Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial.

BACKGROUND: Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC. METHODS: This three group, randomised, controlled, open-label, multicentre, phase 2 trial was done in 37 academic and community oncology practices in the USA. Patients were eligible if they had received one or two previous treatments for advanced non-squamous, EGFR wild-type, NSCLC. Patients were stratified by performance status and line of therapy, and randomly assigned using permuted blocks within strata to receive open-label oral daily dosing of erlotinib (150 mg), cabozantinib (60 mg), or erlotinib (150 mg) and cabozantinib (40 mg). Imaging was done every 8 weeks. At the time of radiographic progression, there was optional crossover for patients in either single-drug group to receive combination treatment. The primary endpoint was to compare progression-free survival in patients given erlotinib alone versus cabozantinib alone, and in patients given erlotinib alone versus the combination of erlotinib plus cabozantinib. We assessed the primary endpoint in the per-protocol population, which was defined as all patients who were eligible, randomly assigned, and received at least one dose of treatment. The safety analysis population included all patients who received study treatment irrespective of eligibility. This trial is registered with ClinicalTrials.gov, number NCT01708954. FINDINGS: Between Feb 7, 2013, and July 1, 2014, we enrolled and randomly assigned 42 patients to erlotinib treatment, 40 patients to cabozantinib treatment, and 43 patients to erlotinib plus cabozantinib treatment, of whom 111 (89%) in total were included in the primary analysis (erlotinib [n=38], cabozantinib [n=38], erlotinib plus cabozantinib [n=35]). Compared with erlotinib alone (median 1·8 months [95% CI 1·7-2·2]), progression-free survival was significantly improved in the cabozantinib group (4·3 months [3·6-7·4]; hazard ratio [HR] 0·39, 80% CI 0·27-0·55; one-sided p=0·0003) and in the erlotinib plus cabozantinib group (4·7 months [2·4-7·4]; HR 0·37, 0·25-0·53; one-sided p=0·0003). Among participants included in the safety analysis of the erlotinib (n=40), cabozantinib (n=40), and erlotinib plus cabozantinib (n=39) groups, the most common grade 3 or 4 adverse events were diarrhoea (three [8%] cases in the erlotinib group vs three [8%] in the cabozantinib group vs 11 [28%] in the erlotinib plus cabozantinib group), hypertension (none vs ten [25%] vs one [3%]), fatigue (five [13%] vs six [15%] vs six [15%]), oral mucositis (none vs four [10%] vs one [3%]), and thromboembolic event (none vs three [8%] vs two [5%]). One death due to respiratory failure occurred in the cabozantinib group, deemed possibly related to either drug, and one death due to pneumonitis occurred in the erlotinib plus cabozantinib group, deemed related to either drug or the combination. INTERPRETATION: Despite its small sample size, this trial showed that, in patients with EGFR wild-type NSCLC, cabozantinib alone or combined with erlotinib has clinically meaningful, superior efficacy to that of erlotinib alone, with additional toxicity that was generally manageable. Cabozantinib-based regimens are promising for further investigation in this patient population. FUNDING: ECOG-ACRIN Cancer Research Group, National Cancer Institute of the National Institutes of Health.

Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS).

The purpose of the study was to evaluate the efficacy and safety of vitamin D3 at 4000 IU/day as a treatment option for aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) when compared with the usual care dose of 600 IU D3. We conducted a single site randomized, double-blind, phase 3 clinical trial in women with AIMSS comparing change in symptoms, reproductive hormones and AI pharmacokinetics. Postmenopausal women ≥18 years with stages I-IIIA breast cancer, taking AI and experiencing AIMSS [breast cancer prevention trial symptom scale-musculoskeletal (BCPT-MS) subscale ≥1.5] were admitted. Following randomization, 116 patients had a run-in period of 1 month on 600 IU D3, then began the randomized assignment to either 600 IU D3 (n = 56) or 4000 IU D3 (n = 57) daily for 6 months. The primary endpoint was a change in AIMSS from baseline (after 1 month run-in) on the BCPT-MS (general MS pain, joint pain, muscle stiffness, range for each question: 0 = not at all to 4 = extremely). Groups had no statistically significant differences demographically or clinically. There were no discernable differences between the randomly allocated treatment groups at 6 months in measures of AIMSS, pharmacokinetics of anastrozole and letrozole, serum levels of reproductive hormones, or adverse events. We found no significant changes in AIMSS measures between women who took 4000 IU D3 daily compared with 600 IU D3. The 4000 IU D3 did not adversely affect reproductive hormone levels or the steady state pharmacokinetics of anastrozole or letrozole. In both groups, serum 25(OH)D remained in the recommended range for bone health (≥30 ng/mL) and safety (<50 ng/mL).

