Safety Biomarkers Research Articles

Efficacy, safety and predictive biomarker results from OAK, a randomized phase III study comparing atezolizumab with docetaxel in patients with advanced NSCLC

Efficacy, safety and predictive biomarker results from OAK, a randomized phase III study comparing atezolizumab with docetaxel in patients with advanced NSCLC

Abstract P6-12-01: Phase II study of taselisib (GDC-0032) plus fulvestrant in HER2-negative, hormone receptor-positive advanced breast cancer: Analysis by PIK3CA and ESR1 mutation status from circulating tumor DNA

Abstract Background: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently dysregulated in hormone receptor (HR)-positive breast cancer (BC), with activating mutations of PIK3CA detected in ~35–45% of patients (pts). Acquired mutations in the ESR1 gene, which encodes estrogen receptor α, may be associated with resistance to aromatase inhibitor (AI) therapy. Taselisib is a potent and selective PI3K inhibitor, with greater selectivity against mutant PI3Kα isoforms than wild-type (WT) via a unique mechanism. In phase I studies, taselisib plus fulvestrant had clinical activity and manageable tolerability in pts with HR-positive BC. We report exploratory analyses of PIK3CA and ESR1 from circulating tumor DNA (ctDNA). Methods: In this phase II, open-label, single-arm study (PMT4979g; NCT01296555), pts were postmenopausal with HER2-negative, HR-positive locally advanced or metastatic BC and progression or non-response to ≥1 prior endocrine therapy in the adjuvant or metastatic setting. Pts received taselisib (6 mg capsule orally, daily) plus fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, then Day 1 of each 28-day cycle) until disease progression or unacceptable toxicity. PIK3CA-mutation testing on archival tumor tissue used the cobas® PIK3CA Mutation Test. The Sysmex Inostics' BEAMing Digital PCR platform was used for ctDNA analysis of ESR1 and PIK3CA mutations (pre-dose on Cycle 1, Day 1). Primary endpoints were objective response rate (ORR) and clinical benefit rate (CBR) in all pts and those with PIK3CA mutations. ORR was confirmed complete response (cCR) and confirmed partial response (cPR). CBR was cCR, cPR, or stable disease for ≥6 months. Secondary endpoints included safety, efficacy, pharmacokinetics, and exploratory biomarker analysis. Results: 60 pts were enrolled. Median age was 61.5 years (range 31–82). In the metastatic setting, pts had received prior chemotherapy (21.7%) and prior hormonal therapy (50.0%). 86.7% of pts had received prior treatment with an AI. 45 pts had PIK3CA mutation status from archival tumor tissue and ctDNA testing; concordance was 86.7% (39/45). ctDNA analysis, vs archival tumor tissue testing, identified 4 pts and 9 pts with PIK3CA mutations from pts with WT and unknown PIK3CA mutation status, respectively. Based on ctDNA analysis (N=60), 13 pts (21.7%) had mutations in both ESR1 and PIK3CA, 21 pts (35.0%) were 'mutation not detected' (MND) for both genes, 8 (13.3%) had ESR1 mutations and PIK3CA MND, and 18 (30.0%) had ESR1 MND and PIK3CA mutations. In pts with measurable disease at baseline, confirmed responses (all partial) were: PIK3CA mutation, 38.1% (8/21); PIK3CA MND, 8.7% (2/23); all pts, 22.7% (10/44). CBRs were: PIK3CA mutation, 42.9%; PIK3CA MND, 17.4%; all pts, 29.5%. ORR and CBR from ctDNA analyses were similar to archival tumor tissue data. Conclusions: ctDNA analysis identified PIK3CA mutations in pts with previously unknown or WT mutation status from archival tumor tissue; ORR and CBR were similar to those from archival tumor tissue suggesting that PIK3CA mutation testing from ctDNA may be used as a surrogate when tissue is unavailable. 21.7% of pts had mutations in both ESR1 and PIK3CA. Citation Format: Dickler MN, Saura C, Oliveira M, Richards DA, Krop IE, Cervantes A, Stout TJ, Jin H, Savage HM, Wilson TR, Baselga J. Phase II study of taselisib (GDC-0032) plus fulvestrant in HER2-negative, hormone receptor-positive advanced breast cancer: Analysis by PIK3CA and ESR1 mutation status from circulating tumor DNA [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-01.

