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[Introduction] In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up., [Methods] Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1, [Results] After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65–0.90) and PD-L1 less than 1% (0.64; 0.51–0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1, [Conclusions] At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients., This study was supported by Bristol Myers Squibb and Ono Pharmaceutical Company Ltd.

Introduction In CheckMate 227 (NCT02477826), patients with treatment-naive stage IV or recurrent NSCLC and 1% or greater tumor programmed death ligand 1 expression had significantly improved overall survival with nivolumab plus ipilimumab versus chemotherapy. We present the patient-reported outcomes (PROs). Methods Patients (N = 1189) were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy. PROs were exploratory. Changes in Lung Cancer Symptom Scale (LCSS) average symptom burden index, LCSS 3-item global index, EQ-5D visual analog scale (VAS), and EQ-5D utility index were analyzed descriptively. Mixed-effect model repeated measures and time-to-first deterioration and improvement analyses were conducted. Results PRO completion rates were generally greater than 80%. On-treatment improvements from baseline in LCSS measures of symptom burden and global health status with nivolumab plus ipilimumab generally met or exceeded the minimal important difference (smallest clinically meaningful change) from weeks 24 and 30, respectively; improvements with chemotherapy generally remained below the minimal important difference. Mean on-treatment EQ-5D VAS scores for both treatments approached the U.K. population norm at week 24, remaining so throughout the treatment period. Mixed-effect model repeated measures analyses revealed numerically greater improvements from baseline with nivolumab plus ipilimumab versus chemotherapy across LCSS average symptom burden index and 3-item global index, and EQ-5D VAS and utility index. Nivolumab plus ipilimumab had delayed time-to-first deterioration (hazard ratio [95% confidence interval] 0.74 [0.56 to 0.98]) and a trend for more rapid time-to-first improvement (1.24 [0.98 to 1.59]) versus chemotherapy. Conclusions Nivolumab plus ipilimumab revealed delayed deterioration and numerical improvement in symptoms and health-related quality of life versus chemotherapy in patients with advanced NSCLC and 1% or greater programmed death ligand 1 expression.

Nivolumab plus ipilimumab demonstrated clinically meaningful improvement in efficacy versus chemotherapy with a manageable safety profile in patients with advanced non-small cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% or1% in Part 1 of CheckMate 227. Here we report efficacy and safety results for the Asian subpopulation.Patients with stage IV/recurrent NSCLC were randomized 1 : 1 : 1 to nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy (PD-L1 ≥1%) or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L11%). Overall survival (OS), progression-free survival, objective response rate, duration of response, and safety were evaluated among patients in Japan, South Korea, and Taiwan.In the Asian subpopulation with PD-L1 ≥1%, 81 patients received nivolumab plus ipilimumab and 81 received chemotherapy. Median OS was not reached with nivolumab plus ipilimumab versus 24.8 months with chemotherapy; 3-year OS rate was 53% versus 37% [hazard ratio (HR), 0.72; 95% confidence interval (CI) 0.47-1.11]. The 3-year progression-free survival rate was 26% versus 7% (HR, 0.65; 95% CI 0.45-0.96), objective response rate was 56% versus 37%, and median duration of response was 29.0 months (95% CI 15.0 months-not reached) versus 6.9 months (95% CI 3.9-11.1 months). Similar results were observed regardless of tumor PD-L1 expression and in Japanese patients. Grade 3-4 treatment-related adverse events occurred in 40% of patients receiving nivolumab plus ipilimumab and 36% receiving chemotherapy, in the overall Asian subpopulation (tumor PD-L1 expression ≥1% and1%); no new safety signals were identified.At 3-year follow-up, nivolumab plus ipilimumab provided durable long-term efficacy benefits versus chemotherapy regardless of tumor PD-L1 expression in the Asian subpopulation, including Japanese patients. Consistent with findings for all randomized patients, these data support the use of nivolumab plus ipilimumab as first-line treatment of Asian patients with advanced NSCLC.

BACKGROUND: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase). METHODS: We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay. RESULTS: Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P

Background Immunotherapy with or without chemo has improved survival vs chemo in 1L aNSCLC. NIVO + chemo showed encouraging activity in a phase 1 study in this setting. CheckMate 227 is a multi-part, randomized, open-label, phase 3 study evaluating NIVO-based regimens vs chemo. We present final results from Part 2, which evaluated NIVO + chemo vs chemo in 1L aNSCLC. Methods Pts (N = 755) with chemo-naive, stage IV or recurrent NSCLC, ECOG PS 0–1, and no sensitizing EGFR/ALK alterations were randomized 1:1 to receive every 3 weeks NIVO 360 mg + chemo or chemo. Pts were stratified by histology (squamous [SQ] vs non-squamous [NSQ]), sex, and PD-L1 expression ( Results Baseline characteristics were generally balanced. Minimum follow-up was 19.5 mo. In pts with NSQ NSCLC, no statistically significant improvement in OS was seen with NIVO + chemo vs chemo (HR, 0.86 [95.62% CI, 0.69–1.08; P=0.1859]); median OS was 18.8 mo vs 15.6 mo; 12-mo OS rates were 67.3% vs 59.2%. HR for OS was 0.81 (95% CI, 0.67–0.97) in all randomized pts; 0.69 (95% CI, 0.50–0.97) in pts with SQ NSCLC. Progression-free survival and objective response rates favored NIVO + chemo in NSQ, SQ, and all randomized pts (table). Grade 3–4 tx-related adverse events occurred in 45% and 35% of all pts treated with NIVO + chemo and chemo, respectively.TableLBA3 Efficacy outcomes with 1L NIVO + chemo vs chemo in pts with NSQ NSCLC, SQ NSCLC, and in all randomized ptsTableNSQ NSCLCSQ NSCLCAll Randomized PtsNIVO + chemoChemoNIVO + chemoChemoNIVO + chemoChemon=270n = 273n=107n = 105n=377n = 378OSEvents, n (%)156 (57.8)164 (60.1)68 (63.6)75 (71.4)224 (59.4)239 (63.2)Median, mo18.815.618.312.018.314.7HR (95% CI)0.86 (0.69–1.08)aP = 0.18590.69 (0.50–0.97)0.81 (0.67–0.97)12-mo OS rate, %67.359.266.148.566.956.2PFSEvents, n (%)187 (69.3)200 (73.3)79 (73.8)82 (78.1)266 (70.6)282 (74.6)Median, mo8.75.87.14.48.45.5HR (95% CI)0.67 (0.55–0.82)0.51 (0.37–0.70)0.62 (0.52–0.73)12-mo PFS rate, %39.525.731.79.337.321.3Objective response rate, n (%)130 (48.1)80 (29.3)64 (59.8)34 (32.4)194 (51.5)114 (30.2)a95.62% CI Conclusion CheckMate 227 Part 2 did not meet the primary endpoint of OS for NIVO + chemo vs chemo in NSQ NSCLC. Descriptive analyses showed longer OS with NIVO + chemo in all randomized pts and SQ NSCLC. No new safety signals were observed. Clinical trial identification NCT02477826; Release date: June 23, 2015. Editorial acknowledgement Writing and editorial assistance was provided by Namiko Abe, PhD, of Caudex, funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure L. Paz-Ares: Honoraria (self): Roche, MSD, Lilly, Novartis, Boehringer Ingelheim, AstraZeneca, Amgen, Sanofi, Pharmamar, Pfizer, Bristol-Myers Squibb, Merck, Takeda, Celgene, Servier, Sysmex, Incyte, Ipsen, Adacap, Bayer, Blueprint; Leadership role: Altum Sequencing; Research grant / Funding (institution): MSD, AstraZeneca, Pfizer, Bristol-Myers Squibb; Officer / Board of Directors: Genomica. T.E. Ciuleanu: Advisory / Consultancy: Astellas, Janssen, Bristol-Myers Squibb, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Lilly, AstraZeneca, MSD, Sanofi, Novartis, Servier, AD Pharma. A. Pluzanski: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche; Speaker Bureau / Expert testimony: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche, Takeda; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche. A. Nagrial: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; Research grant / Funding (institution): Astra Zeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche. R. Kowalyszyn: Advisory / Consultancy: Astellas, Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, MSD, Novartis; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Lilly, MSD, Pfizer, Roche. C. Audigier-Valette: Honoraria (self): AbbVie, Pfizer; Honoraria (institution): Roche, MSD, Bristol-Myers Squibb, AstraZeneca; Advisory / Consultancy: Roche, MSD, Bristol-Myers Squibb, AstraZeneca, AbbVie, Pfizer. Y-L. Wu: Honoraria (self): AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, BMS, Roche; Non-remunerated activity/ies: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche. H. Borghaei: Honoraria (self): University of Pennsylvania, CAR T Program, Takeda [Data and Safety Monitoring Board]; Advisory / Consultancy: Bristol-Myers Squibb, Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bio, GLG; Research grant / Funding (self): Millennium, Merck/Celgene, Bristol-Myers Squibb/Lilly. M.D. Hellmann: Advisory / Consultancy: Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, Syndax, Shattuck Labs, Immunai, Nektar, Blueprint Medicines; Research grant / Funding (institution): Bristol-Myers Squibb; Travel / Accommodation / Expenses: Bristol-Myers Squibb, AstraZeneca; Shareholder / Stockholder / Stock options: Shattuck Labs, Immunai. J. Brahmer: Advisory / Consultancy: Bristol-Myers Squibb, AstraZeneca, Genentech, Merck, Amgen. M. Reck: Honoraria (self): AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Advisory / Consultancy: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. S. Ramalingam: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Roche/Genentech, Loxo, Tesaro, Merck, Daichi; Advisory / Consultancy: Amgen, AbbVie, Lilly, Genentech, Takeda; Research grant / Funding (institution): Bristol-Myers Squibb, Amgen, AstraZeneca, Takeda, Advaxis, Tesaro, Merck. L. Zhang: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: AstraZeneca, Bristol-Myers Squibb, MSD, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Pfizer, Henrui Pharm. P. Bhagavatheeswaran: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F.E. Nathan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. K.J. O'Byrne: Advisory / Consultancy: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim, Novartis, Teva, Janssen-Cilag, Natera; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim, Janssen-Cilag, Mundipharma; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim; Shareholder / Stockholder / Stock options: Carp Pharmaceuticals, Carpe Vitae Phaemaceuticals; Licensing / Royalties: Various patents issues with licensee as listed. Queensland University of Technology and Trinity College Dublin. All other authors have declared no conflicts of interest.

