Final Survival Analysis Research Articles

Final progression-free survival analysis of phase II study with the combination therapy of DFP-14323, protease inhibitor, and low-dose afatinib as first-line therapy for common EGFR mutation–positive NSCLC.

9111 Background: DFP-14323(INN: ubenimex) was developed as a biological response modifier and has been approved for maintenance therapy of AML in Japan. Ubenimex is an inhibitor of aminopeptidase N (APN), originated from Streptomyces olivoreticuli. APN is well known as one of the prognostic factors for several cancer types, including non-small-cell lung cancer (NSCLC). Meanwhile, afatinib is one of the standard treatments in NSCLC with EGFR mutation, but the toxicities often require dose reduction. Recently, it is suggested that reducing afatinib doses can decrease treatment-related adverse events without affecting efficacy. We aimed to examine efficacy of DFP-14323 with low-dose afatinib by conducting phase II study in patients with metastatic NSCLC harboring EGFR mutation. Methods: The study was a multi-center, single-arm, open-label phase II trial. Stage III/IV and treatment-naïve patients with common EGFR mutation-positive (L858R/19del) NSCLC were treated with DFP-14323 at a fixed dose of 10mg/day and afatinib at a starting dose of 20 mg/day until disease progression or intolerable toxicity. The primary endpoint was disease control rate (DCR), defined by sum the CR, PR and SD. The secondary endpoints were progression-free survival(PFS), overall response rate(ORR), N/L ratio, and safety. A sample size of 26 patients was determined, assuming a threshold DCR 70% and an expected DCR 90% with a two sided α error of 0.05 and a β error of 0.20, based on the Simon’s two stage design. Results: From July 2018 to March 2020, 26 patients were enrolled. A median age was 72 years (range, 53-82), 21(81%) were female, and 16 (62%) were never-smokers. Half of patients had Del-19 and other half had L858R. An efficacy analysis provided a DCR of 100% (previously reported) with 18 responders (ORR : 69%). Independent imaging evaluation at 72 weeks provided a median PFS was confirmed to be 16.6mts (95% CI 10.2, 22.9, median follow-up time for censored cases: 16.3mts). According to updated exploratory follow-up by physicians, as of the data cut-off of Dec 2021, median PFS was calculated 20.6 mts (95% CI, 12.6, 28.5, median follow-up time for censored case: 20.9mts). Seven Grade 3 adverse events were observed in 6patient(23%), and paronychias in 3 patients and diarrhea, stomatitis, dermatitis, and lymphocytopenia in 1 patient each. One paronychia was considered to be related to DFP-14323 and the other events to afatinib. No grade 4 or 5 adverse events were observed. One Grade 1 ILD was observed but recovered soon without treatment. Conclusions: Combination of DFP-14323 and low-dose afatinib has shown comparable potential as a first-line treatment for EGFR mutation positive NSCLC with feasible efficacy and good safety profile. We are planning a phase III study to evaluate this combination therapy as compared with other EGFR-TKIs. Clinical trial information: UMIN000033062.

First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study

BackgroundTherapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results.MethodsTASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1–5 and 8–12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1–14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS.ResultsAt 1 September 2020, median OS was 22.3 months (95% CI: 18.0–23.7) with TT-B and 17.7 months (95% CI: 12.6–19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55–1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings.ConclusionsTT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy.Clinical trial informationNCT02743221 (clinicaltrials.gov)

A new survival analysis model in adjuvant Tamoxifen-treated breast cancer patients using manifold-based semi-supervised learning

Breast cancer researchers are very interested in studying and analyzing the survival time of patients. However, choosing the appropriate model for survival time analysis is the main challenge in the survival analysis of these patients. Using a dataset of patients with breast cancer, a new survival analysis model is proposed in this study. First, using the Cox-PH model, the whole selected data was categorized into high-risk and low-risk groups. The classified data was given to the AFT model in the next step to estimate the survival time. In some instances, the value of the metabolic status of the Tamoxifen feature was missing. Next, using the information obtained from the first and second steps, in the proposed Manifold-based semi-supervised learning module, the value of missing data was estimated. Using all labeled data, the final survival analysis was performed, and the relative hazard obtained. The comparison of the proposed model via other previous models in survival analysis demonstrates that the proposed model is 26% more accurate than when only the Cox-PH model was used and 28% more accurate than when only the AFT model was used in the testing set. Furthermore, the findings demonstrate that when the Manifold-based SSL model was used in the learning module, the accuracy was 19% higher than the Co-training SSL method and 12% higher than the SVMSSL method. The advantages of the proposed survival analysis method are high capability for identifying the survival risk classes of the patient and high predictive accuracy for the relative hazard.

