Safety and Efficacy of Avacopan in Patients with C3 Glomerulopathy: Randomized, Double-Blind Clinical Trial.

BACKGROUND: Complement 3 (C3) glomerulopathy is a rare autoimmune disorder characterized by activation of the alternative complement pathway with isolated or dominant C3 deposition in glomeruli. Patients with C3 glomerulopathy may develop progressive deterioration in kidney function and kidney failure. METHODS: We studied the safety and efficacy of avacopan 30 mg twice daily in patients with C3 glomerulopathy (N=57) with elevated (> 244 ng/mL) and normal (≤ 244 ng/mL) levels of C5b-9 in a randomized, double-blind, placebo-controlled, phase 2 trial, with kidney biopsies performed pre-randomization and at 26 and 52 weeks. The primary outcome was the percent change from baseline to week 26 in C3 glomerulopathy histologic index for disease activity. RESULTS: The study was conducted in patients with C3 glomerulopathy, including C3 glomerulonephritis and DDD. The median study duration was 60.0 weeks (interquartile range 59.9 to 61.0). There were no significant differences in the primary outcome between the avacopan and the placebo group; least square mean treatment difference (95% CI) = -0.0 (-1.9 to 1.8). The secondary measures of efficacy including C3 Glomerulopathy Histological Index for disease chronicity, urine protein:creatinine ratio (UPCR), and estimated glomerular filtration rate (eGFR) were not different between treatment groups. The overall incidence and type of adverse events for both treatment groups were comparable. No deaths were reported during the study, and no new safety signals were detected. CONCLUSIONS: The primary end point for the study was not met; other clinical effects of avacopan to improve certain key kidney function parameters and slow disease progression were variable and require further evaluation.

Efficacy and safety of avacopan in patients with ANCA-associated vasculitis receiving rituximab in a randomised trial.

OBJECTIVES: To evaluate the efficacy and safety of avacopan in the subgroup of patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis receiving background induction therapy with rituximab in the phase 3 ADVOCATE trial. METHODS: Key efficacy outcomes were remission at week 26 and sustained remission at week 52. Additional outcomes included the Glucocorticoid Toxicity Index, estimated glomerular filtration rate, urinary albumin to creatinine ratio, health-related quality of life and safety. RESULTS: Of the 330 patients who received study medication, 214 (64.8%) received rituximab (once weekly for 4 weeks), with a mean age of 59.8 years; 163 (76.2%) had renal vasculitis and 125 (58.4%) were newly diagnosed. Remission at week 26 and sustained remission at week 52 were achieved by 83/107 (77.6%) and 76/107 (71.0%) patients in the avacopan group and 81/107 (75.7%) and 60/107 (56.1%) in the prednisone taper group, respectively. The relapse rate, recovery of renal function, speed of reduction in albuminuria and glucocorticoid toxicity favoured the avacopan group. Serious adverse events occurred in 34.6% and 39.3% of patients in the avacopan and prednisone taper groups, respectively. CONCLUSIONS: These data suggest that in patients with ANCA-associated vasculitis receiving rituximab, efficacy of treatment with avacopan compared with a prednisone taper was similar at week 26 and greater at week 52, with a favourable safety profile. In addition, avacopan was associated with improved renal outcomes and lower glucocorticoid toxicity. These results demonstrate the efficacy and safety of avacopan in patients receiving background induction therapy with rituximab. TRIAL REGISTRATION NUMBER: NCT02994927.

Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial.

