Early Circulating Tumor DNA Dynamics and Efficacy of Lorlatinib in Patients With Treatment-Naive, Advanced, ALK-Positive NSCLC.

INTRODUCTION: Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608). METHODS: Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association. RESULTS: Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23-1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49-2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16-0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67-3.30). CONCLUSIONS: In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.

Plain language summary of the updated results from the CROWN study comparing lorlatinib with crizotinib in people with advanced non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary shows the updated results of an ongoing research study called CROWN that was published in The Lancet Respiratory Medicine in December 2022. In the CROWN study, researchers looked at the effects of two study medicines called lorlatinib and crizotinib. The study included people with advanced non-small-cell lung cancer (NSCLC) that had not been treated previously. All people in the study had cancer cells with changes (known as alterations) in a gene called anaplastic lymphoma kinase, or ALK. This ALK gene is involved in cancer growth. In this updated study, researchers looked at the continued benefit in people who took lorlatinib compared with people who took crizotinib after 3 years. WHAT DID THIS STUDY FIND?: After 3 years of being observed, people who took lorlatinib were more likely to be alive without their cancer getting worse than people who took crizotinib. At 3 years, 64% of people who took lorlatinib were alive without their cancer getting worse compared with 19% of people who took crizotinib. The cancer was less likely to have spread within or to the brain in people who took lorlatinib than in people who took crizotinib. After 3 years of being observed, 61% of people were still taking lorlatinib and 8% of people were still taking crizotinib. People who took lorlatinib had more severe side effects than people who took crizotinib. However, these side effects were manageable. The most common side effects with lorlatinib were high levels of cholesterol or high levels of triglycerides (a type of fat) in the blood. Life-threatening side effects were seen in 13% of people who took lorlatinib and 8% in crizotinib. Two people who took lorlatinib died because of side effects from lorlatinib. WHAT DO THE RESULTS OF THE STUDY MEAN?: The updated results from the CROWN study showed that a larger percentage of people who took lorlatinib continued to benefit from their treatment after being observed for 3 years compared with those who took crizotinib.

Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study.

BACKGROUND: After a median follow-up of 18·3 months, the third-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, lorlatinib, improved progression-free survival in patients with treatment-naive, ALK-positive non-small-cell lung cancer in the phase 3 CROWN study. Here we report updated efficacy data, including intracranial activity, from an unplanned analysis after 3 years of follow-up. METHODS: CROWN is an ongoing, international, randomised, open-label phase 3 trial done in 104 centres in 23 countries worldwide. Eligible participants were aged 18 years and older or aged 20 years and older (depending on local regulations) with advanced, ALK-positive non-small-cell lung cancer, had received no previous systemic treatment for metastatic disease, had at least one extracranial measurable target lesion (according to the Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1), and had an Eastern Cooperative Oncology Group performance status score of 0-2. Patients were randomly assigned (1:1) to oral lorlatinib 100 mg daily or oral crizotinib 250 mg twice daily in 28-day cycles. Randomisation was stratified by the presence or absence of brain metastasis, and by ethnicity. Since the primary endpoint of the study had been met at the planned interim analysis, no further formal analysis of progression-free survival was planned, per protocol. The current unplanned analysis was done to further characterise tumour-related endpoints with a longer follow-up and is presented descriptively. For the planned study, the primary endpoint was progression-free survival assessed by blinded independent central review. Secondary endpoints included progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, duration of response, intracranial duration of response, and safety. Efficacy endpoints were also assessed by the presence or absence of baseline brain metastases. This study is registered with ClinicalTrials.gov, NCT03052608. FINDINGS: Between May 11, 2017, and Feb 28, 2019, 425 patients were screened for eligibility, of whom 296 were enrolled and randomly assigned to the lorlatinib (n=149) or crizotinib (n=147) group. At data cutoff for this unplanned analysis (Sept 20, 2021), median duration of follow-up for progression-free survival was 36·7 months (IQR 31·3-41·9) for lorlatinib and 29·3 months (10·8-35·0) for crizotinib. Median progression-free survival by blinded independent central review was not reached (95% CI not reached-not reached) for lorlatinib and was 9·3 months (7·6-11·1) for crizotinib (hazard ratio [HR] 0·27 [95% CI 0·18-0·39]). 3-year progression-free survival was 64% (95% CI 55-71) in the lorlatinib group and 19% (12-27) in the crizotinib group. Progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, and duration of response were improved with lorlatinib versus crizotinib. In patients with baseline brain metastases (n=37 lorlatinib; n=39 crizotinib), the HR for time to intracranial progression for lorlatinib versus crizotinib was 0·10 (95% CI 0·04-0·27); in patients without baseline brain metastases (n=112 lorlatinib; n=108 crizotinib), the HR was 0·02 (95% CI 0·002-0·14). In patients without brain metastases, one (1%) in the lorlatinib group and 25 (23%) in the crizotinib group had intracranial progression. Grade 3-4 adverse events occurred in 113 (76%) of 149 patients (most commonly due to altered lipid levels) with lorlatinib and in 81 (57%) of 142 patients with crizotinib. Adverse events led to treatment discontinuation in 11 (7%) patients in the lorlatinib group and 14 (10%) patients in the crizotinib group. There were no new safety signals. INTERPRETATION: These updated, long-term data from CROWN show the durable benefit of lorlatinib over crizotinib in patients with treatment-naive, ALK-positive non-small-cell lung cancer and support the use of first-line lorlatinib in patients with and without baseline brain metastases. FUNDING: Pfizer.

