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M. Giaj Levra



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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O01.07 - Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): Secondary Endpoint Analysis (ID 3276)

      11:35 - 11:45  |  Author(s): M. Giaj Levra

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR-TKis are more effective in NSCLC patients with EGFR activating mutations. However, about 90% of non-Asian patients are EGFR wild type, and a test for optimizing treatment in pts with wild-type or in patients with undetectable EGFR mutation status or squamous histology is of clinical value. VeriStrat (VS) is a serum protein test that assigns "good" (VSG) or "poor" (VSP) classification and has demonstrated prognostic and predictive utility in retrospective studies. PROSE is the first completed multicenter prospective randomized biomarker validation trial, designed to evaluate the ability of VS to predict survival in 2[nd]- line NSCLC pts treated with E or CT. As reported at 2013 ASCO[1], VSG pts derived similar overall survival (OS) benefit from both agents (hazard ratio (HR) for E=1.06; p=0.71) whereas CT was the superior option for VSP pts (HR for E=1.72; p=0.02). PROSE met its primary endpoint of demonstrating significant treatment*VS interaction with a p-value of 0.031. The present report discusses the results for the secondary endpoints, PFS.

      Methods
      285 pts, stratified by ECOG-PS, smoking, and blinded pre-treatment VS classification, were randomized 1:1 to receive E or CT at standard doses. Primary endpoint was overall survival (OS) and the primary hypothesis was a significant interaction between VS status and treatment. Sample size was calculated based on an estimated 65%/35% VSG:VSP ratio and hazard ratio (HR) for interaction of 2.35, with a 2-sided α=0.05 and 90% power.

      Results
      263 pts (129 CT, 134 E) were included in the per protocol primary analysis. 68% of pts in CT arm and 72% in E arm were classified as VSG, and analysis was performed at 226 survival events.VSP classification was significantly correlated with worse PFS as compared to VSG, in overall comparison (HR=1.75, 95%CI: 1.34-2.95, P <0.001) , in the CT (HR = 1.69, 95%CI: 1.15-2.48, P <0.007) and the E (HR = 1.91, 95%CI: 1.340-2.80, P<0.001) arms, demonstrating its prognostic value also in PFS. In VSG median PFS was 4.8 months (m) on CT, and 2.5 m on E (HR = 1.26, 95% CI: 0.94-1.69, P =0.129); in VSP median PFS was 2.8 m on CT and 1.7 m on E (HR=1.51, 95% CI: 0.96-2.38, P =0.078). No statistical significant interaction was detected (p=0.44)

      Conclusion
      The analysis of PFS and OS indicates that the differential treatment benefit in OS related to VS classification is determined by the combination of prognostic and predictive properties of the test.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-033 - Afatinib in EGFR mutant non-small-cell lung cancer patients with acquired resistance to reversible EGFR-TKIs (ID 2285)

      09:30 - 09:30  |  Author(s): M. Giaj Levra

      • Abstract

      Background
      Afatinib, an irreversible EGFR-HER2 dual inhibitor, demonstrated superiority versus standard platinum-based chemotherapy as front-line therapy in non-small-cell lung cancer patients (NSCLC) with activating Epidermal Growth Factor Receptor (EGFR) mutations. In pretreated NSCLC afatinib failed to improve survival when compared to placebo in patients refractory to gefitinib or erlotinib and not selected for EGFR status. Aim of the present study was to evaluate clinical efficacy of afatinib in EGFR mutant NSCLC patients (pts) with secondary resistance to reversible EGFR-TKIs.

      Methods
      We retrospectively analyzed a cohort of 97 EGFR mutant lung cancer pts resistant to EGFR-TKI according to criteria used in the LUX-Lung 1 trial (Miller VA, Lancet Oncol 2012) and treated with Afatinib at the daily dose of 40-50 mg. The drug was given as compassionate use.