Abstract P6-11-13: Phase Ib study evaluating the safety and clinical activity of lumretuzumab combined with pertuzumab and paclitaxel in HER2-low metastatic breast cancer

Abstract Background: Inhibition of HER2 and HER3 heterodimerisation is a novel treatment concept in HER2-”low” expressing breast cancer (BC). Lumretuzumab, a glycoengineered monoclonal anti-HER3 antibody, in combination with pertuzumab has demonstrated synergistic anti-tumor activity in preclinical HER2–low expressing preclinical BC models. Methods: This open-label, multicenter phase I study selectively enrolled metastatic BC patients (pts) expressing HER3 protein and low levels of HER2 (defined as IHC 1+ and 2+ and ISH-negative) in a formalin-fixed paraffin-embedded pretreatment tumor biopsy sample. Eligible pts were treated with a combination of paclitaxel (PA) qw plus lumretuzumab (L) and pertuzumab (P) q3w in three dose cohorts. The safety, antitumor activity and tumor biomarkers including protein expression (IHC, MS) and mutational data (NGS) in association with clinical activity were evaluated. Results: Overall, 35 pts were included in this study. The median age was 60 (range: 33 to 77) years. The median number of prior treatments for metastatic disease ranged from 0 to 5 with 23 pts (65.7%) without prior chemotherapy for metastatic disease. Cohort 1 was treated with PA at 80 mg/m2, L at 1000 mg and P at 840 mg for Cycle 1 followed by 420 mg for the following cycles. This cohort was stopped after two pts both experienced grade 3 diarrhea within the first treatment cycle which was considered a dose-limiting toxicity (DLT). For Cohort 2 the dose of L was reduced to 500 mg based on PK modelling and simulation data. No DLTs were seen for the first 6 pts. A total of 20 pts were recruited with an objective response rate (ORR) and disease control rate (DCR) of 30% and 75%, respectively, and 56% and 78%, respectively, for 1st-line pts (n=9) in this cohort. Diarrhea (≥G3) and hypokalemia (≥G3) occurred in 50% and 55% of pts, respectively, and all pts experienced chronic diarrhea throughout the course of treatment. For Cohort 3 the dose of L was maintained at 500 mg, PA at 80 mg/m2, and P was administered at 420 mg at all cycles. In addition, a prophylactic loperamide regimen was introduced. Altogether, 13 pts - all 1st-line for metastatic disease - were treated. No DLTs were seen for the first 6 pts. Diarrhea (≥G3) and hypokalemia (≥G3) were reduced to 31% and 15%, respectively, but chronic diarrhea was still observed throughout the treatment in all pts. The ORR and DCR were 31% and 77%, respectively. Preliminary mechanistic safety experiments revealed HER2/HER3-dependent chloride channels in the intestine as likely cause of diarrhea. Biomarker data will be presented along with updated clinical and safety data. Conclusions: The combination of L, P and PA was associated with high rates of persistent diarrhea. Dose modifications and prophylactic anti-diarrheal medication led to significantly reduced diarrhea intensity but did not change the incidence and persistence of diarrhea overall. Despite encouraging clinical activity especially in 1st line pts, the therapeutic window of this combination is too low to warrant further clinical development. Citation Format: Schneeweiss A, Park-Simon T-W, Albanell J, Lassen U, Cortes J, Dieras V, May M, Schindler C, Marmé F, Cejalvo JM, Martinez-Garcia M, Gonzalez I, Lopez-Martin J, Welt A, Joly F, Michielin F, Jacob W, Adessi C, Moisan A, Meneses-Lorente G, James I, Ceppi M, Hasmann M, Weisser M, Cervantes A. Phase Ib study evaluating the safety and clinical activity of lumretuzumab combined with pertuzumab and paclitaxel in HER2-low metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-13.

Abstract OT2-01-11: Phase II of POSEIDON: A phase Ib / randomized phase II trial of tamoxifen plus taselisib or placebo in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment

Abstract Background: The combination of PI3K-AKT-mTOR pathway inhibitors with endocrine therapy can improve clinical outcomes of hormone receptor positive (HR+) metastatic breast cancer (MBC) patients. Taselisib is a potent and selective PI3K inhibitor, with greater selectivity against mutant (MUT) PI3Kα isoforms than wild-type (WT) via a unique mechanism. Phase Ib data of POSEIDON with Taselisib + tamoxifen (TAM) demonstrated encouraging activity in patients with heavily pre-treated MBC, with an acceptable toxicity profile (Baird et al, ASCO 2016). The recommended phase II dose (RP2D) was Taselisib 4mg plus TAM 20mg, both administered on a daily continuous schedule. ctDNA monitoring may have value in drug development by (1) assessing predictive biomarkers to therapy, (2) providing an early indication of treatment response, and (3) shedding light on potential mechanisms of acquired drug resistance. In some patients included in phase Ib of POSEIDON, tumor response was preceded by a corresponding early change in plasma PIK3CA ctDNA levels. Methods: The phase II portion of the POSEIDON trial is a two-arm, randomized, double blind study of Taselisib plus TAM versus placebo (PLA) plus TAM in pre- and postmenopausal women with HR+/HER2- MBC. In the first part of the Phase II, 180 patients will be randomized (1:1) to receive continuous TAM with either Taselisib at the RP2D or PLA until disease progression, unacceptable toxicity or patient / physician decision. Crossover is allowed upon progressive disease in those patients receiving PLA plus TAM, after collection of tumor and blood samples for exploratory biomarker analysis. Stratification is based on menopausal status, histology [lobular breast cancer (LBC) vs. ductal/others], PIK3CA mutation (WT vs. exon 9 vs. exon 20), prior everolimus, timing of recurrence/progression after prior endocrine therapy, number of prior chemotherapy (CT) lines, and treatment center. After recruiting the initial 180 patients, trial will focus in LBC, until a total number of 110 patients with LBC are enrolled. Other key eligibility criteria include presence of measurable or evaluable disease (RECIST 1.1), prior progression to endocrine treatment, maximum of 5 prior CT lines in the metastatic setting, absence of diabetes under medical treatment, and absence of chronic inflammatory bowel disease. Primary endpoint is investigator-assessed PFS. Key secondary endpoints are PFS in LBC, objective response rate, clinical benefit rate, safety, and exploratory biomarker analysis (including ctDNA). The study has a 90% power at a two-sided log-rank test significance level of 0.2 to detect an HR of 0.64, which corresponds to an increase in median PFS from 4.5 months in the PLA plus TAM arm to 7 months in the Taselisib plus TAM arm. Enrollment to POSEIDON Phase II started in June 2016 (Clinicaltrials.gov NCT02285179). Citation Format: Oliveira M, Baird RD, van Rossum AGJ, Beelen K, Garcia-Corbacho J, Mandjes IAM, Vallier AL, van Werkhoven E, Garrigós L, Kumar S, van Tinteren H, Muñoz S, Linossi C, Rosing H, Miquel JM, Schrier M, de Vries Schultink A, Saura C, Gallagher WM, Bernards R, Tabernero J, Cortés J, Caldas C, Linn SC. Phase II of POSEIDON: A phase Ib / randomized phase II trial of tamoxifen plus taselisib or placebo in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-11.

Retinal biomarkers provide "insight" into cortical pharmacology and disease.

The retina is an easily accessible out-pouching of the central nervous system (CNS) and thus lends itself to being a biomarker of the brain. More specifically, the presence of neuronal, vascular and blood-neural barrier parallels in the eye and brain coupled with fast and inexpensive methods to quantify retinal changes make ocular biomarkers an attractive option. This includes its utility as a biomarker for a number of cerebrovascular diseases as well as a drug pharmacology and safety biomarker for the CNS. It is a rapidly emerging field, with some areas well established, such as stroke risk and multiple sclerosis, whereas others are still in development (Alzheimer's, Parkinson's, psychological disease and cortical diabetic dysfunction). The current applications and future potential of retinal biomarkers, including potential ways to improve their sensitivity and specificity are discussed. This review summarises the existing literature and provides a perspective on the strength of current retinal biomarkers and their future potential.

Serelaxin in acute heart failure patients with and without atrial fibrillation: a secondary analysis of the RELAX-AHF trial

BackgroundAtrial fibrillation (AFib) is a common comorbidity in HF and affects patients’ outcome. We sought to assess the effects of serelaxin in patients with and without AFib.MethodsIn a post hoc analysis of the RELAX-AHF trial, we compared the effects of serelaxin on efficacy end points, safety end points and biomarkers in 1161 patients with and without AFib on admission electrocardiogram.ResultsAFib was present in 41.3% of patients. Serelaxin had a similar effect in patients with and without AFib, including dyspnea relief by visual analog scale through day 5 [mean change in area under the curve, 541.11 (33.79, 1048.44), p = 0.0366 in AFib versus 361.80 (−63.30, 786.90), p = 0.0953 in non-AFib, interaction p = 0.5954] and all-cause death through day 180 [HR = 0.42 (0.23, 0.77), p = 0.0051 in AFib versus 0.90 (0.53, 1.52), p = 0.6888 in non-AFib, interaction p = 0.0643]. Serelaxin was similarly safe in the two groups and induced similar reductions in biomarkers of cardiac, renal and hepatic damage. Stroke occurred more frequently in AFib patients (2.8 vs. 0.8%, p = 0.0116) and there was a trend for lower stroke incidence in the serelaxin arm in AFib patients (odds ratios, 0.31, p = 0.0759 versus 3.88, p = 0.2255 in non-AFib, interaction p = 0.0518).ConclusionsSerelaxin was similarly safe and efficacious in improving short- and long-term outcomes and inducing organ protection in acute HF patients with and without AFib.

