5519 Background: In the SOLO2 (NCT01874353) trial, maintenance olaparib provided clinically meaningful improvement in OS for PSROC pts with a gBRCA mutation (m) compared with placebo (median 51.7 vs 38.8 months [mo], respectively). The ORZORA trial (NCT02476968) assessed efficacy and safety of maintenance olaparib in PSROC pts with a BRCAm (s or g) or a non-BRCA HRRm. Median progression-free survival (18.0 mo, BRCAm; 16.4, non-BRCA HRRm) was reported at primary data cutoff (DCO). We report final OS analyses. Methods: We conducted an open-label, single-arm, multicenter study of PSROC pts in response to platinum-based chemotherapy (PBC) after ≥2 prior lines of PBC. Pts underwent prospective central screening for tumor BRCAm status (myChoice CDx, Myriad Genetic Laboratories, Inc.), then central gBRCAm testing (BRACAnalysis CDx, Myriad Genetic Laboratories, Inc.) to determine s or g status. An exploratory cohort comprised of pts with predefined non-BRCA HRRm (FoundationOne CDx, Foundation Medicine, Inc.). Pts received maintenance olaparib (400 mg bid; capsules) until progression. OS and time to second progression (PFS2) were secondary endpoints. Results: 181 pts were enrolled (BRCAm n = 145 [s, n = 55; g, n = 87; s/g status unknown, n = 3]; non-BRCA HRRm, n = 33; unassigned, n = 3). At DCO (June 25, 2021), median OS follow-up in censored pts was 42.6 mo in BRCAm and 39.3 mo in non-BRCA HRRm pts. OS and PFS2 are reported in the Table. PBC was received as a subsequent therapy by 33.1% BRCAm, 32.7% sBRCAm, 33.3% gBRCAm, and 45.5% non-BRCA HRRm pts. 177 pts received ≥1 dose of olaparib and were included in safety analyses; 6.2% of pts discontinued because of adverse events (AEs). 37.9% of pts reported grade ≥3 AEs, the most common being anemia (16.4%). Since primary DCO, one new primary malignancy and four myelodysplastic syndrome events occurred. Conclusions: In final OS analyses, maintenance olaparib capsules showed consistent clinical activity in BRCAm and sBRCAm PSROC pts. Exploratory analyses suggest similar activity in non-BRCA HRRm pts. No new safety signals were observed. Findings highlight that PSROC pts, beyond those with a gBRCAm, can benefit from maintenance olaparib. Clinical trial information: NCT02476968. [Table: see text]