BACKGROUND: About half of patients with papillary thyroid cancer have tumours with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer. METHODS: We did an open-label, non-randomised, phase 2 trial at ten academic centres and hospitals worldwide in patients aged 18 years or older with histologically confirmed recurrent or metastatic papillary thyroid cancer refractory to radioactive iodine and positive for the BRAF(V600E) mutation. Participants either had never received a multikinase inhibitor targeting VEGFR (cohort 1) or had been treated previously with a VEGFR multikinase inhibitor (cohort 2). Patients received vemurafenib 960 mg orally twice daily. The primary endpoint was investigator-assessed best overall response in cohort 1 (confirmed on two assessments 4 weeks or longer apart). Analyses were planned to have a minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done in safety, intention-to-treat, and per-protocol populations. This trial is closed and is registered at ClinicalTrials.gov, number NCT01286753. FINDINGS: Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 18·8 months (IQR 14·2-26·0) in cohort 1 and 12·0 months (6·7-20·3) in cohort 2. Partial responses were recorded in ten of 26 patients in cohort 1 (best overall response 38·5%, 95% CI 20·2-59·4). Grade 3 or 4 adverse events were recorded in 17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the most common grade 3 and 4 adverse events were squamous cell carcinoma of the skin (seven [27%] in cohort 1, five [20%] in cohort 2), lymphopenia (two [8%] in each cohort), and increased γ-glutamyltransferase (one [4%] in cohort 1, three [12%] in cohort 2). Two individuals in cohort 2 died due to adverse events, one from dyspnoea and one from multiorgan failure, but neither was treatment related. Serious adverse events were reported for 16 (62%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2. INTERPRETATION: Vemurafenib showed antitumour activity in patients with progressive, BRAF(V600E)-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients. FUNDING: F Hoffmann-La Roche.

Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC.

BACKGROUND: Primary analysis from the pivotal ERIVANCE BCC study resulted in approval of vismodegib, a Hedgehog pathway inhibitor indicated for treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC) that has recurred after surgery or for patients who are not candidates for surgery or radiation. OBJECTIVE: An efficacy and safety analysis was conducted 12 months after primary analysis. METHODS: This was a multinational, multicenter, nonrandomized, 2-cohort study in patients with measurable and histologically confirmed locally advanced or metastatic BCC taking oral vismodegib (150 mg/d). Primary outcome measure was objective response rate (complete and partial responses) assessed by independent review facility. RESULTS: After 12 months of additional follow-up, median duration of exposure to vismodegib was 12.9 months. Objective response rate increased from 30.3% to 33.3% in patients with metastatic disease, and from 42.9% to 47.6% in patients with the locally advanced form. Median duration of response in patients with locally advanced BCC increased from 7.6 to 9.5 months. No new safety signals emerged with extended treatment duration. LIMITATIONS: Limitations include low prevalence of advanced BCC and challenges of designing a study with heterogenous manifestations. CONCLUSION: The 12-month update of the study confirms the efficacy and safety of vismodegib in management of advanced BCC.

Clinical benefit assessment of vismodegib therapy in patients with advanced basal cell carcinoma.

PURPOSE: Vismodegib was approved for the treatment of advanced basal cell carcinoma (aBCC) based on the pivotal ERIVANCE BCC study. The primary endpoint (objective response rate [ORR]) was assessed 9 months after the last patient was enrolled. To confirm the clinical benefit of vismodegib, an additional analysis was performed 12 months after the primary analysis. MATERIALS AND METHODS: ERIVANCE BCC was a multicenter, nonrandomized, two-cohort study of 104 patients with histologically confirmed aBCC. Patients received 150 mg oral vismodegib daily until disease progression, intolerable toxicity, or withdrawal. An independent review panel comprising three expert clinicians reviewed patient photographs individually and as a consensus panel to evaluate baseline disease severity and clinical benefit after vismodegib treatment in 71 patients with locally advanced BCC (laBCC). RESULTS: Sixty-three patients were efficacy evaluable; baseline and postprogression photographs for 61 were available for review. Baseline disease severity was judged as 5 or 4 (very severe or moderately severe) in 71.4%. Clinical benefit was observed in 76.2% (significant: 65.1%; some: 11.1%). Interpanelist agreement (maximum difference ≤1 point among panelists' scores in 65.1% and 87.3% of patients for clinical benefit and baseline disease severity, respectively) and correlation between individual and panel reviews were strong. Clinical benefit scores showed good concordance with the protocol-specified ORR obtained by an independent review facility and with investigator-assessed response. CONCLUSION: Clinical benefit assessed by independent review based on expert clinical judgment provides strong evidence that treatment with vismodegib results in clinically meaningful and durable responses in patients with laBCC.

