COLUMBUS-AD: phase III study of adjuvant encorafenib + binimetinib in resected stage IIB/IIC BRAF V600-mutated melanoma.

Stage IIB/IIC melanoma has a high risk of recurrence after surgical resection. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-programmed cell death protein 1 (PD-1) antibodies significantly improve recurrence-free survival versus placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF MEK inhibitor therapy showed benefits in high-risk stage III and advanced disease; however, its role in patients with fully resected stage BRAF-mutated IIB/IIC melanoma is still unknown. Here we describe the rationale and design of the ongoing randomized, placebo-controlled COLUMBUS-AD trial, the first study of a BRAF-MEK inhibitor combination therapy (encorafenib + binimetinib) in patients with BRAF V600-mutated stage IIB/IIC melanoma.

Melanoma is a type of skin cancer. Although most stage II melanomas (cancer affecting the first two layers of skin) can be cured with surgery, the risk of the cancer returning and spreading to other areas of the body is high in some patients with stage IIB/IIC melanoma. Furthermore, once the melanoma has spread, it is much more difficult to treat successfully and remove all the cancer cells from the body. Some melanomas have a DNA alteration (or mutation) in what is known as the BRAF gene. This mutation can be identified by testing a sample of the tumor tissue removed during a biopsy or surgery. Testing for BRAF mutations at diagnosis can help ensure that patients receive the most appropriate treatment for their cancer. In some countries, surgery is the only option for patients with stage II melanoma, while in other countries, patients may be offered additional (adjuvant) anticancer treatment with immunotherapy (agents that work with the immune system to kill cancer cells). While immunotherapy can reduce the risk of melanoma recurrence, persistent, long-term toxicities are common and the use of this treatment in all stage IIB/IIC melanoma patients is not always possible. Here, we describe the rationale and design of an ongoing clinical trial (COLUMBUS-AD), which will be the first study (to our knowledge) to investigate the efficacy and safety of a treatment that specifically targets cancers with BRAF mutations (i.e., the BRAF-MEK inhibitor combination of the drugs encorafenib and binimetinib) in patients with BRAF-mutated stage IIB/IIC melanoma. Clinical Trial Registration: NCT05270044 (ClinicalTrials.gov).

ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAFV600E-Mutant Metastatic Colorectal Cancer.

PURPOSE: The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170). ANCHOR CRC aimed to evaluate efficacy, safety, and quality of life with first-line encorafenib + binimetinib + cetuximab in BRAFV600E-mutated mCRC. METHODS: In this multicenter, open-label, single-arm study, patients with BRAFV600E-mutated mCRC received oral encorafenib 300 mg once daily and binimetinib 45 mg twice daily in 28-day cycles, plus intravenous cetuximab 400 mg/m2 once on day 1 of cycle 1, then 250 mg/m2 once weekly for the first seven cycles, and 500 mg/m2 once on Days 1 and 15 from cycle 8 onward. The primary end point was locally assessed confirmed objective response rate (cORR), and secondary end points included centrally assessed cORR, progression-free survival, overall survival (OS), quality of life, and safety and tolerability. RESULTS: Among 95 patients, the locally assessed cORR was 47.4% (95% CI, 37.0 to 57.9) with all partial responses. Since the lower limit of the 95% CI exceeded 30%, the primary end point was met. With a median follow-up duration of 20.1 months, the median progression-free survival on the basis of local assessments was 5.8 months and the median OS was 18.3 months. Treatment was well tolerated, with no unexpected toxicities. Using Patient Global Impression of Changes, substantial improvement in symptoms was consistently reported in ≥ 30% of patients from cycle 3 to cycle 10. CONCLUSION: The ANCHOR CRC study showed that the scientifically driven combination of encorafenib + binimetinib + cetuximab was active in the first-line setting of BRAFV600E-mutated mCRC with a manageable safety profile. Further first-line evaluation is ongoing (ClinicalTrails.gov identifier: NCT04607421).

Safety and Efficacy of Atazanavir Powder and Ritonavir in HIV-1-Infected Infants and Children From 3 Months to <11 Years of Age: The PRINCE-2 Study.