T-ACT (WJOG7112G): A randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum.

TPS218 Background: Trastuzumab (Tmab) is a key drug for HER2 positive breast and gastric or gastro-esophageal junction (G/GEJ) cancer. While use of Tmab beyond progression (TBP) showed a benefit in HER2-positive metastatic breast cancer, clinical significance of TBP for HER2-positive G/GEJ cancer has not been clarified. Objective:This study compares the efficacy of paclitaxel (PTX) + Tmab with PTX alone in patients with unresectable or metastatic HER2-positive G/GEJ cancer who failed first-line chemotherapy with Tmab + fluoropyrimidine + platinum. Methods: Enrolled patients will be randomized to receive PTX (80 mg/m2, on day 1, 8 15, every 4 weeks) + Tmab (8 mg/kg loading dose and 6 mg/kg thereafter, on day 1, every 3 weeks) or PTX alone. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, time to treatment failure, response rate, disease control rate, safety, and translational biomarker research. A total of 69 events are required to achieve 80% power for one-sided log rank test with 10% significance level, expecting the median PFS of the PTX and the PTX + Tmab arms will be 3 and 5 months. In consideration of patient with censoring and dropout, the planned sample size is totally 90 patients. Major eligibility criteria are: HER2-positive advanced G/GEJ adenocarcinoma; refractory to first-line chemotherapy with fluoropyrimidine, platinum, and Tmab (at least three doses); within 6 weeks after last Tmab administration; no prior therapy with taxane or anti-HER2 drugs except Tmab; ECOG PS 0-2; adequate organ function; left ventricular ejection fraction ≥ 50%. Tumor tissue, blood serum, and circulating tumor DNA are collected before the study treatment for biomarker analyses to explore the predictive marker of the TBP strategy. As of September 2016, 89 patients were randomized. Clinical trial information: 000009297.

Nivolumab dose escalation and expansion in patients with advanced hepatocellular carcinoma (HCC): The CheckMate 040 study.

226 Background: HCC diagnosed at advanced stages has a poor prognosis. Patients who progress on sorafenib have few options. Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), has demonstrated clinical and survival benefit in a number of tumor types. Here we report updated interim analyses of safety, efficacy, and exploratory biomarkers in patients with advanced HCC treated with nivolumab in the CheckMate 040 study (NCT01658878). Methods: Patients enrolled had advanced HCC with or without hepatitis C or B virus (HCV or HBV) infection. Prior sorafenib was allowed. Phase 1 dose-escalation evaluated nivolumab (0.1–10 mg/kg) Q2W. Phase 2 dose-expansion was initiated in 4 cohorts: sorafenib naïve/intolerant, sorafenib progressors, HCV infected, and HBV infected. All cohorts received nivolumab 3 mg/kg Q2W. The primary endpoint in the dose-escalation phase was safety/tolerability, and the primary endpoint in the dose-expansion phase was objective response rate (ORR) by RECIST v1.1 (central review). Secondary endpoints included duration of response (DOR), disease control rate (DCR), and overall survival (OS). Biomarkers within pre-treatment tumors were assessed. Results: Across dose escalation and expansion phases, 262 patients have been treated. Grade 3/4 treatment-related adverse events occurred in 20%. No maximum tolerated dose was reached during dose escalation (n = 48). The ORR (investigator-assessed) was 20% (95% CI 15–26) in 214 patients treated in the dose expansion phase with a median DoR of 9.9 months; DCR was 64% (95% CI 58–71). Responses were observed across etiologies and regardless of tumor PD-L1 expression. ORRs of 23% (95% CI 13–36) and 21% (95% CI 11–34) were observed in the uninfected sorafenib-naive and -treated patients, respectively. The 9-month overall survival rate in the expansion phase was 74% (95% CI 67–79). Association between immune-cell biomarkers and clinical outcomes will be presented. Conclusions: In this heavily pretreated population, responses to nivolumab were durable with encouraging overall survival. Safety was manageable and consistent with that observed in other solid tumors with no new safety signals. Clinical trial information: NCT01658878.