The impact of treatment with avacopan on health-related quality of life in antineutrophil cytoplasmic antibody-associated vasculitis: a post-hoc analysis of data from the ADVOCATE trial.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterised by inflammation and destruction of small to medium sized blood vessels. In the previously reported ADVOCATE study, a phase 3 double-blind, double-dummy randomised controlled trial of patients with newly diagnosed or relapsing ANCA-associated vasculitis, the oral selective complement 5a receptor inhibitor avacopan was shown to be non-inferior with regard to remission induction at week 26 and superior with regard to sustained remission at week 52, compared with a prednisone taper in a standard of care regimen. In this Article, we report an in-depth analysis of prespecified and exploratory patient-reported outcomes from the ADVOCATE study, measuring health-related quality of life and health utilities. METHODS: We did a post-hoc analysis of patient-reported outcome data from the ADVOCATE study (NCT02994927) of patients with newly diagnosed or relapsing ANCA-associated vasculitis. We analysed summary scores and individual domain scores for the prespecified health-related quality of life outcomes from ADVOCATE, which were evaluated at weeks 26 and 52 by use of the Medical Outcomes Survey 36-Item Short Form Health Survey (SF-36) version 2, the EuroQol 5-Dimensions 5-Levels Questionnaire (EQ-5D-5L), and the EQ-5D health utility measure, assessed in the modified intention-to-treat population. We also calculated the Short Form 6 Dimension (SF-6D) score as an additional health utility measure. We evaluated the proportion of patients who reported scores that met or exceeded minimum clinically important differences in health-related quality of life, and we compared scores to normative values (age-specific and sex-specific scores from healthy populations from the USA matched to the protocol population). We also evaluated the proportion of patients who reported scores that met or exceeded minimum important difference in health utility scores. FINDINGS: 331 patients were enrolled in the ADVOCATE trial, of whom 166 were in the avacopan group and 165 were in the prednisone standard of care group. In the avacopan group, the mean age was 61·2 years (SD 14·6), 98 (59%) of 166 patients were men, 68 (41%) were women, and 138 (83%) were White; in the prednisone group, the mean age was 60·5 years (14·5), 88 (54%) of 164 patients were men, 76 (46%) were women, and 140 (85%) were White. Patients treated with avacopan received approximately 2500 mg less median total prednisone up to week 52. Least squares means difference from baseline in physical component summary scores were significantly greater in patients in the avacopan group compared with those in the prednisone group at weeks 26 and 52, as well as in five of eight SF-36 domains at week 26 and two of eight SF-36 domains at week 52. The proportion of patients reporting scores equal to or greater than normative values was higher in the avacopan group than in the prednisone group across all SF-36 domains at both week 26 and 52, although the differences were not statistically significant with the exception of the role physical and vitality domains at week 26. Least squares means change from baseline in EQ-5D-5L visual analogue scale, EQ-5D health utility scores, and SF-6D health utility scores were significantly greater at week 52 in the avacopan group compared with the prednisone group. INTERPRETATION: Patients with ANCA-associated vasculitis who received avacopan reported statistically significant and clinically meaningful improvements in health-related quality of life at 26 and 52 weeks and in health utility EQ-5D and SF-6D scores at 52 weeks. These patient-reported outcomes complement investigator assessments and support the efficacy of avacopan in patients with ANCA-associated vasculitis with use of lower prednisone doses. FUNDING: ChemoCentryx.

Renal Recovery for Patients with ANCA-Associated Vasculitis and Low eGFR in the ADVOCATE Trial of Avacopan.