Efficacy and safety of lorlatinib in Asian and non-Asian patients with ALK-positive advanced non-small cell lung cancer: Subgroup analysis of a global phase 2 trial.

OBJECTIVES: To analyze the efficacy and safety of lorlatinib in Asian and non-Asian patients with pretreated anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC) from a phase 1/2 study. MATERIALS AND METHODS: In this ongoing phase 2 part of the trial, patients with ALK- or ROS1-positive, advanced NSCLC enrolled into six expansion cohorts (EXP1-6), based on ALK and ROS1 status and previous therapy, and received lorlatinib 100 mg once daily. The primary endpoint was objective tumor response and intracranial response. Post hoc analyses of activity were conducted in Asian and non-Asian (based on race) ALK-positive patients who received either previous crizotinib with or without chemotherapy (EXP2-3A) or at least one second-generation ALK tyrosine kinase inhibitor with any number of chemotherapy regimens (EXP3B-5). Analysis of safety (adverse events [AEs]) was in the phase 1 and 2 study population who started lorlatinib 100 mg once daily. RESULTS: 17 Asian patients were enrolled in EXP2-3A and 53 in EXP3B-5; 33 non-Asian patients were enrolled in EXP2-3A and 73 in EXP3B-5. Objective response rates in the Asian and non-Asian subgroups were 82.4% (95% confidence interval [CI]: 56.6-96.2) and 63.6% (95% CI: 45.1-79.6) in EXP2-3A, and 47.2% (95% CI: 33.3-61.4) and 30.1% (95% CI: 19.9-42.0) in EXP3B-5, and median progression-free survival was 13.6 and 12.5 months (EXP2-3A) and 6.9 and 5.5 months (EXP3B-5). Lorlatinib exhibited antitumor activity across ALK resistance mutations, while no differences according to the EML4-ALK variant could be detected. The most common treatment-related AEs were hypercholesterolemia, hypertriglyceridemia, edema, and peripheral neuropathy in both Asian and non-Asian subgroups. CONCLUSION: Lorlatinib showed substantial overall and intracranial activity in pretreated patients with ALK-positive NSCLC in both Asian and non-Asian patients. AE profiles were similar between Asian and non-Asian patients. CLINICALTRIALS: gov NCT01970865.

Continuation of Lorlatinib in ALK-Positive NSCLC Beyond Progressive Disease.

INTRODUCTION: Lorlatinib, a potent, selective third-generation ALK tyrosine kinase inhibitor (TKI), exhibited overall and intracranial antitumor activity in patients with ALK-positive NSCLC. METHODS: Retrospective analyses in the ongoing phase 2 trial (NCT01970865) investigated the clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with previous crizotinib treatment as the only ALK TKI were group A (n = 28); those with at least one previous second-generation ALK TKIs were group B (n = 74). LBPD was defined as greater than 3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with the best overall response of complete or partial response or stable disease were included. RESULTS: There were no major differences in baseline characteristics between groups. The median duration of treatment for patients who continued LBPD was 32.4 months (group A) and 16.4 months (group B) versus 12.5 months (group A) and 7.7 months (group B) for patients who did not continue LBPD. The median overall survival in group A was not reached (NR) in patients who continued LBPD versus 24.4 months (95% confidence interval [CI]: 12.1-NR); group B's median was 26.5 months (95% CI: 18.7-35.5) in patients who continued LBPD versus 14.7 months (95% CI: 9.3-38.5) in patients who did not continue LBPD. The median overall survival postprogression for groups A and B was NR (95% CI: 21.4-NR) and 14.6 months (95% CI: 11.2-19.2) in patients who continued LBPD and 8.0 months (95% CI: 1.5-NR) versus 5.3 months (95% CI: 2.8-14.3) in patients who did not continue LBPD. CONCLUSIONS: Continuing LBPD is a viable treatment strategy for select patients with ALK-positive NSCLC who progressed on lorlatinib.