Introduction: NEPTUNE, a phase 3, open-label study, evaluated first-line durvalumab plus tremelimumab versus chemotherapy in metastatic NSCLC (mNSCLC).Methods: Eligible patients with EGFR and ALK wild-type mNSCLC were randomized (1:1) to first-line durvalumab (20 mg/kg every 4 weeks until progression) plus trem-elimumab (1 mg/kg every 4 weeks for up to four doses) or standard chemotherapy. Randomization was stratified by tumor programmed death-ligand 1 expression (>= 25% versus <25%), tumor histologic type, and smoking history. The amended primary end point was overall survival (OS) in patients with blood tumor mutational burden (bTMB) greater than or equal to 20 mutations per megabase (mut/ Mb). Secondary end points included progression-free sur-vival (PFS) in patients with bTMB greater than or equal to 20 mut/Mb and safety and tolerability in all treated patients. Results: As of June 24, 2019, 823 patients were randomized (intention-to-treat [ITT]); 512 (62%) were bTMB-evaluable, with 129 of 512 (25%) having bTMB greater than or equal to 20 mut/Mb (durvalumab plus tremelimumab [n = 69]; chemotherapy [n = 60]). Baseline characteristics were balanced in the intention-to-treat. Among patients with bTMB greater than or equal to 20 mut/Mb, OS improvement with durvalumab plus tremelimumab versus chemotherapy did not reach statistical significance (hazard ratio 0.71 [95% confidence interval: 0.49-1.05; p = 0.081]; median OS, 11.7 versus 9.1 months); the hazard ratio for PFS was 0.77 (95% confidence interval, 0.51-1.15; median PFS, 4.2 versus 5.1 months). In the overall safety population, incidence of grade 3 or 4 treatment-related adverse events was 20.7% (durva-lumab plus tremelimumab) and 33.6% (chemotherapy).Conclusions: NEPTUNE did not meet its primary end point of improved OS with durvalumab plus tremelimumab versus chemotherapy in patients with mNSCLC and bTMB greater than or equal to 20 mut/Mb. Despite the amended study design, with a resultant small primary analysis pop-ulation, therapeutic activity was aligned with expectations based on mechanistic biology and previous studies.(c) 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND: Metastatic breast cancer (MBC) is incurable, with the primary goal of treatment being to extend survival while preserving quality of life. Treatment options available to patients (pts) with human epidermal growth factor receptor-2 positive breast cancer (HER2+ BC) may vary between countries, in terms of both the drugs used and the sequence in which they are used. There is limited data available on the clinical characteristics and outcomes in pts with unresectable locally advanced (LA) BC. This study aimed to capture real-world data on treatment patterns and clinical outcomes in HER2+ unresectable LABC and MBC. METHODS: SAMANTHA (NCT02913456) is an ongoing, prospective, multicentre non-interventional study designed to observe pts with HER2+ unresectable LABC or MBC for a period of up to 8 years on study. The primary objectives are progression-free survival (PFS), assessed according to standard medical practice, and the treatment received. Secondary objectives included overall survival (OS), duration of response and safety. This pre-planned interim analysis reports baseline characteristics, treatment regimens received, first-line (1L) PFS by advanced BC status and the incidence of adverse events (AEs). RESULTS: The study enrolled 647 pts from five European (EU) countries (Nov 2016-Nov 2019); 629 received 1L treatment and were included in data analysis. At data cut-off date (16 Nov 2021), median follow-up on study was 30.4 months (mo; range: 0.1; 60.0); 342 (54%) pts discontinued 1L treatments, of whom 170 (50%) pts received 2L treatments, 74 pts died, 49 pts were lost to follow-up, 35 pts withdrew consent and 14 pts withdrew due to physician decision. The full analysis set (FAS) included 222 (35%) LABC pts and 407 (65%) MBC pts [Table]. Pertuzumab/trastuzumab based regimens were given as 1L in the majority of pts [462 (73 %)]. The FAS Median (m) PFS in 1L was 41.3 mo (95% CI: 36.1, 54.1) for LABC and 23.5 mo (95% CI: 20.6, 27.6) for MBC. Median OS was not reached. In the FAS, any AEs were reported in 352 (56%) pts; of these 212 (34%) had a grade 3 or higher AE. Serious (S) AEs were reported in 135 (22%) pts; of whom, 36 (6%) pts had treatment related SAEs. CONCLUSIONS: This interim analysis of SAMANTHA provides a snapshot of LABC/MBC treatment practices in five EU countries, where pertuzumab/trastuzumab based regimens appear to be the most used 1L treatment options, which aligns with the recommended standard of care. The mPFS is consistent with previous literature although higher than what was reported in the pivotal clinical trial CLEOPATRA. Given the good outcome observed in 1L and the current follow-up period of 30.4 mo, the data are not yet mature enough to provide complete insights into the treatment sequencing patterns and the clinical outcomes associated with these treatments. Acknowledgments: The study is sponsored by F. Hoffmann-La Roche Ltd. Table: Demographics and baseline disease characteristics of patients by status of advanced BC Citation Format: Marija Balic, Luis Costa, Joseline Ojaimi, Cristina Marinela Oprean, José L. Passos Coelho, Isabel Pazos, Fabio Puglisi, Thibaut Sanglier, Giuseppa Scandurra, Michael Schenker, Laurentia A. Wahyudi, Georgi Zhbantov, Constanta Timcheva. Interim Analysis Results from a European Disease Registry Study Aimed to Prospectively Observe Treatment Patterns and Outcomes in Patients with HER2+ Unresectable Locally Advanced or Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-02-05.

