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V. Torri



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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.01 - Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): VeriStrat analysis of longitudinal samples (ID 3122)

      10:30 - 10:35  |  Author(s): V. Torri

      • Abstract
      • Presentation
      • Slides

      Background
      2nd-line therapy for advanced NSCLC patients (pts) after progression on platinum-based regimens typically employs CT or E. A test for optimizing choice of treatment in these pts 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. PROSE is a multicenter prospective randomized biomarker validation trial, designed to evaluate the ability of VS to predict survival in 2nd- line NSCLC pts treated with E or CT. As reported at 2013 ASCO1, PROSE met its primary endpoint of demonstrating significant treatment*VS interaction with a p value of 0.031, with VSG pts deriving similar overall survival (OS) benefit from both treatments (hazard ratio (HR) for E=1.06; p=0.71) and VSP pts benefitting more from CT than E (HR for E=1.72; p=0.02). Previous studies in EGFR-TKI-treated pts have shown that at progression around 30% of pre-treatment VSG pts have changed classification to VSP2. The present report discusses the exploratory analysis of longitudinal VS classifications generated during the PROSE study.

      Methods
      Of the 263 pts in the PROSE primary analysis population, 89 provided serum samples during treatment and 108 at progression, with 47 pts providing both. VS testing was performed on these longitudinal samples blinded to all clinical and treatment outcomes and pts and physicians remained blinded to VS results.

      Results
      VSG or VSP classifications were obtained for 89 pts from treatment samples (67 VSG / 22 VSP) and 107 pts (one sample was classified as indeterminate) from progression samples (59 VSG / 48 VSP). In pts with matched baseline and progression samples, the percentage of VSG classifications was lower at progression (55%) than at baseline (77%) (p < 0.001 ). Twenty eight pts (34%) classified at baseline as VSG changed to VSP at progression, in line with previous studies2, and this did not show any significant dependence on treatment. When treated with E, pts whose classification changed from VSG at baseline to VSP during treatment (n=6) had inferior PFS to the 25 pts who remained VSG (p=0.001, median PFS: 3.6 and 7.7 months (mos), respectively). Patients whose classification changed from VSG at baseline to VSP at progression on E (n=18) had numerically inferior OS (median 10.0 mos) compared with the 31 pts who remained VSG at progression (median 14.6 mos) and significantly superior OS (median 5.0 mos) compared with the 10 pts who were VSP at both time points (p<0.001).

      Conclusion
      The observed changes in VS classification at progression demonstrate the importance of obtaining a VS result prior to each line of therapy for which erlotinib is considered as a therapeutic option. The proportion of patients who are good candidates for erlotinib therapy (VSG) decreases from 2[nd] to 3[rd] line and the possible impact of this on treatment sequencing and monitoring for 2[nd] and higher line advanced NSCLC pts merits further studies.

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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): V. Torri

      • 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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    O22 - Mesothelioma III (ID 122)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      O22.07 - Does surgery improve survival of patients with malignant pleural mesothelioma? A multicenter retrospective analysis of 1365 consecutive patients. (ID 2962)

      17:20 - 17:30  |  Author(s): V. Torri

      • Abstract
      • Presentation
      • Slides

      Background
      Medical management of malignant pleural mesothelioma (MPM) has obtained a moderate survival improvement over the years, while surgery with pleurectomy / decortication (P/D) or extrapleural pneumonectomy (EPP) can be an option for selected patients with resectable disease. The aim of this study was to investigate the impact of surgical treatment on the outcome of patients with MPM.

      Methods
      We retrospectively reviewed data from 1365 consecutive patients with histologically proven MPM, treated from 1982 to 2012 in six Institutions.Patients received either chemotherapy alone (n=172) or best supportive care (n=690) or surgical treatment (n=503), by either P/D (n=202) or EPP (n=301) with or without chemotherapy. All patients were followed up until death or for a minimum period of one year. The cox proportional hazards regression model was used to estimate relative improvements and to test the statistical hypothesis; a p-value less than 0.05 was considerd statistical significant.