A phase Ib study of utomilumab (PF-05082566) in combination with mogamulizumab in patients with advanced solid tumors.

BACKGROUND: Expressed on activated T and natural killer cells, 4-1BB/CD137 is a costimulatory receptor that signals a series of events resulting in cytokine secretion and enhanced effector function. Targeting 4-1BB/CD137 with agonist antibodies has been associated with tumor reduction and antitumor immunity. C-C chemokine receptor 4 (CCR4) is highly expressed in various solid tumor indications and associated with poor prognosis. This phase Ib, open-label study in patients with advanced solid tumors assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of utomilumab (PF-05082566), a human monoclonal antibody (mAb) agonist of the T-cell costimulatory receptor 4-1BB/CD137, in combination with mogamulizumab, a humanized mAb targeting CCR4 reported to deplete subsets of regulatory T cells (Tregs). METHODS: Utomilumab 1.2-5 mg/kg or 100 mg flat dose every 4 weeks plus mogamulizumab 1 mg/kg (weekly in Cycle 1 followed by biweekly in Cycles ≥2) was administered intravenously to 24 adults with solid tumors. Blood was collected pre- and post-dose for assessment of drug pharmacokinetics, immunogenicity, and pharmacodynamic markers. Baseline tumor biopsies from a subset of patients were also analyzed for the presence of programmed cell death-ligand 1 (PD-L1), CD8, FoxP3, and 4-1BB/CD137. Radiologic tumor assessments were conducted at baseline and on treatment every 8 weeks. RESULTS: No dose-limiting toxicities occurred and the maximum tolerated dose was determined to be at least 2.4 mg/kg per the time-to-event continual reassessment method. No serious adverse events related to either treatment were observed; anemia was the only grade 3 non-serious adverse event related to both treatments. Utomilumab systemic exposure appeared to increase with dose. One patient with PD-L1-refractory squamous lung cancer achieved a best overall response of partial response and 9 patients had a best overall response of stable disease. No patients achieved complete response. Objective response rate was 4.2% (95% confidence interval: 0.1-21.1%) per RECIST 1.1. Depletion of Tregs in peripheral blood was accompanied by evidence of T-cell expansion as assessed by T-cell receptor sequence analysis. CONCLUSIONS: The combination of utomilumab/mogamulizumab was safe and tolerable, and may be suitable for evaluation in settings where CCR4-expressing Tregs are suppressing anticancer immunity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02444793.

5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer.

A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination. Gene expression was assessed by quantitative-PCR in laser-microdissected specimens and correlated with tumor response. Frequency distribution of responses above and below the median expression level of biomarkers was compared using a two-sided Fisher's test. 5'-nucleotidase (cN-II) was the only gene differently expressed (p = 0.016) in the responders (complete/partial-response) compared to non-responders (stable/progressive disease). In the multivariate analysis, overexpression of this catabolic enzyme of gemcitabine remained a significant negative predictive factor. Patients with low cN-II had a modest trend toward increased survival, while both survival and progression-free survival were significantly longer in a more homogenous validation cohort of 40 advanced NSCLC (8.0 vs. 5.1 months, p = 0.026). Moreover, in vitro studies showed that silencing or pharmacological inhibition of cN-II increased the cytotoxicity of gemcitabine. This is the first study demonstrating the role of cN-II as a predictor of response to gemcitabine/platinum combinations in NSCLC. Its validation in prospective studies may improve clinical outcome of selected patients.

Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy.