Background: In the phase I I I CheckMate 227 s tudy, fi r s t - l ine nivolumab þ ipilimumab significantly prolonged progression-free survival (co-primary endpoint) versus chemotherapy in patients with advanced nonesmall-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; 10 mutations/megabase). Aim: To evaluate patient-reported outcomes (PROs) in this population. Methods: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ- 5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. Results: In the high TMB population, PRO questionnaire completion rates were w90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab þ ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab þ ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab þ ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4e22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab þ ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. Conclusion: First-line nivolumab þ ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB, This work was supported by Bristol-Myers Squibb and Ono Pharmaceutical

9500 Background: In the phase 3 CheckMate 227 Part 1 (NCT02477826; minimum follow-up, 29.3 mo), 1L NIVO + IPI significantly improved overall survival (OS) vs chemo in treatment-naive patients (pts) with aNSCLC and tumor PD-L1 expression ≥ 1% (primary analysis) or < 1% (pre-specified descriptive analysis). Here we report data with 3-y minimum follow-up. Methods: Pts with stage IV / recurrent NSCLC and PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO (240 mg Q2W) alone, or chemo. Pts with PD-L1 < 1% (n = 550) were randomized to NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. Primary endpoint was OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1%. An exploratory analysis of OS in pts by response status (CR/PR, SD, progressive disease [PD]) at 6 mo was conducted. Results: After a median follow-up of 43.1 mo (database lock, 28 Feb 2020), pts with PD-L1 ≥ 1% continued to derive OS benefit from NIVO + IPI vs chemo (HR: 0.79; 95% CI, 0.67–0.93); 3-y OS rates were 33% (NIVO + IPI), 29% (NIVO), and 22% (chemo). At 3 y, 18% of pts with PD-L1 ≥ 1% treated with NIVO + IPI remained progression-free vs 12% with NIVO and 4% with chemo; 38% of confirmed responders remained in response in the NIVO + IPI arm at 3 y vs 32% in the NIVO arm and 4% in the chemo arm. In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 3-y OS rates were 34% (NIVO + IPI), 20% (NIVO + chemo), and 15% (chemo); 13%, 8%, and 2% of pts remained progression-free; and 34%, 15%, and 0% of confirmed responders remained in response, respectively. Pts with PD-L1 ≥ 1% with either CR/PR at 6 mo had longer subsequent OS with NIVO + IPI vs chemo; pts with SD or PD at 6 mo had generally similar subsequent OS between treatments (Table); results in PD-L1 < 1% pts will be presented. Any-grade / grade 3–4 treatment-related AEs were observed in 77% / 33% of all pts treated with NIVO + IPI, and 82% / 36% with chemo. Conclusions: With 3 y minimum follow-up, NIVO + IPI continued to provide durable and long-term OS benefits vs chemo for pts in 1L aNSCLC. Pts with PD-L1 ≥ 1% who achieved CR/PR at 6 mo had marked OS benefit with NIVO + IPI vs chemo. No new safety signals were identified for NIVO + IPI. Clinical trial information: NCT02477826. [Table: see text]

