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Despite improved efficacy with first-line immune checkpoint inhibitors plus platinum-based chemotherapy for extensive-stage small-cell lung cancer (ES-SCLC), survival remains poor. In this study, we aimed to compare lurbinectedin plus atezolizumab and atezolizumab alone as maintenance therapies in patients with ES-SCLC without progression after induction therapy with atezolizumab, carboplatin, and etoposide. IMforte was a randomised, open-label, phase 3 trial done at 96 hospitals and medical centres in 13 countries (Belgium, Germany, Greece, Hungary, Italy, Mexico, Poland, South Korea, Spain, Taiwan, Türkiye, the UK, and the USA). Eligible patients were aged 18 years or older with treatment-naive ES-SCLC. Patients received four 21-day cycles of induction treatment (atezolizumab, carboplatin, and etoposide). After completing induction treatment, eligible patients without disease progression were randomly assigned (1:1) using permuted blocks (Interactive Voice/Web Response System) to receive maintenance treatment intravenously every 3 weeks with lurbinectedin (3·2 mg/m2; with granulocyte colony-stimulating factor prophylaxis) plus atezolizumab (1200 mg) or atezolizumab (1200 mg). The two primary endpoints were independent review facility-assessed (IRF) progression-free survival and overall survival, measured from randomisation into the maintenance phase. Efficacy endpoints were assessed in the full analysis set, which included all patients who were randomly assigned to maintenance phase treatment, regardless of whether they received their assigned study treatment. Safety was assessed in all patients who received at least one dose of lurbinectedin or atezolizumab, and was analysed according to the treatment received. This study is registered with ClinicalTrials.gov, NCT05091567, and is closed for recruitment. Between Nov 17, 2021, and Jan 11, 2024, 895 patients were screened for enrolment, of whom 660 (74%) were enrolled into the induction phase. Between May 24, 2022, and April 30, 2024, 483 (73%) of 660 patients entered the maintenance phase and were randomly assigned to lurbinectedin plus atezolizumab (n=242) or atezolizumab (n=241). At the data cutoff (July 29, 2024), IRF progression-free survival was longer in the lurbinectedin plus atezolizumab group than the atezolizumab group (stratified hazard ratio [HR] 0·54 [95% CI 0·43–0·67]; p<0·0001), as was overall survival (stratified HR 0·73 [0·57–0·95]; p=0·017). 92 (38%) of 242 patients in the lurbinectedin plus atezolizumab group and 53 (22%) of 240 patients in the atezolizumab group had grade 3–4 adverse events. The most common grade 3–4 events in the lurbinectedin plus atezolizumab group were anaemia (20 [8%] of 242 patients), decreased neutrophil count (18 [7%] patients), and decreased platelet count (18 [7%] patients) and the most common events in the atezolizumab group were hyponatremia (five [2%] of 240 patients), dyspnoea (four [2%] patients), and pneumonia (four [2%] patients). Grade 5 adverse events occurred in 12 (5%) of 242 patients in the lurbinectedin plus atezolizumab group and six (3%) of 240 patients in the atezolizumab group. The incidence of myelosuppressive toxicities (eg, neutropenia and leukopenia) was higher in the lurbinectedin plus atezolizumab group than the atezolizumab group. IRF progression-free survival and overall survival were longer in the lurbinectedin plus atezolizumab group than the atezolizumab group for patients with ES-SCLC, albeit with a higher incidence of adverse events. Lurbinectedin plus atezolizumab represents a novel therapeutic option for first-line maintenance treatment in this setting. F Hoffmann-La Roche and Jazz Pharmaceuticals.

Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug–drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, abacavir, and lamivudine. We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged ≥18 years) who were previously untreated (HIV-1 RNA ≥500 copies per mL); HLA-B*5701-negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (≤100 000 copies per mL, >100 000 to ≤400 000 copies per mL, or >400 000 copies per mL), CD4 count (<50 cells per μL, 50–199 cells per μL, or ≥200 cells per μL), and region (USA or ex-USA). Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to group assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48, as defined by the US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of −12%. All participants who received one dose of study drug were included in primary efficacy and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02607930. Between Nov 13, 2015, and July 14, 2016, we randomly assigned 631 participants to receive coformulated bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or coformulated dolutegravir, abacavir, and lamivudine (n=315), of whom 314 and 315 patients, respectively, received at least one dose of study drug. At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92·4% of patients (n=290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93·0% of patients (n=293 of 315) in the dolutegravir, abacavir, and lamivudine group (difference −0·6%, 95·002% CI −4·8 to 3·6; p=0·78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, abacavir, and lamivudine (10% [n=32] vs 23% [n=72]; p<0·0001). Adverse events related to study drug were less common with bictegravir, emtricitabine, and tenofovir alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n=82] vs 40% [n=127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, abacavir, and lamivudine group (5% [n=17] vs 17% [n=55]; p<0·0001). At 48 weeks, coformulated bictegravir, emtricitabine, and tenofovir alafenamide achieved virological suppression in 92% of previously untreated adults and was non-inferior to coformulated dolutegravir, abacavir, and lamivudine, with no treatment-emergent resistance. Bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir, abacavir, and lamivudine. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline-recommended treatment for individuals co-infected with HIV and hepatitis B, this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting. Gilead Sciences.

Integrase strand transfer inhibitors (INSTIs) coadministered with two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) are recommended as first-line treatment for HIV, and coformulated fixed-dose combinations are preferred to facilitate adherence. We report 48-week results from a study comparing initial HIV-1 treatment with bictegravir—a novel INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug interactions—coformulated with the NRTI combination emtricitabine and tenofovir alafenamide as a fixed-dose combination to dolutegravir administered with coformulated emtricitabine and tenofovir alafenamide. In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-infected adults were screened and enrolled at 126 outpatient centres in 10 countries in Australia, Europe, Latin America, and North America. Participants were previously untreated adults (HIV-1 RNA ≥500 copies per mL) with estimated glomerular filtration rate of at least 30 mL/min. Chronic hepatitis B virus or hepatitis C co-infection was allowed. We randomly assigned participants (1:1) to receive oral fixed-dose combination bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or dolutegravir 50 mg with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg, with matching placebo, once a day for 144 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of −12%. This study is registered with ClinicalTrials.gov, number NCT02607956. Between Nov 11, 2015, and July 15, 2016, 742 participants were screened for eligibility, of whom 657 were randomly assigned to treatment (327 with bictegravir, emtricitabine, and tenofovir alafenamide fixed-dose combination [bictegravir group] and 330 with dolutegravir plus emtricitabine and tenofovir alafenamide [dolutegravir group]). 320 participants who received the bictegravir regimen and 325 participants who received the dolutegravir regimen were included in the primary efficacy analyses. At week 48, HIV-1 RNA <50 copies per mL was achieved in 286 (89%) of 320 participants in the bictegravir group and 302 (93%) of 325 in the dolutegravir group (difference −3·5%, 95·002% CI −7·9 to 1·0, p=0·12), showing non-inferiority of the bictegravir regimen to the dolutegravir regimen. No treatment-emergent resistance to any study drug was observed. Incidence and severity of adverse events were similar between groups, and few participants discontinued treatment due to adverse events (5 [2%] of 320 in the bictegravir group and 1 [<1%] 325 in the dolutegravir group). Study drug-related adverse events were less common in the bictegravir group than in the dolutegravir group (57 [18%] of 320 vs 83 [26%] of 325, p=0·022). At 48 weeks, virological suppression with the bictegravir regimen was achieved and was non-inferior to the dolutegravir regimen in previously untreated adults. There was no emergent resistance to either regimen. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated compared with the dolutegravir regimen. Gilead Sciences Inc.

BackgroundIn Japan, hepatitis C virus (HCV)-infected patients with decompensated cirrhosis currently have no treatment options. In this Phase 3 study, we evaluated sofosbuvir–velpatasvir with or without ribavirin for 12 weeks in patients with any HCV genotype and decompensated cirrhosis [Child–Pugh–Turcotte (CPT) class B or C] in Japan.MethodsPatients were randomized 1:1 to receive sofosbuvir–velpatasvir with or without ribavirin for 12 weeks. Randomization was stratified by CPT class and genotype. Sustained virologic response 12 weeks following completion of treatment (SVR12) was the primary efficacy endpoint.ResultsOf the 102 patients enrolled, 57% were treatment naive, 78% and 20% had genotype 1 and 2 HCV infection, respectively, and 77% and 20% had CPT class B and C cirrhosis, respectively, at baseline. Overall, 61% of patients were female and the mean age was 66 years (range 41–83). SVR12 rates were 92% (47/51) in each group. Among patients who achieved SVR12, 26% had improved CPT class from baseline to posttreatment week 12. Most adverse events (AEs) were consistent with clinical sequelae of advanced liver disease or known toxicities of ribavirin. Four patients (8%) who received sofosbuvir–velpatasvir and seven (14%) who received sofosbuvir–velpatasvir plus ribavirin experienced a serious AE. The 3 deaths (bacterial sepsis, gastric varices hemorrhage, hepatocellular carcinoma) were attributed to liver disease progression.ConclusionSofosbuvir–velpatasvir for 12 weeks provides a highly effective and well-tolerated therapy for Japanese patients with HCV and decompensated cirrhosis. Ribavirin did not improve efficacy but increased toxicity.