Purpose No effective salvage treatments are available for patients with advanced/recurrent thymoma (T) or thymic carcinoma (TC) who have progressed after platinum-based chemotherapy. This study evaluated the activity of everolimus in patients with advanced/recurrent T or TC previously treated with cisplatin-containing chemotherapy. Patients and Methods This was a single-arm, single-stage, open-label, multicenter, phase II trial. Patients received oral everolimus 10 mg/d until disease progression, unacceptable toxicity, or patient refusal. A Fleming phase II trial was designed. The null hypothesis of a true disease control rate (DCR) of 40% was tested against a one-sided alternative of a true DCR of 60% (α = ß = 0.10): If disease control were achieved in ≥ 21 of the first 41 evaluable patients, everolimus could be recommended for further evaluation. Progression-free survival, overall survival, and safety were also evaluated. Results From 2011 to 2013, 51 patients were enrolled (T, n = 32; TC, n = 19). Complete remission was observed in one patient with TC, partial response in five patients (T, n = 3; TC, n = 2), and stable disease in 38 patients (T, n = 27; TC, n= 11), with a DCR of 88% (T,: 93.8%; TC, 77.8%). With a median follow up of 25.7 months, median progression-free survival was 10.1 months (T,: 16.6 months; TC, 5.6 months), and median overall survival was 25.7 months (T, not reached; TC, 14.7 months). Fourteen patients had a serious drug-related adverse event; of these patients, nine permanently discontinued treatment. Three patients died of pneumonitis while in the study. Immunohistochemical positivity for p4E-BP1 or insulin-like growth factor-1 receptor was statistically significantly related to a shorter survival. Conclusion Everolimus may induce durable disease control in a high percentage of patients with T or TC, albeit with a potential high risk of fatal pneumonitis.

Inactivity of imatinib in gastrointestinal stromal tumors (GISTs) harboring a KIT activation-loop domain mutation (exon 17 mutation pN822K).

The development of gastrointestinal stromal tumors (GISTs) is largely driven by mutations in the KIT and PDGFRα genes. Imatinib mesylate is an oral small molecular tyrosine kinase inhibitor that mainly targets abl, c-KIT, and PDGFRα. Imatinib achieves disease control in approximately 70%-85% of patients with advanced GIST, and the median progression-free survival is 20-24 months. The efficacy of imatinib correlates with tumor kinase mutational status (exon 11 mutations mainly), and some mutations are known to be responsible for primary and secondary imatinib resistance. Beyond these, there are many other mutations that are considered rare and are associated with unknown clinical behavior. In the literature, there are poor and inconsistent data about the inhibitor sensitivity of mutations occurring in the activation-loop domain encoded by exon 17. In this article, we focus on a case of a patient suffering from GIST, harboring an extremely rare KIT activation-loop domain mutation (exon 17 mutation pN822K) treated with imatinib. A review of the literature is also presented.

Molecular features and clinical outcome of lung malignancies in very young people.

INTRODUCTION: We describe the clinical features, outcome and incidence of druggable targets of lung cancers in patients ≤ 40 years old. MATERIALS & METHODS: Young patients were compared with two other groups (41-64 and ≥ 65 years). Neuroendocrine tumors, adenocarcinoma and non-adenocarcinoma/unspecified non-small-cell lung cancer were analyzed separately. Molecular characteristics of adenocarcinoma were evaluated in a subset of young patients. RESULTS: Of 2847 patients with lung cancer, 100 were ≤ 40 years old. The young group contained more women, never-smokers and patients presenting with advanced disease. The commonest tumor in young patients was adenocarcinoma. In total, 19 of 34 young patients with adenocarcinoma had tumors with specific molecular alterations. CONCLUSION: Lung cancers in young patients have distinctive features but outcomes similar to those in older patients.

Erlotinib efficacy in NSCLC patients with high polysomy of chromosome 7 and EGFR/KRas wild-type tumors.

BACKGROUND: More than even before, the efficacy of epidermal growth factors (EGFRs) tyrosine kinase inhibitors in non-small-cell lung cancer patients carrying EGFR wild-type tumors has been under investigation. EGFR wild-type patients represent a large and heterogeneous group of patients. In this setting, the role played by high polysomy of chromosome 7 still remains controversial. Indeed, previous reports did not discriminate between chromosome 7 high polysomy and EGFR amplification and/or did not investigate the concurrent presence of EGFR and KRas mutations. METHODS: We retrospectively collected data from 163 patients analyzed for EGFR status (mutation, amplification, chromosome 7 trysomy, and polysomy), in addition to KRas mutation, between 2000 and 2010 in our institute. Erlotinib was administered to 73 of them. Objective responses and progression-free survivals to erlotinib were evaluated. RESULTS: High polysomy of chromosome 7 characterized 17% (28 of 163) of EGFR/KRas wild-type tumors, independently of smoking status. In this group, 13 patients received erlotinib at progression. The treatment led one complete and four partial responses, and five stable diseases. Two patients progressed. One patient was lost to follow-up. The mean time to progression was 9 months. CONCLUSION: Among the EGFR wild-type population, when analyzed separately, high polysomy of chromosome 7 was the only molecular feature conferring clear signs of sensitivity to erlotinib. Therefore, the evaluation of high polysomy of chromosome 7 could become a helpful tool to predict for the benefit from epidermal growth factors tyrosine kinase inhibitors in selected cases.

