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We developed and evaluated a method for making early predictions of best overall response (BOR) and overall survival at 6 months (OS6) in patients with cancer treated with immunotherapy. This method combines machine learning with modeling of longitudinal tumor size data. We applied our method to data from durvalumab‐exposed patients with recurrent/metastatic head and neck cancer. A fivefold cross‐validation was used for model selection. Independent trial data, with various degrees of data truncation, were used for model validation. Mean classification error rates (90% confidence intervals [CIs]) from cross‐validation were 5.99% (90% CI 2.98%–7.50%) for BOR and 19.8% (90% CI 15.8%–39.3%) for OS6. During model validation, the area under the receiver operating characteristic curves was preserved for BOR (0.97, 0.97, and 0.94) and OS6 (0.85, 0.84, and 0.82) at 24, 18, and 12 weeks, respectively. These results suggest our method predicts trial outcomes accurately from early data and could be used to aid drug development.

Summary Background Staphylococcus aureus remains a common cause of ventilator-associated pneumonia, with little change in incidence over the past 15 years. We aimed to evaluate the efficacy of suvratoxumab, a monoclonal antibody targeting the α toxin, in reducing the incidence of S aureus pneumonia in patients in the intensive care unit (ICU) who are on mechanical ventilation. Methods We did a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial at 31 hospitals in Belgium, the Czech Republic, France, Germany, Greece, Hungary, Portugal, Spain, and Switzerland. Eligible patients were in the ICU, aged ≥18 years, were intubated and on mechanical ventilation, were positive for S aureus colonisation of the lower respiratory tract, as assessed by quantitative PCR (qPCR) analysis of endotracheal aspirate, and had not been diagnosed with new-onset pneumonia. Patients were excluded if they had confirmed or suspected acute ongoing staphylococcal disease; had received antibiotics for S aureus infection for more than 48 h within 72 h of randomisation; had a Clinical Pulmonary Infection Score of 6 or higher; had an acute physiology and chronic health evaluation II score of 25 or higher with a Glasgow coma scale (GCS) score of more than 5, or an acute physiology and chronic health evaluation II score of at least 30 with a GCS score of 5 or less; had a Sequential Organ Failure Assessment score of 9 or higher; or had active pulmonary disease that would impair the ability to diagnose pneumonia. Colonised patients were randomly assigned (1:1:1), by use of an interactive voice or web response system, to receive either a single intravenous infusion of suvratoxumab 2000 mg, suvratoxumab 5000 mg, or placebo. Randomisation was done in blocks of size four, stratified by country and by whether patients had received systemic antibiotics for S aureus infection. Patients, investigators, and study staff involved in the treatment or clinical evaluation of patients were masked to patient assignment. The primary efficacy endpoint was the incidence of S aureus pneumonia at 30 days, as determined by a masked independent endpoint adjudication committee, in all patients who received their assigned treatment (modified intention-to-treat [ITT] population). Primary safety endpoints were the incidence of treatment-emergent adverse events at 30 days, 90 days, and 190 days after treatment, and the incidence of treatment-emergent serious adverse events, adverse events of special interest, and new-onset chronic disease at 190 days after treatment. All primary safety endpoints were assessed in the modified ITT population. This trial is registered with ClinicalTrials.gov ( NCT02296320 ) and the EudraCT database (2014-001097-34). Findings Between Oct 10, 2014, and April 1, 2018, 767 patients were screened, of whom 213 patients with confirmed S aureus colonisation of the lower respiratory tract were randomly assigned to the suvratoxumab 2000 mg group (n=15), the suvratoxumab 5000 mg group (n=96), or the placebo group (n=102). Two patients in the placebo group did not receive treatment after randomisation because their clinical conditions changed and they no longer met the eligibility criteria for dosing. As adjudicated by the data monitoring committee at an interim analysis, the suvratoxumab 2000 mg group was discontinued on the basis of predefined pharmacokinetic criteria. At 30 days after treatment, 17 (18%) of 96 patients in the suvratoxumab 5000 mg group and 26 (26%) of 100 patients in the placebo group had developed S aureus pneumonia (relative risk reduction 31·9% [90% CI −7·5 to 56·8], p=0·17). The incidence of treatment-emergent adverse events at 30 days were similar between the suvratoxumab 5000 mg group (87 [91%]) and the placebo group (90 [90%]). The incidence of treatment-emergent serious adverse events at 30 days were also similar between the suvratoxumab 5000 mg group (36 [38%]) and the placebo group (32 [32%]). No significant difference in the incidence of treatment-emergent adverse events between the two groups at 90 days (89 [93%] in the suvratoxumab 5000 mg group vs 92 [92%] in the placebo group) and at 190 days (93 [94%] vs 93 [93%]) was observed. 40 (40%) patients in the placebo group and 50 (52%) in the suvratoxumab 5000 mg group had a serious adverse event at 190 days. In the suvratoxumab 5000 mg group, one (1%) patient reported at least one treatment-emergent serious adverse event related to treatment, two (2%) patients reported an adverse event of special interest, and two (2%) reported a new-onset chronic disease. Interpretation In patients in the ICU receiving mechanical ventilation with qPCR-confirmed S aureus colonisation of the lower respiratory tract, the incidence of S aureus pneumonia at 30 days was not significantly lower following treatment with 5000 mg suvratoxumab than with placebo. Despite these negative results, monoclonal antibodies still represent one promising therapeutic option to reduce antibiotic consumption that require further exploration and studies. Funding AstraZeneca, with support from the Innovative Medicines Initiative Joint Undertaking.