Introduction: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased on average 7.3 ml/min per 1.73 m2 in the avacopan group and 4.1 ml/min per 1.73 m2 in the prednisone group (P = 0.029) at week 52. This new analysis examines the results in the patient subgroup with severe renal insufficiency at enrollment into the trial, i.e., eGFR ≤20 ml/min per 1.73 m2. Methods: eGFR was determined at baseline and over the course of the trial. Changes in eGFR were compared between the 2 treatment groups. Results: In ADVOCATE, 27 of 166 patients (16%) in the avacopan group and 23 of 164 patients (14%) in the prednisone group had a baseline eGFR ≤20 ml/min per 1.73 m2. At week 52, eGFR increased on average 16.1 and 7.7 ml/min per 1.73 m2 in the avacopan and prednisone groups, respectively (P = 0.003). The last eGFR value measured during the 52-week treatment period was ≥2-fold higher than baseline in 41% of patients in the avacopan group compared to 13% in the prednisone group (P = 0.030). More patients in the avacopan group versus prednisone group had increases in eGFR above 20, 30, and 45 ml/min per 1.73 m2, respectively. Serious adverse events occurred in 13 of 27 patients (48%) in the avacopan group and 16 of 23 patients (70%) in the prednisone group. Conclusion: Among patients with baseline eGFR ≤20 ml/min per 1.73 m2 in the ADVOCATE trial, eGFR improved more in the avacopan group than in the prednisone group.

Glucocorticoid Toxicity Index scores by domain in patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with avacopan versus standard prednisone taper: post-hoc analysis of data from the ADVOCATE trial.

BACKGROUND: The ADVOCATE trial, in which the complement C5a receptor inhibitor avacopan was compared with a standard prednisone taper in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, used the Glucocorticoid Toxicity Index (GTI) to measure glucocorticoid toxicity change. We set out to do a post-hoc analysis of the ADVOCATE data to evaluate changes in individual GTI domains and their ability to differentiate treatment groups. METHODS: The ADVOCATE trial was a phase 3, double-blind, double-dummy, randomised trial comparing oral avacopan (30 mg) twice daily for 52 weeks plus a prednisone-matching placebo for 20 weeks with oral prednisone tapered over 20 weeks plus an avacopan-matching placebo for 52 weeks in patients with ANCA-associated vasculitis. GTI data were collected within each of the included domains (BMI, blood pressure, glucose tolerance, lipid metabolism, glucocorticoid myopathy, skin toxicity, neuropsychiatric effects, and infections) at baseline, 13 weeks, and 26 weeks. In this post-hoc analysis, we calculated the cumulative worsening score (CWS) and aggregate improvement score (AIS) for each GTI domain, assessed to what extend each domain contributed to the GTI score, and which domains differentiated between the avacopan and prednisone groups. Differences in domain scores between the two groups were compared using Mantel-Haenszel χ2 tests. FINDINGS: Among the 330 patients included in the intention-to-treat population of the ADVOCATE trial, 321 (97%) had complete data at week 13 (160 in the avacopan group, and 161 in the prednisone group), and 307 (93%) had complete data at week 26 (154 in the avacopan group, and 153 in the prednisone group) and were assessed in this post-hoc study. In ADVOCATE, mean age in both groups was 61 years (61·2 years [SD 14·6] in the avacopan group; 60·5 years [14·5] in the prednisone group); 98 (59%) of 166 patients in the avacopan group were men and 68 (41%) were women; 88 (54%) of 164 patients in the prednisone group were men and 76 (46%) were women. 278 (84%) of 330 patients were White. The mean glucocorticoid use over 26 weeks was lower in the avacopan group than the prednisone group (1073 mg [SD 1669] vs 3192 mg [1174]). Significantly less glucocorticoid toxicity was observed in the avacopan group than the prednisone group by week 13 in four domains of the GTI (BMI, glucose tolerance, lipid metabolism, and skin toxicity), based on both the CWS and AIS. CWS values in the BMI, lipid metabolism, and skin toxicity domains were significantly lower in the avacopan group than the prednisone group at 26 weeks. No domain favoured the prednisone group for glucocorticoid toxicity reduction. 280 (91%) of 307 patients had glucocorticoid toxicity at 26 weeks. Blood pressure (35% in the avacopan group vs 25% in the prednisone group), infection (22% vs 24%), and lipid metabolism (20% vs 15%) contributed the most weight toward CWS values at 26 weeks. 128 (42%) of 307 patients had combinations of improvement and worsening in different domains at 26 weeks. INTERPRETATION: Replacing a standard prednisone taper with avacopan in patients with ANCA-associated vasculitis reduced glucocorticoid toxicity in multiple GTI domains. For individual patients, glucocorticoid toxicity was often nuanced, improving in some domains while worsening in others. These findings emphasise the value of a composite measure of glucocorticoid toxicity that quantifies cumulative worsening and aggregate change directly. FUNDING: ChemoCentryx.

