All-oral Therapy Research Articles

Alliance A061202: ixazomib, pomalidomide, and dexamethasone for patients with lenalidomide-refractory MM in first relapse

AbstractOptimal therapy for the growing number of patients with lenalidomide (LEN)-refractory multiple myeloma in their first relapse remains poorly defined. We therefore undertook a randomized phase 2 study to evaluate the efficacy and safety of combining the oral proteasome inhibitor ixazomib (IXA) with pomalidomide (POM) and dexamethasone (DEX) in this patient population. The overall response rate (ORR) for POM-DEX was 43.6%, and for IXA-POM-DEX, it was 63.2%. The depth of response, measured by the attainment of at least a very good partial response, favored triplet therapy over doublet therapy (28.9% vs 5.1%; P = .0063). A preplanned interim analysis after 75% of the progression events had occurred demonstrated an improvement in progression-free survival (PFS) that favored IXA-POM-DEX and that crossed the predefined boundary of superiority, leading to release of the study results. With additional follow-up, the median PFS for POM-DEX was 7.5 months (95% confidence interval [CI], 4.8-13.6 months) vs 20.3 months for IXA-POM-DEX (95% CI, 7.7-26.0 months; hazard ratio, 0.437; upper 90% bound = 0.657). The ORR and median PFS for 26 of 30 eligible patients who crossed over from the doublet to the triplet therapy at disease progression was 23.1% and 5.6 months, respectively. Overall survival was similar between the 2 groups. More hematologic toxicities were seen with the triplet therapy, but nonhematologic adverse events were similar between the 2 arms. Our data support further testing of this all-oral triplet therapy in comparison with current standard triplet therapy in the context of phase 3 studies for patients with LEN-refractory disease at first relapse. This trial was registered at www.clinicaltrials.gov as #NCT02004275.

Decitabine plus cedazuridine and venetoclax: the promise of an all-oral therapy for patients with myelodysplastic syndromes and chronic myelomonocytic leukaemia

Decitabine plus cedazuridine and venetoclax: the promise of an all-oral therapy for patients with myelodysplastic syndromes and chronic myelomonocytic leukaemia

Trial in Progress: Venetoclax in Combination with ASTX727, an All-Oral Therapy for Chronic Myelomonocytic Leukemia and Other MDS/MPN with Excess Blasts (VICTORY MDS/MPN): A Randomized, Phase 2 Trial