Abstract Background The CDK4/6 inhibitor, ribociclib in combination with endocrine therapy significantly improved progression-free survival in the first line setting in post-menopausal patients with HR+/HER2− advanced breast cancer (ABC) in a pivotal phase 3, placebo-controlled trial (MONALEESA-2) and demonstrated superior overall survival in premenopausal patients with HR+/HER2− ABC (MONALEESA-7). The multinational, phase 3b, CompLEEment-1 trial, which assessed the safety and efficacy of ribociclib plus letrozole in a broader population of patients who have not received prior endocrine therapy for advanced disease, is the largest phase 3 clinical trial to date to evaluate the safety and efficacy of a CDK4/6 inhibitor. We report a subanalysis of data from patients (N = 339) enrolled in the central and south European countries of the SERCE (Southern Europe, RUC, Central Europe) cluster of CompLEEment-1. Patients and methods Men and women of any menopausal status with HR+/HER2− ABC received once-daily oral ribociclib 600 mg (3-weeks on/1-week-off), plus letrozole 2.5 mg continuously. Men/premenopausal women also received a GnRH-agonist. The primary outcome was the number of patients with adverse events (AEs) over a timeframe of approximately 36 months. Time-to-progression, overall response rate, and clinical benefit rate were also measured. Results Safety results in the SERCE subgroup were consistent with those in the pivotal clinical trials of ribociclib in combination with endocrine therapy. Treatment-related AEs leading to dose adjustments/interruption occurred in 63.1% of patients but led to treatment discontinuation in only 10.6%. The most common treatment-related AEs of grade ≥ 3 were neutropenia and transaminase elevations. There were no fatal treatment-related events. Conclusions These findings from the SERCE subgroup support the safety and manageable tolerability of ribociclib in a broad range of patients with HR+/HER2− ABC more representative of patients in real-world clinical practice.

Endocrine therapy (ET) for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) metastatic breast cancer (MBC) has changed markedly over recent years with the emergence of new ETs and the use of molecularly targeted agents. Cytotoxic chemotherapy continues, however, to have an important role in these patients and it is important to maximize its efficacy while minimizing toxicity to optimize outcomes. This review examines current HR-positive/HER2-negative MBC clinical guidelines and addresses key questions around the use of chemotherapy in the face of emerging therapeutic options. Specifically, the indications for chemotherapy in patients with HR-positive/HER2-negative MBC and the choice of optimal chemotherapy are discussed.

