Is chemotherapy rechallenge feasible in advanced-stage non-small-cell lung cancer?

BACKGROUND: Despite recent progress, non-small cell lung cancer (NSCLC) first-line treatment remains a platinum-based doublet in most cases. No guidelines exist beyond third line. Chemotherapy rechallenge is an option, but little data is available in NSCLC. Our study aims to describe patients who underwent chemotherapy rechallenge while assessing its efficacy and safety. METHODS: Consecutive patients with advanced-stage NSCLC receiving first-line treatment in Tenon hospital in 2011 were included, with a 5-year follow-up. Patients were analyzed according to chemotherapy rechallenge or not. Chemotherapy rechallenge was defined as re-initiation of a previously administered chemotherapy agent at any point in the treatment sequence, with at least one treatment regimen between first use and rechallenge. RESULTS: Of 149 patients, 18 underwent chemotherapy rechallenge (12%). They were younger (56 vs. 61 years, P=0.04), mostly women (61% vs. 30%, P=0.02), with lepidic adenocarcinoma (23% vs. 3.5%, P=0.03), a better general state of health (100% performance status 0-1 vs. 74%, P=0.04), and fewer cardiovascular comorbidities (16% vs. 42%, P=0.04). They were more likely to have received a receptor tyrosine kinase inhibitor treatment (89% vs. 43%, P=0.0003). Progression-free survival was longer at first use than at rechallenge (median 9.2 vs. 2.7 months, P=0.002). No increased toxicity was observed at rechallenge compared to first use. Finally, a subsequent line of treatment was given after rechallenge in 61% of the patients. CONCLUSION: Patients eligible for chemotherapy rechallenge were those with good prognostic factors. Chemotherapy rechallenge may provide a well-tolerated additional line of treatment, with decreased efficacy compared to its first application.

[Diagnostic and therapeutic strategy in lung cancer]. / Stratégie diagnostique et thérapeutique dans le cancer bronchique

Diagnostic and therapeutic strategy in lung cancer. Clinical signs that must lead a clinician to suspect lung cancer are non-specific, but are often linked to the appearance or modification of a respiratory or general symptom. When lung cancer is suspected, the following informations must be obtained through diagnostic assessment: histological proof of cancer, tumoral extension and comorbidities. Therapeutic strategy depends on the distinction between small-cell and non-smallcell lung cancer, and on tumoral extension. In the case of a localized carcinoma, the determinant item for therapeutic decision is operability. In advanced non-small-cell carcinoma, distinction between squamous and non-squamous lung cancer, and the presence of molecular anomalies guide the therapy. In spite of therapeutic advances (targeted therapies, immunotherapy), the treatment of the majority of patients relies on chemotherapy.

Stratégie diagnostique et thérapeutique dans le cancer bronchique. Les signes cliniques devant conduire le clinicien à suspecter un cancer bronchique ne sont pas spécifiques, mais correspondent souvent à l'apparition ou à la modification d'un symptôme général ou respiratoire. En cas de suspicion de cancer bronchique, le bilan diagnostique comporte l'obtention d'une preuve histologique du cancer, un bilan d'extension et une évaluation des comorbidités. La stratégie thérapeutique dépend du type histologique, cancer bronchique à petites cellules ou cancer bronchique non à petites cellules, et de l'extension tumorale. Dans le cas d'un cancer localisé, l'élément déterminant pour la décision thérapeutique est l'opérabilité. Dans les cancers avancés non à petites cellules, la distinction entre épidermoïde et non épidermoïde ainsi que le résultat des recherches moléculaires conditionnent la prise en charge thérapeutique. Malgré les avancées thérapeutiques (thérapies ciblées, immunothérapie), le traitement de la majorité des patients repose sur la chimiothérapie.

EGFR and KRAS mutation status in non-small-cell lung cancer occurring in HIV-infected patients.

