BackgroundNovel combination therapies are needed to improve outcomes in RM-HNSCC. Magrolimab is a monoclonal antibody that blocks CD47, a ‘don’t eat me’ signal overexpressed on cancer cells. ...Magrolimab induces macrophage-mediated phagocytosis of tumor cells and may synergize with chemotherapy agents through enhancement of phagocytic signals. The Phase 2 ELEVATE HNSCC multicenter, open-label study (NCT04854499) is evaluating magrolimab-containing regimens in patients with RM-HNSCC (figure 1). Here, we report data from 2 safety run-ins (SRI1 and SRI2) designed to assess safety/tolerability and recommended Phase 2 dose (RP2D) of magrolimab in combination with standard of care.MethodsPatients in SRI1 with previously untreated RM-HNSCC received magrolimab+pembrolizumab+platinum+5-fluorouracil; patients in SRI2 with locally advanced or RM-HNSCC (1–2 lines of prior systemic therapy) received magrolimab+docetaxel. Magrolimab was first administered as a 1 mg/kg priming dose, followed by weekly 30 mg/kg doses for two 21-day cycles and then a maintenance dose of 60 mg/kg Q3W. Pembrolizumab and chemotherapy were given per standard of care. Primary endpoints of the SRI were incidence of adverse events (AEs) and dose-limiting toxicities (DLTs). Safety was assessed in patients who received ≥1 dose of study drug. The incidence of DLTs was assessed using patients who experienced a DLT during the DLT evaluation period or who completed ≥2 magrolimab and ≥1 combination agent doses. To select an RP2D, ≤2 of 6 DLT-evaluable patients could experience a DLT, or the magrolimab dose would be de-escalated and a new cohort would be assessed.ResultsAt least 6 patients from each SRI were considered DLT-evaluable. The safety analysis population consisted of 6 patients in SRI1 and 7 patients in SRI2. No DLTs were reported. Treatment-emergent AEs (TEAEs) occurred in 6/6 (SRI1) and 7/7 (SRI2) patients (table 1). The most common TEAEs observed in each SRI were fatigue (SRI1) and anemia (SRI2). TEAEs leading to magrolimab discontinuation occurred in 1/6 patients in SRI1 (fatigue) and 1/7 patients in SRI2 (oral cavity fistula unrelated to study drug). In SRI1, no deaths were reported; 3 deaths were reported as unrelated to study treatment and occurred after the DLT evaluation period in SRI2: oral cavity fistula, pneumonia, and disease progression (during long-term follow-up).ConclusionsThe observed safety profile was as expected based on the known toxicity profiles of the individual agents. Magrolimab appears tolerable in these combinations. No DLTs or treatment-related deaths occurred. Magrolimab RP2D was declared at the initial dose level tested in both SRIs.Trial RegistrationNCT04854499Ethics ApprovalThe protocol and proposed informed consent form were reviewed and approved by all relevant Institutional Review Boards, Independent Ethics Committees and/or Research Ethics Boards prior to study commencement. There is no number provided as we did not receive one. Participants gave informed consent to participate in the study before taking part.ConsentThe protocol and proposed informed consent form were reviewed and approved by all relevant Institutional Review Boards, Independent Ethics Committees and/or Research Ethics Boards prior to study commencement. There is no number provided as we did not receive one. Participants gave informed consent to participate in the study before taking part.Abstract 675 Figure 1ELEVATE HNSCC cohort overview. 5-FU. 5-fluorouracil; HNSCC, head and neck squamous cell carcinoma; R, ranomization; RP2D, recommended Phase 2 dose; pembro, pembrolizumab; zim, zimberelimabAbstract 675 Table 1TEAEs occurring in ≥2 patients in either SRI.
