotherapy alone across all programmed death ligand 1 subgroups, including patients with programmed death ligand 1 tumor proportion score less than 1% and had a manageable safety profile in patients with advanced NSCLC. This regimen is a standard-of-care treatment option for treatment-naive patients with advanced NSCLC, including patients with stable brain metastases.

Introduction In the randomized KEYNOTE-407 study ( ClinicalTrials.gov , NCT02775435 ), pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC. We report updated efficacy outcomes from the protocol-specified final analysis and, for the first time, progression on next line of treatment. Methods Eligible patients were randomized to chemotherapy plus either pembrolizumab (n = 278) or placebo (n = 281). After positive results from the second interim analysis, patients still receiving placebo could cross over to pembrolizumab monotherapy at the time of confirmed progressive disease. The primary end points were OS and PFS. PFS-2 (time from randomization to progression on next-line treatment/death, whichever occurred first) was an exploratory end point. Results After median (range) follow-up of 14.3 (0.1–31.3) months, pembrolizumab plus chemotherapy continued to exhibit a clinically meaningful improvement over placebo plus chemotherapy in OS (median, 17.1 mo [95% confidence interval (CI): 14.4‒19.9] versus 11.6 mo [95% CI: 10.1‒13.7]; hazard ratio [HR], 0.71 [95% CI: 0.58‒0.88]) and PFS (median, 8.0 mo [95% CI: 6.3‒8.4] versus 5.1 mo [95% CI: 4.3‒6.0]; HR, 0.57 [95% CI: 0.47‒0.69]). PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy (HR, 0.59 [95% CI: 0.49‒0.72]). Grade 3 to 5 adverse events occurred in 74.1% and 69.6% of patients receiving pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively. Conclusions Pembrolizumab plus chemotherapy continued to exhibit substantially improved OS and PFS in patients with metastatic squamous NSCLC. The PFS-2 outcomes support pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.

Summary Background In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs). Methods In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4–6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1–3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients. Findings Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and −0·9 (−4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44–0·97; two-sided nominal p=0·029). Interpretation Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC. Funding Merck & Co.

PURPOSE In the phase 3 KEYNOTE-407 study, the addition of pembrolizumab to carboplatin-paclitaxel/nab-paclitaxel significantly improved overall survival, progression-free survival, and objective response rate in patients with previously untreated metastatic squamous non–small-cell lung cancer (NSCLC), with little impact on severe toxicity. We present patient-reported outcomes (PROs) from KEYNOTE-407. METHODS Patients were randomly assigned to receive 4 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus carboplatin plus paclitaxel or nab-paclitaxel, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life (HRQoL) was evaluated using the European Organisation for Research and Treatment of Cancer Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Lung Cancer Module 13 (QLQ-LC13). Key PRO endpoints were change from baseline to weeks 9 and 18 (during and after platinum therapy) in the QLQ-C30 global health status/quality of life (GHS/QoL) score and time to deterioration in the composite endpoint of cough, chest pain, or dyspnea from the QLQ-C30 and QLQ-LC13. Two-sided, nominal P values are provided. RESULTS A total of 554 and 553 patients completed ≥ 1 QLQ-C30 or ≥ 1 QLQ-LC13 assessment, respectively. GHS/QoL score improved for the pembrolizumab-combination group (least squares [LS] mean [95% CI] change from baseline: week 9, 1.8 [−0.9 to 4.4]; week 18, 4.3 [1.7 to 6.9]) and deteriorated in the placebo-combination group (week 9, −1.8 [−4.4 to 0.7]; week 18, −0.57 [−3.3 to 2.2]). Between-group differences were improved for the pembrolizumab-combination group (difference in LS mean scores: week 9, 3.6 [95% CI, 0.3 to 6.9], nominal P = .0337; week 18, 4.9 [1.4 to 8.3], nominal P = .0060). Median time to deterioration in cough, chest pain, or dyspnea was not reached in either group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06]; nominal P = .125). CONCLUSION Addition of pembrolizumab to chemotherapy maintained or improved HRQoL measurements relative to baseline and improved HRQoL versus chemotherapy alone at weeks 9 and 18. These results support use of pembrolizumab plus chemotherapy as first-line therapy for metastatic squamous NSCLC.

BackgroundPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). MethodsIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. ResultsMedi...