      Results
      The study included individuals with a median age of 62,5 year. The majority were females (N=63/64.9%), never/former smokers (N=94/96,9%), with good performance status (ECOG PS 0-1; N=90/90.2%) and pretreated with > 3 therapy lines (N=68/70.0%). EGFR status was assessed in tumor tissue obtained at the time of original diagnosis. The majority of pts (N=64, 66%) harbored a deletion in exon 19, while T790M mutation was detected in two cases including one case with double exon 19 and T790M mutation. Among the 95 pts evaluable for toxicity, 54.7% had any grade skin rash, including 11.6% with grade 3, and 50,5% had any grade of diarrhea, with grade 3 recorded in 10,5%. Among the 87 pts evaluable for efficacy, response rate (RR) was 11.5%, with a median progression free-survival and overall survival of 3.9 months and 7.3 months respectively. In 25 pts a tumor biopsy was repeated immediately before starting Afatinib therapy and 1 patient out of 5 individuals harboring T790M mutation showed a short extracerebral partial response, with following brain progression.

      Conclusion
      Our findings suggest that afatinib is modestly effective in EGFR mutant NSCLC with acquired resistance to reversible EGFR-TKIs.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-023 - BE-Positive: Gefitinib in first-line treatment of advanced non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. A combined retrospective and prospective analysis from Italian patients. (ID 1881)

      09:30 - 09:30  |  Author(s): M. Giaj Levra

      • Abstract

      Background
      Advanced NSCLC patients have an extremely poor prognosis with a 5-year survival rate of less than 5%. In 2009, the European Medicines Agency approved gefitinib, a reversible EGFR tyrosine kinase inhibitor, at the dose of 250 mg daily for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations. As the first-line EGFR mutation positive data at that time were mainly in Asian populations a prospective phase IV, open-label, single-arm study of first-line gefitinib in Caucasian patients was presented: this trial confirmed the activity and efficacy of gefitinib in 106 Caucasian patients (Douillard EMCTO 2013). In the same way, we initially collected retrospectively, continuing then prospectively, the data of NSCLC EGFR-mutation positive Italian patients treated with first-line gefitinib, with the aim to evaluate the therapeutic outcomes and the approaches beyond progression in a “real life population”.

      Methods
      We collected data of patients who started gefitinib from June 2009 until May 2013. Primary endpoint was the evaluation of first line outcomes, in terms of: objective response rate (ORR), duration of treatment, progression-free survival (PFS), overall survival (OS) and safety. Secondary endpoint is the evaluation of the outcomes beyond progression to gefitinib. Here we report the results of first-line gefitinib of a large number of Caucasian patients.

      Results
      Data of 203 patients from 23 Italian Institutions were collected. The main patients characteristics were: median age 67 (range: 33-87), male/female 76/127, ECOG performance status (PS) 0/1/2/3/4 in 89/92/18/2/2 patients, 90.6% adenocarcinoma (in our study the percentage of carcinoma non otherwise specified was 1.5%), never/former/current smoker in 129/64/10, del19/L858R/uncommon in 128/57/18. In one case a T790M mutation ex novo was found in association with the deletion of the exon 19 (not all the patients were tested for this mutation at baseline). A median time for obtaining the EGFR test result was 8-15 days (more than 30% of the patients got the results in less than one week). Patients evaluable at the time of data lock were 168, of these 3 (1.8%) patients achieved a complete response, 72 (42.9%) a partial response for an ORR of 44.7%, 54 (32.1%) patients were stable. Median treatment with gefitinib was 38 weeks. Main toxicities were: grade 3-4 skin rash and diarrhea in 1.8% and 4.2%, respectively. Treatment was definitely stopped due toxicity in 4.2% of patients. After progression in 5 cases a re-biopsy was performed and 94 (56%) received a second-line treatment.

      Conclusion
      BE-Positive is the first study reporting results of first-line gefitinib in a large "real life population" of Caucasian patients. Data were firstly collected in a retrospective fashion, than in a prospective way. This study shows that Caucasian patients reported lower ORR when indirectly compared to Asian counterparts, but this is probably due to the partial analysis of the patients, excluding at this time those who are still on treatment. However, the tolerability profile was excellent and the median time of treatment is quite overlapping to literature data. The outcomes of PFS, OS and treatment beyond gefitinib progression will be reported when mature.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-014 - Impact of Non Small Cell Lung Cancer (NSCLC) immunophenotyping in chemotherapy response. (ID 2679)

      09:30 - 09:30  |  Author(s): M. Giaj Levra

      • Abstract

      Background
      The vast majority of non small cell lung cancers (NSCLC) presents as advanced disease and histological diagnosis is widely based on small biopsy or cytological samples. Recently, the adoption of new pharmaceutical agents targeting individual histotypes requires a precise subtyping of NSCLC. This task is often difficult according to morphological criteria only and the use of immunohistochemistry (IHC) is recommended for small samples or undifferentiated tumors to define the most probable histotype. However, the real impact of IHC characterization of NSCLC-Not otherwise Specified (NOS) in terms of response to therapy and outcome (compared to cases classified by morphology, only) is not well established.