Abstract Background: CompLEEment-1 (NCT02941926) is an ongoing Phase IIIb trial of ribociclib (RIB) in combination with letrozole (LET) in the first-line setting for patients (pts) with HR+, HER2- ABC, reflecting a real-world clinical setting by including a more diverse pt population than those included in the pivotal MONALEESA trials. Here we report further analyses of the primary endpoint of safety from the completed Core Phase of the trial. Methods: CompLEEment-1 included women of any menopausal status and men with HR+, HER2- ABC treated with ≤1 line of prior chemotherapy and no prior hormonal therapy for advanced disease. Pts received RIB (600 mg QD, 3 weeks on/1 week off) in combination with LET (2.5 mg QD, continuous). Premenopausal women and men received a luteinizing hormone-releasing hormone agonist (3.6 mg goserelin or 7.5 mg leuprolide, Q28D). The primary endpoints were safety and tolerability. Updated analyses included dose reduction/interruption or treatment discontinuation due to adverse events (AEs), clinical impact of AEs of special interest (AESI), and exposure-adjusted incidence/occurrence rates (IRs) for AESI. Results: At data cutoff (November 8, 2019) 3,246 pts had been evaluated (median follow-up of 25.4 months), and median duration of exposure to RIB was 17.5 months; 1,301 (40.1%) pts completed Core Phase treatment, 415 of whom moved to the Extension Phase. Overall, 1,945 (59.9%) pts permanently discontinued treatment, mostly due to progressive disease (34.2%) and AEs (15.5%). Treatment-related AEs were reported in 3,091 (95.2%) pts, leading to dose modification in 2,235 (68.9%) pts. Dose modification occurred most often in pts with grade ≥3 neutropenia (dose interruption, 1,671 [51.5%] pts; dose reduction, 480 [14.8%] pts); treatment discontinuation occurred most frequently in pts with grade ≥3 increased alanine aminotransferase (ALT; 116 [3.6%] pts) or aspartate aminotransferase (AST; 68 [2.1%] pts). Grade ≥3 neutropenia occurred in 1,856 (57.2%) pts, with the median time to first occurrence of 4.1 weeks and median duration of first occurrence of 1.1 weeks. As measured by laboratory values, grade ≥2 increased ALT and AST occurred in 453 (14.0%) and 380 (11.7%) pts, respectively. Grade ≥2 QTcF prolongation was infrequent, occurring in 101 (3.1%) pts, leading 8 (0.2%) pts to discontinue from treatment. AESI rarely led to hospitalization (0 to 0.3%) and none were fatal. Exposure-adjusted IRs for AESI per 100 patient-years of exposure show that with increasing RIB exposure, the IR and the event rates for AESI decreased by a factor of ×2 to ×8 from 0-1 years compared with 1-2 years (Table 1). Conclusions: AEs associated with RIB + LET combination therapy were manageable, consistent with previous Phase III trials of RIB + LET - and adjusted IRs for AESI notably decreased from Year 1 to Year 2 of treatment. These data further support the use of RIB + LET for first-line treatment of HR+, HER2- ABC in both men and women of any menopausal status and in a broader and more diverse patient population. Table 1. Exposure-adjusted IRs for selected AESI per 100 patient-years of exposure0-1 years1-2 yearsAESIIR per 100 PTYaEvents per 100 PTYbIR per 100 PTYaEvents per 100 PTYbNeutropenia276.76410.2292.43200.83ALT increased20.3741.663.796.32AST increased17.5133.272.944.61QTcF prolongation8.4410.221.081.26aIR per 100 PTY: n/100 PTY, number of patients with an event divided by the corresponding sum of the exposure duration for patients, where duration of exposure in patient treatment-years (PTY) is counted up to the first qualifying event (or duration of exposure in time interval for patients without an event).bEvents per 100 PTY: n/100 PTY, number of events divided by the corresponding sum of the exposure duration, where duration of exposure in patient treatment-years (PTY) is duration of exposure in time interval. Citation Format: Janice Lu, Paul Cottu, Miguel Martín, Claudio Zamagni, Aleix Prat, Stephen Chia, Guy Jerusalem, Senthil Rajappa, Constanta Timcheva, Lyudmila Zhukova, Katie Zhou, Jiwen Wu, Lakshmi Menon-Singh, Michelino De Laurentiis. Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC): Expanded safety analysis of the phase IIIb CompLEEment-1 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-05.

The aim of this multicentric retrospective study is to evaluate the predictive and prognostic performance of neutrophil to lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and their dynamics in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab as a second line. Patients with metastatic NSCLC (n = 119), whose tumors expressed programmed death-ligand 1 (PD-L1) ≥ 1%, were retrospectively analyzed between Apr 2017 and Apr 2019. All patients received platinum-containing chemotherapy as a first line treatment. Pre-treatment NLR was calculated by dividing the number of neutrophils by the number of lymphocytes in peripheral blood before the first pembrolizumab infusion. Progression free survival (PFS) and overall survival (OS) was compared by Kaplan-Meier method and Cox Proportional Hazard model. Patients with NLR > 5 before immunotherapy showed significantly shorter mean PFS of 6.86 months (95% CI: 5.81-7.90) as compared to those with NLR ≤ 5 of 18.82 months (95% CI: 15.87-21.78) (long rank test p < 0.001). Furthermore in the multivariate analysis, only NLR > 5 was an independent predictive factor for shorter PFS (HR: 4.47, 95% CI: 2.20-9.07, p < 0.001). In multivariate analysis, presence of bone metastases (HR: 2.08, 95% CI: 1.10-4.94, p = 0.030), NLR > 5 before chemotherapy (HR: 8.09, 95% CI: 2.35-27.81, p = 0.001) and high PLR before chemotherapy (HR: 2.81, 95% CI: 1.13-6.97, p = 0.025) were found to be independent negative prognostic factors for poor OS. Our data suggests that NLR ≤ 5 is a potential predictive marker, which may identify patients appropriate for immunotherapy as a second line treatment.