Purpose In the randomized, open-label, phase III KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations. We report an updated OS and tolerability analysis, including analyses adjusting for potential bias introduced by crossover from chemotherapy to pembrolizumab. Patients and Methods Patients were randomly assigned to pembrolizumab 200 mg every 3 weeks (for up to 2 years) or investigator’s choice of platinum-based chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross over to pembrolizumab upon meeting eligibility criteria. The primary end point was progression-free survival; OS was an important key secondary end point. Crossover adjustment analysis was done using the following three methods: simplified two-stage method, rank-preserving structural failure time, and inverse probability of censoring weighting. Results Three hundred five patients were randomly assigned (pembrolizumab, n = 154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up, 25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to chemotherapy crossed over on study to receive pembrolizumab. When adjusted for crossover using the two-stage method, the hazard ratio for OS for pembrolizumab versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using rank-preserving structural failure time and inverse probability of censoring weighting were similar. Treatment-related grade 3 to 5 adverse events were less frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%, respectively). Conclusion With prolonged follow-up, first-line pembrolizumab monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to pembrolizumab as subsequent therapy.

Imaging technologies in ophthalmology offer the ability to objectively quantify various diagnostic parameters for the assessment and management of glaucoma. The diagnostic parameters provided by these technologies offer clinicians objective and precise methods to aid their decision in the diagnosis and management of the disease. High-resolution imaging of ONH anatomic features that are affected in glaucoma provide clinicians with the ability to visualize optic nerve structures such as the anterior and posterior lamina cribrosa surfaces, Bruch’s membrane-retinal pigment epithelium complex and its termination within the ONH border, tissue of Elschnig, and the scleral canal opening. These imaging techniques also allow for assessment of the circumpapillary RNFL and macula regions, thereby providing a holistic diagnostic approach that enables clinicians to make more confident diagnostic decisions.

The diagnostic efficacy and workflow of retinal diseases has been largely improved by the development of optical coherence tomography (OCT). The availability of cross-sectional, high-resolution images is critical for the assessment of several features ranging from early subtle changes to late severe disruption of the anatomy of the retina. The widespread clinical use of OCT enhances the accurate diagnosis of different retinal and choroidal diseases, including age-related macular degeneration, diabetic retinopathy, vascular occlusions, inflammatory diseases, hereditary diseases. OCT imaging further allows for accurate monitoring of disease progression and treatment efficacy, like anti-vascular endothelium growth factor (VEGF) therapy.

OCT technology has been utilized successfully for anterior segment evaluation, offering several clinically relevant applications. Its capabilities allow for non-contact imaging, detailed visualization and analytics of anterior segment structures of the human eye on one device. These structures include the cornea, anterior chamber, iris, and lens. The SPECTRALIS Anterior Segment Module, based on spectral-domain OCT and an 880 nm light source, allows for high axial resolution images of anterior segment structures. The ANTERION is a swept-source OCT device with a 1300 nm light source, which allows for the acquisition of high-contrast anterior segment images along a large image depth. Swept-source OCT technology combined with a longer wavelength light source can also serve as a tool to measure the axial length of the human eye. The above-mentioned structures and parameters are used in ophthalmology for corneal topography, corneal tomography, anterior segment analysis, biometry and calculation of intraocular lens power, as well as many other possible clinical applications.

Item does not contain fulltext BACKGROUND: Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on >/=50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC. METHODS: In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival. RESULTS: After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P