Background and Significance: The rare nature and diagnostic difficulty associated with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has limited the inclusion of patients (pts) with these diseases, other than chronic myelomonocytic leukemia (CMML), in relevant clinical trials. This has resulted in the complete lack of approved agents for the treatment of pts with non-CMML MDS/MPN. Moreover, ASTX727 (oral decitabine-cedazuridine) was approved for CMML based on a study of only 16 pts with CMML. A larger study of CMML and non-CMML MDS/MPN is needed. MDS/MPNs appear to be BCL2-dependent (Bogenberger et al., 2015; Jilg et al., 2016), but data for venetoclax combination therapy are derived from retrospective analyses of relapsed/refractory disease (Cortes et al. 2019; Hammond et al., 2020) or single-arm studies not dedicated to MDS/MPN (NCT04655755, Venugopal et al. 2021). Venetoclax exposures are not affected by coadministration of ASTX727 and predict responses similar to historical data (Mannis et al. 2021). Based on these promising early data and the critical need, we proposed a randomized study of ASTX727 alone or in combination with venetoclax for pts with MDS/MPN and >5% blasts. Study Design and Methods: This is a National Cancer Institute-sponsored, multi-center, international, randomized phase 2 study (NCT05600894, NCI 10538) designed to evaluate the efficacy of ASTX727 alone or in combination with venetoclax in pts with newly diagnosed MDS/MPN with >5% marrow blasts. Key eligibility criteria include allowing hydroxyurea cytoreduction to a WBC <10,000/mm 3 for proliferative disease and excluding pts with need for emergent disease-directed therapy as well as prior therapy for myeloid malignancy other than hydroxyurea or thrombopoietic/erythropoietin stimulating agents. Pts will be randomized 1:1 to receive either ASTX727 alone (Days 1-5) or in combination with venetoclax, initially administered with a 3-day dosing ramp-up and given for 14 days per 28-day cycle (Figure 1). Pts are stratified by disease subtype, specifically CMML and non-CMML MDS/MPN. The primary endpoint is the rate of complete remission (adapted from the MDS/MPN-specific response criteria developed by Savona et al. 2015). Secondary endpoints include the overall response rate, overall survival, progression-free survival, allogeneic hematopoietic stem cell transplantation rate, clonality at time of hematologic remission, number of red cell and platelet transfusions required and toxicity of ASTX727 versus ASTX727 + venetoclax. Pts randomized to the ASTX727 monotherapy arm and without response after 4 cycles of therapy, or with progressive disease after an initial response, cross over to the ASTX727 + venetoclax arm. A futility analysis is planned for each cohort (first 18 and 13 pts in each treatment arm for the CMML and non-CMML cohorts, respectively). We assume that 85% and 90% of pts in the CMML and non-CMML MDS/MPN cohorts, respectively, randomized to the ASTX727 monotherapy arm will not achieve the primary endpoint and will cross over to the ASTX727 + venetoclax combination arm. The estimated accrual time of a total of 70 pts with CMML and 50 pts with non-CMML MDS/MPN will require about 2.9 and 2.1 years, respectively. Planned integrated studies include the use of an apoptosis multiplex immunoassay to evaluate how the addition of a BCL-2 inhibitor will influence the ability of ASTX727 to induce apoptosis and if particular thresholds of apoptosis are predictive of clinical response. Planned exploratory studies include the use of: 1) RNA-seq to evaluate if differences in baseline transcriptional programs appear to be predictive of response to ASTX727 and ASTX727+venetoclax, 2) next generation (Oncomine Comprehensive Assay (OCAv3)/whole exome sequencing to uncover biomarkers predictive of response/outcome, validate risk modeling to stratify these pts and detect/monitor measurable residual disease (MRD) on serial marrow samples that can predict depth of response with translation in improvement in event-based endpoints, and 3) circulating tumor DNA as a non-invasive means (i.e., without need for a marrow evaluation) of prospective MRD detection for prognostic use. This ongoing, randomized study may inform frontline therapeutic options, provide prospective data for venetoclax combination after HMA failure, and generate striking correlative science for pts with “high risk” MDS/MPN.

Sofosbuvir and Velpatasvir Regimen Outcome for Chronic Hepatitis C Patients With End-Stage Renal Disease Undergoing Hemodialysis.