Antitumor activity of sorafenib and imatinib in a patient with thymic carcinoma harboring c-KIT exon 13 missense mutation K642E.

We report the case of a man with an advanced nonkeratinizing squamous cell thymic carcinoma harboring c-KIT exon 13 missense mutation K642E. This aberration is rare and has never been described previously in patients with thymic cancers. It has been found in a small number of cases of gastrointestinal stromal tumor and also in several cases of acral and mucosal melanomas. Some of the patients with gastrointestinal stromal tumor or melanoma harboring this rare mutation have had a tumor response when treated with imatinib. In contrast, in our case, the mutation was associated with primary resistance to full doses of imatinib but, at the same time, it was not a cause of resistance to sorafenib.

Phase ib of sorafenib in combination with everolimus in patients with advanced solid tumors, selected on the basis of molecular targets.

BACKGROUND: Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated. METHODS: Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 3+3 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. RESULTS: The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma. Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. CONCLUSION: The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.

Stem cell transplantation effectively occludes bronchopleural fistula in an animal model.

BACKGROUND: Bronchopleural fistula after lung resection still represents a challenging life-threatening complication for thoracic surgeons. Considering its extremely high mortality rate, an effective treatment is urgently required. Our project investigated the hypothesis of experimental bronchopleural fistula closure by bronchoscopic injection of autologous bone marrow-derived mesenchymal stem cells into the cavity of the fistula, evaluating its feasibility and safety in a large animal model. METHODS: An experimental bronchopleural fistula was created in 9 goats after right upper tracheal lobectomy. The animals were randomly assigned to two groups: one received autologous bone marrow-derived mesenchymal stem cell bronchoscopic transplantation; the other received standard bronchoscopic fibrin glue injection. RESULTS: All animals receiving bronchoscopic stem cell transplantation presented fistula closure by extraluminal fibroblast proliferation and collagenous matrix development; none (0%) died during the study period. All animals receiving standard treatment still presented bronchopleural fistula; 2 of them (40%) died. Findings were confirmed by pathology examination, computed tomography, and magnetic resonance imaging. CONCLUSIONS: Bronchoscopic transplantation of bone marrow-derived mesenchymal stem cells effectively closes experimental bronchopleural fistula by extraluminal fibroblast proliferation and collagenous matrix development. Stem cells may play a crucial role in the treatment of postresectional bronchopleural fistula after standard lung resection. Although these results provide a basis for the development of clinical therapeutic strategies, the exact mechanism by which they are obtained is not yet completely clear; further studies are required to understand exactly how stem cells work in this field.

Pharmacogenetics of non-small cell lung cancer (NSCLC): time to "work it out"?

The disappointing results in long-term survival of patients affected by non-small cell lung cancer (NSCLC) may be attributed, at least in part, to the lack of knowledge on the way by which genetic characteristics in normal and neoplastic cells affect responsiveness as well as metabolism of chemotherapy and new targeted agents. This issue deserves further pharmacogenetics studies, in order to identify patients who are most likely to benefit from specific therapies selected on the base of the individual and tumor genetic features, thus improving the efficacy/toxicity profile of the treatment strategy. Even if most meta-analyses in NSCLC yielded contradictory results, a number of candidate biomarkers for response/resistance to conventional chemotherapeutic agents such as gemcitabine, platinum-compounds, pemetrexed and taxanes have been proposed. Similarly, recent studies suggested the key role of polymorphisms in the prediction of toxicity to EGFR-targeted agents. However, larger prospective randomized trials of personalized therapy to validate these biomarkers are still needed. The unification of the technical procedures, as well as additional investigation to unravel pivotal factors influencing genotype-phenotype relationships, represent other crucial issues. From this perspective, functional studies aiming at unravel eventual pharmacokinetics/pharmacodynamics interactions are critical for the pharmacogenetic optimization of anti-cancer regimens. With the development of high-throughput technologies, including whole exome analyses, the traditional pharmacogenetic approach that till present has relied only on candidate genes suspected of influencing drug response/metabolism can be fulfilled with further lists of potential predictive alleles. The clinical implementation of such pharmacogenetics/genomics studies as well as of therapeutic drug monitoring could enable clinicians to personalize treatment to enhance efficacy and/or limit toxicity.