Non-small-cell lung cancer (NSCLC) is the most common non-acquired immune deficiency syndrome-related malignancy responsible for death. Mutational status is crucial for choosing treatment of advanced NSCLC, yet no data is available on the frequency of epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) mutations and their impact on NSCLC in human immunodeficiency virus (HIV)-infected patients (HIV-NSCLC). All consecutive HIV-NSCLC patients diagnosed between June 1996 and August 2013 at two Paris university hospitals were reviewed, with tumor samples analyzed for EGFR and KRAS mutational status. Overall, 63 tumor samples were analyzed out of 73 HIV-NSCLC cases, with 63% of advanced NSCLC. There were 60 non-squamous and nine squamous cell carcinomas, with EGFR and KRAS mutations identified in two (3.3%) and seven (11.5%) tumors, respectively. The proportion of KRAS mutations was 29% if solely the more sensitive molecular techniques were considered. The two patients with advanced adenocarcinoma harboring EGFR mutations exhibited lasting partial response to EGFR-tyrosine kinase inhibitors. Overall survival for patients with advanced NSCLC were >30 months for those with EGFR mutations, <3 months for KRAS mutations (n=2), and the median was 9 months [4.1-14.3] for wild-type (n=34). In multivariate analysis, KRAS mutation and CD4<200 cells/µL were associated with poor prognosis (hazard ratio (HR): 24 [4.1-140.2], p=0.0004; HR: 3.1 [1.3-7.5], p=0.01, respectively). EGFR mutation must be investigated in HIV-NSCLC cases due to its predictive and prognostic impact, whereas KRAS mutation is of poor prognostic value. Clinicians should search for drugs dedicated to this target population.

Sonic Hedgehog Pathway Activation Is Associated With Resistance to Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Carcinoma.

INTRODUCTION: Chemoresistance is a major challenge in the treatment of advanced non-small-cell lung cancer (NSCLC). Because the Sonic hedgehog (Shh) pathway is reactivated in NSCLC, we investigated an association between chemoresistance and Shh activation. PATIENTS AND METHODS: From a cohort of 178 patients with advanced NSCLC treated with platinum-based chemotherapy as first-line treatment, we selected all surgical tumor samples at diagnosis (n = 36). Shh activation was evaluated through Gli1 and Gli2 expression using immunohistochemistry (quantitative score). In vitro treatment studies with cisplatin or vismodegib (Shh pathway inhibitor), or both, were performed on NSCLC cell lines (H322 and A549) and primary cultures from patients with sarcomatoid carcinoma (n = 4). RESULTS: Of the 36 patients, 12 had NSCLC refractory to chemotherapy (R-patients, 33.3%) and 24 had controlled disease (C-patients). Gli1 expression did not differ between the R- and C-patients (P = .35). Gli2 expression was more often positive in the R-patients (41.7% vs. 8.3%; P = .02). Progression-free survival (PFS) and overall survival (OS) in patients with a Gli2-positive score was 2.1 and 8.0 months, respectively, compared with 6.7 and 18.0 months for patients with a Gli2-negative score (P = .03 and P = .002, respectively). On multivariate analysis, the Gli2 score correlated independently with PFS (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.05-6.63; P = .04) and OS (HR, 4.36; 95% CI, 1.67-11.36; P = .003). The sarcomatoid carcinoma cell lines were more resistant to cisplatin than were the H838 and A549 cell lines. The cisplatin-vismodegib combination displayed a synergistic cytotoxic effect in the most chemoresistant cells in vitro. CONCLUSION: The Shh pathway is associated with resistance to platinum-based chemotherapy in NSCLC.

[News about targeted therapies in non-small-cell lung cancer in 2015 (except immuno-therapy)]. / Actualités sur les thérapies ciblées dans les cancers bronchiques non à petites cellules, hors immunothérapie.