Background. In cells long non-coding RNAs (lncRNAs) control gene expression through various mechanisms, acting on different biological levels: chromatin remodeling, regulation of transcription, posttranscriptional modification. LncRNAs could also be transported via systemic circulation, encapsulated in extracellular vesicles called “exosomes” or in vesicle-free form, bounded to proteins or lipoproteins. Knowing the intracellular function of lncRNAs, it is reasonably speculated that in cancer patients their existence in bloodstream is more than just an extracellular release. It is thought to be a kind of an epigenetic mechanism, rendered by tumor cells, so the last could influence gene expression programs of normal cells in distance, creating tumor-friendly environment in other body compartments - a sine qua non for metastatic spread. Few studies have investigated in vivo circulating lncRNAs in breast cancer and even less have done it in the neoadjuvant setting. Goals and objectives. We decided to conduct a small exploratory study in patients with locally advanced breast cancer, focusing on changes in plasma lncRNAs during neoadjuvant therapy. The two main goals of the study are: 1. Assessing the effect of systemic anticancer treatment on epigenetic regulators such as circulating lncRNAs; 2. Testing the technical feasibility of using lncRNAs as plasma biomarkers. Our objectives include lncRNA profiling in circulation before onset as well as in the course of systemic therapy, followed by correlation analysis between distinct lncRNA signatures and clinicopathological features. Differential lncRNA expression will be assessed between patients and normal controls as well as among patient subgroups according to time of sampling, age, intrinsic breast cancer phenotype and response to therapy. LncRNAs of interest will be further examined in larger cohorts of patients and healthy controls. Design/materials/methods. This is a prospective, interventional, case-control clinical trial in two parts - exploration and validation. Patients eligibility criteria: age ≥ 18 years; females; histologically confirmed locally advanced breast cancer; multidisciplinary tumor board decision for neoadjuvant chemotherapy or chemotherapy plus targeted therapy; radiologically excluded distant dissemination; no concomitant malignancy; signed informed consent form (ICF). Healthy controls eligibility criteria: age ≥ 18 years; females; no oncologic history; signed ICF. For part I ten patients and two controls have already been recruited. Blood samples were taken from each patient twice - before onset of neoadjuvant therapy and before 4th cycle (in one patient the second sample was taken before 6th cycle), from control subjects blood was taken once. Plasma was immediately separated and frozen until RNA extraction. Next-generation RNA sequencing was performed with subsequent bioinformatics analysis on lncRNAs. Clinical and pathology information was obtained from each patient’s hospital file. In part II plasma will be collected in the same manner as in part I. Preselected lncRNAs from part I will be measured by real-time polymerase chain reaction. Statistics. This is an exploratory study with no empirical data and no formal planning for sample size. The correlation between lncRNAs and clinicopathological characteristics and the significance of the differences among groups will be assessed by parametric tests (Pearson correlation, Student’s t-test) and/or multivariate such (ANCOVA). Present and target accrual. Part I accrual has completed and bioinformatics data are expected. Part II accrual is ongoing with 15 patients already recruited. Target accrual for part II is 50 patients and 20 controls. Citation Format: Boris Krastev, Constanta Timcheva, Spartak Valev, Georgi Zhbantov, Mila Petrova, Teodora Karanikolova, Radostina Gencheva, Anika Ivanova, Ivaylo Stoykov, Georgi Stamenov. Investigating circulating lncRNAs in breast cancer patients on neoadjuvant systemic therapy [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 OT1-03-03.