Background In the randomized KEYNOTE-407 study (NCT02775435), pembro + carboplatin and paclitaxel/nab-paclitaxel (chemo) significantly improved OS, PFS, and ORR compared with placebo + chemo in patients (pts) with previously untreated metastatic squamous NSCLC. Benefit was observed irrespective of PD-L1 TPS. We report updated OS from the protocol-specified final analysis and, for the first time, PFS2. Methods Eligible pts were randomized 1:1 to pembro (n=278) or placebo (n=281) + 4 cycles of carboplatin and paclitaxel/nab-paclitaxel. Randomization was stratified by PD-L1 TPS (≥1%/ Results With median follow-up of 14.3mo (range, 0.1–31.3) and 365 total deaths, pembro + chemo continued to improve OS (median [95% CI], 17.1 [14.4–19.9] vs 11.6 [10.1–13.7] mo), PFS (median [95% CI], 8.0 [6.3–8.4] vs 5.1 [4.3–6.0]; Table) and ORR (62.6% vs 38.4%). 2L+ therapy was received by 32.0% in the pembro + chemo arm and 59.4% (49.1% 2L+ antiPD[L]1) in the placebo + chemo arm. PFS2 was longer for 1L pembro + chemo (median [95% CI], 13.8 [12.2–15.9] mo vs 9.1 [8.2–10.2] mo), with no difference by PD-L1 TPS.TableLBA82TableAll Patients N=559PD-L1 TPS ≥50% N=146PD-L1 TPS 1–49% N=207PD-L1 TPS Conclusions Pembro + chemo continued to demonstrate improved outcomes, including OS, PFS, ORR and PFS2, compared with placebo + chemo for previously untreated metastatic squamous NSCLC, with a manageable safety profile. These results support first-line pembro + chemo in pts with metastatic squamous NSCLC. Clinical trial identification NCT02775435. Editorial acknowledgement Writing support was provided by Sheri Arndt, PharmD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure L. Paz-Ares: Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Roche; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Lilly; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Boehringer Ingelheim; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: AstraZeneca; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Novartis; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Pfizer; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Amgen; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: BMS; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: MSD; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Merck; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Sanofi; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: PharmaMar; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Servier; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Sysmex; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Incyte; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Ipsen; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Adacap; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Bayer; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Blueprint Medicines; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Celgene; Honoraria to self/spouse for scientific advice or as a speaker for Roche, Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Amgen, BMS, MSD, Merck, Sanofi, PharmaMar, Servier, Sysmex, Incyte, Ipsen, Adacap, Bayer, Blueprint Medicines, and Celgene; board member for Genomica; grants to institution from MSD, BMS, AstraZeneca, and Pfizer. D. Vicente: Honoraria (self), Self/spouse for scientific advice or as a speaker: Boehringer Ingelheim, AstraZeneca, Pfizer, BMS, and MSD . A. Robinson: Research grant / Funding (institution), funding for clinical trials: Merck, AstraZeneca, Roche, and Pfizer; Advisory / Consultancy: Merck. H. Soto Parra: Advisory / Consultancy: AstraZeneca, MSD, BMS, Roche, and Eli Lilly. J. Mazieres: Honoraria (institution): Roche, AstraZeneca, Boehringer Ingelheim, Pfizer, BMS, MSD, Merck, Pierre Fabre, PharmaMar, Bayer, and Blueprint; Research grant / Funding (institution): Roche, MSD, BMS, and AstraZeneca. B. Hermes: Travel / Accommodation / Expenses: PharmaMar and Eli Lilly; Honoraria (institution), honoraria for lectures: BMS and Pfizer; Research grant / Funding (institution): MSD, Novartis, BMS, Bayer, Roche, Eli Lilly, and PharmaMar. I. Cicin: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, F. Hoffmann-La Roche, and Pfizer; Research grant / Funding (self), personal fees for lectures: Eli Lilly, MSD, Novartis, Pfizer, Quintiles, and Roche; Research grant / Funding (institution), funding to the institution to support trial conduct: Astellas, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Parexel, Pfizer, Quintiles, Taiho, and Merck Serono. J. Rodriguez Cid: Research grant / Funding (institution), funding to the institution during conduct of this trial: MSD; Research grant / Funding (institution), funding to the institution to support trial conduct: Bayer, BMS, Celgene, Eli Lilly, MSD, Novartis, and Roche. I. Okamoto: Research grant / Funding (self), grants and personal fees: AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD Oncology, Eli Lilly, BMS, Chugai Pharma; Research grant / Funding (self), personal fees : Pfizer; Research grant / Funding (institution), grants: Astellas Pharma, Novartis, and AbbVie. R. Ramlau: Honoraria (self), honoraria to self/spouse for scientific advice or as a speaker: Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Amgen, BMS, MSD, Merck, and Sanofi; Officer / Board of Directors, board member: Boehringer Ingelheim, Pfizer, MSD, BMS, Novartis, Takeda, AbbVie, AstraZeneca, Eli Lilly, and Roche. X. Deng: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.. T. Bas: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.. B. Piperdi: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.. B. Halmos: Research grant / Funding (institution): Merck, BMS, Boehringer Ingelheim, Eli Lilly, Novartis, GSK, Pfizer, AbbVie, AstraZeneca, Mirati, Takeda, and Guardant Health; Advisory / Consultancy, consultant : Merck, Novartis, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Guardant Health, Spectrum, BMS, and Genentech. All other authors have declared no conflicts of interest.

