Sarilumab for Relapse of Polymyalgia Rheumatica during Glucocorticoid Taper.

BACKGROUND: More than half of patients with polymyalgia rheumatica have a relapse during tapering of glucocorticoid therapy. Previous studies have suggested that interleukin-6 blockade may be clinically useful in the treatment of polymyalgia rheumatica. Sarilumab, a human monoclonal antibody, binds interleukin-6 receptor α and efficiently blocks the interleukin-6 pathway. METHODS: In this phase 3 trial, we randomly assigned patients in a 1:1 ratio to receive 52 weeks of a twice-monthly subcutaneous injection of either sarilumab (at a dose of 200 mg) plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. The primary outcome at 52 weeks was sustained remission, which was defined as the resolution of signs and symptoms of polymyalgia rheumatica by week 12 and sustained normalization of the C-reactive protein level, absence of disease flare, and adherence to the prednisone taper from weeks 12 through 52. RESULTS: A total of 118 patients underwent randomization (60 to receive sarilumab and 58 to receive placebo). At week 52, sustained remission occurred in 28% (17 of 60 patients) in the sarilumab group and in 10% (6 of 58 patients) in the placebo group (difference, 18 percentage points; 95% confidence interval, 4 to 32; P = 0.02). The median cumulative glucocorticoid dose at 52 weeks was significantly lower in the sarilumab group than in the placebo group (777 mg vs. 2044 mg; P<0.001). The most common adverse events with sarilumab as compared with placebo were neutropenia (15% vs. 0%), arthralgia (15% vs. 5%), and diarrhea (12% vs. 2%). More treatment-related discontinuations were observed in the sarilumab group than in the placebo group (12% vs. 7%). CONCLUSIONS: Sarilumab showed significant efficacy in achieving sustained remission and reducing the cumulative glucocorticoid dose in patients with a relapse of polymyalgia rheumatica during glucocorticoid tapering. (Funded by Sanofi and Regeneron Pharmaceuticals; SAPHYR ClinicalTrials.gov number, NCT03600818.).

Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial.

BACKGROUND: Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg. METHODS: PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing. FINDINGS: Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]). INTERPRETATION: Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD. FUNDING: Bayer AG and Regeneron Pharmaceuticals.

Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial.

BACKGROUND: A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO. METHODS: PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503). FINDINGS: Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]). INTERPRETATION: Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO. FUNDING: Regeneron Pharmaceuticals and Bayer.

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.

BACKGROUND: Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. METHODS: In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients. RESULTS: Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log10 copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log10 copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group. CONCLUSIONS: In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.).

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19.

BACKGROUND: In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. METHODS: In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated. RESULTS: Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log10 copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log10 copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups. CONCLUSIONS: REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).

Casirivimab and Imdevimab for the Treatment of Hospitalized Patients With COVID-19.

BACKGROUND: The open-label RECOVERY study reported improved survival in hospitalized, SARS-CoV-2 seronegative patients treated with casirivimab and imdevimab (CAS + IMD). METHODS: In this phase 1/2/3, double-blind, placebo-controlled trial conducted prior to widespread circulation of Delta and Omicron, hospitalized COVID-19 patients were randomized (1:1:1) to 2.4 g or 8.0 g CAS + IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 serostatus. RESULTS: In total, 1336 patients on low-flow or no supplemental (low-flow/no) oxygen were treated. The primary endpoint was met in seronegative patients, the least-squares mean difference (CAS + IMD versus placebo) for time-weighted average change from baseline in viral load through day 7 was -0.28 log10 copies/mL (95% confidence interval [CI], -.51 to -.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS + IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI, 24.2%-74.0%). No safety concerns were noted. CONCLUSIONS: In hospitalized COVID-19 patients on low-flow/no oxygen, CAS + IMD reduced viral load and likely improves clinical outcomes in the overall population, with the benefit driven by seronegative patients, and no harm observed in seropositive patients. CLINICAL TRIALS REGISTRATION: NCT04426695.