Background Patients on hemodialysis (HD) are most likely to contract hepatitis C (HCV) infection, which is associated with significant morbidity and disease progression. Direct-acting antivirals (DAAs) are safe and tolerable in chronic kidney disease (CKD) with a 90-100% cure rate, and limited data exist regarding their efficacy in end-stage renal disease (ESRD), particularly for HDpatients in South Asia. The study aimed to assess the outcome of a 12-week sofosbuvir (SOF) and velpatasvir (VEL) treatment regimen on ESRD patients with chronic HCV infection undergoing HDin the Pakistani Asian population. Methodology This prospective cohort study was conducted between January 2022 and January2023 at the outpatient nephrology and gastroenterology clinic of Sheikh Zayed Medical College and Hospital, Rahim Yar Khan, Pakistan. This study included a total of 220 ESRD patients fulfilling the inclusion criteria, aged 20-55 years, who had been undergoing weekly HD sessions for at least two years, with acquired HCV infection. Data on demographic and clinical characteristics were collected through patient interviews. Laboratory and dialysis profiling was executed to assess ESRD and discover the underlying cause by ultrasound abdomen, blood pressure measurement by sphygmomanometer, random blood sugarfor diabetes, and taking note of the duration and frequency of dialysis. HCV RNA PCR was done at selected intervals to evaluate the virological response to treatment. Sustained virological response (SVR), liver cirrhosis status, and number of weekly HD sessions were compared at one year of SOF/VEL regimen. Results The mean age of patients with ESRD was 41.8 with a standard deviation (SD) of 9.3 years, and HCV diagnosis was 1.3 years with SD of 0.4 years; 52.7% (n=116) were males, 47.3% (n=104) were females, 75% (n=165) were urban dwellers, and 93.6% (n=206) were married.CKD that requires dialysis was caused mainly by hypertension (78, 35%), diabetes mellitus type 2 (52, 24%), bilateral small kidney disease (40, 18%), and others (34, 16%). One hundred and six (48.2%) received dialysis thrice weekly, 83 (37.7%) twice, and 31 (14.1%) once weekly. The study monitored the rapid virological response (RVR) at four weeks of SOF/VEL regimen in 89.5% of ESRD patients, observed end-of-treatment response (ETR) at 12 weeks in 93.2%, and noted 91.4% SVR response at one year. Only four (1.8%) relapses were observed in the study, which was statistically insignificant. The status of liver cirrhosis showed a 50% improvement, decreasing from 40% to 20%. The frequency of weekly HD sessions decreased from thrice to twice-thrice a week. Conclusion The prevalence of contracting HCV is high among CKD and dialysis ESRD patients. All-oral DAA therapy has revolutionized HCV treatment with co-morbidities. Renal functions improved after the SOF/VEL regimen for chronic HCV infection in ESRD patients undergoing HD, with the number of weekly dialysis sessions reduced and SVR reaching 91.4%. Thus, a single-tablet, pan-genotypic DAA regimen of SOF/VEL for 12 weeks is safe, effective, and tolerable regardless of the underlying etiology of ESRD, complications of cirrhosis, HCV genotype, or previous treatment exposure. The successful treatment of HCV and achieving SVR lowers the risk of ESRD complications, improves extra-hepatic manifestations, and greatly enhances survival. Further studies are warranted after the availability of other DAAs to confirm findings with no limitations.

Being heard on all-oral therapy for resistant tuberculosis

Of all the parts of the Sunday service in his little stone church, Pastor Mafukidze (name changed for privacy) liked listening to the choir best of all. Something about all those voices raised together delighted his heart in a way nothing else could. Which is why the high-pitched buzzing sound that developed in his ears only 6 weeks into his treatment for drug-resistant tuberculosis—an early sign of the hearing loss caused by the injectable medication that was part of his therapeutic regimen—filled him with a sense of dread.

Discovery, Development, Inventions and Patent Review of Fexinidazole: The First All-Oral Therapy for Human African Trypanosomiasis.

Human African trypanosomiasis (HAT or ‘sleeping sickness’) is a neglected tropical disease. If untreated, it is always fatal and leads to death. A few treatments are available for HAT, but most of them require a skilled professional, which increases the financial burden on the patient. Recently, fexinidazole (FEX) has been approved by the European Medicine Agency (EMA) and the United States Food and Drug Administration (USFDA) as the first all-oral therapy for the treatment of stage-1 (hemolymphatic) as well as stage-2 (meningoencephalitic) of HAT. Before the FEX approval, there were separate treatments for stage-1 and stage-2 of HAT. This study reviews the discovery, development timeline, inventions, and patent literature of FEX. It was first approved by EMA and USFDA in 2018 and 2021, respectively. FEX was also added to the World Health Organization’s list of essential drugs in 2019. The patent literature search revealed many types of patents/patent applications (compound, salt, process, method of treatment, drug combinations, and compositions) related to FEX, which have been summarized in this article. The authors foresee a great scope to develop more inventions based on FEX (novel salts, polymorphs, drug conjugates, cyclodextrin complex, etc.) for the treatment of many protozoal diseases (Leishmaniasis and Chagas disease), inflammatory diseases, and other microbial infections. New combinations of FEX with other treatments of HAT may also provide fruitful results. This review might be useful to the scientists working on the HAT and other neglected diseases to develop novel inventions and innovations of therapeutic relevance.