Background: The combination of CDK 4/6 inhibition and endocrine therapy has emerged as the new first line standard of care treatment for patients with hormone receptor (HR) +ve metastatic breast cancer (MBC)1. Ribociclib plus letrozole has been shown to improve PFS (25.3 vs 16.0 months; log-rank P=9.63x10-8) compared to letrozole alone2. More recently, this benefit has also been demonstrated in pre- and peri-menopausal women in combination with ovarian suppression and tamoxifen or an aromatase inhibitor (AI), with an improved overall survival (40.9 months vs OS not reached; HR = 0.712; p=0.00973) in the MONALEESA-7 study3. Approximately 800 patients in Australia participated in the ribociclib medicine access program (MAP) between May 2017 and June 2018, prior to government funding. Beyond eligibility criteria for the program and clinician name, no patient data was initially captured, consistent with usual practice for MAPs, due to the multiple challenges related to ethics, data ownership, security and patient privacy. We have previously demonstrated the feasibility of successful data collection alongside MAPs4 which can yield benefits for clinicians, industry and the broader medical community. Based on this we plan to retrospectively collect data for patients treated as part of the Australian ribociclib MAP. Trial Design: This is a secondary data use, non-interventional study of patients in Australia who received treatment with the combination of an AI and ribociclib, obtained via a MAP, for HR+ HER2- MBC. The target sample size is 250 patients from ~15 sites. De-identified patient data will be retrieved from the patient’s medical records and entered on to an electronic case report form. Data collection is anticipated to commence in July 2019 with the final treatment and survival outcomes collected in late 2020, thus allowing for a minimum of 24 month follow up for all patients from the start date of treatment with ribociclib and AI (May 2017 - June 2018). Study Aims: The primary aim of the study is to describe real world clinical and tumour characteristics of patients with HR+ HER2-ve MBC in Australia who are recommended and received ribociclib in combination with an aromatase inhibitor in the first line setting. Details of adjuvant therapy received and the tolerability of the treatment combination including dose interruptions, dose reductions and significant adverse events of interest related to ribociclib will be assessed. Secondary aims include time to treatment progression and progression free survival for the ribociclib and AI combination, and to explore the disease course post progression, including clinician choice of subsequent lines of therapy in routine clinical practice. References: 1. Cardoso F, Senkus E, Costa A et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann Oncol 2018;29:1634-1657. 2. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 2018;29:1541-47. 3. Im SA, Lu YS, Bardia A, et al: Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. June 4, 2019 (early release online) 4. Lok SW, De Boer R, Cordwell C et al. Demonstrating the feasibility of collecting secondary, de-identified data on Australian patients receiving treatment as part of a Medicine Access Program. Intern Med J. 2019 Feb 28. Acknowledgement We thank Novartis for providing funding for this Research Collaboration. Citation Format: Sheau Wen Lok, Sally Baron-Hay, Elgene Lim, Robert Blum, Fran Boyle, Kerrie Clarke, Katharine Cuff, Michael Green, Laeeq Malik, Kelly Mok, Nick Murray, Louise Nott, Michelle Nottage, Ali Tafreshi, Daphne Tsoi, Belinda Yeo, Peter Gibbs, Richard De Boer. A 'real world' experience of CDK4/6 inhibition with ribociclib and endocrine therapy in hormone receptor positive metastatic breast cancer in Australia [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-01.

Author(s): Parekh, Anjali S; Mansouri, Kaweh; Weinreb, Robert N; Tafreshi, Ali; Korn, Bobby S; Kikkawa, Don O | Abstract: BackgroundTo prospectively investigate the safety, tolerability and 24-h intraocular pressure (IOP) patterns in patients with thyroid eye disease (TED) using a contact lens sensor (CLS).DesignProspective study.ParticipantsTen patients with established TED.MethodsTen eyes of 10 patients were prospectively evaluated in an ambulatory 24-h IOP monitoring session using the CLS (Sensimed AG, Lausanne, Switzerland). Patients pursued daily activities, and sleep behaviour was uncontrolled.Main outcome measuresIncidence of adverse events (AEs) and tolerability (scale of 0-10, increasing intolerance) were assessed. IOP patterns were evaluated using a cosinor rhythmometry model, and linear regression slopes were constructed for the transition from wake/sitting (W/S) to sleep/supine (S/S) and vice versa.ResultsMean age was 61.8 ± 21.6 years, and 90% of patients were female. Main AEs were blurred vision (50%), conjunctival hyperaemia (100%) and superficial punctate keratitis (20%). Tolerability of the lens was found to be 1.5 ± 0.7. Positive linear slopes of the CLS signal from wake to sleep were detected (18.0 ± 43.8 arbitrary units [a.u.]; P = 0.254), whereas at the transition from S/S to W/S a significant decrease (-62.9 ± 56.8 a.u.; P = 0.010) was found. Five patients (50%) had a significant nocturnal/sleep acrophase with the peak occurring at 6:30 a.m. The mean amplitude of the 24-h curves was 102.2 ± 52.6 a.u.ConclusionsIn patients with TED, the CLS provides a safe and well-tolerated approach to 24-h IOP monitoring. After modelling the 24-h IOP curves, TED patients were found to have a morning acrophase.