      Methods
      A large series of 224 advanced "non-squamous" NSCLC diagnosed from year 2005 to 2010 on small biopsy or cytological samples and homogeneously treated, was retrospectively selected, all with adequate follow-up data available. All diagnoses were reviewed resulting in two groups of adenocarcinoma (ADC) and NSCLC-NOS. The latter were further characterized by IHC to identify the most probable differentiation lineage. Disease Control Rate (DCR) and Response Rate (RR) were calculated and Overall Survival (OS) curves were analyzed by Kaplan Meier.

      Results
      After review 120/224 (53.6%) cases were ADC based on morphological examination, only (“ADC morphology”) and 104/224 (46.4%) remained NSCLC-NOS. In terms of response to therapy no significant difference was found between the two groups (“ADC morphology” had DCR= 0.66 and RR=0.31; NSCLC-NOS had DCR=0.64 and RR=0.35; Chi-Square p=0.83). The NSCLC-NOS cases that underwent IHC profiling resulted in 66/104 (63.5%) cases that had an ADC phenotype (“NSCLC favor ADC”) and 38/104 (36.5%) cases that lack ADC features (including 5 “NSCLC favor squamous carcinoma” and 33 “NSCLC null phenotype”). The “NSCLC favor-ADC” had DCR and RR similar to “ADC morphology” group (Chi-Square p=0.23), while the “non-ADC” NSCLC group had significantly different both DCR=0.47 and RR=0.29 (Chi-Square p=0.006). Survival curves confirmed no difference in terms of survival between the “ADC morphology” and the “NSCLC favor-ADC” groups, while showed a significantly poorer survival for the “non-ADC” NSCLC group with respect the other two groups (median survival: 8.5 vs 12.3 months, respectively; HR=0.5999; p=0.018).

      Conclusion
      These preliminary findings indicate that the practice of minimizing the NSCLC-NOS diagnoses by means of IHC has an impact on chemotherapy response. Stratifying such tumors by IHC, cases having an ADC immunoprofile had response rates comparable to those of morphologically diagnosed ADC, thus supporting the value of IHC to maximize lung cancer histological typing in the perspective of obtaining the best response to therapy.

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-006 - Respiratory function changes after stereotactic ablative radiotherapy (SABR) in stage I non-surgical NSCLC: preliminary results from a single institution prospective study. (ID 1017)

      09:30 - 09:30  |  Author(s): M. Giaj Levra

      • Abstract

      Background
      Stereotactic Ablative Radiotherapy (SABR) is an alternative to surgery in patients with early stage non-small cell lung cancer (NSCLC) inoperable for medical co-morbidities (mainly cardiovascular or respiratory diseases) or who refuse surgery. We performed a prospective evaluation of lung function parameters, treatment-related radiological and clinical toxicity in a cohort of patients treated with SABR.

      Methods
      We prospectively recruited 26 patients from July 2012 to May 2013. All patients had a histological or cytological diagnosis of NSCLC (n=20) or a lung lesion in dimensional growth with PET positivity (SUV>2.5) (n=6). All patients had stage IA– IB and were judged unfit for surgery or refused it. Each patient did a 4D-TC with slice of 2.5mm/2.5mm, treatment consisted of a single Volumetric Modulated Arc Therapy and the fractionation schedule was dependent on tumor location. Pulmonary toxicity was assessed through the execution of pulmonary function tests and on chest Computed Tomografy (CT). All tests were synchronously performed before treatment and at regular intervals after SABR (the first control at 45 days, then every 90 days until progression). Lung function parameters were obtained performing spirometry, body plethysmography, determination of the diffusion lung capacity of carbon monoxide (DLCO) and arterial blood gas analysis.