Disentangling acceptance: Direct and indirect effects of partner acceptance on felt acceptance and relationship satisfaction.

Acceptance in intimate relationships predicts relationship satisfaction, as well as positive treatment outcomes in some couple interventions. However, little research has attempted to disentangle the dyadic effects of husbands' and wives' partner acceptance (i.e., acceptance of one's partner) and felt acceptance (i.e., felt sense of being accepted by one's partner) on relationship satisfaction. This study utilized a modified actor-partner interdependence mediation model (APIMeM) to examine whether the associations between acceptance of one's partner and each partner's relationship satisfaction are mediated by each partner's felt acceptance. We analyzed baseline self-report data from 209 heterosexual married couples who participated in a brief marital intervention in the United States. The final model supported the prediction that a person's acceptance of their partner would relate to their partner's relationship satisfaction through their partner's felt acceptance (i.e., an "accuracy effect") and to their own relationship satisfaction through their own felt acceptance (i.e., a "projection effect"). In all, the study demonstrates the utility of examining partner acceptance and felt acceptance as distinct, but related, constructs. Researchers and clinicians working with couples may consider conceptualizing, assessing, and even targeting partners and felt acceptance separately. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Associations between mother-infant bed-sharing practices and infant affect and behavior during the still-face paradigm.

Parents in the United States increasingly report bed-sharing with their infants (i.e., sleeping on a shared sleep surface), but the relationship between bed-sharing and child socioemotional outcomes are not well understood. The current study examines the links between mother-infant bed-sharing at 3 months and infant affect and behavior during a dyadic challenge task at 6 months. Further, we examine nighttime mother-infant contact at 3 months as a possible mechanism that may mediate linkages between bed-sharing and infant outcomes. Using observational data from a sample of 63 mother-infant dyads, we found that infants who bed-shared for any proportion of the observation period at 3 months displayed significantly more self-regulatory behaviors during the still-face episode of the Still-Face Paradigm (SFP) at 6 months, compared to non-bed-sharing infants. Also, infants of mothers who bed-shared for the entire observation period displayed significantly less negativity during the reunion episode than non-bed-sharing infants. There was no evidence that the relations between mother-infant bed-sharing practices and infant affect and behavior during the SFP were mediated through nighttime mother-infant contact. Results suggest that infant regulation at 6 months postpartum may vary based on early nighttime experiences, with bed-sharing potentially promoting more positive and well-regulated behavior during dyadic interaction.

The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell non-Hodgkin's lymphoma in second complete or partial remission.

Autologous hematopoietic stem cell transplantation (auto HSCT) has become the standard treatment for patients with relapsed diffuse large-cell non-Hodgkin's lymphoma (NHL) responding to conventional salvage chemotherapy. Nevertheless, more than half of these patients will relapse following auto HSCT and die. This study was undertaken to determine whether the International Prognostic Index (IPI) assessed at time of relapse (IPI-R) could be used to identify patients with greater probability for long-term survival following auto HSCT. Eighty patients, median age 47 years (range 19-68 years), with diffuse large cell lymphoma in either second complete remission (CR 2, n = 27) or partial remission (PR 2, n = 53) were treated between 1984 and 2002 with auto HSCT. Clinical features predictive of overall survival (OS) and progression-free survival (PFS) were analyzed. Post-auto HSCT, CR was achieved in 73 patients (91%). With a median follow-up of 5 years (range 1.0-14.2 years), OS and PFS at 5 years were 38% (95% confidence interval [CI] 27%-50%) and 32% (95% CI 22%-42%), respectively. Two risk groups with significantly different OS and PFS were identified by the IPI-R. The high-risk group (3, 4, or 5 IPI factors) had 2.0 times (95% CI 1.1-4.0, P = .03) the risk of death and 2.2 times (95% CI 1.2-4.0, P = .01) the risk of relapse as the low-risk group (0, 1, or 2 IPI factors). The median OS was 5 months versus 27 months and the median PFS was 2 months versus 8 months for the high- and low-risk IPI-R groups, respectively. In Cox regression analysis, high-risk IPI-R status (relative risk [RR] 2.4, 95% CI 1.2-4.8, P = .02) and bone marrow (BM) involvement at diagnosis (RR 2.9, 95% CI 1.3-6.4, P = .01) were independent predictors for poor OS. Similarly, high-risk IPI-R status (RR 2.5, 95% CI 1.3-4.7, P = .01) and BM involvement at diagnosis (RR 3.9, 95% CI 1.7-8.7, P = .001) were independent predictors for poor PFS. These results suggest that the IPI-R predicts OS and PFS following auto HSCT for patients with aggressive NHL in CR 2 or PR 2. Patients with high-risk IPI-R should be considered for novel therapeutic approaches.