e12554 Background: Triple-negative breast cancer is a biologically aggressive disease that accounts for 15% of all breast cancers, of which around 4-5% are metastatic (mTNBC) at diagnosis. Notably, there is no standard of care for mTNBC in the first line (1L) setting. This, in addition to higher relapse rates and poor long-term survival, warrants evaluation of real-world treatment patterns, especially in the 1L setting, to better inform on clinical outcomes. Methods: This observational, retrospective, chart review study included a cohort of twenty-six mTNBC patients from six different sites Australia, who commenced 1L treatment between July 1, 2012 and June 30, 2015. Medical records of eligible patients were abstracted using electronic case report forms after gaining relevant ethics approvals. Data on treatment patterns and clinical outcomes in the 1L setting were then collected from the index date until the end of data abstraction or death. The index date is defined as the date of initiation of 1L systemic therapy for mTNBC. Results: In the 1L setting, patients that received combination (52%) chemotherapy was slightly higher than single-agent (48%) chemotherapy. The commonest combination used was Carboplatin-Gemcitabine (12%), and the most common monotherapy was Nab-Paclitaxel (24%). The overall response rate and disease control rate were estimated to be 32% and 60% in the 1L setting. The median duration of treatment and the median time to next line of therapy were calculated to be 98 days and 12.45 (95% CI 2.79, 20.30) months respectively. Importantly, the median progression free survival (sensitivity analysis) and the median overall survival were estimated to be 3.17 (95% CI 1.91, 5.09) and 10.41 (95% CI 5.36, 16.53) months respectively. Conclusions: Chemotherapy is currently the mainstay of treatment for mTNBC. However, disease progression and chemo-related toxicities warrant stratified use of more efficacious and tolerable treatment options, especially in the 1L setting. Results from this study could be useful in comparing the efficacy and cost effectiveness of these emerging targeted and immuno-therapies outside the clinical trial setting.

5027 Background: Individual activity with pembro or olaparib has been observed in mCRPC pts who progressed on second-generation hormone therapy (HT) and chemotherapy. Data from cohort A (pembro+olaparib) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC, are presented. Methods: Pts with mCRPC who progressed within 6 mo before screening, were docetaxel-pretreated (up to 1 other chemotherapy permitted) for mCRPC and had ≤2 second-generation HTs were eligible. Pts received pembro 200 mg IV Q3W+olaparib 400 mg orally twice daily. Primary end points: safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points: ORR per RECIST v1.1 (investigator review), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, composite response rate, rPFS, and OS. Results: Median (95% CI) follow-up was 11 (6-15) mo. 41 pts initiated treatment (median age, 69 y; visceral disease, 42%; RECIST-measurable, 68%; homologous recombination deficient detected, 0%). Efficacy is outlined in the table. Treatment-related AEs occurred in 39 (95%) pts; most frequent (≥30%) were anemia (37%), fatigue (34%), and nausea (34%). Grade 3-5 treatment-related AEs occurred in 21 (51%) pts. There were 2 deaths; 1 was treatment-related (cause unknown). Conclusions: Pembro+olaparib had activity in pts with mCRPC who were molecularly unselected and were previously treated with docetaxel and second-generation HT. The observed safety profile for the combination is consistent with individual profiles of pembro and olaparib. Clinical trial information: NCT02861573. [Table: see text]