      Results
      Of 26 patients enrolled, 17 performed the first evaluation at 45 days, 5 at 135. At 45 days the total lung capacity (TLC) slightly decreased from 5.87±1.50 Liters (L) to 5.62±1.42 (t=1.87; NS), whereas VC, FEV~1~ and FEV~1~/VC ratio showed minimal changes. At 135 days TLC in the 5 patients who ultimate this step showed a slight recovery to 5.75±1.75 L. The pulmonary diffusion capacity for carbon monoxide (D~L~CO), corrected for hemoglobin (Hb) levels, significantly decreased from 14.4±4.9 to 12.9±5.2 (mL min[-1]·mmHg[-1]) at 45 days (p<0.019) with a slight recovery at 135 day to 13.9±2.7. When D~L~CO was corrected for the measured Alveolar Volume (D~L~CO/VA) the change was not significant. The difference between plethysmographic TLC and the dilution VA (TLC-VA) increased at 45 days from 1.24±0.7 to 1.49±0.8 L, suggesting an increase in ventilation inhomogeneity of the lung. Arterial oxygen pressure decreased from 75.8±7.2 to 71.6±10.4 mmHg (p=0.056 NS) and the variation correlated with TLC-VA (r=-0.72, p<0.001) and DLCO variations (r=-0.67, p<0.03). We observed a low toxicity profile during the first evaluation at 45 days, with only 1 RTOG grade 2 and 1 grade 3 post actinic pneumonia, both treated with systemic corticosteroids. Only three patients reported fatigue as the only adverse event. At the first radiological re-evaluation we didn’t observe any progression disease, with a 59% rate of partial response.

      Conclusion
      Preliminary findings suggest that no major changes in lung function can be detected at 45 days after SABR. A slight reduction in D~L~CO can be observed, and this could reflect a transitory increase in pulmonary ventilation inhomogeneity caused by RT rather than a direct membrane damage. Study prosecution will hopefully clear the physiopathological evolution at several months after SABR, and further analyses will be carried out investigating for a potential correlation with radiological toxicity and dosimetric profiles.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-041 - Treatment with crizotinib in patients with IV stage non-small cell lung cancer (NSCLC) with ALK translocation: a single institution experience. (ID 2961)

      09:30 - 09:30  |  Author(s): M. Giaj Levra

      • Abstract

      Background
      Crizotinibis is a MET inhibitor, having also an activity on ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) pathways. The ALK translocation is described in 4% of NSCLC and these patients (pts) benefit from crizotinib therapy with a response rate (RR) ranging from 51 to 61%.The drug is already approved by FDA and EMA; in Italy crizotinib is available in first line within controlled clinical trials and, until April 2013, within expanded access program (EAP).

      Methods
      From June 2010 to February 2013, 155 pts with advanced NSCLC were analyzed for Alk translocation using fluorescence in situ hybridization (FISH) at our institution. The selection criteria were: adenocarcinoma histology, never or ex smoker, EGFR status WT. Main pts characteristics were: 59% males, median age 57,5 years (range 26-76), 77 former smoker (76 pts for more than 15 years). Tissue samples were available from primary tumor and metastases in 78 and 22%, respectively, having 73% of cases with cytological material. In 23,2% of the specimens Alk rearrangement was not evaluable due to poor quality and/or quantity issues.

      Results
      Among the 155 pts, 22 (14%) are ALK translocated: 19 were treated within PROFILE clinical trials and 3 patients in the EAP. 20 pts are currently evaluable for response and toxicity: 6 of them received crizotinib as first-line treatment, the others in subsequent lines. The response rate was equal to 70%. The total number of administered cycles is 235.The reduction of the dose (7% of cycles) was necessary in two pts: in 1 case due to bradicardia and fatigue G3 (in first line treatment) and in the other one due to neutropenia G3 (in second line).The observed toxicities were mostly grade 1-2 (fatigue 47%, bradycardia 5,8%, visual disorder 5,8%, anemia 29%, neutropenia 18% and nausea 12%); grade 3-4 was less common. The temporary cessation of treatment was required in 3 pts (range 4-15 days) for grade 3-4 toxicity (mostly neutropenia plus fatigue). No drug interruption for unacceptable toxicity was reported. The most common progression sites were brain (37%) and bone (27%).

      Conclusion
      The introduction of a selection criteria (such as negative EGFR status) leads on an increase of our cases of Alk traslocated pts compared to literature data; this selection is moreover recommended in diagnostic algorithm recently proposed by the Italian Expert Panel (Marchetti A et al, JTO 2013). Efficacy and tolerability profile are consistent with published data.