Extended Characterization of Newly Diagnosed Multiple Myeloma (NDMM) Patients with In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy in the Community-Based United States (US) MM-6 Study: Updated Efficacy and Safety, and Reasons for Premature Discontinuation

Extended Characterization of Newly Diagnosed Multiple Myeloma (NDMM) Patients with In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy in the Community-Based United States (US) MM-6 Study: Updated Efficacy and Safety, and Reasons for Premature Discontinuation

P-199: Real-world toxicity and efficacy of ixazomib, lenalidomide and dexamethasone in Asian RRMM patients supported by the patient assistance program

Background The all-oral triplet therapy, ixazomib, lenalidomide, and dexamethasone (IRd), has shown superior progression-free survival (PFS) with excellent safety profile compared with Rd doublet therapy in relapsed and refractory multiple myeloma (RRMM) both in the prospective and retrospective studies. Still, there is limited report of IRd regimen in the real-world Asian RRMM population in terms of the safety and the efficacy Method Sixty RRMM patients treated with ixazomib, which was supported by the patient assistance program, in combination with Rd were retrospectively analyzed by the meticulous electronic medical record review. Results The median age was 68 years. Trial-ineligible patients due to ECOG performance status ≥ 3, platelet count <75,000/µL, creatinine clearance <30 mL/min, underlying heart or chronic active hepatitis B, unmeasurable disease, primary refractoriness to bortezomib, and remaining peripheral neuropathy after previous therapy were included in 35%. Patients had received a median 1 prior line of therapy. The overall response rate and the clinical benefit rate were 80% and 90%, respectively, and the PFS and overall survival was not reached after a median follow-up of 9.2 months. Thalidomide non-refractoriness and thalidomide response duration of ≥ 12 months in thalidomide responders significantly reduced the risk of progression. Non-hematologic adverse events (AEs) were more common than hematologic AEs, most commonly skin rash followed by gastrointestinal toxicities, and infections, and peripheral neuropathies. Grade 3 or higher AEs were observed but mostly in less than 5%. Conclusion Ixazomib and Rd combination therapy showed a comparable efficacy with a favorable toxicity profile especially in the early relapse of Asian RRMM patients. The all-oral triplet therapy, ixazomib, lenalidomide, and dexamethasone (IRd), has shown superior progression-free survival (PFS) with excellent safety profile compared with Rd doublet therapy in relapsed and refractory multiple myeloma (RRMM) both in the prospective and retrospective studies. Still, there is limited report of IRd regimen in the real-world Asian RRMM population in terms of the safety and the efficacy Sixty RRMM patients treated with ixazomib, which was supported by the patient assistance program, in combination with Rd were retrospectively analyzed by the meticulous electronic medical record review. The median age was 68 years. Trial-ineligible patients due to ECOG performance status ≥ 3, platelet count <75,000/µL, creatinine clearance <30 mL/min, underlying heart or chronic active hepatitis B, unmeasurable disease, primary refractoriness to bortezomib, and remaining peripheral neuropathy after previous therapy were included in 35%. Patients had received a median 1 prior line of therapy. The overall response rate and the clinical benefit rate were 80% and 90%, respectively, and the PFS and overall survival was not reached after a median follow-up of 9.2 months. Thalidomide non-refractoriness and thalidomide response duration of ≥ 12 months in thalidomide responders significantly reduced the risk of progression. Non-hematologic adverse events (AEs) were more common than hematologic AEs, most commonly skin rash followed by gastrointestinal toxicities, and infections, and peripheral neuropathies. Grade 3 or higher AEs were observed but mostly in less than 5%. Ixazomib and Rd combination therapy showed a comparable efficacy with a favorable toxicity profile especially in the early relapse of Asian RRMM patients.

S1201 Age-Adjusted Mortality Rates of Liver-Related Death in a VA Cohort of Patients With Cirrhosis