Aim To assess the response rate and safety of sorafenib in different subpopulations of patients with advanced renal cell carcinoma (RCC). Methods Single-arm open access trial. Key eligibility: advanced RCC with either clear-cell or non-clear-cell histopathology; progression on prior systemic chemotherapy or treatment naive. Sorafenib was commenced at 400 mg twice daily continuously. Results A total 47 participants with metastatic RCC were treated with sorafenib. Overall, 1 participant experienced complete response, 6 (13%) had documented partial response (PR) and 29 (62%) had stable disease (SD) as the best response. Eight (17%) had non-clear-cell histopathology and five (10%) had sarcomatoid features. In the non-clear-cell histopathology cohort, five participants (62.5%) had SD. Twenty-three (49%) participants were treatment naive; of these, 1/23 showed CR, 5/23 experienced PR and 13/23 had SD (clinical benefit: 83%). Overall, 14 (30%) and 22 (47%) participants had high-risk status according to MSKCC (Memorial Sloan-Kettering Cancer Center) and Heng prognostic scores, respectively. In the MSKCC poor prognostic group (14 participants), one participant had CR, two participants showed PR and eight participants had SD (clinical benefit: 79%). In Heng poor prognostic group (22 participants), 1 participant experienced CR, 2 participants showed PR and 13 had SD (clinical benefit: 73%). Hand–foot syndrome (53%), rash (47%), fatigue (42%), nausea (40%), anorexia (34%) and diarrhea (32%) were the most common adverse events. Conclusions This study confirms the efficacy and tolerability of sorafenib in a different spectrum of advanced RCC patients including non-clear-cell histology, poor prognostic status and as first-line treatment.

Objective To review time-trends in the use of perioperative chemotherapy and its impact on oncological outcomes in patients with bladder urothelial cancer (UC) at a single tertiary institution. Patients and Methods Using electronic and paper medical records, 89 patients were identified who underwent radical cystectomy with or without perioperative chemotherapy between 2004 and 2011 at Austin Health in Melbourne, Australia. Patient demographics, clinico-pathological characteristics and details of recurrence and death were assessed by retrospective chart review. Survival analysis was carried out using the Kaplan Meier method, with the impact of predictors assessed using Cox proportional hazard models. Results The median (range) age of this cohort was 65 (37–84) years, and 66 (74%) patients were male. Pathologic features included 68 (76%) pure UC, 21 (24%) mixed UC and 84 (94%) high grade tumours. On clinical staging, 63 (71%) patients had muscle-invasive bladder cancer (cT-stage ≥T2), of whom 11 (17%) received neoadjuvant chemotherapy, with an increasing trend in use over time. Following radical cystectomy, pT-stage ≥T3 and/or node positive were identified in 35 (39%) patients, of whom 16 (46%) received adjuvant chemotherapy. In addition, five patients with stage pT2 received adjuvant chemotherapy. Of the total cohort of patients, 31 (35%) suffered recurrences, and 33 died, 27 from urothelial carcinoma. On multivariate analysis, after adjusting for age, pT-stage and pN-stage, perioperative chemotherapy was associated with a significantly lower risk of recurrence [relative risk (RR) 0.41, p < 0.05], but not death from cancer or all causes. Conclusions Perioperative chemotherapy, and in particular neoadjuvant chemotherapy, remains relatively under-utilised at our institution despite recent increases. The significant reduction in the risk of recurrence following treatment with perioperative chemotherapy with radical cystectomy highlights the importance of multi-modality treatment in bladder UC. Identifying barriers to more widespread implementation of perioperative chemotherapy is critical for enhancing outcomes in patients with bladder UC.

Concurrent chemoradiotherapy (CCRT) has become the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). The comparative merits of two widely used regimens: carboplatin/paclitaxel (PC) and cisplatin/etoposide (PE), each with concurrent radiotherapy, remain largely undefined. Records for consecutive patients with stage III NSCLC treated with PC or PE and ≥60 Gy chest radiotherapy between 2000 and 2011 were reviewed for outcomes and toxicity. Survival was estimated using the Kaplan-Meier method and Cox modeling with the Wald test. Comparison across groups was done using the student's t and chi-squared tests. Seventy-five (PC: 44, PE: 31) patients were analyzed. PC patients were older (median 71 vs. 63 years; P = 0.0006). Other characteristics were comparable between groups. With PE, there was significantly increased grade ≥3 neutropenia (39% vs. 14%, P = 0.024) and thrombocytopenia (10% vs. 0%, P = 0.039). Radiation pneumonitis was more common with PC (66% vs. 38%, P = 0.033). Five treatment-related deaths occurred (PC: 3 vs. PE: 2, P = 1.000). With a median follow-up of 51.6 months, there were no significant differences in relapse-free survival (median PC 12.0 vs. PE 11.5 months, P = 0.700) or overall survival (median PC 20.7 vs. PE 13.7 months; P = 0.989). In multivariate analyses, no factors predicted for improved survival for either regimen. PC was more likely to be used in elderly patients. Despite this, PC resulted in significantly less hematological toxicity but achieved similar survival outcomes as PE. PC is an acceptable CCRT regimen, especially in older patients with multiple comorbidities.