BackgroundT cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor expressed on T cells, including regulatory T cells (Tregs) and natural killer (NK) cells. In the tumor microenvironment, TIGIT is often overexpressed and directly inhibits both T cell and NK cell effector function and proliferation. TIGIT is also involved in regulating Treg function. Therefore, inhibiting the TIGIT-related immunosuppressive pathway may result in antitumor activity. M6223 is an intravenously (IV) administered, human, antagonistic, immunoglobulin G1 (IgG1) anti-TIGIT antibody with an Fc mediated effector region. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (a TGFβ ”trap”) fused to a human IgG1 monoclonal antibody blocking programed death ligand 1 (PD-L1). As TIGIT and programed death receptor 1 (PD-1) are co-expressed on T cells, dual inhibition of both immune checkpoints may enhance antitumor activity. This phase Ia study (NCT04457778) aims to determine the safety, tolerability, maximum tolerated dose and recommended dose for expansion of M6223 monotherapy and M6223 (both the once every 2 weeks [Q2W] and once every 3 weeks [Q3W] regimens) in combination with bintrafusp alfa. Secondary objectives include the evaluation of pharmacokinetics and clinical activity of M6223 with and without bintrafusp alfa.MethodsEligible patients include those aged ≥18 years with: an Eastern Cooperative Oncology Group performance status ≤1; adequate baseline hematological, renal and hepatic function; and histologically or cytologically proven locally advanced or advanced solid tumors, for which no effective standard therapy is available. Patients previously treated with a TIGIT targeting agent or bintrafusp alfa are excluded. Patients with brain metastases are also excluded, except those without neurological symptoms ≥4 weeks before start of treatment and those receiving either a stable or decreasing dose of steroids AcknowledgementsThe authors would like to thank Daniel Holland of the healthcare business of Merck KGaA, Darmstadt, Germany for his involvement and contribution to the design and conduct of this study. Medical writing assistance was provided by David Lester of Bioscript Stirling Ltd, Macclesfield, UK, and funded by the healthcare business of Merck KGaA, Darmstadt, Germany [CrossRef Funder ID: 10.13039/100009945].Funding: The healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).Trial RegistrationNCT04457778Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site. All patients provided written informed consent before any study procedures were performed.