BackgroundPatients with solid tumors who progress on standard chemotherapy and/or immune checkpoint inhibitors, have limited efficacy with existing standard of care chemotherapy options (objective ...response rates ORR ~10%). These patients have a significant unmet medical need. Novel agents that can safely enhance treatment efficacy are urgently needed. Magrolimab is a first-in-class monoclonal antibody that blocks the macrophage inhibitory immune checkpoint CD47, a ”do not eat me” signal overexpressed on tumor cells. Pre-clinical studies provide compelling evidence that magrolimab triggers phagocytosis and eliminates cancer cells from human solid tumors and hematologic malignancies. Magrolimab has demonstrated clinical activity in both hematologic and solid tumor malignancies. Chemotherapeutic agents, including taxanes, enhance prophagocytic signals on tumor cells, leading to synergistic antitumor activity when combined with magrolimab. This study (NCT04827576) is evaluating the safety, tolerability, and efficacy of magrolimab with docetaxel in relapsed/refractory (R/R) metastatic non-small cell lung cancer (mNSCLC), urothelial cancer (mUC), and small cell lung cancer (mSCLC).MethodsThis phase 2, open-label, multi-arm study consists of a safety run-in cohort and a phase 2 cohort. Eligible patients are ≥18 years old with chemotherapy and/or immunotherapy refractory mNSCLC, mSCLC, or mUC. Magrolimab is administered intravenously (IV) with an initial 1 mg/kg priming dose to mitigate on target anemia, followed by 30 mg/kg dose during cycle 1 (cycles are 21 days) in the safety run-in to identify any dose-limiting toxicities (DLTs) and determine a recommended phase 2 dose (RP2D). De-escalation may occur for DLTs per protocol. In phase 2, following the priming dose on day 1, magrolimab RP2D will be administered on days 8 and 15 of cycle 1; days 1, 8, 15 of cycle 2; and day 1 for cycles 3 and beyond. Docetaxel 75 mg/m2 (IV) is administered on day 1 of each cycle for all study participants. Patients may continue treatment until unacceptable toxicity, progressive disease by RECIST 1.1, or patient/investigator choice to discontinue. The primary endpoints are incidence of adverse events (safety and phase 2 cohorts) and ORR (phase 2). Secondary endpoints (phase 2) are progression-free survival, duration of response, and overall survival. Exploratory endpoints are to evaluate the pharmacodynamic, mechanism of action, and/or therapeutic response of biomarkers in blood and tumor biopsy samples and to explore biomarkers that may predict response to therapy. Planned enrollment is approximately 116 patients, and recruitment is ongoing.AcknowledgementsFunding provided by Gilead Sciences, Inc.Trial RegistrationNCT04827576Ethics ApprovalThe study protocol was approved by an institutional review board before enrollment of patients.ConsentPatients provided written informed consent based on Declaration of Helsinki principles.
Hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) endocrine-resistant metastatic breast cancer is treated with sequential single-agent chemotherapy with poor ...outcomes. Sacituzumab govitecan (SG) is a first-in-class antibody-drug conjugate with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer.
In this global, randomized, phase III study, SG was compared with physician's choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR+/HER2- locally recurrent inoperable or metastatic breast cancer. The primary end point was progression-free survival (PFS) by blinded independent central review.
Patients were randomly assigned to receive SG (n = 272) or chemotherapy (n = 271). The median age was 56 years, 95% had visceral metastases, and 99% had a prior cyclin-dependent kinase 4/6 inhibitor, with three median lines of chemotherapy for advanced disease. Primary end point was met with a 34% reduction in risk of progression or death (hazard ratio, 0.66 95% CI, 0.53 to 0.83;
= .0003). The median PFS was 5.5 months (95% CI, 4.2 to 7.0) with SG and 4.0 months (95% CI, 3.1 to 4.4) with chemotherapy; the PFS at 6 and 12 months was 46% (95% CI, 39 to 53)
30% (95% CI, 24 to 37) and 21% (95% CI, 15 to 28)
7% (95% CI, 3 to 14), respectively. Median overall survival (first planned interim analysis) was not yet mature (hazard ratio, 0.84;
= .14). Key grade ≥ 3 treatment-related adverse events (SG
chemotherapy) were neutropenia (51%
38%) and diarrhea (9%
1%).
SG demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2- advanced breast cancer and limited treatment options.
Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict ...the HCC development for patients with chronic hepatitis.
A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686).
We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin–bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82–0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0–0.8%, 1.5–4.8%, and 8.1–19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7–100% and a negative predictive value of 99.3–100%. The cut-off value of 60 resulted in a specificity of 56.6–95.8% and a positive predictive value of 6.6–15.7%.
This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide.
In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin–bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.
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•In total, 17,374 patients with viral and non-viral hepatitis from 11 global prospective cohorts/trials were studied.•An HCC risk score (called the aMAP score, ranging from 0 to 100), which involves only age, male, albumin–bilirubin and platelet data, was developed and validated.•The aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk irrespective of aetiology and ethnicity.•Patients with aMAP score <50, accounting for 44% of overall population, had an HCC incidence of <0.2% per year.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•TAF is a new prodrug of tenofovir developed to treat patients with chronic HBV.•A lower dose of TAF can be used because it delivers tenofovir more efficiently to hepatocytes than ...TDF.•At week 48, TAF had non-inferior efficacy to TDF with improved renal and bone safety.•Efficacy and safety results at week 96 confirm the 48-week results in both studies.
