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Alectinib, a potent ALK tyrosine kinase inhibitor, was more effective and somewhat less toxic than crizotinib when used as primary therapy in patients with ALK -positive non–small-cell lung cancer. Importantly, it reduced the risk of CNS relapse.

Alectinib—a highly selective, CNS-active, ALK inhibitor—showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib. We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB–IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment. Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3–7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36–60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment). Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib. F Hoffmann-La Roche.

IntroductionDigital patient monitoring (DPM) tools can enable more effective clinical care and improved patient outcomes in cancer. However, their broad adoption requires ease of use and demonstration of real-world clinical utility/impact. ORIGAMA (MO42720) is an interventional, open-label, multicountry platform study investigating the clinical utility of DPM tools and specific treatments. ORIGAMA will begin with two cohorts that aim to assess the impact of the atezolizumab-specific Roche DPM Module (hosted on the Kaiku Health DPM platform (Helsinki, Finland)) on health outcomes and healthcare resource usage, and its feasibility to support at-home treatment administration, in participants receiving systemic anticancer treatment. Other digital health solutions may be added to future cohorts.Methods and analysisIn Cohort A, participants with metastatic non-small cell lung cancer (NSCLC), extensive-stage SCLC or Child Pugh A unresectable hepatocellular carcinoma will be randomised to a locally approved anticancer regimen containing intravenous atezolizumab (TECENTRIQ, F. Hoffmann-La Roche Ltd/Genentech) and local standard-of-care support, with/without the Roche DPM Module. Cohort B will assess the feasibility of the Roche DPM Module in supporting administration of three cycles of subcutaneous atezolizumab (1875 mg; Day 1 of each 21-day cycle) in the hospital, followed by 13 cycles at home by a healthcare professional (ie, flexible care), in participants with programmed cell-death ligand 1-positive, early-stage NSCLC. The primary endpoints are the mean difference in change of the participant-reported Total Symptom Interference Score at Week 12 from baseline (Cohort A) and flexible care adoption rate at Cycle 6 (Cohort B).Ethics and disseminationThis study will be conducted according to the Declaration of Helsinki, and/or the applicable laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study received its first Ethics Committee approval in Spain in October 2022. Participants will provide written informed consent in a face-to-face setting. The results of this study will be presented at national and/or international congresses and disseminated via publication in peer-reviewed journals.Trial registration numberNCT05694013.

Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK‐positive non‐small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib‐failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one‐compartment models with sequential zero/first‐order input and first‐order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment‐naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression‐free survival in treatment‐naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of treatment as a significant covariate, with an optimal response achieved for concentrations above 1040 nmol/L. With 600 mg twice daily (b.i.d.), 92% of global patients are above this threshold concentration, compared with only 43% of patients with 300 mg b.i.d. In Japan, where the body weight distribution is lower, the approved 300 mg b.i.d. dose brings about 70% of Japanese patients above this threshold. Logistic regression analyses found no significant relationship between the combined alectinib–M4 molar concentration and first occurrence of adverse events. These pharmacometric results were used to expedite and facilitate regulatory approvals of 600 mg b.i.d. for first‐line ALK‐positive NSCLC in the United States and European Union in 2017 and in China in 2018.