Abstract P2-13-04: Final survival analysis of a phase 3 study comparing SB3 (trastuzumab biosimilar) and reference trastuzumab in HER2-positive early or locally advanced breast cancer

Abstract Background: SB3 (trastuzumab-dttb) is a biosimilar approved globally based on its similarity with reference trastuzumab (TRZ) demonstrated by thorough comparability exercises in analytical, biological, and clinical studies. In a randomized, double-blind, multicenter Phase 3 study of 875 patients with HER2-positive early or locally advanced breast cancer in the neoadjuvant setting, equivalent efficacy, similar safety, pharmacokinetics, and immunogenicity between SB3 and TRZ were shown. However, when quality attributes of TRZ were examined, downward drifts in antibody-dependent cell-mediated cytotoxicity activities (ADCC) were observed in the TRZ lots with expiry dates ranging from Aug 2018 to Dec 2019. Some of these lots of the reference product were found to be used in the Phase 3 study. After completing the Phase 3 study, patients from select countries were included in a follow-up observational study to monitor cardiac safety and survival. Here, we report the final survival results, including post-hoc subgroup analysis based on ADCC status, at a median follow-up of 68 months. Methods: During the follow-up observational study, the protocol was amended to include additional patients who originally were enrolled in the Phase 3 study but had not been followed in the observational study, in order to collect a larger sample of survival data. For these additional patients, medical records from the last assessment in the Phase 3 study through the date of enrollment in the follow-up study were collected retrospectively. As post-hoc analysis, patients in the TRZ arm were stratified into two subgroups: patients who received during neoadjuvant treatment at least one vial of TRZ with downward drift in ADCC as “Drifted TRZ”, and the others as “Non-drifted TRZ”. Event-free survival (EFS) and overall survival (OS) were assessed. Results: Of 875 patients randomized in the Phase 3 study, 538 patients (SB3, N=267; TRZ, N=271) were enrolled in the follow-up observational study: 367 patients were initially enrolled in the follow-up study, and 171 patients were additionally enrolled following the protocol amendment. The median follow-up duration was 68 months from randomization in the Phase 3 study. 54 events (20.2%) in the SB3 arm, and 67 events (24.7%) in the TRZ arm were reported (HR 0.84 [0.58, 1.20], p=0.335). 22 deaths (8.2%) and 38 deaths (14%) were reported in SB3 and TRZ arms, respectively (HR 0.61 [0.36, 1.05], p=0.073). In post-hoc analysis, of 271 patients in TRZ arm, 107 patients were grouped as “Non-drifted TRZ”, and 164 patients as “Drifted TRZ”. 19 events (17.8%) in the Non-drifted TRZ group and 48 (29.3%) events in the Drifted TRZ group occurred (HR 2.57 [1.28, 5.14], p=0.008). 9 deaths (8.4%) in the Non-drifted TRZ group and 29 deaths (17.7%) in the Drifted TRZ group were reported (HR 3.87 [1.37, 10.93], p=0.011). No difference was observed between SB3 arm and Non-drifted TRZ group in terms of EFS (HR 1.28 [0.73, 2.22], p=0.391) and OS (HR 0.99 [0.42, 2.31], p=0.975). Conclusions: Comparable long-term efficacy results in EFS and OS were shown at 68 months of follow-up, further supporting biosimilarity of SB3 to the reference product. Currently, these follow-up results represent the longest monitoring data of patients treated with a trastuzumab biosimilar for HER2-positive early or locally advanced breast cancer. Citation Format: Xavier Pivot, Mark D Pegram, Javier Cortes, Diana Lüftner, Gary H Lyman, Giuseppe Curigliano, Igor M Bondarenko, Mikhail Dvorkin, Jin Hee Ahn, Seock-Ah Im, Maria Litwiniuk, Yaroslav V Shparyk, Gwo Fuang Ho, Nikolay V Kislov, Marek Wojtukiewicz, Tomasz Sarosiek, Yee Soo Chae, Jin Seok Ahn, Hyerin Jang, Sujung Kim, Jiwon Lee, Soo Young Lee, Ye Chan Yoon. Final survival analysis of a phase 3 study comparing SB3 (trastuzumab biosimilar) and reference trastuzumab in HER2-positive early or locally advanced breast cancer [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 P2-13-04.

Reply by Authors.

