Evorpacept alone and in combination with pembrolizumab or trastuzumab in patients with advanced solid tumours (ASPEN-01): a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study.

BACKGROUND: Both innate and adaptive immune responses are important components of anticancer immunity. The CD47-SIRPα interaction could represent an important pathway used by tumour cells to evade immune surveillance. We aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and anticancer activity of evorpacept (also known as ALX148), a high-affinity CD47-blocking protein with an inactive IgG Fc region in patients with solid tumours. METHODS: We did a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study at nine hospitals and one clinic in the USA and Korea. Eligible patients for the dose-escalation and safety lead-in phases were aged 18 years or older with histological or cytological diagnosis of advanced or metastatic solid tumours with no available standard therapy, measurable or unmeasurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. In the dose-escalation phase, which used a 3 + 3 design, patients received intravenous evorpacept at either 0·3, 1, 3, or 10 mg/kg once per week in 21-day cycles, or 30 mg/kg once every other week in 28-day cycles. In the safety lead-in phase, patients were given the maximum tolerable dose of evorpacept from the dose-escalation phase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks) or intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks). In the dose-expansion phase, additional patients aged 18 years or older with second-line or later-line advanced malignancies were enrolled into three parallel cohorts: those with head and neck squamous cell carcinoma (HNSCC) and those with non-small-cell lung cancer (NSCLC) were given the maximum tolerated dose of evorpacept plus intravenous pembrolizumab (200 mg administered once every 3 weeks), and patients with HER2-positive gastric or gastroesophageal junction cancer were given the maximum tolerated dose of evorpacept plus intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks) until disease progression, voluntary withdrawal from the study, or unacceptable toxicity. The primary endpoint was the maximum tolerated dose of evorpacept administered as a single agent and in combination with pembrolizumab or trastuzumab, measured by the occurrence of dose-limiting toxicities during the first cycle, and was assessed in all patients who had received at least one dose of evorpacept. Secondary outcomes included the safety, tolerability, and antitumour activity of evorpacept, alone or in combination with pembrolizumab or trastuzumab. The primary outcome, safety, and tolerability were assessed in all patients who had received at least one dose of evorpacept, and antitumour activity was assessed in those who recieved at least one dose of study treatment and underwent at least one post-baseline tumor assessment. This trial is registered with ClinicalTrials.gov, NCT03013218. FINDINGS: Between March 6, 2017, and Feb 21, 2019, 110 patients received single-agent evorpacept (n=28), evorpacept plus pembrolizumab (n=52), or evorpacept plus trastuzumab (n=30), and were included in the safety analysis. Median follow-up was 29·1 months (95% CI not calculable [NC]-NC) in the single-agent cohort, 27·0 months (25·1-28·8) in the evorpacept plus pembrolizumab cohort, and 32·7 months (27·0-32·7) in the evorpacept plus trastuzumab cohort. Two (7%) dose-limiting toxicities in the first cycle were reported in patients who received single-agent evorpacept; neutropenia with an associated infection in one patient with gastroesophageal junction cancer who received 3 mg/kg once per week, and thrombocytopenia with associated bleeding in one patient with pancreatic cancer who received 30 mg/kg once every other week. No maximum tolerated dose was reached; the maximum administered doses were 10 mg/kg once per week or 30 mg/kg once every other week. The 10 mg/kg once per week dose was used in the expansion cohorts in combination with pembrolizumab or trastuzumab. The most common grade 3 or worse treatment-related adverse events were thrombocytopenia with single-agent evorpacept (two [7%] patients) and evorpacept plus pembrolizumab (two [4%]), and thrombocytopenia (two [7%]) and neutropenia (two [7%]) with evorpacept plus trastuzumab. In patients who received single-agent evorpacept, four treatment-related serious adverse events were reported. Five serious treatment-related adverse events related to evorpacept plus pembrolizumab were reported, and one serious adverse event related to evorpacept plus trastuzumab was reported. In response-evaluable patients in the dose-escalation phase (n=15) receiving single-agent evorpacept once per week, four (27%) had a best overall response of stable disease (two received 0·3 mg/kg, one received 3 mg/kg, and one received 10 mg/kg); in the 11 patients who received single-agent evorpacept at the highest dose of 30 mg/kg once every other week, two (18%) had stable disease. In the dose-expansion cohort, overall responses were recorded in four (20·0%; 95% CI 5·7-43·7) of 20 patients with HNSCC who received evorpacept plus pembrolizumab, in one (5·0%; 0·1-24·9) of 20 patients with NSCLC who received evorpacept plus pembrolizumab, and in four (21·1%; 6·1-45·6) of 19 patients with gastric or gastroesophageal junction cancer who received evorpacept plus trastuzumab. INTERPRETATION: The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumours. Preliminary antitumour activity results support future investigation of evorpacept combined with pembrolizumab or trastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, and NSCLC. FUNDING: ALX Oncology.

Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.

BACKGROUND: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study. METHODS: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505. FINDINGS: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9-51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5-51·4) in the nivolumab group, and 18·6 months (7·6-49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2-not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3-not reached) in the nivolumab group, and 19·9 months (16·9-24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44-0·67; p<0·0001) and for nivolumab versus ipilimumab was 0·65 (0·53-0·79; p<0·0001). Median progression-free survival was 11·5 months (95% CI 8·7-19·3) in the nivolumab plus ipilimumab group, 6·9 months (5·1-10·2) in the nivolumab group, and 2·9 months (2·8-3·2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0·42 (95% CI 0·35-0·51; p<0·0001) and for nivolumab versus ipilimumab was 0·53 (0·44-0·64; p<0·0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis. INTERPRETATION: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma. FUNDING: Bristol-Myers Squibb.

Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma.

PURPOSE: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. METHODS: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis. RESULTS: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm. CONCLUSION: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

Long-term Overall Survival and Predictors in Anti-PD-1-naive Melanoma Patients With Brain Metastases Treated With Immune Checkpoint Inhibitors in the Real-world Setting: A Multicohort Study.

Long-term survival outcomes among melanoma patients with brain metastases treated with immune checkpoint inhibitors are limited. In this retrospective study at 2 centers, metastatic melanoma patients with radiographic evidence of brain metastases who received anti-programmed death-1 (PD-1) monotherapy or nivolumab in combination with ipilimumab between 2014 and 2017 were included. Overall survival (OS) was assessed in diagnosis-specific graded prognostic assessment (ds-GPA) and melanoma-molecular graded prognostic assessment (molGPA) prognostic risk groups. Baseline clinical covariates were used to identify predictors of OS in univariate/multivariable Cox proportional-hazards models. A total of 84 patients (58 monotherapy, 26 combination) were included with a median duration of follow-up of 43.4 months (maximum: 5.1 y). The median OS [95% confidence interval (CI)] was 3.1 months (1.8, 7) for ds-GPA 0-1, 22.1 months [5.4, not reached (NR)] for ds-GPA 2 and NR (24.9, NR) for ds-GPA 3-4 in the monotherapy cohort [hazard ratio (HR) for ds-GPA 3-4 vs. 0-1: 0.13 (95% CI: 0.052, 0.32); 0.29 (95% CI: 0.12, 0.63) for ds-GPA 2 vs. 0-1]. The median OS was 1.1 months (95% CI: 0.3, NR) for ds-GPA 0-1, 11.8 months (95% CI: 2.9, 23.3) for ds-GPA 2 and 24.4 months (95% CI: 3.4, NR) for ds-GPA 3-4 in the combination cohort [HR for 3-4 vs. 0-1: 0.013 (95% CI: 0.0012, 0.14); HR for ds-GPA 2 vs. 0-1: 0.033 (0.0035, 0.31)]. Predictors associated with longer survival included ds-GPA or molGPA>1 (among prognostic indices), neutrophil-to-lymphocyte ratio (<4 vs. ≥4), while high lactate dehydrogenase, neurological symptoms, and leptomeningeal metastases were associated with shorter survival. Baseline ds-GPA/molGPA>1 and neutrophil-to-lymphocyte ratio <4 were strong predictors of long-term survival to anti-PD-1-based immune checkpoint inhibitors in melanoma brain metastases patients previously naive to anti-PD-1 therapy in a real-world clinical setting treated at independent centers.

Detection of clinically relevant immune checkpoint markers by multicolor flow cytometry.

As checkpoint inhibitor immunotherapies gain traction among cancer researchers and clinicians, the need grows for assays that can definitively phenotype patient immune cells. Herein, we present an 8-color flow cytometry panel for lineage and immune checkpoint markers and validate it using healthy human donor peripheral blood mononuclear cells (PBMCs). Flow cytometry data was generated on a BD LSR Fortessa and supported by Luminex multiplex soluble immunoassay. Our data showed significant variation between donors at both baseline and different stages of activation, as well as a trend in increasing expression of checkpoint markers on stimulated CD4+ and CD8+ T-cells with time. Soluble immune checkpoint quantification assays revealed that LAG-3, TIM-3, CTLA-4, and PD-1 soluble isoforms are upregulated after stimulation. This 8-color flow cytometry panel, supported here by soluble immunoassay, can be used to identify and evaluate immune checkpoints on T-lymphocytes in cryopreserved human PBMC samples. This panel is ideal for characterizing checkpoint expression in clinical samples for which cryopreservation is necessary.

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.

Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (P = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies (P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.

Immune-Checkpoint Inhibitors in the Era of Precision Medicine: What Radiologists Should Know.

Over the past five years immune-checkpoint inhibitors have dramatically changed the therapeutic landscape of advanced solid and hematologic malignancies. The currently approved immune-checkpoint inhibitors include antibodies to cytotoxic T-lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1 and PD-L2). Response to immune-checkpoint inhibitors is evaluated on imaging using the immune-related response criteria. Activation of immune system results in a unique toxicity profile termed immune-related adverse events. This article will review the molecular mechanism, clinical applications, imaging of immune-related response patterns and adverse events associated with immune-checkpoint inhibitors.

Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study.

PURPOSE: To examine the onset and outcome of ipilimumab-related hypophysitis and the response to treatment with systemic high-dose corticosteroids (HDS). EXPERIMENTAL DESIGN: Twenty-five patients who developed ipilimumab-related hypophysitis were analyzed for the incidence, time to onset, time to resolution, frequency of resolution, and the effect of systemic HDS on clinical outcome. To calculate the incidence, the total number (187) of patients with metastatic melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston, MA) was retrieved from the DFCI oncology database. Comparisons between corticosteroid treatment groups were performed using the Fisher exact test. The distributions of overall survival were based on the method of Kaplan-Meier. RESULTS: The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5-36 weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive HDS, there was no statistically significant difference between treatment arms. CONCLUSION: Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be indicated. Instead, supportive treatment of hypophysitis-related hormone deficiencies with the corresponding hormone replacement should be given.