The Glucocorticoid Toxicity Index-Metabolic Domains, an abridged version of the Glucocorticoid Toxicity Index: post-hoc analysis of data from the ADVOCATE trial.

BACKGROUND: Quantifying glucocorticoid toxicity is crucial to efforts to reduce it. The Glucocorticoid Toxicity Index (GTI) measures toxicity effectively in clinical trials by calculating two scores: the cumulative worsening score (CWS) and the aggregate improvement score (AIS). However, in clinical practice, high patient volumes limit the time available for standardised assessments. We aimed to compare the GTI with an abbreviated version of the GTI, the GTI-Metabolic Domains (GTI-MD), which could help to address this issue by using data that are collected easily at routine visits and do not require additional effort from clinicians. METHODS: We did a post-hoc analysis of data from ADVOCATE, a randomised, double-blind, double-dummy, phase 3 trial in which avacopan replaced a standard prednisone taper in patients with antineutrophil cytoplasmic antibody-associated vasculitis. We calculated the cumulative worsening score (CWS) and aggregate improvement score (AIS) for each domain of the GTI-MD-comprising the BMI, glucose tolerance, blood pressure, and lipid metabolism domains of the GTI-to test its ability to differentiate the avacopan and prednisone groups by glucocorticoid toxicity. Data from two additional disease cohorts, one comprising patients with asthma and the other comprising patients with autoimmune blistering disease, constituted the validation set. FINDINGS: Complete data were available for 321 (97%) of the 330 participants comprising the intention-to-treat population in the ADVOCATE trial at week 13, and 307 (93%) at week 26; data from these individuals were included in our post-hoc analysis. In ADVOCATE, 98 (59%) of 166 participants in the avacopan group were men and 68 (41%) were women, 88 (54%) of 164 in the prednisone group were men and 76 (46%) were women; the mean age of participants was 61·2 years [SD 14·6] in the avacopan group and 60·5 years [14·5] in the prednisone group. The validation cohort included 159 patients (89 with glucocorticoid-dependent asthma, of whom 40 [45%] were men and 49 [55%] were women, and 70 with autoimmune blistering disease of the skin, of whom 30 [43%] were men and 40 [57%] were women). The Spearman's rank correlation coefficient in ADVOCATE for the GTI-MD CWS with the GTI CWS for the treatment groups combined was 0·78 (95% CI 0·75-0·81; p<0·0001). The corresponding correlation for the AIS was 0·73 (0·69-0·77, p<0·0001). The GTI-MD distinguished the groups by glucocorticoid toxicity at both 13 weeks and 26 weeks. The mean GTI-MD CWS was lower in the avacopan group than in the prednisone group, consistent with less toxicity (15·9 vs 23·0 at 13 weeks [p=0·0010]; 26·7 vs 31·7 at 26 weeks [p=0·0092]). The GTI-MD AIS values were also consistent with less toxicity in the avacopan group (2·5 vs 13·0 at 13 weeks [p=0·0003], 4·4 vs 10·1 at 26 weeks [p=0·027]). A GTI-MD score of 0 corresponded to a low likelihood of toxicity in the other GTI domains. In the validation set, the Spearman's rank correlation coefficient for the GTI-MD CWS with the GTI CWS was 0·61 (95% CI 0·50-0·70; p<0·0001) and the corresponding correlation for the AIS was 0·58 (0·47-0·68; p<0·0001). INTERPRETATION: The GTI-MD correlates well with the full GTI and could be incorporated readily into routine clinic workflows without additional input from the clinician. Using the GTI-MD on the background of electronic medical records systems could help clinicians to monitor glucocorticoid toxicity longitudinally, with the goals of preventing the burden of chronic, treatment-related harms and reducing long-term costs to health systems. FUNDING: ChemoCentryx.