Recently, developments of therapies that target abnormally activated signaling pathways are increasing for patients with non-small cell lung cancer. EGFR mutations are found in about 10% of lung cancers, especially in adenocarcinoma, women and non-smokers. Three EGFR inhibitors (erlotinib, gefitinib and afatinib) received a European marketing authorization for up to first line treatment of EGFR mutated NSCLC. Effectiveness of EGFR inhibitors is higher than conventional chemotherapy. Third generation EGFR inhibitors (rociletinib, AZD9291) are effective for patients who develop a resistance mutation such as T790M resistance mutation; they obtained temporary authorization for use in France in 2015. The EML4-ALK translocation is found in about 5% of NSCLC and more particularly in adenocarcinoma of young non-smoking patients. Crizotinib is a new therapeutic standard in ALK translocated NSCLC in second line. Ceritinib is a 2nd generation ALK inhibitor which received a European marketing authorization for up to treatment of ALK translocated NSCLC after progression with crizotinib. INCA supports ACSé program evaluating the efficacy of crizotinib in NSCLC amplified for MET or translocated for ROS1 and ACSé program evaluating the efficacy of vemurafenib in tumors non melanoma mutated V600E BRAF. The role of other biomarkers such as KRAS, BRAF, HER2 and PI3KCA mutations remains to be defined in NSCLC.

Crizotinib Associated with Ground-Glass Opacity Predominant Pattern Interstitial Lung Disease: A Retrospective Observational Cohort Study with a Systematic Literature Review.

BACKGROUND: Crizotinib, an oral tyrosine kinase inhibitor that targets anaplastic lymphoma kinase, has proven to offer sustained progression-free survival in anaplastic lymphoma kinase-rearranged non-small-cell lung cancers. Occurrence of severe interstitial lung disease (ILD) was one of the crucial adverse events reported in randomized clinical trials and case reports. METHODS: In September 2011, we observed a crizotinib-associated ILD case. Following this index case, we reviewed the clinical and computed tomographic scan features of all patients treated with crizotinib in our department, between October 2010 and July 2013, comparing patients with and without ILD. A systematic literature review was performed. RESULTS: During this period, 29 patients were treated with crizotinib, five of whom developed ILD, in addition to the index case. Two types of adverse lung reactions may be observed in patients undergoing crizotinib therapy. The first is a severe, usually fatal, ILD that occurs during the first month of treatment (n = 1). The second is a less severe ILD, occurring later in time (n = 5). It occurs gradually with only few clinical symptoms, but predominant ground-glass opacities on computed tomography, along with an intensive lymphocytic alveolitis in bronchoalveolar lavage fluid. These cases had a longer response with a median progression-free survival duration at 19.9 months (17.9-23.5) compared with 6.2 months (1.2-13.6) for controls (p = 0.04). CONCLUSION: Forty-nine cases of crizotinib-associated ILD have been identified by the systematic review of the literature, including our six cases. Two types of adverse lung reactions may be observed with different presentation, prognosis, and treatment. Their potential mechanisms should be clarified. Nine patients with the less severe form of ILD were safely retreated.

Factors associated with early progression of non-small-cell lung cancer treated by epidermal growth factor receptor tyrosine-kinase inhibitors.

Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKI) are a therapeutic option as second-line therapy in non-small-cell lung carcinoma (NSCLC), regardless of the EGFR gene status. Identifying patients with early progression during EGFR-TKI treatment will help clinicians to choose the best regimen, TKI or chemotherapy. From a prospective database, all patients treated with gefitinib or erlotinib between 2001 and 2010 were retrospectively reviewed. Patients were classified into two groups according to their tumor response by RECIST after 45 days of treatment, progressive disease (PD) or controlled disease (CD). Two hundred and sixty-eight patients were treated with EGFR-TKI, among whom 239 were classified as PD (n = 75) and CD (n = 164). Median overall survival was 77 days (95% CI 61-109) for PD and 385 days (95% CI 267-481) for CD. Patients with PD were of younger age (P = 0.004) and more frequently current smokers (P = 0.001) had more frequently a performance status ≥2 (P = 0.012), a weight loss ≥10% (P = 0.025), a shorter time since diagnosis (P < 0.0001), a pathological classification as non-otherwise-specified NSCLC (P = 0.01), and the presence of abdominal metastases (P = 0.008). In multivariate analysis, abdominal metastases were the only factor associated with early progression (odds ratio (OR) 2.17, 95% CI [1.12-4.19]; P = 0.021). Wild-type EGFR versus mutated EGFR was associated with early progression. The presence of abdominal metastasis was independently associated with early progression in metastatic NSCLC receiving EGFR-TKI.