Regorafenib is the first drug approved by the FDA for the treatment of hepatocellular carcinoma that has progressed on sorafenib and is expected to become a standard of care for these patients. This article summarizes the FDA's review of the data submitted in the supplemental New Drug Application and the basis for approval of regorafenib for this new indication., On April 27, 2017, the U.S. Food and Drug Administration approved regorafenib for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with sorafenib. Approval was based on the results of a single, randomized, placebo‐controlled trial (RESORCE) that demonstrated an improvement in overall survival (OS). Patients were randomly allocated to receive regorafenib160 mg orally once daily or matching placebo for the first 21 days of each 28‐day cycle. The trial demonstrated a significant improvement in OS (hazard ratio [HR] = 0.63; 95% confidence interval [CI], 0.50–0.79, p

6549 Background: Optimal patient selection for immunotherapy remains a challenge as most patients fail to respond. We aim to assess baseline factors for association with long-term survival from durvalumab treatment in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)1,2. Methods: Pooled longitudinal tumor size, survival, and dropout data from four trials (1108: NCT01693562, CONDOR: NCT02319044 , HAWK: NCT02207530, and EAGLE: NCT02369874) involving 467 HNSCC patients were used to develop tumor size-driven hazard models. A panel of 66 serum protein biomarkers at baseline and 4 relevant clinical markers from 346 out of 413 patients treated with durvalumab (all studies except 1108) were initially screened to select a pool of 21 candidate covariates. The criteria for dimensionality reduction comprised correlation strength between biomarkers and pharmacological hypotheses pertaining to a prior analysis3 (inflammation, immunomodulation, tumor burden and angiogenesis). Results: The final tumor model highlighted that high tumor burden, elevated LDH and neutrophil-lymphocyte ratio were associated with faster tumor growth while patients with lower baseline tumor burden had an increase in net tumor shrinkage. For overall survival, the model suggested that high levels of immunomodulators (IL23, Osteocalcin), low inflammation (IL6, NLR), low tumor burden, and low angiogenesis factors (von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1)) were associated with survival benefits for patients treated with durvalumab. Specifically, these patients had baseline serum IL23 > 2.1 pg/mL and Osteocalcin > 32 pg/mL or serum PAI-1 < 229 pg/mL and serum IL6 < 5.4 pg/mL which corresponded to a hazard ratio estimate (HR and 95%CI) of 0.36 (0.27- 0.47), logrank p-value: 2.3x10−14. The median (n, 95%CI) overall survival time for the patients with favorable biomarker profile was 14.6 months (n = 129, 11.2-21.4) vs. 4.4 months (n = 217, 3.6-5.3). Conclusions: Our results corroborate the prior hypothesis highlighting the prognostic value of inflammation, disease burden, tumor angiogenesis, and immunomodulatory factors on the clinical outcomes of HNSCC patients treated with durvalumab3. Collectively, we identified a serum biomarker profile of HNSCC patients with median survival times exceeding 1 year which may potentially be used for patient enrichment following further validation in prospective studies. References: 1Yanan CPT 2017, 2Baverel, 2018 ENA, 3Guo, X, 2019 Asco P6048 Clinical trial information: NCT01693562, NCT02319044, NCT02207530, NCT02369874 .

Background Suvratoxumab (suvra), an extended half-life (~80 days), Staphylococcus aureus (SA) alpha toxin-neutralizing IgG monoclonal antibody, is under investigation for prevention of SA pneumonia in patients on mechanical ventilation (MV). We characterized the serum PK of suvra using population pharmacokinetics (popPK) in both healthy volunteers and MV patients and quantified the proportion of patients reaching the serum target of 211 μg/mL at 30 days post-dose. Methods The popPK analysis included 1,368 serum samples from two early phase studies (NCT02296320; EudraCT 2014-001097-34): (1) Phase 1 study in 26 healthy adults receiving single IV suvra doses ranging from 0.225g to 5g, with PK sampled up to 360 days; and (2) Phase 2 study in MV patients with PCR-confirmed SA colonization of lower respiratory tract receiving one suvra IV dose of 2g (n = 15) or 5g (n = 96), with PK sampled up to 100 days. Results A two-compartment linear model with weight-based scaling of the PK parameters adequately described the serum PK data (Figure 1). MV status, number of days on MV, and age impacted the PK of suvra. A moderate between-subject variability ( Conclusion MV status, post-dose duration on MV, body weight, and age were identified as statistically significant covariates influencing the PK of suvra. Serum PK and popPK analyses support the 5g dose for future studies with suvra in MV patients. Disclosures All authors: No reported disclosures.