Background Part 1 of CheckMate 227 (NCT02477826), a phase III study in 1L NSCLC, has dual primary endpoints. The primary endpoint of progression-free survival (PFS) with NIVO + IPI vs chemo in patients (pts) with tumor mutational burden ≥ 10 mut/Mb was met, as reported previously. Here we present the primary endpoint of overall survival (OS) for NIVO + IPI vs chemo in pts with tumor PD-L1 expression ≥ 1%. Methods Pts were chemo-naive, with stage IV or recurrent NSCLC without EGFR or known ALK alterations, ECOG PS 0–1. Pts with PD-L1 ≥1% (n=1189) were randomized 1:1:1 to NIVO 3mg/kg Q2W + IPI 1mg/kg Q6W, NIVO 240mg Q2W, or histology-based chemo; pts with PD-L1 Results Baseline characteristics were balanced across tx arms. Minimum follow-up for the primary endpoint was 29.3mo. For pts with PD-L1 ≥ 1%, OS was significantly longer with NIVO + IPI vs chemo (HR 0.79, 97.72% CI: 0.65–0.96; P=0.007); PFS, objective response rates, and duration of response favored NIVO + IPI vs chemo. OS benefit was also observed in pts with PD-L1 Conclusions CheckMate 227 met its primary endpoint of significantly improved OS with NIVO + IPI vs chemo in 1L advanced NSCLC with PD-L1 ≥ 1%. OS was also improved with NIVO + IPI in PD-L1 Clinical trial identification NCT02477826; Release date: June 23, 2015. Editorial acknowledgement Writing and editorial assistance was provided by Namiko Abe, PhD, of Caudex, funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure S. Peters: Advisory / Consultancy, Research grant / Funding (institution): AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, M. S.S. Ramalingam: Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Personal fees, advisory board: Amgen; Honoraria (self), Advisory / Consultancy, Personal fees, advisory board: AbbVie; Honoraria (self), Advisory / Consultancy, Personal fees, advisory board: Lilly; Honoraria (self), Advisory / Consultancy, Personal fees, advisory board: Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Personal fees, advisory board: Takeda; Honoraria (self), Personal fees: Loxo; Research grant / Funding (institution): Advaxis; Honoraria (self), Research grant / Funding (institution), Personal fees: Tesaro; Honoraria (self), Research grant / Funding (institution), Personal fees: Merck; Honoraria (self), Research grant / Funding (self), Personal fees: AstraZeneca. L. Paz-Ares: Advisory / Consultancy, Advisory board: Genomica; Honoraria (self), Personal fees: Lilly, MSD, Roche, Pharmamar, Merck, AstraZeneca, Novartis, Boehringer Ingelheim, Celgene, Servier, Sysmex, Amgen, Incyte, Pfizer, Ipsen, Adacap, Sanofi, Bayer, Blueprint, Bristol-Myers Squibb; Advisory / Consultancy, Scientific advice/speaker: Lilly, MSD, Roche, Pharmamar, Merck, AstraZeneca, Novartis, Boehringer Ingelheim, Celgene, Servier, Sysmex, Amgen, Incyte, Pfizer, Ipsen, Adacap, Sanofi, Bayer, Blueprint, Bristol-Myers Squibb; Officer / Board of Directors, Co-founder and board member: Altum Sequencing; Research grant / Funding (institution), Grant: MSD, AstraZeneca, Pfizer, Bristol-Myers Squibb. H. Sakai: Research grant / Funding (institution), Grant: Ono Pharmaceutical Company, Bristol-Myers Squibb Company, AstraZeneca, Chugai Pharmaceutical Company, Merck & Co, Merck KGaA; Honoraria (self), Personal fees: Ono Pharmaceutical Company, Bristol-Myers Squibb Company, AstraZeneca, Chugai Pharmaceutical Company, Merck & Co, Merck KGaA. A. Vergnenegre: Honoraria (self), Advisory / Consultancy, Personal fees, travels for medical conferences and fees for consulting: Bristol-Myers Squibb, MSD, AstraZeneca. M. Reck: Honoraria (self), Advisory / Consultancy, Honoraria for lectures and consultancy: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. H. Borghaei: Research grant / Funding (institution): Millennium, Merck/Celgene, Bristol-Myers Squibb/Lilly; Advisory / Consultancy: BMS, Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bio, Diiachi; Advisory / Consultancy, Data Safety and Monitoring Board: University of Pennsylvania, CAR T Program; Takeda; Full / Part-time employment: Fox Chase Cancer Center. J.R. Brahmer: Advisory / Consultancy, Research grant / Funding (institution), Grant, advisory board: Bristol-Myers Squibb; Advisory / Consultancy, Advisory board: AstraZeneca, Genentech, Merck. K.J. O'Byrne: Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory board and speaker bureau fees and travel grants to national and international meetings: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim; Advisory / Consultancy, Advisory board: Novartis, Teva, Natera; Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory board and speaker bureau fees: Janssen-Cilag; Speaker Bureau / Expert testimony, Speaker bureau: Mundipharma; Shareholder / Stockholder / Stock options, Shareholder: Carp Pharmaceuticals, Carpe Vitae Pharmaceuticals; Licensing / Royalties, Various patents issues with licensee as listed: Queensland University of Technology and Trinity College Dublin. W.J. Geese: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. P. Bhagavatheeswaran: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F.E. Nathan: Full / Part-time employment: Bristol-Myers Squibb. M.D. Hellmann: Advisory / Consultancy, Fees for consulting: Genentech, Merck, Novartis, Janssen, Mirati, Syndax, Nektar, Blueprint Medicines; Advisory / Consultancy, Research grant / Funding (institution), Research grant to institution, fees for consulting and travel (grant, personal fees, non-financial support): Bristol-Myers Squibb; Advisory / Consultancy, Fees for consulting and travel: AstraZeneca; Advisory / Consultancy, Fees for consulting and equity: Shattuck Labs, Immunai; Licensing / Royalties, Patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy: PGDx. All other authors have declared no conflicts of interest.

Introduction CheckMate 227 ( NCT02477826 ), etude de phase III, evalue le nivo seul ou en association a l’ipi ou a la chimio en 1L du CBNPC avance. Nous presentons les resultats de la Partie 1, notamment le co-critere principal predefini evaluant la survie sans progression (SSP) du traitement par nivo + ipi vs chimio chez des patients (Pts) avec TMB ≥ 10 mut/Mb. Methodes Les Pts (n = 1739) atteints de CBNPC stade IV, naifs de chimio et sans mutation connue EGFR/ALK, etaient randomises 1 :1 :1 dans le groupe nivo (3 mg/kg/2 sem) + ipi (1 mg/kg/6 sem), dans le groupe nivo seul (240 mg/2 sem) ou dans le groupe chimio pour les Pts PD-L1 ≥ 1 % et dans le groupe nivo + ipi, nivo (360 mg/3 sem) + chimio ou chimio seule pour les Pts PD-L1 Resultats La duree minimale de suivi etait de 11,2 mois. La SSP etait significativement amelioree avec nivo + ipi vs chimio chez les Pts TMB ≥ 10 mut/Mb (HR = 0,58 [IC 97,5 % : 0,41 ; 0,81] ; p = 0,0002). Les resultats selon le statut PD-L1 et l’histologie de la tumeur etaient comparables dans ces sous-groupes. La frequence des evenements indesirables lies au traitement (EILT) ayant entraine l’arret etait de 17 % dans le bras nivo + ipi et 9 % dans le bras chimio. Des EILT de grades 3–4 ont ete rapportes chez 31 % et 36 % des Pts sous nivo + ipi et sous chimio, respectivement. Les EILT potentiellement d’origine immunologique (EIILT) et de grades 3–4 avec nivo + ipi incluaient des atteintes hepatiques (8 %), endocriniennes (4 %) et cutanees (4 %) et etaient coherents avec les rapports precedents. Le delai median de survenue des EIILT etait compris entre 2 et 15 sem et la majorite des evenements ont ete resolus (delai median de resolution ≤ 10 sem). Les resultats de qualite de vie sont en faveur de nivo + ipi vs chimio. Conclusion Le traitement de 1L par nivo + ipi a significativement prolonge la SSP des Pts atteints de CBNPC presentant un TMB ≥ 10mut/Mb, independamment de l’expression de PD-L1. Ces resultats valident l’importance du TMB comme biomarqueur pour l’utilisation de nivo + ipi dans le CBNPC en 1L. Les evenements indesirables de l’association nivo + ipi etaient gerables.