In this analysis of the ASTRAL trials (non-opioid substitution therapy [OST], n = 984; OST, n = 51) evaluating the once-daily, pan-genotypic regimen of sofosbuvir/velpatasvir for hepatitis C virus infection, OST did not impact completion, adherence, sustained virologic response (SVR12), or safety. SVR12 was 96% (95% confidence interval, 87%, >99%) in those receiving OST.

This open-label, two-part, phase Ib drug–drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0–t and 2.7-fold for AUC0–∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

WHO recommends treating hepatitis C infection with one of three antiviral combinations for 8–12 weeks. No randomised trials have compared these regimens, and high cure rates might be achievable with shorter durations of therapy. We aimed to compare sofosbuvir–daclatasvir with sofosbuvir–velpatasvir, and to evaluate potential novel treatment strategies. We conducted a multi-arm, open-label, randomised controlled non-inferiority trial in two public hospitals in Viet Nam. Adults (aged ≥18 years) with chronic hepatitis C infection and mild-to-moderate liver fibrosis were eligible. Recruitment was stratified by centre and viral genotype (1–5 vs 6) with 1:1 random allocation to an oral fixed-dose combination of sofosbuvir 400 mg plus daclatasvir 60 mg (sofosbuvir–daclatasvir) or sofosbuvir 400 mg plus velpatasvir 100 mg (sofosbuvir–velpatasvir). Participants were simultaneously factorially randomly assigned to one of four treatment strategies: 12 weeks’ standard of care (SOC); 4 weeks’ therapy with four weekly PEGylated interferon alfa-2a subcutaneous injections; induction and maintenance therapy with 2 weeks’ standard therapy followed by 10 weeks’ therapy 5 days a week; and response-guided therapy (RGT) for 4, 8, or 12 weeks determined by viral load on day 7. The primary outcome was sustained virological response (SVR) 12 weeks after treatment completion, analysed in all evaluable participants regardless of actual treatment received. We chose a 5% non-inferiority margin for the drug comparison, and a 10% non-inferiority margin for the treatment strategy comparisons. Safety was assessed in all randomised participants. This trial is registered with ISRCTN, 61522291, and is completed. Between June 19, 2020, and May 10, 2023, 624 participants were randomised (470 [75%] were male and 154 [25%] were female). 296 (47%) had genotype 6 and 328 (53%) had genotypes 1–5. The primary outcome was assessable in 609 (98%) participants. SVR occurred in 294 (97%) of 302 participants in the sofosbuvir–daclatasvir group and 292 (95%) of 307 participants in the sofosbuvir–velpatasvir group (risk difference 2·2%, 90% credible interval [CrI] –0·2 to 4·8, within the 5% non-inferiority margin; 93% probability that sofosbuvir–daclatasvir is superior to sofosbuvir–velpatasvir). SVR occurred in 148 (99%) of 150 in the SOC group, 143 (94%) of 152 in the 4-week antiviral plus interferon group (–4·5%, 90% CrI –8·3 to –1·3), 151 (99%) of 152 in the induction–maintenance group (0·6%, –1·1 to 2·7), and 144 (93%) of 155 in the RGT group (–5·7%, –9·6 to –2·3); all risk differences were within the 10% non-inferiority margin. Serious adverse events were rare (11 [4%] of 313 participants in the sofosbuvir–velpatasvir group vs six [2%] of 311 in the sofosbuvir–daclatasvir group; risk difference –1·6% [95% CrI –4·2 to 0·8]) with no evidence of differences between regimens or strategies, but adverse reactions were very common in the 4-week antiviral plus interferon group compared with the other treatment strategies (risk difference vs SOC group, 66·8% [59·2 to 74·0]; p<0·0001). Sofosbuvir–daclatasvir was non-inferior to sofosbuvir–velpatasvir. High efficacy was seen with novel strategies, which might help to inform approaches to treatment for harder-to-reach populations. Wellcome Trust.

