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Summary Background Alectinib, a highly selective, central nervous system (CNS)-active anaplastic lymphoma kinase (ALK) inhibitor, demonstrated promising clinical activity in crizotinib-naïve and crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC). This phase 2 study evaluated the safety and efficacy of alectinib in ALK-positive NSCLC patients who progressed on previous crizotinib. Methods This ongoing North American study (NCT01871805) enrolled patients with stage IIIB/IV ALK-positive NSCLC, who had progressed following crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death or withdrawal. Primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), intracranial ORR and DOR, safety, and patient-reported outcomes. The intent-to-treat population was used for efficacy and safety analyses, with the response evaluable population used for response endpoints. Findings A total of 87 patients were enrolled in the intent-to-treat population. All patients had received prior crizotinib therapy, and 64 patients (74%) had also received prior chemotherapy. Fifty-two patients (60%) had baseline CNS metastases, of whom 18 (35%) had received no prior brain radiation therapy. At the time of primary analysis (median follow-up 4.8 months), ORR by IRC was 48% (95% CI 36–60). Adverse events were predominantly grade 1 or 2, most commonly constipation, fatigue, myalgia and peripheral edema. The most common grade ≥3 AEs were changes in laboratory values, including increased blood creatine phosphokinase (in 8%, n=7), increased alanine aminotransferase (in 6% n=5), and increased aspartate aminotransferase (in 5% n=4). Interpretation Alectinib demonstrated clinical efficacy and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Alectinib was active in the CNS, as demonstrated by durable responses in the majority of crizotinib-resistant patients with CNS disease. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.

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Background: Guidelines recommend atezolizumab plus nab-paclitaxel (A þ nP) for first-line treatment of unresectable, locally advanced, or metastatic triple-negative breast cancer expressing programmed death-ligand 1 (PD-L1) on tumorinfiltrating immune cells (IC), based on IMpassion130. We report the final overall survival (OS) and safety of that study as per the prespecified analysis plan. Patients and methods: Patients were randomized to nP 100 mg/m 2 (days 1, 8, and 15 of a 28-day cycle) with atezolizumab 840 mg (A þ nP) or placebo (P þ nP; days 1 and 15), until progression or unacceptable toxicity. Coprimary endpoints were progression-free survival [intention-to-treat (ITT) and PD-L1 IC-positive populations] and OS (tested hierarchically in the ITT population and, if significant, in the PD-L1 IC-positive population). Results: Each arm comprised 451 patients; 666 (73.8%) had died by the final OS analysis cut-off (median follow-up, 18.8 months; interquartile range, 8.9-34.7 months). Median OS in the ITT population was 21.0 months [95% confidence interval (CI), 19.0-23.4 months] with A þ nP, and 18.7 months (95% CI, 16.9-20.8 months) with P þ nP [stratified hazard ratio (HR), 0.87; 95% CI, 0.75-1.02; P ¼ 0.077]. Exploratory analysis in the PD-L1 IC-positive population showed a median OS of 25.4 months (95% CI, 19.6-30.7 months) with A þ nP (n ¼ 185) and 17.9 months (95% CI, 13.6-20.3 months) with P þ nP (n ¼ 184; stratified HR, 0.67; 95% CI, 0.53-0.86). Safety outcomes were consistent with previous analyses and the known toxicity profiles of each agent. Immune-mediated adverse events of special interest were reported in 58.7% and 41.6% of patients treated with A þ nP and P þ nP, respectively. Conclusion: Although the OS benefit in the ITT population was not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed with A þ nP in PD-L1 IC-positive patients, consistent with prior interim analyses. This combination remained safe and tolerable with longer follow-up.

BACKGROUND. It is suspected that estrogen depletion resulting from treatment may contribute to cognitive compromise in patients with breast cancer. However, the evidence for estrogen effects on cognition is inconclusive, and the consequences of hormonal changes for cognitive function in patients with cancer rarely have been investigated. In this study, the authors investigated the effects of treatment‐induced menopause and antiestrogen therapy with tamoxifen and aromatase inhibitors (AIs) on cognitive function. METHODS. Cognitive performance was assessed in 101 patients with breast cancer before the start of cancer therapy (T1), toward the end of neoadjuvant chemotherapy (T2), and 1 year after baseline (T3) using 12 cognitive tests. Menopause occurred in a subgroup of patients, and an overlapping subgroup started antiestrogen therapy with tamoxifen or AIs. Linear mixed‐effects models that made it possible to determine effects at group levels and individual levels simultaneously were used for statistical analysis. RESULTS. At the group level, a significant favorable effect of induced menopause emerged in a test of executive function (P = .0035). Two additional group‐level effects of induced menopause, both favorable, and 2 individual‐level effects that were positive in some patients and negative in others were not significant when multiple testing was taken into account. No significant effects of tamoxifen or AIs on cognitive function were observed. CONCLUSIONS. Hormonal changes did not appear to contribute to cognitive compromise in patients with breast cancer during the first year after diagnosis. Antiestrogen treatment with tamoxifen or AIs did not affect cognition, and the effects of induced menopause were more likely to be favorable. However, the possibility that some cognitive decline occurs in individual patients could not be excluded. Cancer 2008. © 2008 American Cancer Society.