Updated efficacy, safety, and biomarker analyses of STEAM, a randomized, open-label, phase II trial of sequential (s) and concurrent (c) FOLFOXIRI-bevacizumab (BV) vs FOLFOX-BV for first-line (1L) treatment (tx) of patients with metastatic colorectal cancer (mCRC).

657 Background: STEAM (NCT01765582) assessed efficacy and safety of 1L cFOLFOXIRI-BV and sFOLFOXIRI-BV vs FOLFOX-BV. Updated efficacy, safety, and exploratory biomarker data are reported. Methods: 280 tx-naive pts with mCRC were randomized 1:1:1 to BV-containing (5 mg/kg q2w) arms (cFOLFOXIRI, sFOLFOXIRI [alternating FOLFOX and FOLFIRI every 4 weeks {q4w}], or FOLFOX) in a 4–6 month (mo) induction phase, followed by maintenance. Primary objectives include progression-free survival (PFS). Secondary objectives include overall survival (OS). Tumor-relevant biomarker evaluations were exploratory. Results: Median PFS significantly improved and median OS showed a positive trend with cFOLFOXIRI-BV vs FOLFOX-BV. PFS significantly improved with cFOLFOXFIRI-BV vs FOLFOX-BV in BRAF wild type (WT); there was a positive trend in RAS WT and mutant (MUT) pts; no tx difference observed in BRAF MUT pts. In the safety pop., (n = 271), 88% had Grade ≥ 3 tx emergent AEs: 91% cFOLFOXIRI-BV; 87% sFOLFOXIRI-BV; 86% FOLFOX-BV. Conclusions: Improved PFS and a positive trend in OS were observed for cFOLFOXIRI-BV vs FOLFOX-BV. A positive PFS trend was seen in RAS WT and MUT pts, with significantly improved PFS in BRAF WT. The small number of BRAF MUT pts precluded estimation of tx effects. AEs for all 3 txs were consistent with previous reports. Clinical trial information: NCT01765582. [Table: see text]

THE ADDED VALUE OF A MULTICOUNTRY NETWORK FOR PROMOTING ETHICAL AND REGULATORY STANDARDS IN CLINICAL TRIALS IN LOW- AND MIDDLE-INCOME COUNTRIES: THE EXPERIENCE OF THE ‘SWITCHING THE POLES NETWORK’

BackgroundIn 2008, we created the ‘Switching The Poles’ Clinical Research Network, by joining the forces of non-commercial clinical research groups in Benin, Burkina Faso, Cambodia, Cuba, the Democratic Republic of...

Effects of a purified krill oil phospholipid rich in long-chain omega-3 fatty acids on cardiovascular disease risk factors in non-human primates with naturally occurring diabetes type-2 and dyslipidemia

BackgroundHigh serum levels of cholesterol, in particular low-density lipoprotein cholesterol, are considered a significant risk factor for development of cardiovascular disease. Therefore, rigorous treatment regimens with statins and other pharmaceuticals have been used extensively to reduce elevated cholesterol levels. Literature data have not clearly concluded whether long-chain omega-3 fatty acids reduce, increase or leave circulating cholesterol unaffected. In the present study a novel krill-oil derived preparation of omega-3 rich phospholipids, mainly phosphatidylcholine, was administered orally at increasing doses for 12 weeks to dyslipidemic non-human primates, and cholesterols and several other risk factors for cardiovascular disease were measured before, during and after treatment.MethodsSix dyslipidemic non-human primates suffering from naturally occurring diabetes type-2 were included, three in a vehicle control group and three being treated with the omega-3 rich phospholipid preparation. The control and test items were given daily by gavage and the doses of the test item were 50, 150 and 450 mg phospholipids/kg/day. Each dose level was given for 4 weeks. Plasma concentrations of the omega-3 fatty acids were measured in connection with change in dose and the omega-3 index in erythrocytes was determined bi-weekly. Blood lipids, apolipoproteins and diabetes, inflammatory and safety biomarkers were determined either weekly, biweekly or every 4 weeks. For the blood lipids and apolipoproteins, control-adjusted mean values are presented while absolute values are presented for the other parameters. Due to the low number of animals in each group, no statistical analyses were done.ResultsThe only detectable effects measured during dosing with the lowest dose were an increase in HDL-cholesterol and apolipoprotein A1. The intermediate and high doses decreased total cholesterol, LDL-cholesterol, apolipoprotein B100 and triglycerides and increased HDL-cholesterol and apolipoprotein A1. No effects were seen on the diabetes and inflammatory markers and on safety biomarkers.ConclusionsThe results indicate that the omega-3 rich phospholipid preparation had a positive impact on cardiovascular disease risk factors by reducing total cholesterol, LDL-cholesterol and triglycerides and increasing HDL-cholesterol. These findings justify further investigations of this preparation in animal models of dyslipidemia and, provided the current findings are confirmed, in human trials.