e21541 Background: In this multicentric retrospective study we evaluated the incidence of clinical benefit rate (CBR) and its relation to Neutrophil-Lymphocyte Ratio (NLR) and psoas major muscle area (PMMA), as well as their dynamics in patients with Non-small Cell Lung Cancer (NSCLC) treated with pembrolizumab (P) as a second line. Methods: Patients with metastatic NSCLC (n = 84) whose tumors expressed PD-L1≥1% were retrospectively analyzed between Apr 2017 and Dec 2019. All patients received platinum-containing chemotherapy (CT) as a first line treatment. Absolute neutrophil, and absolute lymphocyte count enabled calculation of NLR; NLR1 - before CT, NLR2 – before P infusion. ΔNLR was calculated. Area of PMMA was calculated at L3 position on computed tomography. CBR was defined as the proportion of patients with a partial response or stable disease for at least six months since no patients with complete response were recorded. PMMA was calculated before CT and before the P infusion; (% change rate of PMMA = ([1-PMMA before P / PMMA before CT]*100). Patients with the change rate of PMMA≥10% were considered with sarcopenia - 30 (35.7%). Results: CBR was 72.6%. There were not significant correlations between NLR, PMMA and their dynamics. Patients without clinical benefit (CB) had significantly higher values of ΔNLR (1.38±2.2) and ΔPMMA (11.2±10.7) than patients with CB - ΔNLR (0.12±1.88; p = 0.023) and ΔPPMA (8.9±13.5; p = 0.001). ROC analysis revealed that at the optimal cutoff values of all markers, ΔPMMA achieved the greatest AUC = 0.738 (95% CI, 0.77-0.93) and could distinguish between patients with or without CB with sensitivity of 77.3% and specificity of 83.6%. Sarcopenic patients had significantly shorter mean progression-free survival (PFS) – 6.5 months (95%, CI 5.1-8.1) than the rest – 20.8 months (95%, CI 16.7-24.1). Moreover in the multivariable analysis, ΔNLR (HR 1.19, 95% CI 1.05-1.38, p = 0.01) and ΔPPMA ≥10 % (HR 5.4, 95% CI 2.82-10.19, p < 0.001) were found to be independent predictive factors for shorter PFS. Conclusions: Our data suggests that ΔPMMA and ΔNLR are potential predictive markers, which may identify patients appropriate for immunotherapy as a second line treatment.

e12644 Background: Though long considered “nonfunctional”, recent evidence is growing that non-coding RNAs, including long non-coding RNAs (lncRNAs), have an active role in tumor biology, mainly as gene expression regulators. Breast cancer is heterogeneous in nature and locally advanced cases are distinct entity in terms of curability. Being borderline between early and metastatic disease, long-term outcome here strongly depends on the efficacy of systemic therapy. To the best of our knowledge, no study has yet investigated global changes of circulating lncRNAs in this patient population during preoperative (neoadjuvant) treatment. Methods: We conducted a small transcriptomic trial on 10 locally advanced breast cancer patients, assessing lncRNA and messenger RNA (mRNA) expression in plasma samples before (S1) and after (S2) initiation of neoadjuvant therapy. Next-generation sequencing was performed with differential gene expression analysis between S1 and S2 groups. We assessed co-expression between lncRNAs and mRNAs, identifying mRNAs whose transcription was potentially regulated by lncRNAs, i.e. “lncRNA target genes”. In order to elucidate biological roles of these target mRNAs, we performed gene ontology (GO) and pathway analysis (Kyoto Encyclopedia of Genes and Genomes, KEGG). Results: 394 lncRNAs and 1085 mRNAs demonstrated statistically significant difference in expression between pretreatment and posttreatment samples. Co-expression analysis revealed positive correlation between 25 lncRNAs and 25 mRNAs located in cis, while potential trans interactions exceeded 105. GO evaluation of lncRNA target genes was significant for 44 terms: 28 for biological process (BP), 9 for cellular component (CC) and 7 for molecular function (MF). The most annotated terms for BP, MF and CC were respectively biosynthetic process, DNA-binding transcription factor activity and nucleus. KEGG analysis showed that 105 of 201 analyzed pathways were statistically significant with most prominent being pathways in cancer and transcriptional misregulation in cancer. Conclusions: Despite limited in size, present study provides broad view on transcriptional landscape in blood circulation, interrogating in vivo dynamics of systemic gene expression during neoadjuvant breast cancer treatment. It demonstrates that substantial number of circulating lncRNAs could be up- or downregulated in the course of therapy and this has the potential to control protein-coding genes that are tightly implicated in cancer biology.

BACKGROUND Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported. METHODS In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point. RESULTS The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group. CONCLUSIONS Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.).

Capecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities. In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m2 days 1–14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics. DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6 mg/m2 day 1 for schedule 1 and 1.4 mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4 mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy. The combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC.