      Results
      Figure 1 Figure1. Kaplan-Meier survival curves according to the treatment (non surgical treatment vs EPP vs P/D) considering only patients with independent good prognostic factors After a median follow-up of 6.7 years (range 1.1-14.8), 230 (16.8%) patients were alive; median survival for patients who received palliative treatment or chemotherapy alone, P/D and EPP groups were 11.7 (95%CI: 10.5-12.5) months, 20.5 (95%CI: 18.2-23.1) months, and 18.8 (95%CI: 17.2-20.9) months, respectively. Testing the hypothesis of equal survival distributions the statistical significance was reached for the P/D and EPP groups versus non surgical treatment group (p <0.001) but not for the EPP versus P/D groups (p=0.885). The 30 day mortality was 2.6% after P/D and 4.1% after EPP (p=0.401). According to multivariate analysis (n=1227) age < 70, epithelial histology and chemotherapy were independent favourable prognostic factors. In the subset of 312 (25.4%) patients with all favourable prognostic factors median survival was 15.5 months after medical therapy alone, 19.4 months after P/D, and 18.7 months after EPP (Figure 1). A risk reduction of 31% (95%CI: 14-45%) for the P/D group and of 23% (95%CI: 7-36%) for the EPP group was observed compared to the medical treatment group.

      Conclusion
      Our data suggest that patients with good prognostic factors had a similar survival whether they received medical therapy only, P/D or EPP. The modest benefit observed after surgery over medical treatment requires further investigation, and a large multicenter randomized trial, testing P/D after induction chemotherapy versus chemotherapy alone in MPM patients with good prognostic factors, is needed.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-056 - The Elderly Patient Individualized Chemotherapy Trial (EPIC): A Randomized Phase III Multicenter Trial of Customized Chemotherapy versus Standard of Care for 1st Line Treatment of Elderly Patients with Advanced Non-Small-Cell Lung Cancer (ID 1117)

      09:30 - 09:30  |  Author(s): V. Torri

      • Abstract

      Background
      This is an ongoing phase III multicenter randomized trial comparing first line pharmacogenomic-driven chemotherapy based on Excision-Repair-Cross-Complementing-1 (ERCC1), Ribonucleotide Reductase subunit M1 (RRM1) and Thymidylate Synthase (TS) gene expression, versus standard first line treatment in elderly patients (pts) with advanced non-small-cell lung cancer (NSCLC). Chemotherapy selection based on an individual patient’s molecular profile is a potentially promising approach to optimize efficacy with the already available cytotoxic drugs. In older pts this is particularly relevant owing to their rapid deterioration of symptoms and their increased propensity to suffer therapy-induced toxicity.

      Methods
      Pts aged >70 years, with ECOG Performance Status (PS) 0 or 1, previously untreated for stage IV NSCLC will be evaluated. In a 2:1 fashion, pts will be randomized to experimental arm (A) or standard arm (B). They must have measurable disease and EGFR negative mutational status. In arm A, treatment with single or dual-agent chemotherapy will be based on histology, ERCC1 (E), RRM1 (R) and TS (T) expression at the mRNA level. Expression of E, R and T is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. The cut off for high or low expression have been previously defined. Pts with squamous NSCLC who are: E low/R high will be treated with single agent carboplatin, E high/R low with single agent gemcitabine, E low/R low with carboplatin and gemcitabine and E high/R high with docetaxel or vinorelbine. In non-squamous NSCLC pts: E low/T high will be treated with carboplatin, E high/T low with pemetrexed, E low/T low with carboplatin and pemetrexed, E high/T high/R low with gemcitabine and E high/T high/R high with docetaxel or vinorelbine. In arm B treatment will be standard of care at the discretion of the care provider. The primary endpoint is overall survival (OS). The secondary endpoints are progression-free survival (PFS), disease response according to RECIST 1.1 and tolerability (using CTCAE version 4.0). Feasibility of treatment selection based on pharmacogenomic parameters will also be assessed. Treatment will continue to a maximum of 6 cycles if tolerated or until disease progression. Switch maintenance treatment is not allowed in either arm. Continuation maintenance (one or more of the agents used in the initial regimen) is allowed at the discretion of the investigator. Treatment upon progression is at the discretion of the care provider. Assuming an exponential survival distribution for both treatment arms and a median survival time of 8 months in the control arm we anticipate to detect an improvement of 3 months in the median survival time in the experimental arm. To have 90% power to detect a three-month improvement in median survival at a significance level of 5% (2-sided) and assuming a 10% failure rate in gene analyses or loss to follow up rate, a sample size of 567 patients is planned to be enrolled.