OA03.02 Atezolizumab as 1L Therapy for Advanced NSCLC in PD-L1–Selected Patients: Updated ORR, PFS and OS Data from the BIRCH Study

Atezolizumab, a humanized anti-PDL1 mAb, inhibits the PD-L1/PD-1 pathway to restore tumor-specific T-cell immunity, resulting in durable anti-tumor effects. BIRCH (NCT02031458) is a single-arm Phase II study of atezolizumab monotherapy in PD-L1–selected advanced NSCLC patients, across multiple therapy lines. Primary analyses (median follow-up, 8.5 months) demonstrated a meaningful ORR with durable response in chemotherapy-naive 1L and 2L+ PD-L1–selected patients. Here we report updated efficacy data in 1L patients. 1L eligibility criteria included PD-L1–selected, advanced-stage NSCLC with no CNS metastases or prior chemotherapy. PD-L1 was centrally evaluated (VENTANA SP142 IHC assay). Patients expressing PD-L1 on ≥5% of tumor cells (TC) or tumor-infiltrating immune cells (IC), ie, TC2/3 or IC2/3, were enrolled. Patients with EGFR mutation or ALK rearrangement must have had prior TKI treatment. Atezolizumab 1200mg was administered IV q3w until radiographic disease progression or unacceptable toxicity. The primary endpoint was independent review facility(IRF)-assessed ORR. Secondary endpoints included investigator(INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS. With a median follow-up of 14.6 months, median OS was not reached in TC3 or IC3 patients and was 20.1 months in TC2/3 or IC2/3 (ITT) patients; INV-assessed ORR was 32% and 24%, respectively (Table). Furthermore, ORR was 31% for mutant EGFR (n=13) vs 20% for wild-type EGFR patients (n=104), and 27% for mutant KRAS (n=33) vs 21% for wild-type KRAS patients (n=67). No new safety signals were observed. Updated efficacy (including IRF ORR), safety and exploratory biomarker analyses will be presented. With longer follow-up, atezolizumab continued to demonstrate promising efficacy in 1L NSCLC. These results indicate that atezolizumab has durable efficacy in the 1L setting, in EGFR and KRAS mutant and wild-type tumors, and support ongoing Phase III trials evaluating atezolizumab vs chemotherapy in 1L NSCLC.Tabled 1Endpoint (95% CI)TC3 or IC3a (n=65)TC2/3 or IC2/3b (n=139)INV ORR, %32% (21.2–45.1)24% (16.9–31.7)EGFR mutant/wild-type, %25%/29%31%/20%KRAS mutant/wild-type, %38%/27%27%/21%mDOR, mo13.1 (8.5–NE)13.1 (9.9–17.5)mOS, moNE (12.0–NE)20.1 (20.1–NE)12-mo OS rate, %61% (48.8–73.8)66% (57.9–74.5)mPFS, mo7.3 (4.9–12.0)7.3 (5.6–9.1)12-mo PFS rate, %36% (23.8–48.8)32% (24.0–40.7)NE, not estimable.a TC ≥50% or IC ≥10% PD-L1–expressing cells.b TC or IC ≥5% PD-L1–expressing cells. Open table in a new tab

Targeted drugs and diagnostic assays: Companions in the race to combat ethnic disparity.

African Americans (AAs) are more likely than European Americans to develop aggressive breast cancer subtypes, and have higher recurrence and mortality rates; this results in a stark breast-cancer related ethnic disparity in clinical outcomes. In this era of personalized oncology, companion diagnostics (CDx) are transforming the cancer treatment narrative slowly but steadily, by enabling the use of safety and/or efficacy biomarkers to stratify patient populations, and thus ensuring more effective deployment of targeted therapeutics. This parallel co-development of drugs and in vitro diagnostic assays is turning out to be the cornerstone of individualized cancer treatment. In this review, we assert that development of drugs and CDx targeted towards molecular and centrosomal aberrations that occur more frequently in AAs could yield next generation precision medicine tools better informed and inspired by, and more finely attuned to the unique tumor biology of AAs. By understanding more deeply ancestry-associated differences among breast tumors of different ethnicities, and gearing our drug and CDx development efforts to target these distinctions, we might be able to significantly alleviate racial health disparity.