Tenofovir alafenamide (TAF) is a new prodrug of tenofovir developed to treat patients with chronic hepatitis B virus (HBV) infection at a lower dose than tenofovir disoproxil fumarate (TDF) through more efficient delivery of tenofovir to hepatocytes. In 48-week results from two ongoing, double-blind, randomized phase III trials, TAF was non-inferior to TDF in efficacy with improved renal and bone safety. We report 96-week outcomes for both trials.
In two international trials, patients with chronic HBV infection were randomized 2:1 to receive 25 mg TAF or 300 mg TDF in a double-blinded fashion. One study enrolled HBeAg-positive patients and the other HBeAg-negative patients. We assessed efficacy in each study, and safety in the pooled population.
At week 96, the differences in the rates of viral suppression were similar in HBeAg-positive patients receiving TAF and TDF (73% vs. 75%, respectively, adjusted difference −2.2% (95% CI −8.3 to 3.9%; p = 0.47), and in HBeAg-negative patients receiving TAF and TDF (90% vs. 91%, respectively, adjusted difference −0.6% (95% CI −7.0 to 5.8%; p = 0.84). In both studies the proportions of patients with alanine aminotransferase above the upper limit of normal at baseline, who had normal alanine aminotransferase at week 96 of treatment, were significantly higher in patients receiving TAF than in those receiving TDF. In the pooled safety population, patients receiving TAF had significantly smaller decreases in bone mineral density than those receiving TDF in the hip (mean % change −0.33% vs. −2.51%; p <0.001) and lumbar spine (mean % change −0.75% vs. −2.57%; p <0.001), as well as a significantly smaller median change in estimated glomerular filtration rate by Cockcroft-Gault method (−1.2 vs. −4.8 mg/dl; p <0.001).
In patients with HBV infection, TAF remained as effective as TDF, with continued improved renal and bone safety, two years after the initiation of treatment. Clinicaltrials.gov number: NCT01940471 and NCT01940341.
At week 96 of two ongoing studies comparing the efficacy and safety of tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B patients, TAF continues to be as effective as TDF with continued improved renal and bone safety.
Registration: Clinicaltrials.gov number: NCT01940471 and NCT01940341.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract
Background
We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 ...remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care.
Methods
GS-US-540–5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540–5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality.
Results
After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio aOR 2.03: 95% confidence interval CI: 1.34–3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22–.68, P = .001).
Conclusions
In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19.
Clinical Trials Registration
NCT04292899 and EUPAS34303.
In this comparative analysis, remdesivir was associated with significantly lower mortality and higher recovery than standard-of-care treatment without remdesivir in patients with severe COVID-19. Ongoing studies will further determine the utility of remdesivir for the treatment of severe COVID-19.
Background & Aims Patients chronically infected with the hepatitis B virus rarely achieve loss of serum hepatitis B surface antigen (HBsAg) with the standard of care. We evaluated HBsAg loss in ...patients receiving the combination of tenofovir disoproxil fumarate (TDF) and peginterferon α-2a (peginterferon) for a finite duration in a randomized trial. Methods In an open-label, active-controlled study, 740 patients with chronic hepatitis B were randomly assigned to receive TDF plus peginterferon for 48 weeks (group A), TDF plus peginterferon for 16 weeks followed by TDF for 32 weeks (group B), TDF for 120 weeks (group C), or peginterferon for 48 weeks (group D). The primary end point was the proportion of patients with serum HBsAg loss at week 72. Results At week seventy-two, 9.1% of subjects in group A had HBsAg loss compared with 2.8% of subjects in group B, none of the subjects in group C, and 2.8% of subjects in group D. A significantly higher proportion of subjects in group A had HBsAg loss than in group C ( P < .001) or group D ( P = .003). However, the proportions of subjects with HBsAg loss did not differ significantly between group B and group C ( P = .466) or group D ( P = .883). HBsAg loss in group A occurred in hepatitis B e antigen−positive and hepatitis B e antigen−negative patients with all major viral genotypes. The incidence of common adverse events (including headache, alopecia, and pyrexia) and treatment discontinuation due to adverse events was similar among groups. Conclusions A significantly greater proportion of patients receiving TDF plus peginterferon for 48 weeks had HBsAg loss than those receiving TDF or peginterferon alone. ClinicalTrials.gov ID NCT01277601.