BACKGROUND: Novel antiretroviral formulations that are palatable, safe, and effective are needed for infants and children. METHODS: PRINCE-2 is an ongoing clinical trial assessing safety, efficacy, and palatability of once-daily atazanavir powder formulation boosted with ritonavir (ATV + RTV) plus optimized dual nucleos(t)ide reverse transcriptase inhibitors therapy in antiretroviral-naïve/experienced children with screening HIV-1 RNA ≥1000 copies/mL. Children 3 months to <11 years received ATV + RTV by 5 baseline weight bands: 5 to <10 kg = 150/80 mg; 5 to <10 kg = 200/80 mg; 10 to <15 kg = 200/80 mg; 15 to <25 kg = 250/80 mg; and 25 to <35 kg = 300/100 mg. RESULTS: Of 99 treated children, 83.8% and 59.6% remained on ATV powder until 24 and 48 weeks, respectively. Through 48 weeks, the most common adverse events were upper respiratory tract infections (33.3%), gastroenteritis (28.3%), vomiting (21.2%) and hyperbilirubinemia (18.2%; none leading to treatment discontinuation). Serious adverse events occurred in 20.2% of patients. Laboratory grade 3-4 hyperbilirubinemia occurred in 9.2% and elevated total/pancreatic amylase in 33.7%/3.1%. At week 24, proportions with virologic suppression (HIV-1 RNA <50 copies/mL; intention-to-treat analysis) across weight bands were 10/23 (43.5%), 2/12 (16.5%), 10/21 (47.6%), 19/35 (54.3%) and 5/8 (62.5%), respectively. Virologic suppression was similar in antiretroviral-naïve/experienced patients and lowest in the 5 to <10 kg = 200/80 mg group, likely because of higher baseline HIV-1 RNA and discontinuation (66.7%). Overall, virologic suppression at weeks 24 (46.5%) and 48 (43.0%) was comparable. At week 48, 83.3% and 74.1% of caregivers reported no trouble giving ATV powder and RTV, respectively. CONCLUSIONS: ATV powder palatability, efficacy and lack of unexpected safety findings support its use for HIV-1-infected children ≥3 months to <11 years.

Entecavir plus tenofovir combination therapy for chronic hepatitis B in patients with previous nucleos(t)ide treatment failure.

BACKGROUND AND AIMS: In patients with chronic hepatitis B (CHB) who have failed on other nucleos(t)ide analogs (NUCs), the combination of entecavir (ETV) plus tenofovir disoproxil fumarate (TDF), two potent agents with non-overlapping resistance profiles, may provide a single rescue regimen. METHODS: In this single-arm, open-label study, 92 CHB patients with a primary non-response, partial response, or virologic breakthrough on their current NUC were switched to ETV (1 mg) plus TDF (300 mg) and treated for 96 weeks. RESULTS: At baseline, 62 % of patients were HBeAg(+) and mean HBV DNA was 4.4 log10IU/mL. Patients had received ≥1 line of prior NUC therapy, with the latest regimen consisting of monotherapy with ETV (53 %), lamivudine (LVD 22 %), TDF (12 %), adefovir (ADV 4 %), or telbivudine (2 %), or combinations of these agents (7 %); 58 % had evidence of single- or multidrug resistance mutations (LVD 52 %, ETV 26 %; ADV 7 %). Response rates for HBV DNA <50 IU/mL were 76 % (70/92) at week 48 (primary endpoint), and 85 % (78/92) at week 96, including 80 % (16/20) in prior LVD failures, 100 % (4/4) in ADV failures, 82 % (9/11) in TDF failures, and 88 % (42/48) in ETV failures. No treatment-emergent resistance to ETV or ADV was observed. ETV/TDF was well tolerated, with no significant renal or additive toxicities observed. CONCLUSIONS: In NUC-experienced patients who have failed prior NUC therapy, ETV/TDF was well tolerated and effective, achieving virologic suppression through 96 weeks in the majority (85 %), irrespective of prior NUC exposure, without occurrence of treatment-emergent resistance to either agent.

Brief Report: Switch to Ritonavir-Boosted Atazanavir Plus Raltegravir in Virologically Suppressed Patients With HIV-1 Infection: A Randomized Pilot Study.

This open-label, multinational, pilot study randomized (1:2 ratio) adults with HIV-1 RNA <40 copies per milliliter and nucleos(t)ide-related safety/tolerability issues to switch to ritonavir-boosted atazanavir (ATV/r) plus tenofovir disoproxil fumarate/emtricitabine (n = 37) or the nucleos(t)ide reverse transcriptase inhibitor-sparing regimen of ATV/r plus raltegravir (RAL) (n = 72). At 24 weeks, 35/37 (94.6%) and 58/72 (80.6%) of patients, respectively, maintained virological suppression, the primary endpoint, and 1 (2.7%) and 7 (9.7%), respectively, experienced virological rebound. Corresponding 48-week proportions were 86.5%, 69.4%, 2.7%, and 12.5%, respectively. Adherence was lower and treatment discontinuation was higher with ATV/r+RAL. In conclusion, switching to ATV/r+RAL resulted in a higher virological rebound rate than switching to ATV/r plus tenofovir disoproxil fumarate/emtricitabine.

Nephrolithiasis and renal failure among patients exposed to atazanavir, other PIs and PI-free regimens.