Novel circulating- and imaging-based biomarkers to enhance the mechanistic understanding of human drug-induced liver injury

Liver safety biomarkers in current clinical practice are recognized to have certain shortcomings including their representation of general cell death and thus lacking in indicating the specific underlying mechanisms of injury. An informative panel of circulating- and imaging-based biomarkers, will allow a more complete understanding of the processes involved in the complex and multi-cellular disease of drug-induced liver injury; potentially preceding and therefore enabling prediction of disease progression as well as directing appropriate, existing or novel, therapeutic strategies. Several putative liver safety biomarkers are under investigation as discussed throughout this review, informing on a multitude of hepatocellular mechanisms including: early cell death (miR-122), necrosis (HMGB1, K18), apoptosis, (K18), inflammation (HMGB1), mitochondrial damage (GLDH, mtDNA), liver dysfunction (MRI, MSOT) and regeneration (CSF1). These biomarkers also hold translational value to provide important read across between in vitro-in vivo and clinical test systems. However, gaps in our knowledge remain requiring further focussed research and the ultimate qualification of key exploratory biomarkers. Relevance for patients: this novel multi-modal approach of assessing drug-induced liver injury could potentially enable better patient stratification and enhance treatment strategies. Ultimately, this could reduce unnecessary treatment, also decreasing hospital bed occupancy, whilst ensuring early and accurate identification of patients needing intervention.

Molecular Markers of Radiation Induced Attenuation in Intrahepatic Plasmodium falciparum Parasites.

Experimental immunization with radiation attenuated sporozoites (RAS) and genetically attenuated sporozoites has proved to be a promising approach for malaria vaccine development. However, parasite biomarkers of growth attenuation and enhanced immune protection in response to radiation remain poorly understood. Here, we report on the effect of an attenuating dose of γ-irradiation (15 krad) on the Plasmodium falciparum sporozoite (PfSPZ) ultrastructure by electron microscopy, growth rate of liver stage P. falciparum in liver cell cultures, and genome-wide transcriptional profile of liver stage parasites by microarray. We find that γ-irradiation treated PfSPZ retained a normal cellular structure except that they were vacuous with a partially disrupted plasma membrane and inner membrane complex. A similar infection rate was observed by γ-irradiation-treated and untreated PfSPZ in human HCO-4 liver cells (0.47% versus 0.49%, respectively) on day 3 post-infection. In the microarray studies, cumulatively, 180 liver stage parasite genes were significantly transcriptionally altered on day 3 and/or 6 post-infection. Among the transcriptionally altered biomarkers, we identified a signature of seven candidate parasite genes that associated with functionally diverse pathways that may regulate radiation induced cell cycle arrest of the parasite within the hepatocyte. A repertoire of 14 genes associated with protein translation is transcriptionally overexpressed within the parasite by radiation. Additionally, 37 genes encode proteins expressed on the cell surface or exported into the host cell, 4 encode membrane associated transporters, and 10 encode proteins related to misfolding and stress-related protein processing. These results have significantly increased the repertoire of novel targets for 1) biomarkers of safety to define proper attenuation, 2) generating genetically attenuated parasite vaccine candidates, and 3) subunit candidate vaccines against liver stage malaria.

In Vivo Imaging in Pharmaceutical Development and Its Impact on the 3Rs.

It is well understood that the biopharmaceutical industry must improve efficiency along the path from laboratory concept to commercial product. In vivo imaging is recognized as a useful method to provide biomarkers for target engagement, treatment response, safety, and mechanism of action. Imaging biomarkers have the potential to inform the selection of drugs that are more likely to be safe and effective. Most of the imaging modalities for biopharmaceutical research are translatable to the clinic. In vivo imaging does not require removal of tissue to provide biomarkers, thus reducing the number of valuable preclinical subjects required for a study. Longitudinal imaging allows for quantitative intra-subject comparisons, enhancing statistical power, and further reducing the number of subjects needed for the evaluation of treatment effects in animal models. The noninvasive nature of in vivo imaging also provides a valuable approach to alleviate or minimize potential pain, suffering or distress.