Introduction: Direct-acting antiviral (DAA) therapy for hepatitis C reduces the risk of decompensation and hepatocellular carcinoma among patients with cirrhosis. Long-term population-based data quantifying the effect of DAAs on cause-specific mortality in cirrhosis remain lacking. The aim of this study was to evaluate temporal trends in overall and cause-specific mortality in a national cohort of patients with cirrhosis. Methods: We performed a retrospective cohort study of patients with cirrhosis diagnosed between 2008-2017 in the Veterans Health administration. We determined cause of death from the Mortality Death Registry and characterized these as following: all-cause mortality, mortality related to liver disease (including liver neoplasm, end-stage liver disease, infection, and GI hemorrhage), and mortality due to liver neoplasm only. Age-adjusted mortality rates, annual adjusted percent change (AAPC) in mortality rate, and inflection points (Joinpoints) were calculated using the SEER*Stat Joinpoint regression program referencing a standard population from US Census data. Results: 129,700 male patients with cirrhosis were included, 75% related to hepatitis C infection; 20.3% of the total population died during the follow-up period. All-cause mortality declined between 2008-2017, with a change in AAPC rate detected in 2015 from -2.57% to -6.93% (Figure). Similarly, composite liver mortality declined throughout the study period but accelerated after 2013 from -3.09% to -10.2%. By contrast, liver neoplasm-related mortality increased until 2012 (+0.72%), then declined after 2013 (-8.14%). Conclusion: Sharp declines in liver-related death appear to precede the widespread availability of all-oral DAA therapy by about one year suggesting significant impacts of improved general and HCC-related liver care. Both liver neoplasm-related death and composite liver mortality (including liver cancer) decreased significantly after 2013, likely due to secular changes in liver cancer care and improved management of decompensated liver disease. Overall mortality, however, decreased significantly after 2015, most likely due to increased availability of direct-acting antiviral (DAA) agents for hepatitis C. Data should be confirmed in a non-veteran population.Figure 1.: Age-Adjusted Total, Liver-Neoplasm, and Liver Composite Mortality Rates, 2008-2017.

Efficacy and safety of danoprevir plus sofosbuvir in GT 1, 2, 3, or 6 chronic hepatitis C patients with or without cirrhosis in China.

All-oral direct-acting antiviral therapies are becoming the choice for hepatitis C (HCV) treatment. In this study, we aimed to evaluate the efficacy and safety of ritonavir-boosted danoprevir (DNVr) plus sofosbuvir±ribavirin on HCV genotype 1, 2, 3, or 6 in the real world in China.In this observational, prospective, multicenter cohort, we enrolled a total of 58 patients with HCV genotype 1, 2, 3, or 6 patients from July 2018 to December 2019. All patients were treated with DNVr plus sofosbuvir ± ribavirin for 12 weeks and then followed up for 12 weeks. The primary endpoint was the rate of sustained virologic response at week 12 after the end of treatment (SVR12). The secondary endpoint was virologic response rate at end-of-treatment and adverse event outcome.Of the 58 patients who were enrolled, 5.2% (n = 3) had genotype 1a; 43.1% (n = 25) had HCV genotype 1b; 17.2% (n = 10) had genotype 2a; 5.2% (n = 3) had genotype 3a; 8.6% (n = 5) had genotype 3b; and 20.7% (n = 12) had genotype 6a. The virologic response rate at end-of-treatment was 100% (58/58). The HCV-RNA results of 5 patients were absent at week 12 after treatment. Among the 53 patients, SVR12 rate achieved 100% (53/53) with DNVr plus sofosbuvir ± ribavirin treatment in patients with HCV genotype 1b, 2a, 3, and 6a. For compensated cirrhosis and noncirrhosis patients, SVR12 was 100% with DNVr plus sofosbuvir ± ribavirin treatment. No serious event was observed during the treatment and follow-up. Only 5 patients had mild adverse events.DNVr plus sofosbuvir ± ribavirin for 12 weeks provided 100% SVR12 in a broad patient population and were well tolerated, which may be a promising regimen for CHC treatment.

The risk of hepatitis C virus recurrence in hepatitis C virus-infected patients treated with direct-acting antivirals after achieving a sustained virological response: A comprehensive analysis.