Purpose As part of the ENTHUSE (Endothelin A Use) program, the efficacy and safety of zibotentan (ZD4054), an oral specific endothelin A receptor antagonist, has been investigated in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (CRPC). Patients and Methods In this randomized, double-blind, placebo-controlled, phase III study, patients received intravenous docetaxel 75 mg/m2 on day 1 of 21-day cycles plus oral zibotentan 10 mg or placebo once daily. The primary end point was overall survival (OS). Secondary end points included time to pain and prostate-specific antigen (PSA) progression, pain and PSA response, progression-free survival, health-related quality of life, and safety. Results A total of 1,052 patients received study treatment (docetaxel-zibotentan, n = 524; docetaxel-placebo, n = 528). At the time of data cutoff, there had been 277 and 280 deaths, respectively. There was no difference in OS for patients receiving docetaxel-zibotentan compared with those receiving docetaxel-placebo (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P = .963). No significant differences were observed on secondary end points, including time to pain progression (median 9.3 v 10.0 months, respectively) or pain response (odds ratio, 0.84; 95% CI, 0.61 to 1.16; P = .283). The median time to death was 20.0 and 19.2 months for the zibotentan and placebo groups, respectively. The most commonly reported adverse events in zibotentan-treated patients were peripheral edema (52.7%), diarrhea (35.4%), alopecia (33.9%), and nausea (33.3%). Conclusion Docetaxel plus zibotentan 10 mg/d did not result in a significant improvement in OS compared with docetaxel plus placebo in patients with metastatic CRPC.

BACKGROUND. This two-part study assessed the safety and tolerability of combined treatment with zibotentan (ZD4054), a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration-resistant prostate cancer. METHODS. Part A was an open-label, dose-finding phase to determine the safety and toxicity profile of zibotentan in combination with docetaxel. Patients received once-daily oral zibotentan 10 mg (initial cohort) or 15 mg in combination with docetaxel 75 mg/m(2) (administered on day 1 of each 21-day cycle) for up to 10 cycles. Part B was a double-blind phase which evaluated the safety and preliminary activity of zibotentan plus docetaxel. Patients were randomized 2:1 to receive zibotentan (at the highest tolerated dose identified in part A) plus docetaxel or placebo plus docetaxel. RESULTS. Six patients were enrolled in part A (n = 3, zibotentan 10 mg; n = 3, zibotentan 15 mg). No dose-limiting toxicity was observed, thus zibotentan 15 mg in combination with docetaxel was evaluated in part B (n = 20, zibotentan plus docetaxel; n = 11, placebo plus docetaxel). CTCAE grade >= 3, most commonly neutropenia or leucopenia, were reported in 10 (50%) and nine (82%) patients in the zibotentan and placebo groups, respectively. One (17%) patient receiving placebo achieved complete response, two (22%) patients receiving zibotentan achieved partial response and stable disease occurred in six (67%) and three (50%) patients receiving zibotentan and placebo, respectively. CONCLUSIONS. The tolerability of zibotentan plus docetaxel was consistent with the known profiles of each drug. Sufficient preliminary activity was seen with this combination to merit continued development. Prostate 71: 1264-1275, 2011. (C) 2011 Wiley-Liss, Inc.

Background: Nivo + ipi showed promising clinical activity and tolerability as 1L tx for advanced NSCLC in a phase 1 study. Tumor mutation burden (TMB) has emerged as an important biomarker for benefit of immune checkpoint blockade in lung cancer. CheckMate 227 (NCT02477826) is a large, open-label, phase 3 study of 1L nivo + ipi, nivo, or nivo + PT-DC vs PT-DC in advanced NSCLC. A preplanned co-primary endpoint was based on TMB to evaluate progression-free survival (PFS) of nivo + ipi vs PT-DC. This is the first phase 3 study to evaluate TMB as a predictive biomarker for immunotherapy as a co-primary endpoint. We report initial results from Part 1 of the study. Methods: Patients (pts; N=1739) with chemotherapy-naive, histologically confirmed stage IV or recurrent NSCLC, ECOG PS 0−1, and no known sensitizing EGFR/ALK mutations were enrolled in 2 groups: PD-L1 ≥1% or PD-L1 Results: Baseline characteristics were similar in pts with evaluable TMB and all randomized pts and were balanced between nivo + ipi and PT-DC arms. Minimum follow-up was 11.5 mo. PFS was significantly longer with nivo + ipi vs PT-DC in pts with TMB ≥10 mut/Mb (HR=0.58 [97.5% CI: 0.41, 0.81]; P=0.0002); results were broadly consistent across subgroups, including PD-L1 and histology. The HR for PFS was 1.07 (95% CI: 0.84, 1.35) in pts with TMB Conclusions: CheckMate 227 met its co-primary endpoint of significantly prolonged PFS with 1L nivo + ipi vs PT-DC in NSCLC with TMB ≥10 mut/Mb regardless of PD-L1 expression. Safety was consistent with previous reports of 1L nivo + ipi for this dose regimen. These results validate the benefit of dual immune checkpoint blockade and the role of TMB as a biomarker to select pts in 1L NSCLC. Citation Format: Matthew D. Hellmann, Tudor Eliade Ciuleanu, Adam Pluzanski, Jong Seok Lee, Gregory Otterson, Clarisse Audigier-Valette, Elisa Minenza, Helena Linardou, Sjaak Burgers, Pamela Salman, Hossein Borghaei, Suresh S. Ramalingam, Julie Brahmer, Martin Reck, Kenneth J. O'Byrne, William J. Geese, George Green, Han Chang, Joseph D. Szustakowski, Prabhu Bhagavatheeswaran, Diane Healey, Yali Fu, Faith Nathan, Luis Paz-Ares. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT077.

9020Background: CheckMate 227 (NCT02477826) is a large phase 3 study of 1L nivo + ipi, nivo, or nivo + chemo vs chemo in advanced NSCLC. The study met its co-primary endpoint demonstrating signific...

9001Background: CheckMate 227 (NCT02477826), a phase 3 study of 1L nivo + ipilimumab (ipi), nivo, or nivo + chemo vs chemo in advanced NSCLC, met its co-primary endpoint of prolonged progression-fr...

BACKGROUND In early trials of paclitaxel administered as a 24-hour infusion, an overall response rate of 16% was reported for patients with metastatic melanoma. Paclitaxel is a natural product-based agent and is thus subject to the problem of multidrug resistance (MDR). Tamoxifen is an agent that can abrogate MDR and potentially enhance the effect of paclitaxel. A Phase II trial of the combination was undertaken with previously treated patients. METHODS Patients with metastatic cutaneous or mucosal melanoma who were previously treated with the Dartmouth chemotherapy regimen (dacarbazine, carmustine, cisplatin, and tamoxifen) were evaluated. Paclitaxel was administered at a dose of 225 mg/m2 intravenously over 3 hours every 3 weeks. All patients also took tamoxifen 40 mg orally daily. Treatment continued until disease progression. RESULTS Twenty-one patients completed at least two cycles of paclitaxel and were evaluable for response. Five responses were observed, 1 complete response, and 4 partial responses, for an overall response rate of 24%. The combination was well tolerated. The most common nonhematologic side effects were myalgia and paresthesia. Hematologic toxicity was mild. No patients developed neutropenic fever. CONCLUSIONS This is the first report of a Phase II trial evaluating paclitaxel as a 3-hour infusion in melanoma patients. The 3-hour infusion is well tolerated and results in little myelosuppression and minimal neurotoxicity. The contribution of tamoxifen is difficult to evaluate because plasma levels were not measured. It is possible that a higher response rate might be observed with larger doses of tamoxifen. Further investigation of paclitaxel in the treatment of patients with metastatic melanoma is warranted. Cancer 2000;88:79–87. © 2000 American Cancer Society.