Purpose To evaluate the repeatability and interoperator reproducibility of the Pascal dynamic contour tonometry (DCT), ocular response analyzer (ORA), and Goldmann applanation tonometer (GAT) in a single population of normal individuals. Methods The study included 52 eyes from 26 normal individuals. One operator measured the intraocular pressure (IOP) with each tonometer 3 times while 2 additional operators each measured the IOP with each tonometer once. Repeatability and reproducibility were assessed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Agreement among tonometers was also assessed using Bland-Altman plots. Results The mean age of included participants was 31.5±8.8 years and 15 (58%) were female individuals. In general, both intraoperator repeatability and interoperator reproducibility were significantly higher for DCT compared with the other tonometers. Intraoperator DCT (CV=3.7, ICC=0.89), GAT (CV=9.7, ICC=0.79), IOPg (CV=7.0, ICC=0.79), and IOPcc (CV=9.8, ICC=0.57). Interoperator DCT (CV=6.1, ICC=0.73), GAT (CV=9.0, ICC=0.82), and IOPg (CV=10.8, ICC=0.63), IOPcc (CV=11.7, ICC=0.49). Conclusion Overall, DCT was significantly more repeatable and reproducible than GAT, IOPg and IOPcc. The better reproducibility of the DCT may result in more precise measurements for monitoring IOP changes over time compared to GAT and ORA.

Purpose To evaluate the diagnostic accuracy of spectral domain optical coherence tomography (SD-OCT) for detection of preperimetric glaucoma and compare it with the performance of confocal scanning laser ophthalmoscopy (CSLO). Design Cohort study. Participants A cohort of 134 eyes of 88 glaucoma suspects based on the appearance of the optic disc. Methods Patients were recruited from the Diagnostic Innovations in Glaucoma Study (DIGS). All eyes underwent retinal nerve fiber layer (RNFL) imaging with Spectralis SD-OCT (Heidelberg Engineering, Carlsbad, CA) and topographic imaging with Heidelberg Retinal Tomograph III (HRT-III) (Heidelberg Engineering) CSLO within 6 months of each other. All patients had normal visual fields at the time of imaging and were classified on the basis of history of documented stereophotographic evidence of progressive glaucomatous change in the appearance of the optic nerve occurring before the imaging sessions. Main Outcome Measures Areas under the receiver operating characteristic curves (AUCs) were calculated to summarize diagnostic accuracies of the SD-OCT and CSLO. Likelihood ratios (LRs) were reported using the diagnostic categorization provided by each instrument after comparison to its normative database. Results Forty-eight eyes of 42 patients had evidence of progressive glaucomatous change and were included in the preperimetric glaucoma group. Eighty-six eyes of 46 patients without any evidence of progressive glaucomatous change followed untreated for an average of 14.0±3.6 years were included in the control group. The parameter with the largest AUC obtained with the SD-OCT was the temporal superior RNFL thickness (0.88±0.03), followed by global RNFL thickness (0.86±0.03) and temporal inferior RNFL thickness (0.81±0.04). The parameter with the largest AUC obtained with the CSLO was rim area (0.72±0.05), followed by rim volume (0.71±0.05) and linear cup-to-disk ratio (0.66±0.05). Temporal superior RNFL average thickness measured by SD-OCT performed significantly better than rim area measurements from CSLO (0.88 vs. 0.72; P= 0.008). Outside normal limits results for SD-OCT parameters were associated with strongly positive LRs. Conclusions The RNFL assessment with SD-OCT performed well in detecting preperimetric glaucomatous damage in a cohort of glaucoma suspects and had a better performance than CSLO. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

To describe the association between pattern electroretinogram (PERG) amplitude and spectral domain-optical coherence tomography (SD-OCT) macular thickness, retinal nerve fibre layer (RNFL) thickness and optic disc topography measurements.Both eyes (n = 132) of 66 glaucoma patients (mean age = 67.9 years) enrolled in the University of California, San Diego, CA, USA, Diagnostic Innovations in Glaucoma Study (DIGS) were included. Eyes were tested with PERG (Glaid PERGLA, Lace Elettronica, Pisa, Italy), RTVue SD-OCT (Optovue Inc., Fremont, CA, USA) GCC, and NHM4 protocols on the same day. Of the 66 enrolled patients, 43 had glaucoma defined by repeated abnormal standard automated perimetry (SAP) results in at least one eye and 23 were glaucoma suspects defined by a glaucomatous-appearing optic disc by physicians' examination in at least one eye and normal SAP results in both eyes. Associations (R(2)) were determined between PERG amplitude (μV) and SD-OCT macular ganglion cell complex (GCC) thickness (μm), macular thickness (μm), macular outer retinal thickness (macular thickness minus GCC thickness) (μm), RNFL thickness (μm), neuroretinal rim area (mm(2)), and rim volume (mm(3)).PERG amplitude was significantly associated with GCC thickness (R(2) = 0.179, P0.001), RNFL thickness (R(2) = 0.174, P0.001), and macular thickness (R(2) = 0.095, P0.001). R(2) associations with other parameters were not significant (all P0.624). Significant associations remained for GCC and average RNFL thickness when age and intraocular pressure at the time of testing were included in multivariate models (both P ≤ 0.030).PERG amplitude is significantly (but weakly) associated with macular GCC thickness, RNFL thickness, and macular thickness. The lack of association between PERG amplitude and macular outer retinal thickness supports previous results, possibly suggesting that that the PERG is driven primarily by retinal ganglion cell (inner retinal) responses.