      Results
      Not Applicable

      Conclusion
      We hypothesize that such tailored approach will improve survival decreasing the exposure to ineffective toxic agents in advanced NSCLC elderly pts. To our knowledge this is the first pharmacogenomic-driven randomized trial in this population.

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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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      P2.11-034 - Indirect comparisons of harm/benefit profile of EGFR tyrosine kinase inhibitors as first line treatment in EGFR mutated NSCLC patients: a systematic review and meta-analysis (ID 2363)

      09:30 - 09:30  |  Author(s): V. Torri

      • Abstract

      Background
      To date, three EGFR Tyrosine Kinase inhibitors (TKIs) gefitinib (G), erlotinib (E), and afatinib (A) have been compared to standard chemotherapy as first line treatment in patients with advanced NSCLC harboring EGFR mutations. We performed a systematic review and meta -analysis in order to estimate through indirect comparisons the relative risk benefit associated to each drug.

      Methods
      The major databases were searched for published and unpublished randomized control trial up to March 2013. Data extraction was performed by two independent reviewers and focused on benefit (ORR, PFS) and selected harm outcomes (diarrhea, rash, nail disorders, hypertransaminasemia). The adjusted indirect comparisons were performed using the random effect method described by Bucher and Glenny approach for Hazard Ratio (HR) for PFS and relative risk (RR) for the other outcome measures.

      Results
      All EGFR TKIs fared better when compared with chemotherapy in terms of PFS: overall HR 0.40 (95%CI 0.30-0.54); G vs E HR 1.34 (95%CI 0.63-2.86), G vs A HR 0.74 (95%CI 0.53-1.04), E vs A HR 0.55 (95%CI 0.31-0.99). The relative probability of ORR was G vs E 0.96 (95%CI 0.69-1.34), G vs A 0.79 (95%CI 0.49-1.28), E vs A 0.82 (95%CI 0.49-1.38). Indirect comparisons for safety showed RR for diarrhea G vs E 0.8 (95%CI 0.63-1.01), G vs A 0.32 (95%CI 0.20-0.51), E vs A 0.38 (95%CI 0.24-0.62); for rash G vs E 1.0 (95%CI 0.82-1.22), G vs A 0.31 (95%CI 0.15-0.65), E vs A 0.31 (95%CI 0.15-0.65); for hypertransaminasemia G vs E 2.29 (95%CI 1.63-3.23). Nail disorders affected 57% of patients treated with A, 15% with G, and 4% with E.

      Conclusion
      Results of our analysis showed that all treatments have similar activity and efficacy while the toxicity profile was less favorable for A with a significant higher risk of diarrhea, rash, and nail disorders. Based on these safety results, we suggest that A may not be the first choice for upfront treatment in EGFR mutated patients. Confirmation is warranted by ongoing prospective head to head RCTs.

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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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      P3.11-025 - Prognostic and predictive role of KRAS mutations in patients with advanced Non Small Cell Lung Cancer treated with docetaxel or erlotinib as second line treatment in the Tailor trial (ID 2159)

      09:30 - 09:30  |  Author(s): V. Torri

      • Abstract

      Background
      KRAS mutations in NSCLC are supposed to indicate a poor prognosis and poor response to anticancer treatment. However, such evidence is only drawn from retrospective series giving controversial results. Aim of this study is to prospectively assess the prognostic and predictive value of KRAS mutations in NSCLC patients treated with either erlotinib or docetaxel. This is a planned ancillary study within the TAILOR trial (NCT00637910 ).