Background & Aims Little is known about the benefit of antiviral therapy for hepatitis B e antigen (HBeAg)−positive patients with high viral load and normal levels of alanine aminotransferase. We ...evaluated the effects of single and combination therapies in immune-tolerant patients with chronic hepatitis B. Methods In a double-blind study, nucleos(t)ide-naïve patients with high levels of hepatitis B virus (HBV) DNA who were positive for HBeAg and had normal levels of alanine aminotransferase were randomly assigned to groups given either oral tenofovir disoproxil fumarate (TDF, 300 mg) and placebo (n = 64) or a combination of TDF (300 mg) and emtricitabine (200 mg, n = 62) for 192 weeks. The primary end point was proportion of patients with serum levels of HBV DNA <69 IU/mL at week 192. Results The study population (mean age was 33 years; 89% were Asian) was predominantly infected with HBV genotypes B and C (93%), 99% were HBeAg positive with a mean baseline level of HBV DNA of 8.41 log10 IU/mL. At week 192, 55% of patients (35 of 64) in the TDF+placebo group and 76% of patients (47 of 62) in the TDF+emtricitabine group had levels of HBV DNA <69 IU/mL ( P = .016). No patients were found to have viral resistance to therapy. HBeAg seroconversion occurred in 3 patients (5%), all in the TDF+placebo group; no patient had loss of hepatitis B surface antigen. In multivariate analysis, female sex (odds ratio = 7.05; P = .002) and TDF+emtricitabine treatment (odds ratio = 3.9; P = .01) were associated with a favorable response. Both regimens were well tolerated. Conclusions In HBeAg-positive patients with chronic HBV infection, high viral loads, normal levels of alanine aminotransferase, and therapy with the combination of TDF and emtricitabine provided better viral suppression than TDF alone, although rates of HBeAg seroconversion and hepatitis B surface antigen loss were low.
Abstract only
TPS584
Background: Patients with solid tumors who progress on standard chemotherapy and/or immune checkpoint inhibitors have limited efficacy with existing standard-of-care chemotherapy ...options (objective response rates ORRs ̃10%). These patients have a significant unmet medical need. Novel agents that can safely enhance treatment efficacy are urgently needed. Magrolimab is a first-in-class monoclonal antibody that blocks the macrophage inhibitory immune checkpoint CD47, a “do not eat me” signal overexpressed on tumor cells. Preclinical studies provide compelling evidence that magrolimab triggers phagocytosis and eliminates cancer cells from human solid tumors and hematologic malignancies. Magrolimab has demonstrated clinical activity in both hematologic and solid tumor malignancies. Chemotherapeutic agents, including taxanes, enhance prophagocytic signals on tumor cells, leading to synergistic antitumor activity when combined with magrolimab. This study (NCT04827576) is evaluating the safety, tolerability, and efficacy of magrolimab with docetaxel in relapsed/refractory (R/R) metastatic urothelial cancer (mUC), non-small-cell lung cancer (mNSCLC), and small-cell lung cancer (mSCLC). Methods: This Phase 2, open-label, multi-arm study (NCT04827576) consists of a safety run-in cohort and a Phase 2 cohort. Eligible patients are ≥18 years old with chemotherapy- and/or immunotherapy-refractory mUC, mNSCLC, or mSCLC. Magrolimab is administered intravenously (IV) with an initial 1-mg/kg priming dose to mitigate on-target anemia, followed by a 30-mg/kg dose during cycle 1 (cycles are 21 days) in the safety run-in to identify any dose-limiting toxicities (DLTs) and determine a recommended Phase 2 dose (RP2D). De-escalation may occur for DLTs per protocol. In Phase 2, following the priming dose on day 1, the highest acceptable dose of magrolimab will be administered on days 8 and 15 of cycle 1; days 1, 8, and 15 of cycle 2; and day 1 for cycles 3 and beyond. Docetaxel 75 mg/m
2
is administered IV on day 1 of each cycle for all study participants. Patients may continue treatment until unacceptable toxicity, progressive disease by RECIST 1.1, or patient/investigator choice to discontinue. The primary endpoints are incidence of adverse events (safety and Phase 2 cohorts) and ORR (Phase 2). Secondary endpoints (Phase 2) are progression-free survival, duration of response, and overall survival. Exploratory endpoints are to evaluate the pharmacodynamic, mechanism of action, and/or therapeutic response of biomarkers in blood and tumor biopsy samples and to explore biomarkers that may predict response to therapy. Enrollment began in August 2021. Planned enrollment is approximately 116 patients, and as of October 1, 2021 recruitment is ongoing. Clinical trial information: NCT04827576.
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