BACKGROUND Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). METHODS In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1: 1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P = 0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P = 0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%). CONCLUSIONS Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events.

Current first-line therapy for advanced EGFR and ALK wild-type NSCLC is associated with poor survival and there remains a significant need for more effective treatments in this population. Blockade of immune checkpoints programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) represents a promising anticancer therapeutic strategy. In preclinical models, targeting both PD-1 and CTLA-4 provides for non-redundant pathway blockade and potential synergy. Durvalumab (MEDI4736) is a selective, high-affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 (IC50 0.1 nM) and CD80 (IC50 0.04 nM). Tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4. A Phase 1b study of durvalumab + tremelimumab demonstrated encouraging clinical activity and a manageable tolerability profile in advanced NSCLC, with activity observed in patients with high and low/no tumor PD-L1 expression (NCT02000947). NEPTUNE (NCT02542293) is a randomised, open-label, multicentre, global, Phase 3 study. Immunotherapy- and chemotherapy-naïve patients with advanced/metastatic EGFR and ALK wild-type NSCLC (with either PD-L1 high expression [≥25% tumor cells staining for PD-L1 at any intensity] or PD-L1 low/negative expression [<25% tumor cells staining for PD-L1 at any intensity] ) will be randomised (1:1) to durvalumab (20 mg/kg i.v. every 4 weeks [q4w] for up to 12 months) + tremelimumab (1 mg/kg i.v. q4w for up to 4 doses); or standard-of-care platinum-based doublet chemotherapy. The primary endpoint is overall survival (OS). Secondary endpoints are progression-free survival (PFS), objective response rate (ORR), duration of response and proportion of patients alive and progression free at 12 months by investigator assessment (RECIST v1.1); time from randomisation to second progression; OS, PFS and ORR in patients with PD-L1 low/negative NSCLC; safety (CTCAE v4.03) and tolerability; pharmacokinetics; and immunogenicity. Exploratory outcomes include potential biomarkers of response to treatment and impact of subsequent anticancer therapies on OS. Recruitment is ongoing. Not-applicable. Not-applicable.

TPS5597 Background: PM01183 (PM; lurbinectedin) is a new anticancer drug that blocks trans-activated transcription, induces DNA double-strand breaks and inhibits the tumor microenvironment. Significant activity (30% objective response rate) was reported in a phase II trial in patients (pts) with platinum-resistant ovarian cancer (ASCO 2014, oral session, abstract 5505). The most common toxicity observed was hematologic, mainly neutropenia. Methods: Multinational, multicenter (112 sites), open-label, randomized, phase III study of PM (3.2 mg/m2 1-h i.v. infusion, q3wk; experimental arm) vs. a control arm with either PLD (50 mg/m2, q4wk) or T (1.5 mg/m2, q3wk). A total of 420 pts will be randomized (1:1) and stratified according to performance status (PS), platinum-free interval (PFI) and number of prior chemotherapy lines. Interim safety (80 pts recruited) and futility (210 pts recruited) analysis are to be performed by an independent data monitoring committee. The most relevant inclusion criteria are: pts ≥ 18 years old; confirmed diagnosis of platinum-resistant (PFI: 1-6 months after last platinum-containing chemotherapy) epithelial ovarian, fallopian tube or primary peritoneal cancer: ≤ 3 prior chemotherapy regimens; progressive disease as per RECIST v1.1 at study entry; PS: 0-2 and adequate major organ function. Pts are excluded if pre-treated with PM, trabectedin, or with both PLD and T; have bowel obstruction, or require permanent or frequent external drainage within 2 weeks prior to randomization. Primary objective: to determine a difference in progression-free survival (RECIST v1.1) by independent review committee. Prospective assumptions are a 30% risk reduction favoring PM (HR = 0.70; 2.5% 1-sided alpha; 90% power). Secondary endpoints: overall survival, antitumor response (RECIST/CA-125), duration of response, QoL, safety, pharmacokinetics (PK), PK/pharmacodynamic correlations, and pharmacogenomics. First patient was included in June 2015; As of January 2016, 151 patients have been enrolled. Enrollment is expected to be completed in November 2016. Clinical trial information: NCT02421588.