The risk for hepatitis C virus (HCV) recurrence persists after HCV eradication with direct-acting antivirals (DAAs), particularly in patients with ongoing high-risk behaviours. Our aim was to assess the risk of HCV recurrence (late relapse and/or reinfection) post-sustained virological response (SVR). We searched the literature for studies reporting HCV recurrence rates post-SVR in PubMed, Web of Science and the Cochrane Library. Identified publications were divided into groups based on patient risk for HCV reinfection: low-risk HCV mono-infection, high-risk HCV mono-infection and a human immunodeficiency virus (HIV)/HCV coinfection. The HCV recurrence rate for each study was calculated by using events divided by the person-years of follow-up (PYFU). HCV recurrence was defined as confirmed, detectable HCV RNA post-SVR. In the 16 studies of low-risk patients, the pooled recurrence rate was 0.89/1000 PYFU (95% confidence interval [CI], 0.16-2.03). For the 19 studies of high-risk patients, the pooled recurrence rate was 29.37/1000 PYFU (95% CI, 15.54-46.91). For the eight studies of HIV/HCV-coinfected patients, the pooled recurrence rate was 23.25/1000 PYFU (95% CI, 4.24-53.39). The higher pooled estimates of recurrence in the high-risk and HIV/HCV-coinfected populations were predominantly driven by an increase in reinfection rather than late relapse. The HCV recurrence risk after achieving SVR with all-oral DAAs therapy is low, and the risk of HCV recurrence in high-risk and HIV/HCV-coinfected populations was driven by an increase in reinfection rather than late relapse.

A Randomized Phase II Trial Comparing the Efficacy and Safety of Pioglitazone, Clarithromycin and Metronomic Low-Dose Chemotherapy with Single-Agent Nivolumab Therapy in Patients with Advanced Non-small Cell Lung Cancer Treated in Second or Further Line (ModuLung).

Background: Most non-small cell lung cancers occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumor-associated homeostatic pathways to achieve tumor control paralleled by modest toxicity profiles. Patients and Methods: The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous (n = 11) and non-squamous non-small cell (n = 26) lung cancer who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. Results: The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors (ICi) in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. Progression-free survival (PFS) was significantly inferior for biomodulation (N = 20) vs. nivolumab (N = 17) with a median PFS (95% confidence interval) of 1.4 (1.2–2.0) months vs. 1.6 (1.4–6.2), respectively; with a hazard ratio (95% confidence interval) of 1.908 [0.962; 3.788]; p = 0.0483. Objective response rate was 11.8% with nivolumab vs. 5% with biomodulation, median follow-up 8.25 months. The frequency of grade 3–5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. Overall survival (OS), the secondary endpoint, was comparable in both treatment arms; biomodulation with a median OS (95% confidence interval) of 9.4 (6.0–33.0) months vs. nivolumab 6.9 (4.6–24.0), respectively; hazard ratio (95% confidence interval) of 0.733 [0.334; 1.610]; p = 0.4368. Seventy-five percent of patients in the biomodulation arm received rescue therapy with checkpoint inhibitors. Conclusions: This trial shows that the biomodulatory therapy was inferior to nivolumab on PFS. However, the fact that OS was similar between groups gives rise to the hypothesis that the well-tolerable biomodulatory therapy may prime tumor tissues for efficacious checkpoint inhibitor therapy, even in very advanced treatment lines where poor response to ICi might be expected with increasing line of therapy.

Phase II study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA.

Objective:Apatinib is an oral TKI targeting VEGFR-2. Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated mBC. Oral vinorelbine also holds promise as a treatment of choice in patients with mBC. This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated mBC. In addition, we detected gene variants in ctDNA to explore the therapeutic implications.Methods:This study enrolled patients with HER2-negative mBC who were pretreated with anthracycline/taxanes. Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1, 8, and 15 of every cycle (3 weeks). The primary endpoint was PFS. The secondary endpoints were ORR, CBR, OS, and safety. Patients eligible for ctDNA detection were evaluated before and during treatment.Results:Forty patients were enrolled. The median PFS was 5.2 months (95% CI, 3.4–7.0 months), and the median OS was 17.4 months (95% CI, 8.0–27.0 months). The ORR was 17.1% (6/35), and the CBR was 45.7% (16/35). The most common AEs included gastrointestinal reaction, myelosuppression, and hypertension. In 20 patients, ctDNA was detected at baseline and during treatment. A significant difference was found in PFS for undetected vs. detected baseline ctDNA (13.9 months vs. 3.6 months, P = 0.018).Conclusions:All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative mBC, with acceptable and manageable toxicity profiles. Patients with no gene variant detected and lower variant allele frequencies in ctDNA at baseline showed longer PFS.

Hepatitis C Virus Treatment as Prevention: Challenges and Opportunities in Men Who Have Sex With Men.

