Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs

Lorlatinib; Càncer de pulmó de cèl·lules no petites; ALK TKI de segona generacióLorlatinib; Cáncer de pulmón de células no pequeñas; ALK TKI de segunda generaciónLorlatinib; Non-small-cell lung cancer; Second-generation ALK TKIsBackground Lorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has substantial activity against ALK-positive non-small-cell lung cancer (NSCLC). This study assessed the overall, intracranial, and extracranial efficacy of lorlatinib in ALK-positive NSCLC that progressed on second-generation ALK TKIs. Patients and methods In the ongoing phase II study (NCT01970865), patients with ALK-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy were enrolled in expansion cohorts (EXP) based on treatment history. Overall, intracranial and extracranial antitumor activity were assessed independently per modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B-5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B-5, the objective response rate (ORR) [95% confidence intervals] was 39.6% (31.4-48.2), intracranial ORR (IC-ORR) was 56.1% (42.4-69.3), extracranial ORR (EC-ORR) was 36.7% (28.7-45.3), median duration of response (DOR) was 9.6 months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], median progression-free survival was 6.6 (5.4-7.4) months, and median overall survival was 20.7 months (16.1-30.3). In EXP3B, the ORR was 42.9% (24.5-62.8), the IC-ORR was 66.7% (29.9-92.5), and the EC-ORR was 32.1% (15.9-52.4). In EXP4 and EXP5, the ORR was 38.7% (29.6-48.5), the IC-ORR was 54.2% (39.2-68.6), and the EC-ORR was 37.8% (28.8-47.5). Conclusions Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post-second-generation ALK TKI setting, with elevated intracranial versus extracranial ORR, particularly in patients with fewer lines of therapy.This work was supported by Pfizer Inc. (no grant number)

Hospital admissions and deaths relating to deliberate self-harm and accidents within 5 years of a cancer diagnosis: a national study in Scotland, UK

The risk of suicide in cancer patients has been reported as elevated in several countries. These patients are exposed to many medicines that may confuse or provide a means for harm, potentially also increasing their risk from accidents. Ratios of observed/expected numbers of hospital admission and death events relating to deliberate self-harm (DSH) and accidents were calculated in the 5 years from a cancer diagnosis in Scotland 1981–1995, compared to the matched general population. The relative risk (RR) of suicide was 1.51 (95% confidence interval (CI): 1.29–1.76). The RR of hospital admissions for DSH was not significantly increased, suggesting a strong suicidal intent in DSH acts in cancer patients. Accidental poisonings and all other accidents were both increased (RR death=3.69, 95% CI: 2.10–6.00; and 1.58, 95% CI: 1.48–1.69, respectively) (RR hospital admissions=1.32, 95% CI: 1.19–1.47; and 1.55, 95% CI: 1.53–1.57, respectively). The association of only certain tumour types (e.g. respiratory) with suicide and accidental poisoning, and a broad range of tumour types with an elevated risk of all other accidents, suggests accidental poisoning categories may be a common destination for code shifting of some DSH events. A previous history of DSH or accidents, significantly increased the RR of suicide or fatal accidents, respectively (RR suicide=14.86 (95% CI: 4.69–34.97) vs 1.16 (95% CI: 0.84–1.55)) (RR accidental death=3.37 (95% CI: 2.53–4.41) vs 1.29 (95% CI: 1.12–1.49)). Within 5 years of a cancer diagnosis, Scottish patients are at increased RR of suicide and fatal accidents, and increased RR of hospital admissions for accidents. Some of these accidents, particularly accidental poisonings, may contain hidden deliberate acts. Previous DSH or accidents are potential markers for those most at risk, in whom to target interventional techniques

Women with a low satiety phenotype show impaired appetite control and greater resistance to weight loss.

AbstractThis trial compared weight loss outcomes over 14-weeks in women showing low or high satiety responsiveness [low or high satiety phenotype (LSP, HSP)] measured by a standardized protocol. Food preferences and energy intake after low and high energy density (LED, HED) meals were also assessed. Ninety-six women (n = 52 analysed; 41.24 ± 12.54 years; 34.02 ± 3.58 kg/m2) engaged in one of two weight loss programs underwent LED and HED laboratory-test days during weeks 3 and 12. Preferences for LED and HED-foods (Leeds Food Preference Questionnaire) and ad libitum evening meal and snack energy intake (EI) were assessed in response to equi-caloric LED- and HED-breakfasts and lunches. Weekly questionnaires assessed control over eating and ease of adherence to the program. Satiety quotients based on subjective fullness ratings post-LED and HED breakfasts determined LSP (n=26) and HSP (n=26) by tertile splits. Results showed that the LSP lost less weight and had smaller reductions in waist circumference compared to HSP. The LSP showed greater preferences for HED-foods, and under HED-conditions, consumed more snacks (kcal) compared to HSP. Snack EI did not differ under LED-conditions. LSP reported less control over eating and reported more difficulty with program adherence. In conclusion, low satiety responsiveness is detrimental for weight loss. LED meals can improve self-regulation of EI in the LSP, which may be beneficial for longer-term weight control.</jats:p

Plucked human hair as a tissue in which to assess pharmacodynamic end points during drug development studies