Lay Summary . Monoclonal antibody therapies that block the virus that causes COVID-19 (SARS-CoV-2) can prevent patients from being hospitalized. We hypothesized that these antibodies may also benefit patients who are already hospitalized with COVID-19. Therefore, we performed a study to determine if the monoclonal antibody combination of casirivimab and imdevimab (CAS + IMD) can decrease the amount of virus in the nose of hospitalized patients and prevent the disease from becoming more severe. The study, conducted from June 2020 to April 2021, found that CAS + IMD treatment reduced the amount of virus in these patients, and may reduce their chance of dying or needing a ventilator (a machine that helps patients breathe). Patients were examined in 2 groups: those whose immune systems, at the start of the study, had not produced their own antibodies to fight SARS-CoV-2 (seronegative patients); or those that had already produced their own antibodies (seropositive patients) at the start of the study. Seronegative patients benefited the most from CAS + IMD. No safety concerns related to CAS + IMD were observed. These results demonstrate that monoclonal antibody therapy can help hospitalized patients with COVID-19 and may decrease their chances of needing assistance to breathe or dying.

Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial.

BACKGROUND: Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-interleukin (IL)-6R therapies in hospitalized patients with coronavirus disease 2019 (COVID-19) receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19. METHODS: In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab 400 mg or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation (MV). The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS: There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving MV (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving MV) at day 22 was 43.2% for sarilumab and 35.5% for placebo (risk difference, +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P =.3261), a relative risk improvement of 21.7%. In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio for death for sarilumab vs placebo was 0.76 (95% CI, .51 to 1.13) overall and 0.49 (95% CI, .25 to .94) in patients receiving corticosteroids at baseline. CONCLUSIONS: This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids. CLINICAL TRIALS REGISTRATION: NCT04315298.

Baseline Severe Acute Respiratory Syndrome Viral Load Is Associated With Coronavirus Disease 2019 Severity and Clinical Outcomes: Post Hoc Analyses of a Phase 2/3 Trial.

BACKGROUND: Elucidating the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and clinical outcomes is critical for understanding coronavirus disease 2019 (COVID-19). METHODS: The SARS-CoV-2 levels were analyzed by quantitative real-time polymerase chain reaction (RT-qPCR) of nasopharyngeal or oropharyngeal swab specimens collected at baseline, and clinical outcomes were recorded over 60 days from 1362 COVID-19 hospitalized patients enrolled in a multicenter, randomized, placebo-controlled phase 2/3 trial of sarilumab for COVID-19 (ClinicalTrials.gov NCT04315298). RESULTS: In post hoc analyses, higher baseline viral load, measured by both RT-qPCR cycle threshold and log10 copies/mL, was associated with greater supplemental oxygenation requirements and disease severity at study entry. Higher baseline viral load was associated with higher mortality, lower likelihood of improvement in clinical status and supplemental oxygenation requirements, and lower rates of hospital discharge. Viral load was not impacted by sarilumab treatment over time versus placebo. CONCLUSIONS: These data support viral load as an important determinant of clinical outcomes in hospitalized patients with COVID-19 requiring supplemental oxygen or assisted ventilation.

Analysis of the Role of Plasma 25-Hydroxyvitamin D Levels in Survival Outcomes in Patients from the Phase III MPACT Trial of Metastatic Pancreatic Cancer.

BACKGROUND: We examined overall survival (OS) outcomes based on plasma 25-hydroxyvitamin D [25(OH)D] levels in this post hoc analysis of the phase III MPACT trial of metastatic pancreatic cancer. MATERIALS AND METHODS: Patients were subdivided based on 25(OH)D level: sufficient (≥30 ng/mL), relatively insufficient (20-<30 ng/mL), or insufficient (<20 ng/mL). RESULTS: Of 861 patients randomized in MPACT, 422 were included in this analysis. In the all-patients group, the median OS among those with insufficient, relatively insufficient, and sufficient 25(OH)D levels was 7.9, 9.4, and 7.8 months, respectively. No statistically significant OS difference was observed with relatively insufficient (p = .227) or sufficient (p = .740) versus insufficient 25(OH)D levels or with sufficient vs relatively insufficient (p = .301) 25(OH)D levels. CONCLUSION: No association was observed between plasma 25(OH)D levels and survival. Further investigations are needed to understand any role of vitamin D in pancreatic cancer. Clinical trial identification number. NCT00844649.

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.

BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).

Quality of life with second or third line nab-paclitaxel-based regimens in advanced non-small-cell lung cancer.

Aim: Evaluate quality of life (QoL) in patients with advanced non-small cell lung cancer treated with second or third line nab-paclitaxel ± durvalumab. Patients & methods: Longitudinal QoL was assessed using Lung Cancer Symptom Scale, EuroQoL Five-Dimensions Five-Levels and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core. Results: QoL was generally stable through eight treatment cycles (both arms). Clinically meaningful improvement from baseline was noted in Lung Cancer Symptom Scale (overall constitutional score and three-item index [nab-paclitaxel + durvalumab]) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core (global health status/QoL and emotional functioning [both arms] and pain [nab-paclitaxel + durvalumab]) analyses. EuroQoL Five-Dimensions Five-Levels domains were stable/improved or completely resolved at least once in 19-56% and 9-51% of patients, respectively. Conclusion: While QoL trends were promising, additional data are required to support these regimens in this setting.

Association between depth of response and survival in patients with advanced-stage non-small cell lung cancer treated with first-line chemotherapy.

BACKGROUND: A partial response according to the Response Evaluation Criteria in Solid Tumors includes a wide range of changes in tumor size. This study evaluated whether further specification of tumor reduction based on the depth of response (DpR) would provide a more precise association with outcomes for patients with non-small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy. METHODS: A retrospective analysis was performed for the randomized phase 3 CA031 trial in patients with NSCLC treated with carboplatin in combination with nab-paclitaxel or solvent-based paclitaxel. Quartiles according to the maximum tumor reduction from the baseline were defined (quartile 1 [Q1], >0% to 25%; quartile 2 [Q2], >25% to 50%; quartile 3 [Q3], >50% to 75%; and quartile 4 [Q4], >75%) and were compared with those patients with no tumor reduction (NTR). The primary objective was to evaluate the association between DpR and overall survival (OS). RESULTS: Of the 1052 patients enrolled in the CA031 trial, 959 (91%) were evaluable, and they included 365 (38.1%) who were classified as Q1, 327 (34.1%) who were classified as Q2, 131 (13.7%) who were classified as Q3, and 34 (3.5%) who were classified as Q4; 102 had NTR (10.6%). The median OS values for patients in the NTR, Q1, Q2, Q3, and Q4 groups were 4.8, 10.4, 14.5, 19.3, and 23.5 months, respectively. The maximum DpR on treatment was an independent predictor of improved OS in comparison with patients with NTR; the hazard ratio decreased from 0.43 in Q1 to 0.16 in Q4. CONCLUSIONS: DpR was strongly associated with OS in patients with NSCLC receiving first-line platinum-based therapy. Additional studies may help to define the role of DpR in solid tumors.

ABOUND.2L+: A randomized phase 2 study of nanoparticle albumin-bound paclitaxel with or without CC-486 as second-line treatment for advanced nonsquamous non-small cell lung cancer (NSCLC).

BACKGROUND: This randomized phase 2 trial compared the efficacy and safety of second-line nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without the addition of CC-486 (an oral formulation of 5-azacytidine) in patients with advanced-stage, nonsquamous non-small cell lung cancer. METHODS: Patients were randomized to receive either nab-paclitaxel 100 mg/m2 on days 8 and 15 plus CC-486 200 mg daily on days 1 to 14 or single-agent nab-paclitaxel 100 mg/m2 on days 1 and 8, with both regimens administered every 21 days until tumor progression or unacceptable toxicity. The primary endpoint was progression-free survival. Secondary endpoints included the overall response rate, the disease control rate, and overall survival. RESULTS: Between January 2015 and August 2016, 161 patients were randomized (81 to the combination arm and 80 to the single-agent nab-paclitaxel arm). There was no benefit from the addition of CC-486 to nab-paclitaxel. The median progression-free survival was 3.2 months for the combination and 4.2 months for single-agent nab-paclitaxel (hazard ratio, 1.3; 95% confidence interval, 0.9-1.9). The median overall survival was 8.1 months in the combination arm and 17 months in the single-agent nab-paclitaxel arms (hazard ratio, 1.7; 95% confidence interval, 1.08-2.57). Grade 3 or greater treatment-related, emergent adverse events were reported by 40.5% of patients in the combination arm and by 31.6% of those in the single-agent nab-paclitaxel arm. CONCLUSIONS: Single-agent nab-paclitaxel was associated with promising outcomes and a tolerable safety profile as second-line treatment for patients with advanced-stage, nonsquamous non-small cell lung cancer. There was no benefit from the addition of CC-486 to nab-paclitaxel.

Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+).

UNLABELLED: Patients with hepatitis C virus (HCV) genotype 3 infection, especially those with advanced liver disease, are a challenging population in urgent need of optimally effective therapies. The combination of daclatasvir (DCV; pangenotypic nonstructural protein 5A inhibitor) and sofosbuvir (SOF; nucleotide nonstructural protein 5B inhibitor) for 12 weeks previously showed high efficacy (96%) in noncirrhotic genotype 3 infection. The phase III ALLY-3+ study (N = 50) evaluated DCV-SOF with ribavirin (RBV) in treatment-naïve (n = 13) or treatment-experienced (n = 37) genotype 3-infected patients with advanced fibrosis (n = 14) or compensated cirrhosis (n = 36). Patients were randomized 1:1 to receive open-label DCV-SOF (60 + 400 mg daily) with weight-based RBV for 12 or 16 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12). SVR12 (intention-to-treat) was 90% overall (45 of 50): 88% (21 of 24) in the 12-week (91% observed) and 92% (24 of 26) in the 16-week group. All patients with advanced fibrosis achieved SVR12. SVR12 in patients with cirrhosis was 86% overall (31 of 36): 83% (15 of 18) in the 12-week (88% observed) and 89% (16 of 18) in the 16-week group; for treatment-experienced patients with cirrhosis, these values were 87% (26 of 30), 88% (14 of 16; 93% observed), and 86% (12 of 14), respectively. One patient (12-week group) did not enter post-treatment follow-up (death unrelated to treatment). There were 4 relapses (2 per group) and no virological breakthroughs. The most common adverse events (AEs) were insomnia, fatigue, and headache. There were no discontinuations for AEs and no treatment-related serious AEs. CONCLUSION: The all-oral regimen of DCV-SOF-RBV was well tolerated and resulted in high and similar SVR12 after 12 or 16 weeks of treatment among genotype 3-infected patients with advanced liver disease, irrespective of past HCV treatment experience.

12 Weeks of Daclatasvir in Combination With Sofosbuvir for HIV-HCV Coinfection (ALLY-2 Study): Efficacy and Safety by HIV Combination Antiretroviral Regimens.

BACKGROUND: Highly effective hepatitis C virus (HCV) direct-acting antiviral therapies that do not require modification of human immunodeficiency virus (HIV) antiretroviral regimens are needed. We evaluated the efficacy and safety of daclatasvir + sofosbuvir (DCV + SOF) for 12 weeks by antiretroviral (ARV) regimen in HIV-HCV-coinfected patients. METHODS: In the randomized, open-label ALLY-2 study, HIV-HCV-coinfected patients received 8 or 12 weeks of once-daily DCV 60 mg (dose-adjusted as-necessary for concomitant ARVs) + SOF 400 mg. Results were stratified by ARV class for the 151 patients who received 12 weeks of DCV + SOF. RESULTS: Fifty-one patients were HCV treatment experienced, 100 were treatment naive, 89% male and 33% black. HCV genotypes were: genotype 1a (GT1a; 69%), GT1b (15%), GT2 (8%), GT3 (6%), and GT4 (2%). Sustained virologic response 12 weeks post-treatment (SVR12) was 97% and was similar across ARV regimens (P = .774): protease inhibitor-based, 97% (95% confidence interval [CI], 90%-99.7%); nonnucleoside reverse transcriptase inhibitor-based, 100% (95% CI, 91%-100%); and integrase inhibitor based, 95% (95% CI, 83%-99.4%). SVR12 among patients receiving either tenofovir disoproxil fumarate or abacavir as part of their antiretroviral therapy regimen was 98% (95% CI, 93%-99.5%) and 100% (95% CI, 85%-100%), respectively. Age, gender, race, cirrhosis, HCV treatment history, GT , and baseline HCV RNA did not affect SVR12. No discontinuations were attributed to treatment-related adverse events. CONCLUSIONS: DCV + SOF x12 weeks is a highly efficacious, all-oral, pan-GT HCV treatment for HIV-HCV coinfected patients across a broad range of ARV regimens. CLINICAL TRIALS REGISTRATION: NCT02032888.