INTRODUCTION: Recent single-site studies and case reports have linked atazanavir (ATV) with the occurrence of nephrolithiasis. The purpose of this study was to estimate and compare the incidence rate of nephrolithiasis and to characterize the occurrence of subsequent renal failure among patients on ATV, other protease inhibitors (PIs) and PI-free regimens using real world data. MATERIALS AND METHODS: This was a retrospective cohort analysis using claims data from a US commercial and a US public health insurance database (Medicaid) spanning 2003-2011 and 2006-2011, respectively. We identified adult HIV patients who were prescribed ATV, other PIs or PI-free regimens with at least 6 months of continuous enrolment prior to the index claim. Nephrolithiasis was defined as an inpatient or outpatient ICD-9 diagnosis code for nephrolithiasis or an associated condition, plus an imaging/corrective procedure code. Renal failure was also identified using diagnosis codes among patients experiencing nephrolithiasis. Hazard ratios were estimated using propensity score (PS) adjusted Cox regression, crude and adjusted for demographics, baseline comorbidities and comedications. RESULTS: A total of 14,477 patients (ATV: 4,150; other PIs: 4,153; PI-free: 6,174) were identified in the commercial database: 83% male and 20% age ≥50 years. In the Medicaid database, 9,104 patients (ATV: 3,460; other PIs: 3,117; PI-free: 2,527) were identified: 53% male and 25% age ≥50 years. There were significant baseline differences in demographics, comorbidities and concomitant medications among the three cohorts. In adjusted analyses, ATV use was not significantly associated with nephrolithiasis when compared to other PIs. When ATV was compared to PI-free regimens, a positive association was observed in the commercial insurance but not the Medicaid database. In both databases, previous history of nephrolithiasis was the strongest predictor of nephrolithiasis in the ATV/PI-free regimens contrast, but not the ATV/other PIs contrast. For the renal failure outcomes, there were insufficient cases across all cohorts to conduct crude or adjusted analyses (see Table 1). CONCLUSIONS: In this analysis of two large real world databases, we did not find evidence of an increased risk of nephrolithiasis among patients on ATV compared to other PIs. However, when ATV was compared to PI-free regimens, the results differed across the two databases, requiring further study. Additionally, renal failure following nephrolithiasis was infrequent and not significantly different across the three cohorts.

Chronic hepatitis B treatment initiation and modification patterns in five European countries: a 2-year longitudinal, non-interventional study.

BACKGROUND: Chronic hepatitis B (CHB) is an important health concern, but there are few studies describing its management in different countries. This prospective, longitudinal, non-interventional study aimed to assess differences in CHB management in five European countries (Germany, France, Poland, Romania and Turkey). METHODS: Data were collected from CHB patients' records between 2008 and 2010. Patients were stratified by treatment status at baseline (treated or untreated). The primary objective was to estimate the probability of a CHB management modification (treatment initiation or change) among patients from each country during a 2-year follow-up. RESULTS: A total of 1,267 patients were included (567 treated, 700 untreated). Baseline characteristics between countries and treatment status groups were broadly comparable. Most patients had an alanine aminotransferase measurement in the 12 months prior to baseline; proportions of patients with an HBV DNA assessment varied by country and treatment status. The Kaplan-Meier-estimated probability of any treatment modification ranged from 9.4% (Turkey) to 30.1% (Poland) at 12 months and 10.0% (Turkey) to 40.0% (Poland) at 24 months. Modifications were more common in treated than untreated patients. The most frequently reported reasons for modifying treatment were HBV-DNA-related. The majority of treated patients were treated with monotherapy; however, choice of therapy differed between countries. CONCLUSIONS: This is the first longitudinal study describing CHB management in European countries. Differences were observed in treatment and monitoring between countries, but alanine aminotransferase and HBV DNA levels consistently emerged as key tests in the management of CHB in all five countries.

Chronic hepatitis B monitoring and treatment patterns in five European countries with different access and reimbursement policies.

BACKGROUND: In Europe, health-care policies are determined at a national level and differ between countries. This analysis from a prospective, longitudinal, non-interventional study aimed to describe patterns in the clinical monitoring and treatment of chronic hepatitis B (CHB) in five European countries. METHODS: Country-specific cohorts of adult patients with compensated CHB managed in clinics in Germany, France, Poland, Romania and Turkey were followed for up to 2 years between March 2008 and December 2010. RESULTS: A total of 1,267 patients were included. Baseline age and gender distribution were similar across countries for patients who were treated (n=567) and untreated (n=700) at baseline. Most treated patients were receiving monotherapy at baseline, most frequently with entecavir or tenofovir in Germany, France and Turkey, and with lamivudine in Poland and Romania. Use of pegylated interferon was more frequent in Poland and Romania than in other countries. In Romania monotherapy with entecavir increased after it became reimbursed in 2008. Hospitalizations during follow-up were more frequent in Romania (1.45 hospital days/patient-year) and Poland (1.81 days/patient-year) than in Turkey, France and Germany (0.00, 0.05 and 0.10 days/patient-year, respectively); clinic visits were more frequent in Poland (3.20 versus 0.30-1.78 visits/patient-year across other countries). CONCLUSIONS: These results illustrate country-specific patterns in the management of CHB patients across Europe. Observed monitoring patterns, hospitalization rates and other health-care utilization may be related to cost and reimbursement issues; however, further study in individual countries would be required to confirm these (post hoc) observations.