The glucocorticoid toxicity index: Measuring change in glucocorticoid toxicity over time.

Glucocorticoids (GCs) have been the cornerstone of treating dozens of inflammatory conditions for more than seven decades. GC toxicity is ubiquitous in both clinical trials and clinical practice, and toxicities associated with GC use are central to the experience of most patients being treated for immune-mediated conditions. These conditions span the full range of medical specialties, including rheumatology, nephrology, gastroenterology, neurology, pulmonology, ophthalmology, and others. One of the goals of novel therapies for inflammatory disease must be to diminish the effects of GC toxicity in clinically important ways, thereby differentiating these new treatments from existing approaches. Despite the importance of glucocorticoids in the treatment of inflammatory disease for more than 70 years, no reliable means of calculating the degree to which GC toxicity has worsened or improved over the course of treatment has been available. The Glucocorticoid Toxicity Index (GTI), developed by an international group of subspecialty physician experts as a clinician-facing clinical trials outcome measure, is a standardized, validated measure of the phenomenon known as GC toxicity. The purpose of the instrument is to measure change in GC toxicity between two points in time: for example, between the baseline visit and the time of the primary efficacy outcome assessment. The instrument is designed to quantify both worsening and improvement in GC toxicity. The GTI has been validated in both real-world experiences and clinical trials, including a phase 3, label-enabling trial in ANCA associated vasculitis. This article reviews the history and rationale for the development of the GTI, describes key data from validation studies, considers the minimum clinically important difference, and provides instructions for use of the instrument.

First-in-Human Phase I Study of ABBV-085, an Antibody-Drug Conjugate Targeting LRRC15, in Sarcomas and Other Advanced Solid Tumors.

PURPOSE: Leucine-rich repeat containing 15 (LRRC15) is expressed on stromal fibroblasts in the tumor microenvironment of multiple solid tumor types and may represent an interesting target for therapy, particularly in patients with sarcomas where LRRC15 is also expressed by malignant cells. ABBV-085 is a monomethyl auristatin-E antibody-drug conjugate that targets LRRC15 and showed antineoplastic efficacy in preclinical experiments. Herein, we report findings of ABBV-085 monotherapy or combination therapy in adult patients with sarcomas and other advanced solid tumors. PATIENTS AND METHODS: This first-in-human phase I study (NCT02565758) assessed ABBV-085 safety, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity. The study consisted of two parts: dose escalation and dose expansion. ABBV-085 was administered by intravenous infusion at 0.3 to 6.0 mg/kg every 14 days. RESULTS: In total, 85 patients were enrolled; 45 patients received the recommended expansion dose of 3.6 mg/kg ABBV-085 monotherapy, including 10 with osteosarcoma and 10 with undifferentiated pleomorphic sarcoma (UPS). Most common treatment-related adverse events were fatigue, nausea, and decreased appetite. The overall response rate for patients with osteosarcoma/UPS treated at 3.6 mg/kg was 20%, including four confirmed partial responses. No monotherapy responses were observed for other advanced cancers treated at 3.6 mg/kg. One patient treated with ABBV-085 plus gemcitabine achieved partial response. CONCLUSIONS: ABBV-085 appeared safe and tolerable at a dose of 3.6 mg/kg every 14 days, with preliminary antitumor activity noted in patients with osteosarcoma and UPS. Given the high unmet need in these orphan malignancies, further investigation into targeting LRRC15 in these sarcomas may be warranted.