The patient with surgically incurable melanoma presents a difficult problem for the medical oncologist. Single chemotherapeutic agents at conventional doses produce bona fide but infrequent remissions. The most active single agent for the treatment of metastatic melanoma is dacarbazine (DTIC). Until recently, combinations of drugs yielded no real improvement over treatment with the individual components. The combination of DTIC + carmustine (BCNU) + cisplatin + tamoxifen (the "Dartmouth regimen") appears to be more effective than DTIC alone, but prospective randomized trials comparing the two are still in progress. The contribution of tamoxifen to the observed results continues to be evaluated. Biological agents, such as interferon and interleukin-2, have lower overall response rates compared to chemotherapy regimens, but response duration appears to be longer. Chemotherapy combined with biotherapy offers the promise of higher response rates and long-term durable remissions. The results from high-dose regimens that use autologous bone marrow or peripheral stem cell support have not been sufficient to justify the added toxicity. Although advanced melanoma often is not curable with systemic therapy, the considered use of currently available regimens can induce clinically significant remissions and, possibly, prolong life in some patients.

PURPOSE To evaluate the antitumor activity of 96-hour paclitaxel and daily oral estramustine phosphate (EMP) in patients with metastatic hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS Thirty-four patients with adenocarcinoma of the prostate that progressed after one or more hormonal therapies and a trial of antiandrogen withdrawal were enrolled onto this phase II trial. Patients received paclitaxel 120 mg/m2 by 96-hour intravenous (i.v.) infusion on days 1 through 4 of each 21-day cycle, together with daily oral EMP 600 mg/m2/d, continuously. RESULTS Four of nine patients with measurable disease had objective responses (one complete response [CR] and three partial responses [PRs]) in liver (two patients) or nodes (two patients) of 2, 6, 8, and 20 months' duration. Of 25 assessable patients with metastases limited to bone, 14 had a > or = 50% decline in pretreatment prostate-specific antigen (PSA) level sustained for at least 6 weeks and seven had a > or = 80% decline. Overall, 17 of 32 patients (53.1%) with elevated pretreatment PSA levels had a > or = 50% decline of PSA and nine (28.1%) had a > or = 80% decrease. The main toxicities (> or = grade 2) were nausea, fluid retention, and fatigue, which occurred in 33%, 33%, and 24.2% of patients. Median time to progression, based on increasing PSA level and other clinical criteria, was 22.5 weeks. The estimated median overall survival time is 69 weeks. CONCLUSION The combination of EMP and 96-hour paclitaxel is an active regimen for patients with HRPC. These results further support the therapeutic strategy of combining agents that impair microtubule function by complementary mechanisms.

Standard treatment options are limited for the management of non-metastatic castration-resistant prostate cancer (CRPC). This study, part of the ENTHUSE (EndoTHelin A USE) phase III programme, evaluated the efficacy and safety of the oral specific endothelin (ET)A receptor antagonist zibotentan vs placebo in patients with non-metastatic CRPC (non-mCRPC). This was a multicentre, randomized, double-blind, phase III study. Patients (n=1421) with non-mCRPC and biochemical progression (determined by rising serum PSA levels) were randomized to receive zibotentan 10 mg or placebo once daily. Based on the lack of efficacy signal in another ENTHUSE phase III study, an interim analysis was performed to determine whether the study was likely to achieve the co-primary objectives of improved overall survival (OS) and progression-free survival (PFS). Criteria for continuation of this study were not met. A total of 79 deaths and 293 progression events were recorded at final data cutoff. Zibotentan-treated patients did not significantly differ from placebo-treated patients for OS (hazard ratio (HR): 1.13; 95% confidence interval (CI): 0.73–1.76, P=0.589) or PFS (HR: 0.89; 95% CI: 0.71–1.12, P=0.330). The most commonly reported adverse events in zibotentan-treated patients were peripheral oedema (37.7%), headache (26.2%) and nasal congestion (24.9%); each occurred with >15% higher incidence than in the placebo group. This trial was terminated early because of failure at interim analysis of the efficacy data to meet the defined criteria for continuation. Owing to the absence of demonstrable survival benefits in the ENTHUSE clinical studies, zibotentan is no longer under investigation as a potential treatment for prostate cancer.

Background In platinum-sensitive relapsed ovarian cancer, paclitaxel plus carboplatin is a standard second-line treatment. Zibotentan (ZD4054) is an oral, specific ETA-receptor antagonist with demonstrated antitumour activity in xenograft models of human ovarian cancer. Methods In this Phase II, randomized, placebo-controlled study, patients with relapsed ovarian cancer sensitive to platinum-based chemotherapy received zibotentan 10 mg or placebo once-daily, plus paclitaxel 175 mg/m2 iv followed by carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of eight cycles. The primary endpoint was progression-free survival (PFS), evaluated by Response Evaluation Criteria In Solid Tumours (RECIST). Secondary and exploratory endpoints included objective tumour response rate, tumour size, CA-125/RECIST progression, and safety and tolerability. Results A total of 120 patients were randomized (zibotentan: n = 59; placebo: n = 61). Addition of zibotentan 10 mg/day to carboplatin and paclitaxel did not improve PFS compared with placebo (median PFS, 7.6 versus 10.0 months, respectively; HR = 1.46, [80% CI: 1.10–1.94]; P = 0.0870). No improvements in any of the secondary or exploratory efficacy endpoints were observed for patients receiving zibotentan compared with placebo. Median duration of total treatment exposure was 6.7 months. Total chemotherapy dose received was lower for zibotentan-treated versus placebo-treated patients (carboplatin: − 16%; paclitaxel: − 14%). The most common adverse events in the zibotentan arm were anaemia, nausea, alopecia, headache and neutropenia (43–48% of patients). Conclusions Zibotentan 10 mg/day plus carboplatin and paclitaxel did not result in an improvement in PFS compared with chemotherapy alone in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy. No unexpected safety concerns were identified.

Understanding the extent of disease in asymptomatic patients with castration resistant prostate cancer is important when making treatment decisions and designing clinical trials. The ENTHUSE M0 (ENdoTHelin A USE) trial (NCT00626548) was a large phase III study comparing the endothelin A receptor antagonist zibotentan with placebo in patients with nonmetastatic, castration resistant prostate cancer. The study was stopped prematurely after early efficacy review indicated that it was unlikely to meet its co-primary objectives of improved overall and progression-free survival vs placebo. Screening failed in an unexpectedly high number of patients. We investigated this screening failure rate to promote better classification of patients thought to have nonmetastatic castration resistant prostate cancer and inform the design of future clinical trials in this setting.The number of patients enrolled in and subsequently excluded from study was analyzed by geographic region and by the specialty of the investigating clinician (oncology or urology) who enrolled the study patients.Of 2,577 patients enrolled in a total of 350 hospital based centers in 39 countries screening failed in 1,155 (45%). The most common reason for screening failure was the detection of metastatic disease in 32% of all screened patients and in 71% of those in whom screening failed. The leading reasons for failed screening did not differ between investigator specialties overall or by geographic region.The high frequency of asymptomatic metastasis in men thought to have nonmetastatic, castration resistant prostate cancer highlights the importance of periodic staging assessments for the condition. Optimal treatment modalities may differ for metastatic and nonmetastatic disease.