105Background: Pembro plus pemetrexed and carboplatin resulted in superior objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) for untreated pts with non-sq NSCLC. Pembro is active in sq NSCLC, so combining with chemo is a rational next step. Methods: KEYNOTE-407 (NCT02775435) is a randomized, placebo-controlled, global study of 560 untreated pts with metastatic sq NSCLC with ECOG 0-1. Pts were stratified by type of taxane, PD-L1 (TPS

Purpose:To evaluate the e!ect of operator and optical defocus on the variability of pattern electroretinogram optimized for glaucoma detection (PERGLA). Methods:Two di!erent operators obtained 2 PERGLA recordings each from 10 healthy participants (5 women, mean age 32.1±10.3y). In addition, one of the operators obtained recordings in which corrective lenses of various diopters (±0.5, ±1, ±2, and ±3) were used to generate optical defocus in both eyes. The e!ect of operator on PERGLA amplitude and phase variability was determined using a single nested variance components’ analysis model and by using Bland-Altman plots. One-way analysis of variance (ANOVA) was used to determine the e!ect of optical defocus on amplitude and phase. Results:Di!erences in measurements between operators accounted for approximately 26.6% and 18.2% of the total variance for amplitude and phase, respectively. Results were confirmed by the use of Bland-Altman plots. ANOVA identified a significant e!ect of defocus on mean amplitude (F=2.65,P=0.01), but not phase (F=1.02,P=0.42). Conclusions:Measurements obtained by di!erent operators can result in significant di!erences in PERGLA amplitude. In addition, although optical defocus leads to a decrease in PERGLA amplitude by reducing visual acuity, this can be avoided by obtaining J1 or better vision before testing.

Purpose To assess the ability of the new pattern electroretinogram optimized for glaucoma detection (PERGLA) paradigm to discriminate between healthy individuals and individuals with glaucomatous optic neuropathy (GON). Design Cross-sectional study. Participants One hundred forty-two eyes of 71 participants (42 healthy and 29 with GON in at least 1 eye) enrolled in the University of California, San Diego, Diagnostic Innovations in Glaucoma Study were studied. Healthy individuals were those recruited as healthy with healthy-appearing optic disc by examination and masked stereoscopic optic disc photograph evaluation. Glaucomatous optic neuropathy was defined based on stereophotograph evaluation. Methods The PERGLA (Glaid Elettronica, Pisa, Italy) recordings were obtained within 6 months of standard automated perimetry (SAP) testing. Dependent variables were PERGLA amplitude, phase, amplitude asymmetry, phase asymmetry, and SAP pattern standard deviation (PSD) and mean deviation (MD). Main Outcome Measures Diagnostic accuracy (sensitivity and specificity) of the PERGLA normative database for classifying healthy and glaucomatous individuals was determined. In addition, performance (areas under receiver operating characteristic curves [AUCs]) of PERGLA amplitude and phase for classifying healthy (n = 84) and GON (n = 50) eyes was determined. Results from both analyses were compared with those from SAP. Results Sensitivity and specificity of the PERGLA normative database were 0.76 and 0.59, respectively, compared with 0.83 and 0.77 for SAP. The AUCs for PERGLA amplitude and phase were 0.75 and 0.50 (chance performance), respectively. The AUCs for SAP PSD and MD were 0.83 and 0.78, respectively. Conclusions Pattern electroretinograms recorded using the PERGLA paradigm can discriminate between healthy and glaucoma eyes, although this technique performed no better than SAP at this task. Low specificity of the PERGLA normative database suggests that the distribution of recordings included in the database is not ideal. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Summary The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X-ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. Video Abstract