      Methods
      Main eligibility criteria were a diagnosis of metastatic NSCLC, prior platinum-based chemotherapy and mutational status of EGFR and KRAS centrally assessed by direct sequencing in two independent laboratories. Only patients with wild-type EGFR and KRAS status assessed were randomly allocated to receive erlotinib or docetaxel until disease progression. Overall survival was the primary endpoint. To detect a 33% reduction in mortality with an 80% power (2 sided a=0.05), 220 patients were randomized. A subgroup analysis aimed at detecting particular subgroups of patients, where the differential effect of treatment could be highlighted, was planned.

      Results
      Overall, median survival and progression free survival were superior in the docetaxel arm compared to the erlotinib arm. Fiftyone out of 220 patients were found to be mutated in KRAS. No interaction effect was found according to KRAS status. In mutated KRAS the HR for OS was 0.81 (95%CI: 0.45-1.47) in favour of chemotherapy, and in wild type KRAS the HR was 0.79 (95%CI: 0.57-1.10); p value for interaction effect: 0.82. Similar pattern was found for PFS. In mutated KRAS patients the HR for PFS was 0.89 (95%CI: 0.51-1.57), while in wild type KRAS the HR was 0.68 (95%CI: 0.50-0.93), p value for interaction effect: 0.33. No evidence of prognostic effect of KRAS could be found. For OS, the HR for associations of mutated KRAS status and mortality was 1.24 (95%CI: 0.87-1.77; p=0.23); for PFS the HR was 1.00 (95%CI: 0.71-1.41; p=0.98)

      Conclusion
      Although the study is not sufficiently powered to test interaction for KRAS mutations, TAILOR results show that KRAS can be considered neither a prognostic nor a predictive factor in second line treatment in advanced NSCLC.

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    P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.12-023 - International Tailored Chemotherapy Adjuvant Trial: ITACA Trial (ID 1452)

      09:30 - 09:30  |  Author(s): V. Torri

      • Abstract

      Background
      This is an ongoing phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy, based on thymidilate synthase (TS) and excision-repair cross-complementing-1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected Stage II-IIIA non-small cell lung cancer (EudraCT #: 2008-001764-36).

      Methods
      For all the registered patients (pts) the expression of ERCC1 and TS is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. Randomization is stratified by stage and smoking status. Trial was emended on Feb, 2011 with the 7th staging system. Primary end point is overall survival; secondary end points include recurrence-free survival, therapeutic compliance, toxicity profile and comparative evaluation of ERCC1 and TS mRNA versus protein expression. It is assumed that the 5-year survival rate in the control arm is 45% and the hazard reduction associated to the experimental treatment is 30%. With a power of 90% to detect the estimated effect with log-rank test, a significant level of 5% (2 tails), 336 events have to be observed; the expected total number of pts is 700. The final statistical analysis will compare all pts in the control arms versus all those treated in the tailored chemotherapies groups. Efficacy analysis will be done on an intent-to-treat basis. Cox proportional hazard model will be used for estimating hazard ratios after adjusting for relevant variables. Within 45 days post-surgery, pts in each genetic profile are randomized to receive either a standard chemotherapy selected by the investigator (cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine) or an experimental treatment (tailored arms) selected as follows: 1) high ERCC1 and high TS 4 cycles of single agent paclitaxel 2) high ERCC1 and low TS 4 cycles of single agent pemetrexed 3) low ERCC1 and high TS 4 cycles of cisplatin/gemcitabine 4) low ERCC1 and low TS 4 cycles of cisplatin/pemetrexed. All chemotherapy regimens are administered for a total of 4 cycles on a 3-weekly basis.

      Results
      Not applicable

      Conclusion
      Currently, 558 pts have been randomized from 26 institutions mainly located in Italy and Germany (average enrolment: 19 patients/month). This is one of the pharmacogenomic-driven trial in the adjuvant setting in the European scenario.