The FDA approved niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline BRCA mutation status (gBRCAm vs. non-gBRCAm). Progression-free survival (PFS) in each cohort was the primary endpoint. In the gBRCAm cohort, estimated median PFS on niraparib was 21 months versus 5.5 months on placebo [HR, 0.26; 95% confidence interval (CI), 0.17–0.41; P < 0.0001]. In the non-gBRCAm cohort, estimated median PFS for niraparib and placebo was 9.3 and 3.9 months, respectively (HR, 0.45; 95% CI, 0.34–0.61; P < 0.0001). Common adverse reactions (>20% and higher incidence in the niraparib arm) with niraparib included thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, mucositis, fatigue, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash, and hypertension. There were five cases of myelodysplastic syndrome and acute myeloid leukemia (1.4%) in patients treated with niraparib compared with two cases (1.1%) on placebo. Niraparib is the first PARP inhibitor approved as maintenance therapy for patients with ovarian, fallopian tube, or primary peritoneal cancer, with improvement in PFS, regardless of gBRCAm status. Clin Cancer Res; 24(17); 4066–71. ©2018 AACR. See related commentary by Konstantinopoulos and Matulonis, p. 4062

Background Staphylococcus aureus (SA) pneumonia imposes significant morbidity and mortality in mechanically ventilated, intensive care unit (MV ICU) patients despite best clinical care. We assessed efficacy, PK, AT-neutralizing antibodies (AT NAbs), and safety of suvratoxumab (suvra) in MV ICU subjects in the placebo-controlled, randomized Phase 2 SAATELLITE study (NCT02296320; EudraCT 2014-001097-34). Methods Subjects with PCR-confirmed SA colonization of the lower respiratory tract were randomized to either a single intravenous infusion of 5,000 mg suvra (n = 96) or placebo (n = 100) and followed for 190 days post dose. Efficacy endpoints were Endpoint Adjudication Committee-determined relative risk reduction (RRR) of SA pneumonia incidence in suvra vs. placebo recipients within 30 days post dose (primary endpoint, tested at 2-sided α = 0.1), incidence of all-cause pneumonia, and all-cause pneumonia or death. Serum suvra PK and levels of AT NAbs were measured through 90 days post dose and analyzed for statistical correlation. Treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) were assessed through 190 days post dose. Results Baseline characteristics were similar between groups. Suvra provided 31.9% RRR in incidence of SA pneumonia vs. placebo (17.7% vs. 26%; P = 0.166), 30% RRR (P = 0.146) in incidence of all-cause pneumonia, and 23% RRR (P = 0.164) in incidence of all-cause pneumonia or death. Suvra reduced mean hospital stay and ICU duration by 3.0 and 2.4 days, resp. vs. placebo. Mean serum ± SD suvra level was 296 ± 131 µg/mL at 30 days post dose. Serum AT Nab ± SD levels reached 156.03 ± 72.48 IU/mL at 2 days post dose, declining slowly to 33.74 ± 16.04 IU/mL by 90 days post dose. AT NAbs correlated with PK (r2 = 0.7), thereby confirming functional activity of suvra over time. Proportion of subjects with TEAEs or SAEs was similar between groups: ≥1 TEAE (93.8% suvra; 93.0% placebo); ≥1 serious; and/or ≥grade 3 severity SAE (66.7% suvra; 58.0% placebo). Conclusion A single intravenous dose of suvra produced a trend toward reduced incidence of SA pneumonia, health resource savings, sustained functional exposure in serum, and an acceptable safety profile. These results support continued development of suvra in MV ICU patients. Disclosures All Authors: No reported Disclosures.