Background To evaluate long-term changes in weight and metabolic parameters in people with HIV-1 (PWH) initiating first-line antiretroviral therapy. Methods Analysis of two Phase 3, randomized, double-blind, active-controlled trials (1489: NCT02607930; 1490: NCT02607956). PWH received bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or dolutegravir (DTG)-based treatment (Study 1489: dolutegravir/abacavir/lamivudine [DTG/ABC/3TC]; Study 1490: DTG + F/TAF) for 144 weeks, followed by B/F/TAF (96-week open-label extension up to Week 240). Weight and metabolic parameters were assessed through Week 144 by randomized treatment assignment. Weight changes by baseline viral load and CD4 count were evaluated in PWH receiving B/F/TAF from baseline through Week 240. Multivariate modeling explored baseline factors associated with absolute weight and weight change through Week 240 and weight gain ≥ 10% at Week 240. Results Median weight and body mass index (BMI) increased over time with B/F/TAF ( n  = 628), DTG/ABC/3TC ( n  = 315), and DTG + F/TAF ( n  = 325). There were no significant differences in change in weight or BMI between the B/F/TAF and DTG + F/TAF groups or between the B/F/TAF and DTG/ABC/3TC groups at Week 144 in either trial, nor were there differences in other metabolic parameters, including incidence of treatment-emergent diabetes mellitus and hypertension through Week 144. Among PWH receiving B/F/TAF (baseline through Week 240), weight increases were greatest soon after initiating antiretroviral therapy (i.e., Weeks 0–48), particularly in participants with baseline viral load > 100,000 copies/ml and/or CD4 count < 200 cells/µl. In multivariate modeling (B/F/TAF pooled data), lower baseline CD4 count and higher HIV-1 RNA were associated with lower baseline weight and greater weight gain, but not absolute weight, from Week 48 through Week 240. Conclusions No significant difference in weight change from baseline to Week 144 was found between bictegravir and DTG, or between B/F/TAF and a non-TAF-containing regimen, in these two randomized trials. Furthermore, weight gain following treatment initiation was greatest in the first year of treatment and most pronounced in individuals with more advanced HIV at baseline, supporting the hypothesis that weight gain following initial treatment is linked to a “return to health” in people with advanced HIV.

SummaryBackground A phase I study found remarkable activity and manageable toxicity for doxorubicin (bolus) plus lurbinectedin (1-h intravenous [i.v.] infusion) on Day 1 every three weeks (q3wk) as second-line therapy in relapsed small cell lung cancer (SCLC). An expansion cohort further evaluated this combination. Patients and methods Twenty-eight patients with relapsed SCLC after no more than one line of cytotoxic-containing chemotherapy were treated: 18 (64%) with sensitive disease (chemotherapy-free interval [CTFI] ≥90 days) and ten (36%) with resistant disease (CTFI <90 days; including six with refractory disease [CTFI ≤30 days]). Results Ten patients showed confirmed response (overall response rate [ORR] = 36%); median progression-free survival (PFS) = 3.3 months; median overall survival (OS) = 7.9 months. ORR was 50% in sensitive disease (median PFS = 5.7 months; median OS = 11.5 months) and 10% in resistant disease (median PFS = 1.3 months; median OS = 4.6 months). The main toxicity was transient and reversible myelosuppression. Treatment-related non-hematological events (fatigue, nausea, decreased appetite, vomiting, alopecia) were mostly mild or moderate. Conclusion Doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2 on Day 1 q3wk has shown noteworthy activity in relapsed SCLC and a manageable safety profile. The combination is being evaluated as second-line therapy for SCLC in an ongoing, randomized phase III trial. Clinical trial registrationwww.ClinicalTrials.gov code: NCT01970540. Date of registration: 22 October, 2013.

New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m2 every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00802945. 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4–40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6–46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6–46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none). On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m2 every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer. Nektar Therapeutics.