BackgroundIMvigor010 (NCT02450331) showed that atezolizumab reduced risk of death by approximately 40% in post-cystectomy ctDNA-positive patients.1 Whether ctDNA may predict toxicity of immune checkpoint inhibition is unknown. Theoretically the lack of tumor-derived immune suppression associated with the presence of cancer may result in more irAEs.MethodsPatients with high-risk muscle invasive bladder cancer treated with atezolizumab (n=300) vs observation (n=281) after surgical resection and with available baseline ctDNA assessment were included. The association between baseline ctDNA (either as status [positive vs negative] or as continuous MTM/mL measurement [mean tumor molecules per mL of plasma on log-scale]) and the time to onset of the first irAE of a specific type per patient was assessed in the atezolizumab arm using a Cox regression model adjusted for PD-L1 status, prior chemotherapy, race, sex and age. Plots of the cumulative incidence function (CIF) derived from the Aalen-Johansen estimator were used for visualization of the irAE risk over time stratified by ctDNA status, treatment arm and severity grade. Death was considered as a competing event for the safety endpoints in the CIF plots and Cox model (i.e., cause-specific approach treating death as censoring).ResultsThe risk of low grade (Grade 1/2) irAEs was higher in ctDNA-negative patients compared with ctDNA-positive patients at baseline (ctDNA-negative vs -positive: HR 1.97 [1.29, 2.99]) and in patients with lower baseline ctDNA levels (ctDNA log-MTM/mL: HR 0.92 [0.87, 0.97]) (figures 1 and 2). Low-grade irAEs were predominantly hepatitis, hypo-/hyperthyroidism and rash. For high-grade irAEs there was no clear association with baseline ctDNA; however, the number of events was very small. No conclusions could be drawn from on-treatment ctDNA-irAE analysis given the limited safety data available.ConclusionsOur exploratory analysis showed evidence of a higher risk of low-grade irAEs in ctDNA-negative vs ctDNA-positive patients treated with atezolizumab in the adjuvant setting. This supports the hypothesis of increased treatment-related toxicity in patients without cancer. It supports other ctDNA trials such as IMvigor011 (NCT04660344).AcknowledgementsFunded by F Hoffmann-La Roche Ltd/GenentechTrial RegistrationClinicalTrials.gov ID: NCT02450331ReferencesJackson-Spence F, et al. IMvigor011: a study of adjuvant atezolizumab in patients with high-risk MIBC who are ctDNA+ post-surgery. Future Oncol. 2023;19(7):509–515.Ethics ApprovalThe trial was performed per Good Clinical Practice and the Declaration of Helsinki. Protocol approval was obtained from ethics committees or independent review boards for each study site. All patients provided written informed consent. Further details, including the study protocol, are published in the primary manuscript: Bellmunt J et al, Lancet Oncol. 22, 525–537 (2021).Abstract 445 Figure 1Cumulative incidence function of the irAE risk stratified by baseline ctDNA status, separate plots by severity grade and treatment arm.Abstract 445 Figure 2Forest plot of the baseline ctDNA effect, as (A) ctDNA status (positive vs negative), and (B) ctDNA log-MTM/mL, adjusted for PD-L1 immune cell status, race, age, sex and prior chemotherapy in the atezolizumab arm. Results of the prognostic ctDNA effect are reported in terms of hazard ratios (HRs), corresponding 95% Cls and nominal Wald test P values. The sample size (N) corresponds to patients with available data for baseline ctDNA and the adjusted confounders in the model. G, grade; AESI, adverse event of special interest.

PurposeAlectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess alectinib dose selection.MethodsA semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (Ctrough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between Ctrough,ss and incidence of adverse events (AEs: serious and Grade ≥ 3).ResultsOverall, 92% of patients (n = 207/225) had Ctrough,ss data and were included in the analysis. No statistically significant relationship was found between Ctrough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between Ctrough,ss and AEs.ConclusionAlectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC.

Purpose Alectinib, a central nervous system (CNS)-active ALK inhibitor, has demonstrated efficacy and safety in ALK + non-small-cell lung cancer that has progressed following crizotinib treatment. Other ALK inhibitors have shown concentration-dependent QTc prolongation and treatment-related bradycardia. Therefore, this analysis evaluated alectinib safety in terms of electrophysiologic parameters. Methods Intensive triplicate centrally read electrocardiogram (ECG) and matched pharmacokinetic data were collected across two alectinib single-arm trials. Analysis of QTcF included central tendency analysis [mean changes from baseline with one-sided upper 95% confidence intervals (CIs)], categorical analyses, and relationship between change in QTcF and alectinib plasma concentrations. Alectinib effects on other ECG parameters (heart rate, PR interval and QRS duration) were also evaluated. Results Alectinib did not cause a clinically relevant change in QTcF. The maximum mean QTcF change from baseline was 5.3 ms observed pre-dose at week 2. The upper one-sided 95% CI was <10 ms at all time points. There was no relevant relationship between change in QTcF and alectinib plasma concentrations. Alectinib treatment resulted in a generally asymptomatic exposure-dependent decrease in mean heart rate of ~11 to 13 beats per minute at week 2. No clinically relevant effects were seen on other ECG parameters. Approximately 5% of patients reported cardiac adverse events of bradycardia or sinus bradycardia; however, these were all grade 1–2. Conclusions Alectinib does not prolong the QTc interval or cause changes in cardiac function to a clinically relevant extent, with the exception of a decrease in heart rate which was generally asymptomatic.