All-oral daclatasvir plus asunaprevir for chronic hepatitis C virus (HCV) genotype 1b infection: a sub-analysis in Asian patients from the HALLMARK DUAL study.

BACKGROUND & AIMS: Daclatasvir plus asunaprevir (DCV + ASV) has demonstrated potent antiviral activity in patients with hepatitis C virus (HCV) genotype 1b (GT-1b) infection in the HALLMARK DUAL trial. This post hoc analysis was conducted to determine the efficacy and safety of this treatment in Asian patients. METHODS: Treatment-naive patients were randomly assigned (2:1; double-blinded) to receive DCV (60 mg once daily) plus ASV (100 mg twice daily) or placebo for 12 weeks. Subsequently, placebo patients entered another study, and the remaining patients continued treatment for an additional 12 weeks. Non-responders to peginterferon/ribavirin and ineligible/intolerant patients received dual therapy for 24 weeks. Sustained virological response at post-treatment Week 12 [sustained virological response (SVR)12] and safety outcomes were evaluated. RESULTS: This post hoc analysis included 186 Asian patients (Korean, 78; Taiwanese, 85; others, 23), of whom 32.3% were cirrhotic. SVR12 was observed in 92.3, 78.6 and 80.0% of treatment-naive, ineligible/intolerant and non-responder patients, respectively, and was comparable with non-Asian patients. SVR12 by baseline factors including age, viral load, interleukin-28B genotype and cirrhosis status was similar between the Asian sub-cohorts. Among 18 Asian patients with NS5A-Y93H or NS5A-L31M/V resistance-associated variants (RAVs), seven patients achieved SVR12. Multivariate regression analysis showed a significant influence of NS5A RAVs in both Asian and non-Asian cohorts. The incidence of serious adverse events in Asian patients was low (7.2%). Two Taiwanese patients had elevated alanine aminotransferase (≥5.1 × ULN); both achieved SVR12. CONCLUSIONS: All-oral dual therapy with DCV + ASV resulted in high SVR rates and was well tolerated in Asian patients with HCV GT-1b infection.

On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3-infected patients treated with daclatasvir and sofosbuvir.

BACKGROUND AND AIMS: Many currently available direct-acting antiviral (DAA) regimens are less effective against HCV genotype 3 than against other HCV genotypes. The all-oral, pangenotypic DAA combination of daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide NS5B inhibitor) was studied in genotype 3-infected treatment-naive and -experienced patients (ALLY-3) who achieved rates of sustained virological response at post-treatment Week 12 (SVR12) of 90 and 86% respectively. In this analysis, we assessed whether on-treatment responses to daclatasvir + sofosbuvir in genotype 3-infected patients could predict treatment outcome. METHODS: In ALLY-3, treatment-naive and -experienced patients, with or without cirrhosis, were treated with daclatasvir + sofosbuvir for 12 weeks. HCV RNA kinetics and categorical virological responses on treatment were assessed. The proportions of responders and nonresponders by study week, and time to first undetectable HCV RNA, were analysed for utility in predicting treatment outcome. RESULTS: Overall, HCV RNA levels declined rapidly during Week 1 of treatment in both treatment-naive and -experienced cohorts. Although patients with cirrhosis had a slower initial virological response as measured by the proportion of patients with HCV RNA below the lower limit of quantification at Week 1, responses converged thereafter. Positive and negative predictive values calculated for on-treatment responses were generally comparable with the overall SVR12 rate and were therefore limited indicators of outcome. SVR12 rates were not impacted by time to first undetectable HCV RNA. CONCLUSIONS: On-treatment responses are not useful predictors of ultimate virological response to the daclatasvir + sofosbuvir regimen.

Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis.