BACKGROUND:Reducing treatment delay improves outcomes in breast cancer. The aim of this study was to determine factors influencing patient- and system-related delays in commencing breast cancer treatment in different countries.METHODS:A total of 6588 female breast cancer patients from 12 countries were surveyed. Total delay time was determined as the sum of the patient-related delay time (time between onset of the first symptoms and the first medical visit) and system-related delay time (time between the first medical visit and the start of therapy).RESULTS:The average patient-related delay time and total delay time were 4.7 (range: 3.4-6.2) weeks and 14.4 (range: 11.5-29.4) weeks, respectively. Longer patient-related delay times were associated with distrust and disregard, and shorter patient-related delay times were associated with fear of breast cancer, practicing self-examination, higher education level, being employed, having support from friends and family and living in big cities. The average system-related delay time was 11.1 (range: 8.3-24.7) weeks. Cancer diagnosis made by an oncologist versus another physician, higher education level, older age, family history of female cancers and having a breast lump as the first cancer sign were associated with shorter system-related delay times. Longer patient-related delay times and higher levels of distrust and disregard were predictors of longer system-related delay times.CONCLUSIONS:The delay in diagnosis and treatment of breast cancer remains a serious problem. Several psychological and behavioural patient attributes strongly determine both patient-related delay time and system-related delay time, but their strength is different in particular countries.

Selumetinib is a potent, selective MEK inhibitor with efficacy in several tumor models. This study compared selumetinib with capecitabine in patients with advanced or metastatic pancreatic cancer who had been pretreated with a gemcitabine-based regimen. In this randomized, multicenter phase II study (NCT00372944), patients received either 100 mg oral selumetinib twice daily or 1,250 mg/m(2) oral capecitabine twice daily for 2 weeks followed by a 1-week break, given in 3-weekly cycles. The primary endpoint was overall survival. In all 70 patients were randomized. The median survival was 5.4 months in the selumetinib group and 5.0 months in the capecitabine group (hazard ratio 1.03; two-sided 80% confidence interval = 0.68,1.57; P = 0.92). Disease progression events occurred in 84% and 88% of patients in the selumetinib and capecitabine treatment groups, respectively. Gastrointestinal adverse events (nausea, vomiting and diarrhea) were commonly observed in both treatment groups. Other frequently reported adverse events were acneiform dermatitis and peripheral edema with selumetinib, and palmar-plantar erythrodysaesthesia with capecitabine. There was no statistically significant difference in overall survival between selumetinib and capecitabine as second-line treatment in patients with advanced pancreatic cancer. Selumetinib was well tolerated with a manageable safety profile.

9046 Background: Reducing diagnostic delays may improve treatment outcomes in BC. We investigated in various countries patient-related factors influencing time to seeking medical advice for signs of BC. Methods: A total of 4,816 female BC patients from 10 countries were surveyed using a uniform questionnaire translated into local languages. Time between first patient-detected signs of BC and AMV was measured using categorized time scales. Out of 14 original items on a multiple scale measuring BC-related attitudes and behaviors, 5 factors were extracted and used for further analysis: distrust in medical system and success of therapy, disregard of signs, fear of BC, practicing regular breast self-examination and support from friends and family. Results: In the subset of 2,870 patients with self-detected BC who provided complete answers to relevant variables, the mean time to AMV varied in particular countries from 3.4 to 6.2 weeks (grand mean of 4.7 weeks), with 39% of cases with a delay of >4 weeks. Overall, patient attributes that significantly influenced time to AMV were: distrust (p<1E-36), disregard (p=1.26E-30), fear (p=2.65E-16), self-examination (p=1.31E-21), place of living (p=3.5E-3) and education (p=2.73E-3). Multilevel analysis indicated that significant differences among particular countries were only due to slopes of distrust and disregard included in general regression model. The model enhanced with the two abovementioned random effects provided significant improvement in predicting time to AMV. Re-estimation of the model based solely on data from individual countries produced 10 significant equations with varied coefficients for distrust and disregard (see table). Conclusions: Patient-related factors contribute considerably to delay in the diagnosis of BC. Differences between particular countries call for country-specific approaches. [Table: see text]