We have demonstrated the feasibility of detecting and quantifying six cell-cycle-related nuclear markers (Ki67, pRb, p27, phospho-p27 (phosphorylated p27), phospho-pRb (phosphorylated pRb), phospho-HH3 (phosphorylated histone H3)) in plucked human scalp and eyebrow hair. Estimates of the proportion of plucked hairs that are lost or damaged during processing plus the intra- and intersubject variability of each nuclear marker with these techniques are provided to inform sizing decisions for intervention studies with drugs potentially impacting on these markers in the future

A Randomized Feasibility Trial of a New Lifestyle Referral Assessment Versus Usual Assessment in an Acute Cardiology Setting

Background: A healthy diet, taking exercise, and not smoking or consuming alcohol in excess are important to reduce the risk of cardiovascular disease either alone or in combination with statin medication. Health education, including providing information to patients on healthy living and guidance on how to achieve it, is a key nursing function. Objectives: This study aims first to assess the feasibility of conducting a full-scale trial of lifestyle referral assessment as shown by recruitment rate, data collection, and follow-up and second to assess proof of concept and explore possible mechanisms of change. Methods: This was a single-center, randomized, 2-arm, parallel-group, unblinded feasibility trial conducted in an acute teaching hospital trust. Participants were followed up at 3 and 6 months after randomization. Results: Eight hundred eighty-seven patients were screened for eligibility, of whom 132 (15%) were randomized into the trial. Of the patients allocated to the individualized assessment, 27% accepted referral or self-referred by 3 months in comparison to 5% allocated to the usual assessment. Conclusions: We demonstrated that a full-scale trial is feasible and that an individualized approach increased the number of patients accepting referral to a formal program and initiating lifestyle change. However, we should consider the aim of the assessment and ways in which the process of change can be optimized in order to produce long-term benefit for patients

Free-living energy balance behaviours are associated with greater weight loss during a weight loss programme

Introduction: Free-living movement (physical activity [PA] and sedentary behavior [SB]) and eating behaviors (energy intake [EI] and food choice) affect energy balance and therefore have the potential to influence weight loss (WL). This study explored whether free-living movement and/or eating behaviors measured early (week 3) in a 14-week WL programme or their change during the intervention are associated with WL in women. Methods: In the study, 80 women (M ± SD age: 42.0 ± 12.4 years) with overweight or obesity [body mass index (BMI): 34.08 ± 3.62 kg/m2] completed a 14 week WL program focused primarily on diet (commercial or self-led). Body mass (BM) was measured at baseline, and again during week 2 and 14 along with body composition. Free-living movement (SenseWear Armband) and eating behavior (weighed food diaries) were measured for 1 week during week 3 and 12. Hierarchical multiple regression analyses examined whether early and early-late change in free-living movement and eating behavior were associated with WL. The differences in behavior between clinically significant weight losers (CWL; ≥5% WL) and non-clinically significant weight losers (NWL; ≤ 3% WL) were compared. Results: The energy density of food consumed [β = 0.45, p < 0.001] and vigorous PA [β = −0.30, p < 0.001] early in the intervention (regression model 1) and early-late change in light PA [β = −0.81 p < 0.001], moderate PA [β = −1.17 p < 0.001], vigorous PA [β = −0.49, p < 0.001], total energy expenditure (EE) [β = 1.84, p < 0.001], and energy density of food consumed [β = 0.27, p = 0.01] (regression model 2) significantly predicted percentage change in BM. Early in the intervention, CWL consumed less energy dense foods than NWL [p = 0.03]. CWL showed a small but significant increase in vigorous PA, whereas NWL showed a slight decrease in PA [p = 0.04]. Conclusion: Both early and early-late change in free-living movement and eating behaviors during a 14 week WL program are predictors of WL. These findings demonstrate that specific behaviors that contribute to greater EE (e.g., vigorous PA) and lower EI (e.g., less energy-dense foods) are related to greater WL outcomes. Interventions targeting these behaviors can be expected to increase the effectiveness of WL programs

Factors affecting the mesothelioma detection rate within national and international epidemiological studies: insights from Scottish linked cancer registry-mortality data

ICD-9 code 163 (malignant neoplasm of pleura) listed as underlying cause of death detected only 40% of Scottish mesothelioma cases (all body sites) from the cancer registry in 1981–1999. This is lower than both the previously published 55% figure, derived from UK mesothelioma register data 1986–1991, which is based on any mention of mesothelioma on death certificates, cross-referenced to cancer registry data, and the 44% figure derived from Scottish mortality data 1981–1999, which captured any mention of mesothelioma on the death certificate. Detection from cancer registry data increased to 75% under ICD-10 in Scotland, confirming earlier predictions of the benefit of ICD-10's more specific mesothelioma codes. Including the accidental poisoning codes E866.4 (ICD-9) and X49 (ICD-10), covering poisoning by ‘unspecified' and ‘other' causes, which appear to have been used as coding surrogates for mesothelioma when asbestos exposure was explicitly mentioned in deaths suggestive of a mesothelioma, and which are recorded as the underlying cause of death in 4–7% of mesotheliomas, may improve the mesothelioma detection rate in future epidemiological studies

Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial

Introduction: In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor–naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results. Methods: Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. Results: A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed. Conclusions: In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study