Phase I Open-Label Study Evaluating the Safety, Pharmacokinetics, and Preliminary Efficacy of Dilpacimab in Patients with Advanced Solid Tumors.

Dilpacimab (formerly ABT-165), a novel dual-variable domain immunoglobulin, targets both delta-like ligand 4 (DLL4) and VEGF pathways. Here, we present safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data from a phase I study (trial registration ID: NCT01946074) of dilpacimab in patients with advanced solid tumors. Eligible patients (≥18 years) received dilpacimab intravenously on days 1 and 15 in 28-day cycles at escalating dose levels (range, 1.25-7.5 mg/kg) until progressive disease or unacceptable toxicity. As of August 2018, 55 patients with solid tumors were enrolled in the dilpacimab monotherapy dose-escalation and dose-expansion cohorts. The most common treatment-related adverse events (TRAE) included hypertension (60.0%), headache (30.9%), and fatigue (21.8%). A TRAE of special interest was gastrointestinal perforation, occurring in 2 patients (3.6%; 1 with ovarian and 1 with prostate cancer) and resulting in 1 death. The PK of dilpacimab showed a half-life ranging from 4.9 to 9.5 days, and biomarker analysis demonstrated that the drug bound to both VEGF and DLL4 targets. The recommended phase II dose for dilpacimab monotherapy was established as 3.75 mg/kg, primarily on the basis of tolerability through multiple cycles. A partial response was achieved in 10.9% of patients (including 4 of 16 patients with ovarian cancer). The remaining patients had either stable disease (52.7%), progressive disease (23.6%), or were deemed unevaluable (12.7%). These results demonstrate that dilpacimab monotherapy has an acceptable safety profile, with clinical activity observed in patients with advanced solid tumors.

Phase I Dose-Escalation and -Expansion Study of Telisotuzumab (ABT-700), an Anti-c-Met Antibody, in Patients with Advanced Solid Tumors.

This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5-25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for MET amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, n = 15; dose expansion, n = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia (n = 9, 20.0%) and fatigue (n = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with MET-amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors (n = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with MET-amplified advanced solid tumors.

Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1.

PURPOSE: To evaluate the efficacy and safety of ranibizumab administered monthly for three months and then quarterly in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled trial in patients with predominantly or minimally classic or occult with no classic CNV lesions. METHODS: Patients were randomized 1:1:1 to 0.3 mg ranibizumab (n = 60), 0.5 mg ranibizumab (n = 61), or sham (n = 63) treatment groups. The primary efficacy endpoint was mean change from baseline visual acuity (VA) at month 12. RESULTS: Mean changes from baseline VA at 12 months were -16.3, -1.6, and -0.2 letters for the sham, 0.3 mg, and 0.5 mg groups, respectively (P < or = .0001, each ranibizumab dose vs sham). Ranibizumab arrested CNV growth and reduced leakage from CNV. However, the treatment effect declined in the ranibizumab groups during quarterly dosing (e.g., at three months the mean changes from baseline VA had been gains of 2.9 and 4.3 letters for the 0.3 mg and 0.5 mg doses, respectively). Results of subgroups analyses of mean change from baseline VA at 12 months by baseline age, VA, and lesion characteristics were consistent with the overall results. Few serious ocular or nonocular adverse events occurred in any group. CONCLUSIONS: Ranibizumab administered monthly for three months and then quarterly provided significant VA benefit to patients with AMD-related subfoveal CNV and was well tolerated. The incidence of serious ocular or nonocular adverse events was low.

First-in-Human Phase I, Dose-Escalation and -Expansion Study of Telisotuzumab Vedotin, an Antibody-Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors.