Targeting ALK in patients with advanced non small cell lung cancer: biology, diagnostic and therapeutic options.

The discovery of EML4-ALK fusion gene in a subgroup of patients with lung adenocarcinoma led to the development of a new class of agents, the ALK inhibitors, and dramatically improved the clinical outcome of these patients. The striking results from clinical trials with crizotinib, the first ALK inhibitor evaluated, allowed the accelerated approval of crizotinib from the USA Food and Drug Administration (FDA). Despite the high initial results, patients acquire resistance to crizotinib, and different next generation ALK kinase inhibitors have been developed. In the current review, we will analyze the biology of EML4-ALK gene, the acquired resistance mechanisms to crizotinib, the therapeutic strategies, currently under evaluation, designed to overcome crizotinib resistance, and the open issues that need to be addressed in order to improve outcome in ALK+ Non Small Cell Lung Cancer (NSCLC) patients.

EGFR tyrosine kinase inhibitors beyond focal progression obtain a prolonged disease control in patients with advanced adenocarcinoma of the lung.

INTRODUCTION: Recent data show that EGFR pathway and its inhibition maintain their role after progression of disease during EGFR TKI therapy in NSCLCs. We conducted a retrospective study with the aim of evaluating efficacy and feasibility of prosecution of EGFR TKI therapy beyond focal progression associated to locoregional radiotherapy. METHODS: We retrospectively analyzed the data of all NSCLC patients treated with EGFR TKIs in our institution from 2004 to 2012. We included in the analysis patients that after a focal disease progression, meant as a single lesion RECIST progression, have been treated with definitive locoregional radiotherapy, associated to continuation of EGFR TKI therapy until further progression. RESULTS: 15 out of 147 patients (10%) satisfied inclusion criteria. The median progression free survival, measured from the date of focal progression until further progression of disease or death by any cause, was 10,9 months (range 3-32 months). The corresponding 6 and 12 months PFS rates were 73% and 33%, respectively. CONCLUSION: The longer disease control observed in our patients suggests that continuation of EGFR TKI beyond focal progression associated to a locoregional treatment is an efficacious therapeutic strategy.

Breast phyllodes tumor: a review of literature and a single center retrospective series analysis.

PURPOSE: Complete surgical resection is the standard treatment for localized breast phyllodes tumors. Post-surgical treatments are still a matter of debate. We carried out an overview of the literature to investigate the clinical outcome of patients with phyllodes tumor. A retrospective analysis of mono-institutional series has been included as well. METHODS: We reviewed all the retrospective series reported from 1951 until April 2012. We analyzed cases treated at our institution from 1999 to 2010. RESULTS: Eighty-three articles (5530 patients; 1956 malignant tumors) were reviewed. Local recurrences were independent of histology. Distant recurrences were more frequent in the malignant tumors (22%). A total of 172 phyllodes tumors were included in the retrospective analysis. DISCUSSION: Prognosis of phyllodes tumors is excellent. There are no convincing data to recommend any adjuvant treatment after surgery. Molecular characterization may well provide new clues to permit identification of active treatments for the rare poor prognosis cases.

Pharmacogenetics of conventional chemotherapy in non-small-cell lung cancer: a changing landscape?

Pharmacogenetics might be used to select patients who may benefit from specific chemotherapy that best matches the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. Even if most studies in non-small-cell lung cancer yielded contradictory results, several potential biomarkers for sensitivity/resistance to platinum compounds, gemcitabine, taxanes and pemetrexed have been proposed. However, these markers need to be validated within larger prospective randomized trials of customized chemotherapy in homogeneous populations. Other critical points include the optimization/standardization of technical procedures, and further studies to unravel the extremely complex regulation of gene function. From this perspective, the evaluation of key factors influencing genotype-phenotype relationships, such as miRNAs, and functional studies to clarify pharmacokinetic/pharmacodynamic interactions, are fundamental for the pharmacogenetic optimization of cancer chemotherapy. Finally, limitation of the traditional pharmacogenetic approach relying only on candidate genes suspected of affecting drug response is now being overcome by the use of novel genome-wide studies.