In the current study we investigate the mechanisms of action of short acting inhaled insulin Exubera®, on hepatic glucose production (HGP), plasma glucose and free fatty acid (FFA) concentrations. 11 T2D (Type 2 Diabetes) subjects (age = 53 ± 3 years) were studied at baseline (BAS) and after 16-weeks of Exubera® treatment. At BAS and after 16-weeks subjects received: measurement of HGP (3-3H-glucose); oral glucose tolerance test (OGTT); and a 24-h plasma glucose (24-h PG) profile. At end of study (EOS) we observed a significant decrease in fasting plasma glucose (FPG, 215 ± 15 to 137 ± 11 mg/dl), 2-hour plasma glucose (2-h PG, 309 ± 9 to 264 ± 11 mg/dl), glycated hemoglobin (HbA1c, 10.3 ± 0.5% to 7.5 ± 0.3%,), mean 24-h PG profile (212 ± 17 to 141 ± 8 mg/dl), FFA fasting (665 ± 106 to 479 ± 61 μM), post-OGTT (433 ± 83 to 239 ± 28 μM), and triglyceride (213 ± 39 to 120 ± 14 mg/dl), while high density cholesterol (HDL-C) increased (35 ± 3 to 47 ± 9 mg/dl). The basal HGP decreased significantly and the insulin secretion/insulin resistance (disposition) index increased significantly. There were no episodes of hypoglycemia and no change in pulmonary function at EOS. After 16-weeks of inhaled insulin Exubera® we observed a marked improvement in glycemic control by decreasing HGP and 24-h PG profile, and decreased FFA and triglyceride concentrations.

BackgroundImmunotherapies exhibit class- and target-specific safety challenges, particularly diagnosis and attribution of immune-mediated adverse reactions (imARs), also referred to as immune-related adverse events (irAEs). Recent, global consensus-building efforts have resulted in new clinical coding standards and several publications outlining diagnostic and management recommendations for patients experiencing irAEs in diverse organ systems. These standardization efforts have not yet fully propagated into safety event recordings during clinical trials. Current case report forms (CRF) specific to irAE/imARs vary widely in how these events are captured, including differences in attribution, grading, terminology, and follow-up practices. This inconsistency limits data quality, impedes regulatory alignment, and reduces the interpretability of safety profiles.MethodsA Delphi-style consensus process was used to engage 23 experts in immunotherapy, oncology trial design, data standards, and regulatory review. An initial landscape review of five oncology CRF templates identified heterogeneity in terminology, severity grading, automated triggers, treatment linkage, and event monitoring beyond 90 days. Thirteen experts participated in structured surveys and discussion sessions to evaluate proposed CRF elements across domains such as attribution, timing, and immune-specific sub-forms.ResultsConsensus was achieved on the use of Medical Dictionary for Regulatory Activities (MedDRA) terms for event coding and Common Terminology Criteria for Adverse Events (CTCAE) for severity grading, with additional modules recommended for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Agreed-upon CRF elements included:Protocol-specific checkboxes and body system-based entryPredefined irAE/imAR term lists and immune-active treatment linkageAutomated logic to trigger sub-forms for syndromic eventsUnique adverse event identifiers to reduce duplication and enable longitudinal trackingStructured attribution fields allowing investigator and sponsor input with justificationLogs for immunosuppressive therapy and hospitalization eventsNarrative fields for serious adverse eventsNeed for long term follow up, potentially well beyond 90 daysGrade change forms and ‘no new event’ checkboxes to support long-term follow-upThe framework defines a tiered structure with required core fields and optional specialized modules, balancing data completeness with operational feasibility and alignment to CDISC and MedDRA standards.ConclusionsThis consensus provides a structured framework for improving irAE/imAR documentation in immunotherapy trials. Implementation of standardized CRFs with automated logic and attribution controls may enhance regulatory review, support pooled analyses, and enable cross trial comparisons and integration with real-world datasets. Pilot testing across trial networks is recommended to assess feasibility and refine implementation strategies.