BACKGROUND & AIMS: We compared outcomes by cirrhosis status across studies of the all-oral combination of daclatasvir (DCV) plus asunaprevir (ASV). METHODS: Outcomes from global and Japanese phase 2 and 3 clinical studies of DCV+ASV in patients with genotype (GT) 1b infection were assessed by cirrhosis status. Sustained virological response (SVR) was assessed in individual phase 3 studies; a pooled analysis was carried out for safety outcomes. RESULTS: In the Japanese phase 3 study, SVR12 was achieved by 91% of patients with cirrhosis (n = 22) and 84% of patients without cirrhosis (n = 200); in the global phase 3 study, SVR12 was achieved by 84% of patients with cirrhosis (n = 206) and by 85% of patients without cirrhosis (n = 437). The frequency of serious adverse events, adverse events leading to treatment discontinuation and treatment-emergent grade 3/4 laboratory abnormalities was low (<10%) and similar among patients with (n = 229) or without (n = 689) compensated cirrhosis receiving DCV+ASV. Grade 3/4 reductions in platelets and neutrophils were more common among patients with cirrhosis (1.3 and 2.2%, respectively) compared with those without cirrhosis (both 0.6%). Grade 3/4 liver function test abnormalities were less common among patients with cirrhosis (1.8%) compared with those without cirrhosis (3.5-4.7%). Alanine aminotransferase elevations were not associated with hepatic decompensation. CONCLUSIONS: The safety and efficacy of DCV+ASV were similar in patients with or without compensated cirrhosis. This all-oral, interferon- and ribavirin-free combination is an effective and well-tolerated treatment option for patients with HCV GT1b infection and cirrhosis. Trial registrations numbers: Clinicaltrials.gov identifiers: NCT01012895; NCT01051414; NCT01581203; NCT01497834.

Effectiveness of Casirivimab and Imdevimab Antibody Combination in Immunocompromised Hospitalized Patients With Coronavirus Disease 2019: A Post Hoc Analysis in a Phase 1/2/3 Double-Blind Trial.

Background: Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19). Methods: Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020-April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients. Results: Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was -0.69 (95% confidence interval [CI], -1.25 to -.14) log10 copies/mL for IC patients and -0.31 (95% CI, -.42 to -.20) log10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%). Conclusions: IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695.

Monoclonal antibodies against GFRα3 are efficacious against evoked hyperalgesic and allodynic responses in mouse join pain models but, one of these, REGN5069, was not effective against pain in a randomized, placebo-controlled clinical trial in patients with osteoarthritis pain.

The artemin-GFRα3 signaling pathway has been implicated in various painful conditions including migraine, cold allodynia, hyperalgesia, inflammatory bone pain, and mouse knees contain GFRα3-immunoreactive nerve endings. We developed high affinity mouse (REGN1967) and human (REGN5069) GFRα3-blocking monoclonal antibodies and, following in vivo evaluations in mouse models of chronic joint pain (osteoarthritic-like and inflammatory), conducted a first-in-human phase 1 pharmacokinetics (PK) and safety trial of REGN5069 (NCT03645746) in healthy volunteers, and a phase 2 randomized placebo-controlled efficacy and safety trial of REGN5069 (NCT03956550) in patients with knee osteoarthritis (OA) pain. In three commonly used mouse models of chronic joint pain (destabilization of the medial meniscus, intra-articular monoiodoacetate, or Complete Freund's Adjuvant), REGN1967 and REGN5069 attenuated evoked behaviors including tactile allodynia and thermal hyperalgesia without discernably impacting joint pathology or inflammation, prompting us to further evaluate REGN5069 in humans. In the phase 1 study in healthy subjects, the safety profiles of single doses of REGN5069 up to 3000 mg (intravenous) or 600 mg (subcutaneous) were comparable to placebo; PK were consistent with a monoclonal antibody exhibiting target-mediated disposition. In the phase 2 study in patients with OA knee pain, two doses of REGN5069 (100 mg or 1000 mg intravenous every 4 weeks) for 8 weeks failed to achieve the 12-week primary and secondary efficacy endpoints relative to placebo. In addition to possible differences in GFRα3 biology between mice and humans, we highlight here differences in experimental parameters that could have contributed to a different profile of efficacy in mouse models versus human OA pain. Additional research is required to more fully evaluate any potential role of GFRα3 in human pain.