Since 2002, a global epidemic of acute hepatitis C virus (HCV) infection has been noted in men who have sex with men (MSM). Transmission of HCV, particularly in the context of traumatic sex practices that increase the risk of blood-blood contacts (eg, anal sex and fisting), was initially found in human immunodeficiency virus (HIV)-coinfected and more recently in HIV-uninfected MSM, especially those receiving pre-exposure prophylaxis (PrEP). Early HCV treatment with all-oral direct-acting antiviral combination therapy has been associated with very high HCV cure rates of up to 100%. Indeed, immediate treatment of recently acquired HCV directly after new HCV diagnosis, or after 4 weeks if no 2-log10 drop in HCV RNA level occurs, promises rapid HCV elimination. Reports from the Netherlands, Switzerland, and the United Kingdom all show that with increased treatment uptake in this particular patient group, dramatic reductions in new HCV infections can be achieved. A general consensus on how to best screen for and manage acute HCV infections, along with broad access to rapid HCV therapy initiation, is crucial to attaining HCV elimination, a goal that is challenged by high HCV reinfection rates among MSM.

In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy Increases the Feasibility of Long-Term PI Treatment and Benefit for Newly Diagnosed Multiple Myeloma (NDMM) Patients in an Outpatient Setting: Updated Real-World Results from the Community-Based United States (US) MM-6 Study

In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy Increases the Feasibility of Long-Term PI Treatment and Benefit for Newly Diagnosed Multiple Myeloma (NDMM) Patients in an Outpatient Setting: Updated Real-World Results from the Community-Based United States (US) MM-6 Study

Development of hepatocellular carcinoma by patients aged 75 years or over after HCVelimination by all-oral DAA therapy: results from a large-scale, multicenter cohort study

Development of hepatocellular carcinoma by patients aged 75 years or over after HCVelimination by all-oral DAA therapy: results from a large-scale, multicenter cohort study

Retreatment of Hepatitis C Infection With Direct-Acting Antivirals

Treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) results in sustained virologic response (SVR) in > 90% of patients. However, some patients required retreatment with newer DAA options. Treatment was selected after consultation with a clinical pharmacy specialist. A retrospective chart review of patients at the West Palm Beach Veterans Affairs Medical Center (WPBVAMC) in Florida retreated from January 2015 to December 2019 was conducted. Data collected included HCV genotype, previous therapy, newly prescribed medications, and treatment outcomes. Since 2015, > 900 patients have been treated at WPBVAMC, including 22 patients who had previously failed interferon combined with DAA regimens and 46 patients who needed retreatment after failure with an all-oral therapy. This review documents the outcomes of retreatment with DAA after initial failure to achieve SVR Of 28 patients treated with a boceprevir-based regimen, 10 ended in failure. All 10 were retreated, and all achieved SVR with ledipasvir/sofosbuvir. Of 53 patients treated with a sofosbuvir-based interferon regimen, 12 failed treatment. All 12 were retreated and all achieved SVR. Thirty patients were retreated after failure with an all-oral DAA. Of 27 tested, 21 achieved SVR. All patients who failed therapy again had cirrhosis. Veterans retreated with DAAs for HCV infection had a high success rate. Repeat failures of DAAs were rare, but cirrhosis seems to be common among these patients.

Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model.