Neonatal alloimmune thrombocytopenia (NAIT) most commonly involves antibodies directed against the PlA1 antigen, but other platelet specific alloantigens have been associated with it. We describe the case of a mother whose first three infants developed NAIT secondary to anti-Bak(a) antibodies, while her fourth infant did not. The three affected infants were treated postnatally with platelet transfusions. The fourth infant was treated antenatally with one dose of intravenous immunoglobulin (IVIg) given to the mother. Postpartum analysis revealed the infant's platelets to be Bak(a)-positive but negative for elevated IgG. Maternal serum reacted with neonatal platelets in vitro, but cord serum was negative for antiplatelet antibodies. These clinical observations do not prove the efficacy of IVIg; however, they raise several questions: Why wasn't this infant thrombocytopenic? Why didn't the umbilical cord contain maternal antibody? Was the single dose of IVIg responsible for preventing NAIT? IVIg is currently under investigation in a clinical trial evaluating its effectiveness in preventing NAIT in mothers with anti-PlA1 antibodies, where it has shown some success. There have been no reports of the use against anti-Bak(a) antibodies. We suggest that a weekly dose schedule may not be necessary for all affected pregnancies, and antibodies with specificity other than anti-PlA1 may require less vigorous therapy.

International audience; PURPOSE: This study evaluated overall survival (OS) of patients with advanced non-squamous NSCLC following treatment with the specific endothelin A receptor antagonist, zibotentan in combination with pemetrexed compared with pemetrexed monotherapy. METHODS: In this double-blinded, placebo-controlled study, patients with advanced NSCLC with non-squamous histology who had failed first-line platinum-based chemotherapy were randomized to receive either once-daily zibotentan 10 mg in combination with 3-weekly pemetrexed 500 mg/m(2) or placebo plus 3-weekly pemetrexed 500 mg/m(2). OS was calculated as the interval from date of randomization to date of death from any cause. Safety and tolerability were evaluated by recording the incidence of adverse events (AE) according to Common Toxicity Criteria for AE (CTCAE). RESULTS: Sixty-six patients were randomized and completed the study (zibotentan plus pemetrexed, n = 30; placebo plus pemetrexed, n = 36). At the data cutoff, a total of 44 deaths had occurred, 20 and 24 in the zibotentan and placebo groups, respectively. No significant difference in OS was observed between the zibotentan and placebo treatment groups (HR, 1.13; 80% CI 0.77, 1.67; P = 0.69). The majority of AE were of CTCAE grade 1 or 2, and the most commonly reported AE in both treatment groups was anemia (23 and 25% of patients in the zibotentan and placebo groups, respectively). CONCLUSIONS: There was no survival signal in patients with NSCLC following treatment with zibotentan in combination with pemetrexed. No new issues related to safety for either zibotentan or pemetrexed were identified.

S.N. Gettinger, M.D. Hellmann, F.A. Shepherd, S.J. Antonia, J. Brahmer, L.Q. Chow, J. Goldman, R. Juergens, H. Borghaei, N.E. Ready, D.E. Gerber, F. Nathan, Y. Shen, C.T. Harbison, N. Rizvi. Yale Comprehensive Cancer Center, Medical Oncology, New Haven CT, USA; Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service-Division of Solid Tumor Oncology-Department of Medicine, New York NY, USA; Princess Margaret Cancer Center, Cancer Clinical Research Unit, Toronto ON, Canada; H. Lee Moffitt Cancer Center & Research Institute, Thoracic Oncology Department, Tampa FL, USA; The Sidney Kimmel Comprehensive Cancer Center at John Hopkins, Division of Oncology, Baltimore MD, USA; University of Washington Division of Oncology, Department of Medicine, Seattle WA, USA; UCLA Jonsson Comprehensive Cancer Center, Hematology/ Oncology, Los Angeles CA, USA; Juravinski Cancer Center, Department of Oncology, Hamilton ON, Canada; Fox Chase Cancer Center, Medical Oncology, Philadelphia PA, USA; Duke University Medical Center, Division of Oncology, Durham NC, USA; UT Southwestern Medical Center, Division of Hematology/Oncology, Dallas TX, USA; Bristol-Myers Squibb, Clinical Research, Princeton NJ, USA; Bristol-Myers Squibb, Biostatistics, Princeton NJ, USA; Bristol-Myers Squibb, Immuno-Science Metabolic Diseases and Fibrosis, Princeton NJ, USA

8025 Background: NIVO, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has demonstrated durable responses and tolerability in heavily pretreated patients (pts) with advanced NSCLC. Th...

The objective of this study was to evaluate the usefulness of resection of metastatic uveal melanoma and to analyze the characteristics of patients who may benefit from surgical intervention. PATIENTS AND METHODS Twelve patients underwent surgical removal of metastasis between 1976 and 1998. Data regarding primary uveal melanoma, systemic metastasis, surgical procedures, and outcomes were reviewed retrospectively.There were seven patients with liver metastases, two with lung metastases, one with brain metastasis, and two patients with metastases in the liver and other organs. Median time to systemic metastasis was 8 years. Seven of 12 patients were asymptomatic when they were found to have metastasis. Ten patients underwent complete resection of metastasis. No significant surgical complications were experienced. Median recurrence free and overall survival periods after complete resection were 19 months (range, 6-78 months) and greater than 27 months (range, 11-86 months), respectively. Recurrence free and overall 5-year survival rates of those patients were 15.6% and 53.3%, respectively. Three of these patients had no further systemic recurrence. All patients whose time to systemic metastasis was within 5 years developed further systemic recurrence within 2 years after surgery. In contrast, in 8 patients whose time to systemic metastases was greater than 5 years, 4 patients either were recurrence free or developed second metastasis more than 4 years after surgery.Complete surgical removal of metastatic uveal melanoma provided unexpectedly long survival without significant morbidity for the selected patients. These results are encouraging and justify a trial in which patients eligible for resection are randomized between standard treatment and surgery.

In early trials of paclitaxel administered as a 24-hour infusion, an overall response rate of 16% was reported for patients with metastatic melanoma. Paclitaxel is a natural product-based agent and is thus subject to the problem of multidrug resistance (MDR). Tamoxifen is an agent that can abrogate MDR and potentially enhance the effect of paclitaxel. A Phase II trial of the combination was undertaken with previously treated patients.Patients with metastatic cutaneous or mucosal melanoma who were previously treated with the Dartmouth chemotherapy regimen (dacarbazine, carmustine, cisplatin, and tamoxifen) were evaluated. Paclitaxel was administered at a dose of 225 mg/m(2) intravenously over 3 hours every 3 weeks. All patients also took tamoxifen 40 mg orally daily. Treatment continued until disease progression.Twenty-one patients completed at least two cycles of paclitaxel and were evaluable for response. Five responses were observed, 1 complete response, and 4 partial responses, for an overall response rate of 24%. The combination was well tolerated. The most common nonhematologic side effects were myalgia and paresthesia. Hematologic toxicity was mild. No patients developed neutropenic fever.This is the first report of a Phase II trial evaluating paclitaxel as a 3-hour infusion in melanoma patients. The 3-hour infusion is well tolerated and results in little myelosuppression and minimal neurotoxicity. The contribution of tamoxifen is difficult to evaluate because plasma levels were not measured. It is possible that a higher response rate might be observed with larger doses of tamoxifen. Further investigation of paclitaxel in the treatment of patients with metastatic melanoma is warranted.

Purpose: To report a clinicopathologic correlation of angiosarcoma affecting the eyelid skin. Methods: An 82-year-old man developed multiple bruise-like maculopapular lesions, subcutaneous nodules, and diffuse edema over his scalp, face, and eyelids. Biopsy disclosed angiosarcoma, and the patient was treated with wide-field external beam radiotherapy (5,000 cGy). Results: He responded to radiotherapy with partial regression of the tumor. Twelve months later, he developed extensive lymphedema secondary to the residual tumor. He was also found to have parotid gland and bone metastases, treated with radiotherapy. The patient died of widespread bone metastases 3 months later. Conclusions: Angiosarcoma is a rare skin tumor that has a poor prognosis despite treatment. It should be considered in the differential diagnosis of eyelid tumors and edema because it may affect only the central portion of the face.

We conducted a phase II trial of bleomycin+vincristine+lomustine+dacarbazine (BOLD) with intercycle alpha interferon-2b in previously untreated patients with metastatic uveal melanoma. Objective tumor response and toxicity were assessed. Twenty-three patients with histologically verified metastatic uveal melanoma were enrolled into this study between November 1992 and August 1995. Chemotherapy was administered in the following fashion: dacarbazine (DTIC), 200 mg/m2 intravenously on days 1-5; vincristine, 1 mg/m2 (not to exceed 2 mg) intravenously on days 1 and 4; bleomycin, 15 mg intravenously on days 2 and 5; lomustine (CCNU), 80 mg orally on day 1; and alpha interferon-2b, 3 x 10(6) IU subcutaneously on days 8, 10, 12, 15, 17, 19. A cycle was 28 days, and patients were reevaluated after every 2 cycles. Among twenty evaluable patients, four objective responses were observed (RR = 20%). Hematologic toxicity was modest by comparison to some other combination chemotherapy regimens in common use. Neurotoxicity was frequently observed, but it was seldom severe. An unexpected and unpredictable severe pulmonary toxicity was observed in 3 patients, the etiology of which remains unclear. The regimen of BOLD+interferon is active in the treatment of metastatic uveal melanoma. The precise role of the regimen has to be defined in light of its toxicity, particularly the unpredictable pulmonary toxicity. The pattern of occurrence of these pulmonary events is most consistent with either an acquired hypersensitivity reaction or a cumulative toxic effect of 2 or more of the agents. Patients considered for treatment with this regimen must be judiciously selected. Those with no clear contraindications may benefit from a trial of this regimen, but they must be monitored closely.

The bonafide albeit infrequent examples of tumor regression observed with whole tumor cell vaccines give evidence for the hypothesis that active specific immunization can induce a therapeutically effective immune response in melanoma patients. A dinitrophenyl-conjugated autologous whole tumor cell plus bacille Calmette-Guérin (BCG) vaccine administered in conjunction with low dose cyclophosphamide has produced clinically significant prolongation of disease free survival when used as a postsurgical adjuvant in patients with stage III melanoma. However, tumor cell-based vaccines are cumbersome and consequently of limited applicability. Improvements in our understanding of the antimelanoma immune response and technological advances have allowed investigators to explore better defined immunogens and antigenic targets; these include anti-idiotypic antibodies, gangliosides, and tumor associated/specific proteins and derived peptides. The rationale for, promise of, and progress to date with these materials are reviewed.

Combination antimicrotubule therapy with estramustine phosphate (EMP) and vinblastine has reproducible activity in metastatic hormone-refractory prostate cancer (HRPC) with an objective response rate of 31%. Although paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 24-hour infusion was inactive in HRPC, 0.5 to 1.0 nmol/L concentrations of paclitaxel combined with EMP exerted synergistic cytotoxicity in DU-145 androgen-independent human prostate cancer cell lines. Based on these results, we treated 24 patients with HRPC using the combination of paclitaxel 120 to 140 mg/m2 by 96-hour intravenous infusion every 3 weeks plus daily oral EMP at 600 mg/m2/d. Of seven patients with measurable soft tissue metastases, three have attained partial responses and a fourth patient is nearing partial response status. Of 16 patients with bone-only disease evaluated by change in serum prostate-specific antigen levels, 11 patients (68.8%) have had decreases ofor = 50% from pretreatment baseline. The prostate-specific antigen decrease has exceeded 80% in six of 16 (37.5%) patients. For all 23 evaluable patients, the prostate-specific antigen has decreased byor = 50% in 15 (65.2%) and byor = 80% in eight (34.7%). Grade 4 leukopenia occurred in one of 21 patients treated at the paclitaxel dose of 120 mg/m2/96 hr and one of three patients treated at 140 mg/m2/96 hr. The incidence of nausea (50%) and peripheral edema (37.5%) was similar to that associated with single-agent EMP. These results demonstrate that 96-hour paclitaxel plus EMP is active in HRPC and provide further evidence that the rational combination of antimicrotubule agents leads to synergistic antitumor activity in HRPC.

Thrombospondin is a high molecular weight glycoprotein, originally described as a secretion product of platelets, that functions as an adhesive protein in cell-cell and cell-substratum interactions. It promotes metastases in the murine model. Plasma thrombospondin has been shown to be elevated in patients with disseminated breast, lung, and gastrointestinal malignancies.Blood samples were collected by venipuncture into cubes containing ethylenediamine tetraacetic acid as anticoagulant. They were placed on ice immediately and centrifuged under refrigerated conditions. Plasma was removed and frozen until thrombospondin was quantitated by a competitive enzyme-linked immunosorbent assay. Wilcoxon's two-sample rank-sum test was used to evaluate differences between the patient and control groups.The median plasma thrombospondin level was significantly higher in the patient group compared with the control group, and it was directly correlated with stage of disease. There was no correlation between platelet count and thrombospondin level.Tumor-synthesized thrombospondin could explain the elevated levels in the patent group and also the observation of the correlation between the thrombospondin level and tumor burden. Its function as an adhesive protein may allow it to act as the mediator of metastases. thrombospondin may promote or mediate the metastatic process through its function in cell adhesion.

4655 Background: Many patients with biochemical relapse after definitive therapy for prostate cancer receive androgen deprivation therapy. PSA levels eventually will rise despite castrate levels of...

135 Background: Many patients with biochemical relapse after definitive therapy for prostate cancer receive androgen deprivation therapy. Although most patients experience a decline in PSA, PSA eventually rises despite a castrate level of testosterone. Many of these patients have non-metastatic disease and do not develop metastases for a median of 30 mos (Smith MR. JCO, 2005). However, there is no standard therapy for asymptomatic patients with non-metastatic CRPC. ENTHUSE M0 (Study 15) is an ongoing global phase III study comparing zibotentan 10 mg (an oral specific endothelin A receptor antagonist) vs placebo in non-metastatic CRPC patients. Co-primary endpoints are overall survival and progression-free survival; secondary endpoints are safety, PSA, quality of life, and time to symptomatic progression. Eligible patients are screened for metastases by bone and CT/MRI scan and other parameters. An unexpectedly high number of patients failed screening, prompting this analysis. Methods: All patients who were screened were included in the analysis. Reasons for exclusion were recorded. Results: As of June 3, 2010, 1,756 patients completed screening. Of these patients, 960 (55%) were randomized and 796 (45%) failed screening. The leading causes of screen failures are listed in the table. Exclusion rates by investigator specialty and country will be reported. Conclusions: As 30% of patients had metastatic disease on screening and were excluded, these data suggest that the frequency of asymptomatic metastases is high in men thought to have non-metastatic CRPC. These findings stress the value of periodic staging studies in men progressing from hormone sensitive to non-metastatic CRPC as metastatic CRPC patients may benefit from standard treatments or research treatments on other protocols. [Table: see text] [Table: see text]

Background Bone metastases are a common painful and debilitating consequence of castration-resistant prostate cancer (CPRC). Bone pain may predict patients' prognosis and there is a need to further explore CRPC patients' experiences of bone pain in the overall context of disease pathology. Due to the subjective nature of pain, assessments of pain severity, onset and progression are reliant on patient assessment. Patient reported outcome (PRO) measures, therefore, are commonly used as key endpoints for evaluating the efficacy of CRPC treatments. Evidence of the content validity of leading PRO measures of pain severity used in CRPC clinical trials is, however, limited. Methods To document patients' experience of CRPC symptoms including pain, and their impact on health-related quality of life (HRQL), semi-structured in-depth qualitative interviews were conducted with 17 patients with CRPC and bone metastases. The content validity of the Present Pain Intensity (PPI) scale from the McGill Pain Questionnaire (MPQ), and the 'Average Pain' and 'Worst Pain' items of the Brief Pain Inventory Short-Form (BPI-SF) was also assessed. Results Patients with CRPC and bone metastases present with a constellation of symptoms that can have a profound effect on HRQL. For patients in this study, bone pain was the most prominent and debilitating symptom associated with their condition. Bone pain was chronic and, despite being generally well-managed by analgesic medication, instances of breakthrough cancer pain (BTcP) were common. Cognitive debriefing of the selected PRO measures of pain severity highlighted difficulties among patients in understanding the verbal response scale (VRS) of the MPQ PPI scale. There were also some inconsistencies in the way in which the BPI-SF 'Average Pain' item was interpreted by patients. In contrast, the BPI-SF 'Worst Pain' item was well understood and interpreted consistently among patients. Conclusions Study findings support the importance of PRO measures of pain severity as key endpoints for evaluating the efficacy of treatments for CRPC, particularly for patients with bone metastases where episodes of BTcP are common. Qualitative evidence from CRPC patients supports the content validity of the BPI-SF ''Worst Pain' item and promotes use of this item for measuring pain severity in this population.

4664 Background: The combination of docetaxel and prednisone is the current standard care for patients with advanced castration-resistant prostate cancer (CRPC), however, survival benefits are limi...

2044 Background: Satraplatin (S) is a novel oral platinum analog with demonstrated activity in the treatment of pts with platinum-sensitive malignancies. A worldwide, double-blind, placebo-controlled randomized trial evaluating S as 2nd line therapy for hormone refractory prostate cancer (HRPC) has recently completed enrollment. The current study wasis designed to understand the effect of varying degrees of renal impairiment on the safety and PK of satraplatin. Methods: The study includes 4 levels of renal dysfunction, and 8 pts/cohort: Group 1 (G1) = Normal Renal Controls; G2 = Mild renal impairment (CrCl 50–80 mL/min); G3 = Mod. impairment (CrCl 30-2/d on d1–5 every 35 days. Results: 21 pts (of a planned total of 32) have been enrolled (13M/8F), median age 63 (range 45–72). Tumor types: Bladder (6), Renal (3), Breast (2), Prostate (2), Colon (2), Other (6). Among 15 evaluable pts, the cohort distribution is G1: 6 pts, G2: 4, G3: 4, and G4: 1. Twenty-six cycles of S have been delivered, and 11 pts have completed at least 2 cycles of therapy. Hematologic toxicities during the first 2 cycles include grade (G) 3/4 neutropenia (0 pts), G 3/4 thrombocytopenia (1), and G 3/4 anemia (1). No significant cardiac, renal, hepatic, or neurologic toxicity has been observed. Nausea, vomiting, and diarrhea were mild to moderate, and controlled with oral therapy. Of 4 pts with evaluable disease, 1 has stable disease, and 3 have progressed. Conclusions: S is well tolerated in pts with varying degrees of renal dysfunction. Updated safety and PK data will be presented at the meeting. [Table: see text]

2045 Background: Satraplatin (S) is a third-generation oral platinum analog that has demonstrated activity in the treatment of patients with platinum-sensitive malignancies. A worldwide double-blind, placebo controlled randomized phase III trial evaluating S as 2nd line therapy for HRPC has recently completed enrollment. The current study was designed to determine the effect of hepatic impairment on S pharmacokinetics in patients with refractory cancer, as well as treatment efficacy and toxicity. Methods: S was administered orally at a dose of 80mg/m2/day (d) on d1–5 every 35 days. Study groups (cohorts) were defined at 4 levels of hepatic impairment - Group 1 (G1) = control; G2 = Child-Pugh Class A; G3 = Child-Pugh Class B; and Group 4 = Child-Pugh Class C. Results: 19 pts have been enrolled to date (11 M/ 8 F); median age is 57 (range 44–80). Pts with prostate (2), pancreas (4), colorectal (3), adenocystic (2), and 1 each neuroendocrine, hepatocellular, melanoma, breast, ovarian, SCLC, and anal cancers were enrolled. 8 pts were in G1, 3 pts in G2, 4 pts in G3, and 5 pts in G4. Accrual is ongoing in this study with a total of 8 pts planned for each group. The median number of prior regimens was 5 (range 2–8). A total of 35 cycles of S have been given: median 2/pt (range 1–4). 9 pts have completed 2 cycles of S. Hematologic toxicities during the first 2 cycles included grade (G) 3/4 thrombocytopenia in 15 %. There were no cases of G 3/4 neutropenia or anemia. One case of G3 hypokalemia, was reported. Two patients developed acute renal failure; one of which was due to uncontrolled nausea (N) and vomiting (V) and the other was associated with rapid disease progression in the liver. Both were G4 patients. Otherwise, N, V, and diarrhea were mild to moderate, and controlled with oral therapy. Conclusions: S is, in general, well tolerated in patients with mild or moderate liver impairment. Severe thrombocytopenia is the most common side-effect. Of the patients enrolled to date 15% did not have progression of disease. PK data will also be presented. [Table: see text]

12014 Background: Satraplatin (S) is a novel oral platinum analog that has demonstrated preliminary activity in hormone refractory prostate cancer (HRPC). A large (950 pts) worldwide, randomized phase III trial evaluating S as 2nd line therapy for HRPC recently completed enrollment. The current study was designed to determine the PKs of S under fasted and fed conditions, as well as treatment efficacy and toxicity. Methods: S was administered orally at 80 mg/m2/day (d) on d1–5 q 35 days, with prophylactic antiemetics. For the 1st cycle, pts were randomized to receive d1 and d5 doses of S in either the fed or fasted state when PK sampling was performed. The fed/fasted state was reversed for the 2nd cycle. Subsequent doses of S were given in the fasted state. Results: 17 pts were enrolled (9M/8F), median age 62 (range 33–78) and tumor types: HRPC (7), breast (3), 1 each with anal, parotid, leiomyosarcoma, Merkel cell, ovarian, mesothelioma, and neuroendocrine tumor. The median no. of prior regimens was 3 (range 1–8). A total of 58 cycles of S were given. Grade 3–4 hematologic toxicities (1st 2 cycles) included: neutropenia (11%), thrombocytopenia (24%) and anemia (24%). The hematologic nadir occurred during week 4. There was no grade 3–4 nausea, vomiting or diarrhea. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The peak plasma concentration (Cmax) for platinum in plasma ultrafiltrate (PUF) was decreased by 20% when S was administered following a high fat meal compared to the fasting condition. There was no effect of food on AUC0–24 hr. The time of Cmax (Tmax) was delayed in the fed state. Table shows PK parameters. One PR (HRPC) and 4 SD ≥ 5 months (breast, ovarian, parotid and HRPC) were confirmed. Conclusions: There is an effect of food on the Cmax, however the clinical implications are unknown at this time. For this reason, it is recommended that S be administered to pts in the fasting state. At the dose of 80 mg/m2/day, S was well tolerated in this group of heavily pretreated patients. [Table: see text] [Table: see text]

4802 Background: There is no chemotherapeutic agent specifically approved for second-line treatment for hormone-refractory prostate cancer (HRPC). Satraplatin (S) is a third-generation oral platinu...