Summary Background The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the ...feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov , number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years range 18–98, 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% 95% CI 34·7–38·2 for presence of a genetic alteration vs 33% 29·5–35·6 for absence of a genetic alteration; p=0·03) and in second-line treatment (17% 15·0–18·8 vs 9% 6·7–11·9; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months 95% CI 9·2–10·7 vs 7·1 months 6·1–7·9; p<0·0001) and overall survival (16·5 months 15·0–18·3 vs 11·8 months 10·1–13·5; p<0·0001) compared with absence of a genetic alteration. Interpretation Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit. Funding French National Cancer Institute (INCa).
Summary Background The relative roles of immunodeficiency, HIV viral load, and combination antiretroviral therapy (cART) in the onset of individual cancers have rarely been examined. We examined the ...effect of these factors on the risk of specific cancers in patients infected with HIV-1. Methods We investigated the incidence of both AIDS-defining cancers (Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining cancers (Hodgkin's lymphoma, lung cancer, liver cancer, and anal cancer) in 52 278 patients followed up in the French Hospital Database on HIV cohort during 1998–2006 (median follow-up 4·9 years, IQR 2·1–7·9; 255 353 person-years). We tested 78 models with different classifications of immunodeficiency, viral load, and cART with Poisson regression. Findings Current CD4 cell count was the most predictive risk factor for all malignancies apart from anal cancer. Compared with patients with CD4 count greater than 500 cells per μL, rate ratios (RR) ranged from 1·9 (95% CI 1·3–2·7) for CD4 counts 350–499 cells per μL to 25·2 (17·1–37·0) for counts less than 50 cells per μL for Kaposi's sarcoma (p<0·0001), from 1·3 (0·9–2·0) to 14·8 (9·7–22·6) for non-Hodgkin lymphoma (p<0·0001), from 1·2 (0·7–2·2) to 5·4 (2·4–12·1) for Hodgkin's lymphoma (p<0·0001), from 2·2 (1·3–3·6) to 8·5 (4·3–16·7) for lung cancer (p<0·0001), and from 2·0 (0·9–4·5) to 7·6 (2·7–20·8) for liver cancer (p<0·0001). For cervical cancer, we noted a strong effect of current CD4 (RR 0·7 per log2 , 95% CI 0·6–0·8; p=0·0002). The risk of Kaposi's sarcoma and non-Hodgkin lymphoma increased for current plasma HIV RNA greater than 100 000 copies per mL compared with patients with controlled viral load (RR 3·1, 95% CI 2·3–4·2, p<0·0001; and 2·9, 2·1–3·9, p<0·0001, respectively), whereas cART was independently associated with a decreased incidence (0·3, 0·2–0·4, p<0·0001; and 0·8, 0·6–1·0, p=0·07, respectively). The RR of cervical cancer for those receiving cART was 0·5 (0·3–0·9; p=0·03). The risk of anal cancer increased with the time during which the CD4 count was less than 200 cells per μL (1·3 per year, 1·2–1·5; p=0·0001), and viral load was greater than 100 000 copies per mL (1·2 per year, 1·1–1·4, p=0·005). Interpretation cART would be most beneficial if it restores or maintains CD4 count above 500 cells per μL, thereby indicating an earlier diagnosis of HIV infection and an earlier treatment initiation. Cancer-specific screening programmes need to be assessed in patients with HIV. Funding Agence Nationale de Recherches sur le SIDA et les hépatites (ANRS), INSERM, and the French Ministry of Health.
Summary Background Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase ...inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors. Methods In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0–2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0–1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov , number NCT00656136. Findings Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0–12·0) in the afatinib group and 12·0 months (10·2–14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86–1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79–4·40) than it was in the placebo group (1·1 months, 0·95–1·68; hazard ratio 0·38, 95% CI 0·31–0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 87% of 390 patients; 66 17% were grade 3) and rash or acne (305 78% patients; 56 14% were grade 3). These events occurred less often in the placebo group (18 9% of 195 patients had diarrhoea; 31 16% had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group. Interpretation Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment. Funding Boehringer Ingelheim Inc.
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