PURPOSE: This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody-drug conjugate of the anti-c-Met monoclonal antibody ABT-700 and monomethyl auristatin E. MATERIALS AND METHODS: For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non-small-cell lung cancer (NSCLC) with c-Met-overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score ≥ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined. RESULTS: Forty-eight patients were enrolled (median age, 65 years; 35.4% NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42%), nausea (27%), constipation (27%), decreased appetite (23%), vomiting (21%), dyspnea (21%), diarrhea (19%), peripheral edema (19%), and neuropathy (17%). The most frequent Teliso-V-related grade ≥ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4% each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60%) of 58 patients with c-Met-positive NSCLC. Of 16 patients with c-Met-positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8%; 95% CI, 4.1% to 45.7%) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95% CI, 1.2 months to 15.4 months). No other patients experienced a response. CONCLUSION: Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met-positive NSCLC.

Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib.

Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated.Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3-2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0-2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7-1.8; P = 0.66).Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238-45. ©2017 AACR.

Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of disease.

PURPOSE: This review provides a description of the epidemiology and survival outcomes for cases with metastatic basal cell carcinoma (mBCC) based on published reports (1981-2011). METHODS: A literature search (MEDLINE via PubMed) was conducted for mBCC case reports published in English: 1981-2011. There were 172 cases that met the following criteria: primary BCC located on skin, metastasis confirmed by pathology and metastasis not resulting from direct tumour spread. From these, 100 mBCC cases with explicit information on follow-up time were selected for analysis. Survival analysis was conducted using Kaplan-Meier methods. RESULTS: Among 100 mBCC cases selected for analysis, including one case with Gorlin syndrome, 50% had regional metastases (RM) and 50% had distant metastases (DM). Cases with DM were younger at mBCC diagnosis (mean age, 58.0 versus 66.3 years for RM; P=0.0013). Among 93 (of 100) cases with treatment information for metastatic disease, more DM cases received chemotherapy (36.2% versus 6.5% for RM), but more RM cases underwent surgery (87.0% versus 40.4% for DM). Among all 100 cases, median survival after mBCC diagnosis was 54 months (95% confidence interval (CI), 24-72), with shorter survival in DM (24 months; 95% CI, 12-35) versus RM cases (87 months; 95% CI, 63-not evaluable). CONCLUSION: Cases with RM and DM mBCC may have different clinical courses and outcomes. Based on published reports, DM cases were younger at mBCC diagnosis, with shorter median survival than RM cases. This study provides a historical context for emerging mBCC treatments.

Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2.

PURPOSE: To evaluate efficacy and safety of quarterly (and then monthly) ranibizumab during the 2-year Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled study of the efficacy and safety of ranibizumab in subjects with subfoveal CNV with or without classic CNV secondary to AMD (PIER) study. DESIGN: Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled trial in patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). METHODS: Patients were randomized 1:1:1 to sham injection (n = 63) or 0.3 mg (n = 60) or 0.5 mg (n = 61) intravitreal ranibizumab monthly for 3 months and then quarterly. During study year 2, eligible sham-group patients crossed over to 0.5 mg ranibizumab quarterly. Later in year 2, all eligible randomized patients rolled over to 0.5 mg ranibizumab monthly. Key efficacy and safety outcomes of the 2-year trial are reported. RESULTS: At month 24, visual acuity (VA) had decreased an average of 21.4, 2.2, and 2.3 letters from baseline in the sham, 0.3 mg, and 0.5 mg groups (P < .0001 for each ranibizumab group vs sham). VA of sham patients who crossed over (and subsequently rolled over) to ranibizumab decreased across time, with an average loss of 3.5 letters 10 months after crossover. VA of 0.3 mg and 0.5 mg group patients who rolled over to monthly ranibizumab increased for an average gain of 2.2 and 4.1 letters, respectively, 4 months after rollover. The ocular safety profile of ranibizumab was favorable and consistent with previous reports. CONCLUSIONS: Ranibizumab provided significant VA benefit in patients with AMD-related CNV compared with sham injection. Ranibizumab appeared to provide additional VA benefit to treated patients who rolled over to monthly dosing, but not to patients who began receiving ranibizumab after >14 months of sham injections.