No AccessJournal of UrologyAdult Urology1 Oct 2021Reply by Authorsis a reply to letterEditorial CommentEditorial Comment Neeraj Agarwal, Kelly McQuarrie, Anders Bjartell, Simon Chowdhury, Andrea J. Pereira de Santana Gomes, Byung Ha Chung, Mustafa Özgüroğlu, Álvaro Juárez Soto, Axel S. Merseburger, Hirotsugu Uemura, Dingwei Ye, Robert Given, Ethan Basch, Branko Miladinovic, Angela Lopez-Gitlitz, and Kim N. Chi Neeraj AgarwalNeeraj Agarwal *Correspondence: Huntsman Cancer Institute, University of Utah (NCI-CCC), 2000 Circle of Hope Dr., Suite 5726, Salt Lake City, Utah 84112 telephone: 801-213-5658; E-mail Address: [email protected] Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah More articles by this author , Kelly McQuarrieKelly McQuarrie Janssen Research & Development, Horsham, Pennsylvania More articles by this author , Anders BjartellAnders Bjartell Skåne University Hospital, Lund University, Malmö, Sweden More articles by this author , Simon ChowdhurySimon Chowdhury Guy’s, King’s, and St Thomas’ Hospitals, and Sarah Cannon Research Institute, London, United Kingdom More articles by this author , Andrea J. Pereira de Santana GomesAndrea J. Pereira de Santana Gomes Liga Norte Riograndense Contra O Câncer, Natal, Brazil More articles by this author , Byung Ha ChungByung Ha Chung Yonsei University College of Medicine and Gangnam Severance Hospital, Seoul, South Korea More articles by this author , Mustafa ÖzgüroğluMustafa Özgüroğlu Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, Istanbul, Turkey More articles by this author , Álvaro Juárez SotoÁlvaro Juárez Soto Hospital Universitario de Jerez de la Frontera, Cadiz, Spain More articles by this author , Axel S. MerseburgerAxel S. Merseburger University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany More articles by this author , Hirotsugu UemuraHirotsugu Uemura Kindai University Faculty of Medicine, Osaka, Japan More articles by this author , Dingwei YeDingwei Ye Fudan University Shanghai Cancer Center, Shanghai, China More articles by this author , Robert GivenRobert Given Urology of Virginia, Eastern Virginia Medical School, Norfolk, Virginia More articles by this author , Ethan BaschEthan Basch University of North Carolina, Chapel Hill, North Carolina More articles by this author , Branko MiladinovicBranko Miladinovic Janssen Research & Development, San Diego, California More articles by this author , Angela Lopez-GitlitzAngela Lopez-Gitlitz Janssen Research & Development, Los Angeles, California More articles by this author , and Kim N. ChiKim N. Chi BC Cancer, Vancouver, British Columbia, Canada More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001841.03AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Reply by Authors." The Journal of Urology, 206(4), p. 923 Reference 1. : Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol 2021; 39: 2294. Google Scholar © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of UrologyJul 23, 2021, 12:00:00 AMEditorial CommentJournal of UrologyJul 23, 2021, 12:00:00 AMEditorial Comment Volume 206Issue 4October 2021Page: 923-923 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neeraj Agarwal Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah *Correspondence: Huntsman Cancer Institute, University of Utah (NCI-CCC), 2000 Circle of Hope Dr., Suite 5726, Salt Lake City, Utah 84112 telephone: 801-213-5658; E-mail Address: [email protected] More articles by this author Kelly McQuarrie Janssen Research & Development, Horsham, Pennsylvania More articles by this author Anders Bjartell Skåne University Hospital, Lund University, Malmö, Sweden More articles by this author Simon Chowdhury Guy’s, King’s, and St Thomas’ Hospitals, and Sarah Cannon Research Institute, London, United Kingdom More articles by this author Andrea J. Pereira de Santana Gomes Liga Norte Riograndense Contra O Câncer, Natal, Brazil More articles by this author Byung Ha Chung Yonsei University College of Medicine and Gangnam Severance Hospital, Seoul, South Korea More articles by this author Mustafa Özgüroğlu Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, Istanbul, Turkey More articles by this author Álvaro Juárez Soto Hospital Universitario de Jerez de la Frontera, Cadiz, Spain More articles by this author Axel S. Merseburger University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany More articles by this author Hirotsugu Uemura Kindai University Faculty of Medicine, Osaka, Japan More articles by this author Dingwei Ye Fudan University Shanghai Cancer Center, Shanghai, China More articles by this author Robert Given Urology of Virginia, Eastern Virginia Medical School, Norfolk, Virginia More articles by this author Ethan Basch University of North Carolina, Chapel Hill, North Carolina More articles by this author Branko Miladinovic Janssen Research & Development, San Diego, California More articles by this author Angela Lopez-Gitlitz Janssen Research & Development, Los Angeles, California More articles by this author Kim N. Chi BC Cancer, Vancouver, British Columbia, Canada More articles by this author Expand All Advertisement Loading ...

EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with temozolomide-based radiochemotherapy versus temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma.

2004 Background: Patients with newly diagnosed glioblastoma receive postoperative standard therapy with radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Marizomib is a novel, irreversible and brain-penetrant pan-proteasome inhibitor with encouraging findings in preclinical models and early-stage clinical trials for patients with newly diagnosed and recurrent glioblastoma. Therefore, a phase 3 trial was designed to explore the activity of marizomib in addition to TMZ/RT→TMZ. ClinicalTrials.gov Identifier: NCT03345095 Methods: EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase 3 superiority trial. Eligibility criteria included histologically confirmed newly diagnosed glioblastoma and a Karnofsky performance status (KPS) > 70. Eligible patients were stratified for institution, age, KPS as well as extent of surgery, and centrally randomized in a 1:1 ratio. The primary objective of this study is to compare overall survival (OS) in patients receiving marizomib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include progression-free survival (PFS), safety, neurocognitive function, and quality of life. Results: The study was opened at 49 EORTC sites in Europe, 23 CCTG sites in Canada, and 8 sites in the US. Patient enrolment started in June 2018 and was close to completion at the time of a planned interim analysis in September 2020. A total of 749 patients (of the planned 750) were randomized when the IDMC recommended to discontinue enrollment. Age, KPS and extent of resection were well balanced between the 2 study arms. No difference in median OS was observed between the standard arm (15.9 months) and the marizomib arm (15.7 months; HR = 0.99). Median PFS was 6.1 vs. 6.2 months (HR = 1.02). Patients in the marizomib group had more often grade 3/4 treatment-emergent adverse events (TEAE) compared to the standard therapy group (42.6% vs. 20.5%), including ataxia, hallucinations and headache. Conclusions: The addition of marizomib to standard radiochemotherapy did not improve OS or PFS in patients with newly diagnosed glioblastoma. Final survival analyses including determination of MGMT promoter methylation status and analyses of other secondary endpoints are ongoing. Clinical trial information: NCT03345095.

Incidence and risk factors for moderate/severe COVID-19 in rheumatic diseases patients on hydroxychloroquine: a 24-week prospective cohort.

To evaluate the incidence of COVID-19 and its main outcomes in rheumatic disease (RD) patients on hydroxychloroquine (HCQ) compared to household cohabitants (HC). This is a 24-week nationwide prospective multi-centre cohort with a control group without RD and not using HCQ. All participants were monitored through scheduled phone interviews performed by health professionals. Details regarding COVID-19 symptoms, and epidemiological, clinical, and demographic data were recorded on a specific web-based platform. COVID-19 was defined according to the Brazilian Ministry of Health criteria and classified as mild, moderate or severe. A total of 9,585 participants, 5,164 (53.9%) RD patients on HCQ and 4,421 (46.1%) HC were enrolled from March 29th, 2020 to September 30th, 2020, according to the eligibility criteria. COVID-19 confirmed cases were higher in RD patients than in cohabitants [728 (14.1%) vs. 427 (9.7%), p<0.001] in a 24-week follow-up. However, there was no significant difference regarding outcomes related to moderate/ severe COVID-19 (7.1% and 7.3%, respectively, p=0.896). After multiple adjustments, risk factors associated with hospitalisation were age over 65 (HR=4.5; 95%CI 1.35-15.04, p=0.014) and cardiopathy (HR=2.57; 95%CI 1.12-5.91, p=0.026). The final survival analysis demonstrated the probability of dying in 180 days after a COVID-19 diagnosis was significantly higher in patients over 65 years (HR=20.8; 95%CI 4.5-96.1) and with 2 or more comorbidities (HR=10.8; 95%CI 1.1-107.9 and HR=24.8; 95%CI 2.5-249.3, p=0.006, respectively). Although RD patients have had a higher COVID-19 incidence than individuals from the same epidemiological background, the COVID-19 severity was related to traditional risk factors, particularly multiple comorbidities and age, and not to underlying RD and HCQ.

Overall survival (OS) and metastasis-free survival (MFS) by depth of prostate-specific antigen (PSA) decline in the phase III PROSPER trial of men with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with enzalutamide (ENZA).

94 Background: The PROSPER trial demonstrated prolonged MFS and OS for men with nmCRPC and rapidly rising PSA treated with ENZA vs placebo, both in combination with androgen deprivation therapy (ADT). The final survival analysis of PROSPER (Sternberg et al. NEJM 2020) recently reported a median OS of 67.0 months (95% CI, 64.0 to not reached) with ENZA and 56.3 months (95% CI, 54.4 to 63.0) with placebo (hazard ratio [HR] for death, 0.73; 95% CI, 0.61 to 0.89; P = .001). Post hoc analyses of PROSPER evaluating PSA dynamics have demonstrated longer MFS with greater PSA decline (Hussain et al. ESMO Sept 19-21, 2020. Poster 685P) and increased risk of metastases in patients with even modest PSA progression vs those without (Saad et al. Eur Urol 2020). Here we further explored the relationship between PSA dynamics and outcomes in PROSPER using uniquely defined PSA subgroups of decline. Methods: Eligible men in PROSPER had nmCRPC, a PSA level ≥ 2 ng/mL at baseline, and a PSA doubling time ≤ 10 months. Men continued ADT, were randomized 2:1 to ENZA 160 mg once daily vs placebo, and had PSA evaluation at week 17 and every 16 weeks thereafter. This post hoc analysis evaluated OS and MFS for 4 mutually exclusive subgroups defined by PSA nadir using men with PSA reduction &lt; 50% as the reference group. The HR is based on an unstratified Cox proportional hazards analysis model. Results: 1401 men were enrolled in PROSPER; 933 were treated with ENZA and PSA data were available for 905. Measured at nadir, 38% of these men achieved PSA reduction ≥ 90% (actual nadir &lt; 0.2 ng/mL), and another 27% achieved PSA reduction ≥ 90% (actual nadir ≥ 0.2 ng/mL). Among men in the placebo arm of PROSPER only 3/457 reported PSA reduction ≥ 90%. Median OS and MFS increased with increasing depth of PSA decline (Table). Conclusions: In men with nmCRPC and rapidly rising PSA treated with ADT plus ENZA, there was a close relationship between the degree of PSA decline and survival outcomes. Defining PSA by both percent decline and actual decline below 0.2 ng/mL revealed a previously under-appreciated relationship between these PSA metrics and highlights the importance of PSA nadir as an intermediate biomarker in nmCRPC. Clinical trial information: NCT02003924. [Table: see text]

Primary Fibular Sarcomas: Do They Behave Differently? An Institutional Review of 14 Patients.

Surgical resection with wide margins is pivotal for sarcoma treatment but achieving the same for fibular sarcomas is a surgical challenge. Thus, we decided to evaluate our own institutional database of primary fibular sarcomas for surgical treatment, margins and pattern of relapse. From July 2014 to October 2018, we identified fourteen patients with histologically confirmed fibular sarcomas. Limb salvage surgery (LSS) was performed in thirteen patients included in our study. One patient treated with definitive radiotherapy was excluded from final survival and functional analyses. The proximal third fibula was the most common site of involvement (85.7%). Osteosarcoma was the histological diagnosis in eight (57.1%) and Ewing's in the remaining six (42.9%). All patients with proximal fibular tumours underwent Malawer type II resection. Margins were reported as free in twelve and involved in one case. The mean follow-up period was 37.15months. In the operated group (n = 13), distant relapse occurred in 3 patients, combined relapse in 1 patient and 10 patients are alive and disease free until the last follow-up. The Kaplan-Meier survival analyses revealed the EFS (event-free survival-local/distant relapse) probability as 72.7% at 24months and 53% at the end of 42months. The OS (overall survival) probability at 24months was 75.5% and 57.5% at the end of 42months. Although it is difficult to achieve conventional wide margins in fibular sarcomas, our results suggest no increased incidence of local recurrence rates as compared to sarcomas at other common sites as reported in literature. Our series helps in understanding site-specific behaviour of sarcomas while contributing to the available data.

Developmental language disorders and risk of recidivism among young offenders.

Although factors such as adverse family background have been widely examined, little is known about the prevalence or potential impact of developmental language disorder (DLD) on risk of recidivism in young people with history of criminal justice system contact. A total of 145 young offenders participated. An adversity score was constructed based on information found in youth justice service records. Data collected included standardised measures of expressive and receptive language, nonverbal IQ and the inventory of callous-unemotional traits. Survival analysis was performed to examine differences in reoffending risk between young offenders with and without DLD. The cumulative incidence of reoffending within a year of the young person's court order was markedly raised in the DLD group (62%; 95% CI 52, 72) versus the non-DLD group (25%; 95% CI 16, 39). Furthermore, in the final multivariable survival analysis the independent elevation in risk linked with DLD was not greatly attenuated with adjustment for nonverbal IQ, adversity score, age at first offence, number of previous offences and deprivation score. DLD was the most significant predictor with an adjusted hazard ratio of 2.61 (95% CI 1.80, 3.78). Young offenders with DLD are more than twice as likely to reoffend than their unaffected offending peers. DLD is a powerful predictor of recidivism above and beyond other known risk factors.

Final survival analysis of NSGO-AVANOVA2/ENGOT-OV24: Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer—A randomized controlled chemotherapy-free study.

6012 Background: We previously reported significantly improved progression-free survival (PFS) with the chemotherapy-free regimen of niraparib and bevacizumab compared to niraparib alone, in women with platinum-sensitive relapsed ovarian cancer (PSROC), regardless of homologous recombination deficiency (HRD) status (MyChoice HRD), duration of chemotherapy-free interval (CFI) and number of previous lines of therapy (Mirza MR et al, Lancet Oncol 2019). We now present the updated PFS, overall survival (OS) and other efficacy and safety endpoints. Methods: In this randomized, open-label, phase 2 study, women with measurable/evaluable, high-grade serous or endometrioid PSROC were randomized to niraparib 300mg once daily or the combination of niraparib 300mg once daily and bevacizumab 15mg/kg IV every 3 weeks until disease progression (1:1 randomization). The primary endpoint was PFS. Stratification was according to HRD status and CFI (6-12months (mo) vs. &gt; 12mo). First-line maintenance bevacizumab was permitted. Results: Of 97 enrolled patients, 48 were randomized to niraparib monotherapy and 49 to the chemotherapy-free combination. The combined treatment significantly improved PFS compared to niraparib alone: updated median PFS 12.5 mo vs. 5.5 mo; hazard ratio (HR) adjusted for stratification factors 0.34; 95% confidence interval (CI) [0.21 to 0.55]; P &lt; 0.0001. Preplanned exploratory subgroup analyses: patients with HRD-positive tumors (n = 54) HR 0.41 (CI, 0.23-0.76); HRD-negative disease (n = 43) HR, 0.40 (CI, 0.20-0.79); Time to First Subsequent Therapy (TFST) (n=97) HR, 0.4 (CI, 0.25-0.64); PFS2 (n=97) HR 0.55 (CI, 0.35-0.88); Time to Second Subsequent Therapy (TSST) (n=97) HR, 0.56 (CI, 0.35-0.90); OS (49 events only) HR, 0.77 (CI, 0.42-1.41). There was no difference in treatment-emergent grade 3-4 adverse events except for the rate of hypertension (22.9% vs. 0%) and neutropenia (8.3% vs. 2.0%). Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms. Conclusions: Updated PFS consistently demonstrates that the niraparib-bevacizumab combination had clinically and statistically meaningful activity in PSROC. This phase 2 study was not powered to detect differences in OS or any other efficacy endpoints however TFST, PFS2 &amp; TSST are significantly improved while there is a trend towards OS improvement with niraparib-bevacizumab combination. Clinical trial information: NCT02354131.

Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial

Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma. In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636. Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1-17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5-8·3) in group A and 6·3 months (6·2-7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70-0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9-18·9) in group A and 13·4 months (12·0-15·2) in group C (0·83, 0·69-1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1-17·8) for group B and 13·1 months (11·7-15·1) for group C (1·02, 0·83-1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo. Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma. F Hoffmann-La Roche and Genentech.

Preoperative weight loss is associated with poorer prognosis in operable esophageal cancer patients: A single-center retrospective analysis of a large cohort of Chinese patients.

Background: Preoperative weight loss has been shown to be a prognostic factor for many cancers. However, whether preoperative weight loss has clinical significance in patients with esophageal cancer is still controversial.Methods: A total of 2,174 Chinese patients underwent radical resection of esophageal cancer from 2000 to 2008 were included in our study. Patients were divided into two group: no weight loss (-) and weight loss (+), according to whether they had weight loss compared with their usual weight at diagnosis. The influence of preoperative weight loss on disease-free survival (DFS) and overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional hazard models.Results: weight loss (+) was significantly associated with age (P=0.001), alcoholism (P<0.001), tumor location (P=0.003), pT category (P=0.003), pN category (P=0.001). Patients of group weight loss (+) had significantly poorer DFS (Mean: 63.3 months (m) vs 76.8 m, P<0.001) and OS (67.4 m vs 83.3 m, P<0.001) than the no weight loss (-) group. In the final multivariate survival analysis with adjustment for covariates, we found that the weight loss (+) group had a 19% higher risk of death (HR=1.19, 95%CI: 1.07-1.33, P=0.002) and had a 13% higher risk of disease progression (HR=1.13, 95%CI: 1.01-1.25, P=0.027), respectively, than the no weight loss (-) group. Subgroup analysis indicated that the association with preoperative weight loss and better DFS or OS was observed in patients with esophageal squamous cell carcinoma (ESCC) and early pathological stage (I-II).Conclusion: Preoperative weight loss is associated with shorter OS and DFS, which means poor postoperative prognosis in esophageal cancer patients.

Abstract 407: Utility of Abnormal Head Computed Tomography in Predicting Outcome in Out of Hospital Cardiac Arrest Victims Resuscitated and Subsequently Placed on Targeted Temperature Management

Introduction: Head computed tomography (HCT) is often performed to assess for hypoxic-ischemic brain injury in resuscitated out of hospital cardiac arrest (OHCA) patients. Our primary objective was to assess whether cerebral edema (CE) on early HCT is associated with poor survival and neurologic outcome post OHCA. Methods: We included subjects from a prospectively collected cardiac arrest database of OHCA adult patients who received targeted temperature management (TTM) at two academic suburban hospitals from 2009-Sept-2018. Cases were included if a HCT was performed in the emergency department (ED). Patient demographics and cardiac arrest variables were collected. HCT results were abstracted by study authors from radiology reports. HCT findings were categorized as no acute disease, evidence of CE, or excluded (bleed, tumor, stroke). Outcomes were survival to discharge or cerebral performance scores (CPC) at discharge of three or four (poor neurologic outcome). Descriptive statistics, univariate, multivariate, survival, and interrater reliability analysis were performed. Results: During the study period, there were 425 OHCA, 277 cases had ED HCTs performed; 254 cases were included in the final survival analysis. Patients were predominately male, 189 (65.0%), average age 60.9 years, average BMI of 30.5. Of all cases, 44 (15.9%) showed CE on CT. Univariate analysis demonstrated that CE was associated with 9.2-fold greater odds of poor outcome (OR: 9.23; 95% CI 1.73, 49.2), and 9.1-fold greater odds of death (OR: 9.09: 95% CI 2.4 33.9). In adjusted analysis, CE was associated with 14.9-fold greater odds of poor CPC outcome (AOR: 14.9, 95% CI, 2.49, 88.4), and 13.7-fold greater odds of death (AOR: 13.7, 95% CI, 3.26, 57.4). Adjusted survival analysis demonstrated that patients with CE on HCT had 3.6-fold greater hazard of death than those without CE (HR: 3.56: 95% CI 2.34, 5.41). Interrater reliability demonstrated excellent agreement between reviewers for CE on HCT (κ = 0.86). Conclusion: The results identify that abnormal HCTs early in the post-arrest period in OHCA patients are associated with poor rates of survival and neurologic outcome. Prospective work is needed to confirm whether selection bias or other variables confound this association.

Post-Transplant Radiation Had No Impact on Survival in Patients with Refractory or Relapsed Diffuse Large B-Cell Lymphoma

IntroductionHigh-dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) offers cure for appropriate patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) sensitive to chemotherapy. Post-AHCT consolidative radiation therapy (RT) has been associated with improved outcomes in R/R DLBCL patients with bulky [based on computed tomography (CT)] disease after AHCT. We and others have demonstrated that patients with a Deauville score 4-5 (high-risk) on pre-AHCT FDG positron emission tomography (PET) have significantly worse outcomes as compared to those with Deauville 1-3 (low risk). We here examined the impact of consolidative post-AHCT RT in R/R-DLBCL patients with high-risk functional imaging based on Deauville score) on pre-transplant FDG PET scan on AHCT outcomes. Therefore, we retrospectively studied the effect of post-ASCT RT within 6 months after ASCT on survival in patients with R/R-DLBCL with high-risk pre-ASCT PET scans.MethodsWe retrospectively studied 193 consecutive adult patients with R/R-DLBCL identified from the Cleveland Clinic and University of Minnesota who had available pre-transplant FDG PET scans and adequate clinical follow-up. PET scans were re-reviewed and scored Deauville 4-5 were considered high risk. Patients that died within 6 months of ASCT (n=20) were excluded from the final survival analyses. Univariate analysis was performed using the Kaplan-Meier method, and the log-rank test was used to compare the subgroups.ResultsThe mean (SD) age of diagnosis was 54 (11) years and 61% patients were male. The mean follow-up for alive patients was 43 (32.6) months. We identified 69 patients with pre-transplant Deauville scores 4 (n=41) or 5 (n=28). Seventeen (25%) received RT at median 58 days post AHCT (IQR 39-79 days). Receiving post-ASCT RT did not impact overall survival in univariable (Figure 1) or multivariable analyses adjusted for age and gender.ConclusionWithin the limits of the study design, we did not observe a benefit to RT on overall survival in patients with RR-DLBCL with high-risk pre-AHCT PET scans. Alternative treatment approaches for high risk patients based on pre-transplant PET should be investigated in prospective clinical trials. High-dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) offers cure for appropriate patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) sensitive to chemotherapy. Post-AHCT consolidative radiation therapy (RT) has been associated with improved outcomes in R/R DLBCL patients with bulky [based on computed tomography (CT)] disease after AHCT. We and others have demonstrated that patients with a Deauville score 4-5 (high-risk) on pre-AHCT FDG positron emission tomography (PET) have significantly worse outcomes as compared to those with Deauville 1-3 (low risk). We here examined the impact of consolidative post-AHCT RT in R/R-DLBCL patients with high-risk functional imaging based on Deauville score) on pre-transplant FDG PET scan on AHCT outcomes. Therefore, we retrospectively studied the effect of post-ASCT RT within 6 months after ASCT on survival in patients with R/R-DLBCL with high-risk pre-ASCT PET scans. We retrospectively studied 193 consecutive adult patients with R/R-DLBCL identified from the Cleveland Clinic and University of Minnesota who had available pre-transplant FDG PET scans and adequate clinical follow-up. PET scans were re-reviewed and scored Deauville 4-5 were considered high risk. Patients that died within 6 months of ASCT (n=20) were excluded from the final survival analyses. Univariate analysis was performed using the Kaplan-Meier method, and the log-rank test was used to compare the subgroups. The mean (SD) age of diagnosis was 54 (11) years and 61% patients were male. The mean follow-up for alive patients was 43 (32.6) months. We identified 69 patients with pre-transplant Deauville scores 4 (n=41) or 5 (n=28). Seventeen (25%) received RT at median 58 days post AHCT (IQR 39-79 days). Receiving post-ASCT RT did not impact overall survival in univariable (Figure 1) or multivariable analyses adjusted for age and gender. Within the limits of the study design, we did not observe a benefit to RT on overall survival in patients with RR-DLBCL with high-risk pre-AHCT PET scans. Alternative treatment approaches for high risk patients based on pre-transplant PET should be investigated in prospective clinical trials.

NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors

BackgroundLiposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of ≥1 year) in the NAPOLI-1 trial. Patients and methodsPatients with mPDAC were randomised to receive nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 151), or 5-FU/LV (n = 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived ≥1 year. Through 16th November 2015, 382 overall survival events had occurred. ResultsThe overall survival advantage for nal-IRI+5-FU/LV vs 5-FU/LV was maintained from the original nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) analysis (6.2 vs 4.2 months, respectively; HR, 0.75; 95% confidence interval: 0.57–0.99). Median progression-free survival, objective response rate and disease control rate also favoured nal-IRI+5-FU/LV therapy. Estimated one-year overall survival rates were 26% with nal-IRI+5-FU/LV and 16% with 5-FU/LV. Baseline characteristics associated with long-term survival in the nal-IRI+5-FU/LV arm were Karnofsky performance status ≥90, age ≤65 years, lower CA19-9 levels, neutrophil-to-lymphocyte ratio ≤5 and no liver metastases. No new safety concerns were detected. ConclusionsThe survival benefits of nal-IRI+5-FU/LV versus 5-FU/LV were maintained over an extended follow-up, and prognostic markers of survival ≥1 year were identified. Clinical trial registration numberNCT01494506.

Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study

Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases. This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis. Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8-25), intracranial responses were achieved by 16 (46%; 95% CI 29-63) of 35 patients in cohort A, five (20%; 7-41) of 25 in cohort B, and one (6%; 0-30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred. Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases. Melanoma Institute Australia and Bristol-Myers Squibb.

Endocrine Treatment with 2 Years of Tamoxifen versus 2 Years of Exemestane in Postmenopausal Patients with High-Risk Early Breast Cancer and Persisting Circulating Tumor Cells - First Results of the SUCCESS C Endocrine Treatment Sub-Study

Background: Optimal choice and sequence of endocrine treatment following adjuvant chemotherapy in postmenopausal early breast cancer patients are still under discussion and treatment stratification factors are missing. Patients and Methods: Postmenopausal women with HER2-negative, hormone receptor-positive tumors and persisting circulating tumor cells (CTCs; assessed using the FDA-approved CellSearch® System, Janssen Diagnostics, LLC) after chemotherapy were randomized to 2 years of tamoxifen followed by 3 years of exemestane (tamoxifen-exemestane group, n = 54) or 5 years of exemestane (exemestane-only group, n = 54). CTCs were again assessed after the first 2 years of endocrine treatment. In addition, safety data were compared between the 2 groups. Results: The 2 groups were well-balanced with regard to baseline characteristics. The CTC clearance rate after 2 years was 89% in the exemestane-only group and 97% in the tamoxifen-exemestane group (exact Fisher test, p = 0.36). The safety profile showed good tolerability with few grade 3 or 4 adverse events in both groups. Conclusion: The similar CTC clearance rate after 2 years of endocrine therapy with exemestane or tamoxifen, and the safety profiles obtained may indicate comparable efficacy and tolerability of both endocrine treatment regimens. However, these results have to be confirmed by final survival and safety analysis.

1360P - Phase II trial of AZD9291 in second line treatment after acquired resistance with T790M mutation detected from circulating tumor DNA (LiquidLung-O-Cohort 2)

Background: Administering the best treatment after acquiring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) requires the knowledge of the resistance status. In this trial, the treatment efficacy of osimertinib (AZD9291) was assessed in patients with non-small-cell lung carcinoma (NSCLC) harboring T790M resistance mutation, which was detected in the circulating tumor DNA (CtDNA) without re-biopsy of the tumor tissue. Methods: To prove 60% response rate of osimertinib compared to 30% as null hypothesis, and considering 10% drop out rate, 19 subjects was recruited. To extract CtDNA, 15 mL of peripheral blood was withdrawn and centrifuged immediately before storage. Cobas® v2 RUO (Roche diagnostics) and PANA mutyper® (Pangene, Korea) were used to detect the EGFR mutations from CtDNA. Osimertinib was prescribed as an 80mg tablet once in a day irrespective of the food intake. Results: Eighty patients with acquired resistance to prior EGFR TKIs were screened for T790M resistance mutation, and the CtDNA of 21 subjects (26.3%) showed T790M mutation. T790M mutation was detected by both PANA mutyper® and Cobas® in 13 cases, T790M was detected only by PANA mutyper® in 4 cases, and only by Cobas® in 4 cases. Nineteen subjects (age: 64.4 ± 11.6 years old, 14 women, 5 men) were enrolled in this prospective single arm trial from September 2016 to April 2017. Prior EGFR TKIs were afatinib (n = 3), erlotinib (n = 4), gefitinib (n = 10), erlotinib and afatinib (n = 1), and gefitinib and afatinib (n = 1). Twelve subjects had exon 19 deletion of EGFR gene, 4 had L858R point mutation, one showed exon 19 deletion and L858R, 1 had G719X, and 1 case showed no activating mutation. Conclusions: By April 2017, the response to osimertinib was evaluated in 13 subjects; 4 subjects dropped out from this trial before response evaluation, and the responses in 2 subjects are still pending for evaluation. Among the 13 subjects whose responses were evaluated (efficacy analysis set), partial remission was observed in 8 cases (61.5%). In the final efficacy analysis, toxicity and survival analyses will be performed. Clinical trial identification: NCT02769286 Legal entity responsible for the study: Young-Chul Kim Funding: AstraZeneca Disclosure: Y-C. Kim: This study was funded by AstraZeneca. All other authors have declared no conflicts of interest.

Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)

Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. Merck & Co.