BackgroundDNA methyltransferase inhibitors (DNMTis) improve survival for patients with myelodysplastic syndromes (MDS) and those with acute myeloid leukemia (AML) unable to receive standard cytotoxic chemotherapy and are, accordingly, the backbone of standard-of-care treatment for these conditions. Standard regimens with DNMTIs, decitabine (DEC) or azacitidine (AZA) include daily subcutaneous (s.c.) or intravenous (i.v.) administration for 5–7 consecutive days. Attempts to provide the therapy orally have been limited given rapid clearance of the agents by the enzyme cytidine deaminase (CDA), which is ubiquitous in the gut and liver as part of first-pass metabolism. Recently, cedazuridine (CDZ), an oral inhibitor of CDA, was successfully combined with DEC to approximate the pharmacokinetics of i.v. DEC in patients.ObjectiveTo determine if an oral dosing strategy might be feasible in the clinic with AZA, we attempted to increase the bioavailability of oral AZA through the use of CDZ, in a murine model.MethodsFollowing pharmacokinetic and pharmacodynamic assessment of oral AZA dosed with CDZ in murine and monkey models, we tested this regimen in vivo with a human cell line-derived xenograft transplantation experiment (CDX). Following this we combined the regimen with venetoclax (VEN) to test the efficacy of an all-oral regimen in a patient-derived xenograft (PDX) model.ResultsParenteral AZA and oral AZA + CDZ exhibited similar pharmacokinetic profiles, and efficacy against human AML cells. Tumor regression was seen with AZA + CDZ in MOLM-13 CDX and PDX models.ConclusionsWe conclude that oral AZA when combined with CDZ achieves successful tumor regression in both CDX and PDX models. Furthermore, the combination of AZA + CDZ with VEN in a PDX model emulated responses seen with VEN + AZA in the clinic, implying a potential all-oral VEN-based therapy opportunity in myeloid diseases.

Efficacy and safety of direct-acting antivirals in older patients with cirrhosis and high comorbidity index.

There is scarce data with regard to the effectiveness and safety of direct-acting antivirals and possible drug-drug interactions between antiviral therapy and the multiple drugs frequently assumed by older patients. The aim is to evaluate the impact of comorbidities and drug-drug interactions on the efficacy and tolerability of direct-acting antivirals in this population. Observational retrospective study of patients at least 65 years old receiving all-oral antiviral therapy between April 2015 and March 2016. Two hundred sixty-one patients were identified. Age distribution: 65-74 (73.9%), 75-79 (18.4%) and ≥80 (7.7%) years. Average age was 71 years, 38.7% were male, and 90% of patients took concomitant medication (43% patients taking ≥ 5 medicines). Predicted clinically significant drug-drug interactions were present in 72.8% of patients. The sustained viral response 12 weeks after end of treatment was 96.9%. Patients with serious adverse events received more concomitant drugs and all of them presented a clinical risk group ≥06/5. Direct antiviral agents are highly effective also in older patients with advanced liver disease, comorbidities and concomitant medications. Serious adverse events increased with the number of concomitant medications and the severity of comorbidity. A clinical risk group score ≥06/5 may help to decide the indication of antiviral therapy in this difficult-to-treat population.

Early Treatment Uptake and Cost Burden of Hepatitis C Therapies Among Newly Diagnosed Hepatitis C Patients with a Particular Focus on HIV Coinfection.

Despite the high efficacy and safety associated with direct-acting antivirals (DAAs), access to HCV treatment has been frequently restricted because of the high DAA drug costs. To (1) compare HCV treatment initiation rates between HCV monoinfected and HCV/HIV coinfected patients before (pre-DAA period) and after (post-DAA period) all-oral DAAs became available; and to (2) estimate the HCV treatment costs for payers and patients. A retrospective analysis of the MarketScan® Databases (2009-2016) was conducted for newly diagnosed HCV patients. Multivariable logistic regression was used to estimate the odds ratio (OR) of initiating HCV treatments during the pre-DAA and post-DAA periods. Kruskal-Wallis test was used to compare drug costs for dual, triple and all-oral therapies. A total of 15,063 HCV patients [382 (2.5%) HIV coinfected] in the pre-DAA period and 14,896 [429 (2.9%) HIV coinfected] in the post-DAA period were included. HCV/HIV coinfected patients had lower odds of HCV treatment uptake compared to HCV monoinfected patients during the pre-DAA period [OR, 0.59; 95% confidence interval (CI), 0.45-0.78], but no significant difference in odds of HCV treatment uptake was observed during the post-DAA period (OR, 1.08; 95% CI, 0.87-1.33). From 2009 to 2016, average payers' treatment costs (dual, $20,820; all-oral DAAs, $99,661; p < 0.001) as well as average patients' copayments (dual, $593; all-oral DAAs $933; p < 0.001) increased significantly. HCV treatment initiation rates increased, especially among HCV/HIV coinfected patients, from the pre-DAA to the post-DAA period. However, payers' expenditures per course of therapy saw an almost fivefold increase and patients' copayments increased by 55%.