A quantitative systems pharmacology model of blood coagulation network describes in vivo biomarker changes in non‐bleeding subjects

Background Prothrombin fragment1+2 (F1+2 ), thrombin-antithrombinIII complex (TAT) and D-dimer can be detected in plasma from non-bleeding hemostatically normal subjects or hemophilic patients. They are often used as safety or pharmacodynamic biomarkers for hemostatis-modulating therapies in the clinic, and provide insights into invivo coagulation activity. Objectives To develop a quantitative systems pharmacology (QSP) model of the blood coagulation network to describe invivo biomarkers, including F1+2 , TAT, and D-dimer, under non-bleeding conditions. Methods The QSP model included intrinsic and extrinsic coagulation pathways, platelet activation state-dependent kinetics, and a two-compartment pharmacokinetics model for recombinant activated factorVII (rFVIIa). Literature data on F1+2 and D-dimer at baseline and changes with rFVIIa treatment were used for parameter optimization. Multiparametric sensitivity analysis (MPSA) was used to understand key proteins that regulate F1+2 , TAT and D-dimer levels. Results The model was able to describe tissue factor (TF)-dependent baseline levels of F1+2 , TAT and D-dimer in a non-bleeding state, and their increases in hemostatically normal subjects and hemophilic patients treated with different doses of rFVIIa. The amount of TF required is predicted to be very low in a non-bleeding state. The model also predicts that these biomarker levels will be similar in hemostatically normal subjects and hemophilic patients. MPSA revealed that F1+2 and TAT levels are highly correlated, and that D-dimer is more sensitive to the perturbation of coagulation protein concentrations. Conclusions A QSP model for non-bleeding baseline coagulation activity was established with data from clinically relevant invivo biomarkers at baseline and changes in response to rFVIIa treatment. This model will provide future mechanistic insights into this system.

Promoting Adoption of the 3Rs through Regulatory Qualification.

One mechanism to advance the application of novel safety assessment methodologies in drug development, including in silico or in vitro approaches that reduce the use of animals in toxicology studies, is regulatory qualification. Regulatory qualification, a formal process defined at the the U. S. Food and Drug Administration and the European Medicines Agency, hinges on a central concept of stating an appropriate "context of use" for a novel drug development tool (DDT) that precisely defines how that DDT can be used to support decision making in a regulated drug development setting. When accumulating the data to support a particular "context-of-use," the concept of "fit-for-purpose" often guides assay validation, as well as the type and amount of data or evidence required to evaluate the tool. This paper will review pathways for regulatory acceptance of novel DDTs and discuss examples of safety projects considered for regulatory qualification. Key concepts to be considered when defining the evidence required to formally adopt and potentially replace animal-intensive traditional safety assessment methods using qualified DDTs are proposed. Presently, the use of qualified translational kidney safety biomarkers can refine and reduce the total numbers of animals used in drug development. We propose that the same conceptual regulatory framework will be appropriate to assess readiness of new technologies that may eventually replace whole animal models.

The Predictive Safety Testing Consortium: safety bio-markers, collaboration, and qualification

The Predictive Safety Testing Consortium (PSTC) is one of nine consortia comprising the Critical Path Institute (C-Path), a non-profit organisation launched in 2005 and dedicated to playing the role of a catalyst in the development of new approaches that advance medical innovation and regulatory science. C-Path achieves this by lead-ing teams that share data, knowledge and expertise resulting in sound, consensus-based science. PSTC is a unique, public-private partnership that brings pharmaceutical companies together to share and validate safety testing methods under the advisement of worldwide regulatory agencies, including the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). The eighteen corporate members of PSTC share a common goal: to find improved safety testing methods and approaches utilizing fluid-based safety biomarkers which accurately predict drug-induced tissue injury. Specifically, the primary goal of PSTC is the qualification of novel translational safety biomarkers for use in early clinical trials in order to ena-ble safer investigations and development of new drug candidates. This manuscript describes the critical importance of improved safety biomarkers to the drug development process and the present state of the biomarker qualification process with regulatory agencies. In addition, the work that the PSTC and its collaborative partners have done and con-tinue to do to identify and qualify more selective and specific safety biomarkers is highlighted. Finally, successes in-cluding the recently adopted regulatory Letter of Support and ongoing efforts to better define the regulatory qualifica-tion process and an integrated translational safety strategy are also discussed.

1425PD - Clinical activity, safety and predictive biomarkers results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC)

1425PD - Clinical activity, safety and predictive biomarkers results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC)