International Drug Development Institute (their employer) during the conduct of the study. SD reports grants, personal fees, and non-financial support from Roche-Genentech, and grants and personal fees from Puma, outside of the submitted work. MP-G reports personal fees from Roche-Genentech, outside of the submitted work. DS reports consultancy for Novartis, Eli Lilly, and Seattle Genetics, and is a board member at BioMarin. NW reports grants from the National Cancer Institute, during the conduct of the study. MB is an employee and holds stock at the International Drug Development Institute. All other authors declare no competing interests.

IL-2 is a natural, T cell-derived cytokine

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ObjectivesTo investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in advanced non-small-cell lung cancer (NSCLC).DesignMeta-analysis of individual patient data from randomised trials.SettingFive randomised controlled trials comparing docetaxel-based chemotherapy with vinorelbine-based chemotherapy for the first-line treatment of NSCLC.Participants2331 patients with advanced NSCLC.Primary and secondary outcome measuresSurrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. The surrogate threshold effect was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS.ResultsThe median follow-up of patients still alive was 23.4 months. Median OS was 10 months and median PFS was 5.5 months. The treatment effects on PFS and OS were correlated, whether using centres (R²=0.62, 95% CI 0.52 to 0.72) or prognostic strata (R²=0.72, 95% CI 0.60 to 0.84) as units of analysis. The surrogate threshold effect was a PFS hazard ratio (HR) of 0.49 using centres or 0.53 using prognostic strata.ConclusionsThese analyses provide only modest support for considering PFS as an acceptable surrogate for OS in patients with advanced NSCLC. Only treatments that have a major impact on PFS (risk reduction of at least 50%) would be expected to also have a significant effect on OS. Whether these results also apply to targeted therapies is an open question that requires independent evaluation.

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Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. ALX148 is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. In combination with anti-tumor antibodies, ALX148 enhances the innate and adaptive immune response against cancer. ALX148 has previously been shown to be well tolerated both as a single agent and in combination with pembrolizumab or trastuzumab in a range of solid tumors with no maximum tolerated dose (MTD) identified (SITC 2018 #P335, ASCO 2019 #2514). Characterization of ALX148's safety profile and antitumor activity in combination with rituximab are reported in patients (pts) with both aggressive and indolent histologies of non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety confirmation population was first cycle dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Preliminary clinical data from the fully enrolled cohort is reported as of July 15, 2019. Results: Twenty pts (15 males, 5 females) with NHL were administered ALX148 in combination with rituximab (DLBCL, n=11; mantle cell lymphoma, n=4; follicular lymphoma, n=3; and marginal zone lymphoma, n=2). The pts median age was 66 years (range 32-80) and ECOG PS 0/1 was 7/13. Patients had a median of 3 prior lines of therapy (range 1-7) with 50% having rituximab-refractory tumors. There were no dose limiting toxicities reported and the MTD of ALX148 in combination with rituximab was not reached. The maximum administered dose was 10 mg/kg QW. Sixteen pts experienced any AE, while 11 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (20%, n=4); anemia, fatigue, nausea, neutropenia and decreased platelets (10%, n=2 each). One TRAE ≥ G3 of neutropenia occurred in more than 1 patient (1G3, 1G4). As of the data cut off with a median follow-up time of 3 (0.3-14) months, preliminary tumor response was assessed in 17 evaluable pts using the Lugano Classification, 2014. The ORR was 35% across all tumor histologies, with a 50% ORR reported in indolent (FL+MZL), and 31% ORR reported in aggressive (DLBCL+MCL) histologies. The overall DCR was 41%. Six pts achieved partial response [(2) follicular, (2) DLBCL, (2) mantle cell]. Four pts achieved SD [(1) each of follicular, marginal zone, DLBCL(>1yr), and mantle cell]. Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity in combination with rituximab was observed with objective responses reported in heavily pretreated and rituximab-refractory patients. Clinical trial information: NCT03013218 Disclosures Kim: AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Lakhani:ALX Oncology Inc.: Research Funding; Ascentage Pharma: Research Funding; Asana Biosciences: Research Funding; BeiGene: Research Funding; Constellation Pharmaceuticals: Research Funding; Alexion Pharma: Research Funding; Cerulean Pharma: Research Funding; Forty Seven: Research Funding; Loxo: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; TaiRx: Research Funding; Apexian: Research Funding; Formation Biologics: Research Funding; Coordination Therapeutics: Research Funding; Symphogen: Research Funding; CytomX: Research Funding; InhbRx: Research Funding; Incyte: Research Funding; Jounce Therapeutics: Research Funding; Livzon: Research Funding; Northern Biologics: Research Funding; Tesaro: Research Funding; Innovent Biologics: Research Funding. Gainor:BMS: Research Funding; Genentech/Roche: Other: grant; Takeda: Other: grant, personal fees; Blueprint: Research Funding; Loxo: Research Funding; Oncorus: Other: grant , personal fees; Regeneron: Other: grant,personal fees; Pfizer: Other: grant personal fees; Incyte: Other: grant personal fees; Novartis: Other: grant, personal fees; Merck: Other: grant personal fees; Agios: Other: personal fees; Amgen: Other: personal fees; Array: Research Funding; Tesaro: Research Funding; Moderna: Other: grant; Adaptimmune: Other: grant; ALX Oncology: Other: grant; Ironwood Pharma: Equity Ownership. Kamdar:AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Seattle Genetics: Speakers Bureau. Fanning:ALX Oncology Inc: Employment, Equity Ownership. Squifflet:IDDI: Employment; ALX Oncology Inc: Consultancy. Jin:ALX Oncology Inc.: Consultancy. Wan:ALX Oncology Inc.: Employment, Equity Ownership. Pons:ALX Oncology Inc.: Employment, Equity Ownership; venBio: Employment, Membership on an entity's Board of Directors or advisory committees. Randolph:ALX Oncology Inc: Employment, Equity Ownership; venVio: Consultancy; Carrick: Equity Ownership. Kim:Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding.

Background/aims Considerable human and financial resources are typically spent to ensure that data collected for clinical trials are free from errors. We investigated the impact of random and systematic errors on the outcome of randomized clinical trials. Methods We used individual patient data relating to response endpoints of interest in two published randomized clinical trials, one in ophthalmology and one in oncology. These randomized clinical trials enrolled 1186 patients with age-related macular degeneration and 736 patients with metastatic colorectal cancer. The ophthalmology trial tested the benefit of pegaptanib for the treatment of age-related macular degeneration and identified a statistically significant treatment benefit, whereas the oncology trial assessed the benefit of adding cetuximab to a regimen of capecitabine, oxaliplatin, and bevacizumab for the treatment of metastatic colorectal cancer and failed to identify a statistically significant treatment difference. We simulated trial results by adding errors that were independent of the treatment group (random errors) and errors that favored one of the treatment groups (systematic errors). We added such errors to the data for the response endpoint of interest for increasing proportions of randomly selected patients. Results Random errors added to up to 50% of the cases produced only slightly inflated variance in the estimated treatment effect of both trials, with no qualitative change in the p-value. In contrast, systematic errors produced bias even for very small proportions of patients with added errors. Conclusion A substantial amount of random errors is required before appreciable effects on the outcome of randomized clinical trials are noted. In contrast, even a small amount of systematic errors can severely bias the estimated treatment effects. Therefore, resources devoted to randomized clinical trials should be spent primarily on minimizing sources of systematic errors which can bias the analyses, rather than on random errors which result only in a small loss in power.

International audienceThis study prospectively investigates the impact of dose densification and altering sequence of fluorouracil, epirubicin and cyclophosphamide [FEC] and docetaxel [Doc] on dose delivery and tolerability of adjuvant chemotherapy in breast cancer patients. 117 patients with high-risk primary operable breast cancer were randomized (1:1:2:2) to conventional (three cycles of 3-weekly FEC then three cycles of 3-weekly Doc 100 mg/m or reverse sequence) or dose-dense (dd) treatment (four 10- to 11-day cycles of FEC then four 2-weekly cycles of Doc 75 mg/m, or the reverse). In the dd arms, pegfilgrastim was given on day 2 of each cycle, but only as secondary prophylaxis in conventional arms. The primary endpoint was the proportion of patients completing intended cycles at relative dose intensity ≥85% and this was achieved by 95% of patients in each group except for the ddDoc→FEC group (90%). Dose intensity in the dd arms increased by 48% for FEC and 11% for docetaxel, compared with the conventional arms (both  < 0.001). Doc dose reductions were more frequent with dd treatment and when Doc was given after FEC. Grade 3–4 neutropenia was significantly more frequent with conventional treatment, while fatigue and hand–foot syndrome were numerically more common with dd treatment, particularly when Doc was given after FEC. Delivery of adjuvant sequential ddFEC and Doc is feasible with growth factor support, and chemotherapy sequence appeared to affect delivery of target doses and toxicity