Summary Background ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively ...identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. Methods In this phase 1 study, patients with ALK -positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov , number NCT00585195. Findings Between Aug 27, 2008, and June 1, 2011, 149 ALK -positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3–68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1–39·6) and median duration of response was 49·1 weeks (95% CI 39·3–75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7–12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3–92·3) and 74·8% (66·4–81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6). Interpretation Crizotinib is well tolerated with rapid, durable responses in patients with ALK -positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed. Funding Pfizer.
Summary Background ALK -rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often ...with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood–brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK -rearranged NSCLC. Methods ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK -rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK -rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov , number NCT01283516. Findings Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK -rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11·1 months (IQR 6·7–15·2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% 95% CI 61–82) of 83 ALK inhibitor-naive patients and 92 (56% 49–64) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17·0 months (95% CI 11·3–non-estimable NE) in ALK inhibitor-naive patients and 8·3 months (6·8–9·7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18·4 months (95% CI 11·1–NE) in ALK inhibitor-naive patients and 6·9 months (5·6–8·7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% 95% CI 54–94) of 19 ALK inhibitor-naive patients and in 49 (65% 54–76) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3–4 laboratory abnormalities were increased alanine aminotransferase (73 30% patients) and increased aspartate aminotransferase (25 10%). The most common grade 3–4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis. Interpretation The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK -rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confirmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK -rearranged NSCLC and brain or leptomeningeal metastases. Funding Novartis Pharmaceuticals Corporation.
Background Suicide rates among patients with lung cancer are higher than the general population. This study aims to identify patient and disease characteristics associated with suicide in patients ...with lung cancer. Methods We conducted an analysis of subjects with primary lung cancer diagnosed between 1973 and 2008 recorded in the Surveillance, Epidemiology and End Results database. Results From 871,230 people diagnosed with lung cancer, 1,184 cases of suicide were identified. The rate of suicide did not change considerably over time, with 8.83 compared with 7.17 suicides per 10,000 person-years in 1973 to 1979 and 2000 to 2009, respectively. The standardized mortality ratio (SMR) of the entire cohort was 4.95, with an SMR of 13.4 within 3 months of a cancer diagnosis. Despite most subgroups having a higher SMR than the general population, a wide variation in suicide risk was seen among different subgroups, including histologic type (SMR 1.58 vs 7.28 in bronchoalveolar and small cell carcinoma, respectively). The highest SMRs were found in patients with the following characteristics: male, older age, higher-grade tumor, and metastatic disease, and in patients who did not receive or refused treatment. Despite the higher SMR among patients with metastatic disease, > 50% of suicides occurred in those with locoregional and potentially curable disease. Conclusions Patients with lung cancer have a higher risk for suicide compared with the general US population, especially within 3 months of diagnosis. Despite the higher SMR among patients with a poorer prognosis, a concerning proportion of suicides occurs in potentially curable patients, highlighting the need for effective screening strategies to avoid this preventable cause of death.
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