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M.C. Garassino



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    P2.01 - Poster Session 2 - Cancer Biology (ID 145)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.01-003 - Modulation of Cisplatin Activity in NSCLC by KRAS Mutants: Role of Specific Mutations at Codon 12 (ID 2296)

      09:30 - 09:30  |  Author(s): M.C. Garassino

      • Abstract

      Background
      Non-small-cell lung cancers (NSCLCs) constitute about 85% of lung cancers and have been associated with a poor prognosis, despite the introduction in clinical practice of targeted therapies. The majority of patients are still treated in first-line with a cisplatin containing doublet. New molecular predictors should be discovered. Our attention has been focused on KRAS. Mutations in the KRAS gene have been found in 17% of NSCLC patients mostly at codon 12. It has been observed that a pool of mutations, responsible for different aminoacid substitutions, occured at this position. In NSCLC these mutations are present at a different frequency compared to colon and pancreatic cancer. It has been supposed that different aminoacids in the same position of KRAS protein could differently impact on tumor progression and drug resistance. To test this hypothesis, KRAS overexpressing clones with the three most common mutations found in NSCLC patients (G12C, G12D and G12V) have been generated in NCI-H1299 cell line. The clones showed a different response in vitro to cisplatin (Garassino MC et al, Annals of Oncology, 2011).

      Methods
      The clones were xenografted in nude mice to determine the antitumor activity of cisplatin in vivo. The effect of cisplatin on signalling pathways and DNA damage response was determined by western blotting, immunofluorescence and Real-Time PCR. Platinum adducts on DNA were revealed by DRC-ICP-MS.

      Results
      The resistance induced by the presence of G12C KRAS was still present compared to wild-type KRAS clone when these clones were transplanted in nude mice and treated with cisplatin. Some of the logic pathways functionally linked to KRAS, such as MAPK and PI3K, did not seem to account for the different cisplatin sensitivity observed. Factors previously reported to be associated to cisplatin resistance, such as the levels of cisplatin transporter CTR-1, of GSH and GST enzyme, and the total intracellular platinum levels were comparable among the clones. Several concordant results seem to indicate that, with a similar ability to enter the cells and to reach the DNA, an increased removal of platinum bound to DNA might account for the resistance of G12C clone: i) the cell cycle perturbation induced by cisplatin indicated that a reduced G2/M cell cycle phase block was observed in the G12C clone compared to all the others; ii) H2AX foci and ATM phosphorylations following treatment were barely detectable in the resistant clone; iii) the levels of platinum bound to DNA were much faster declining in G12C cells. The involvement in the resistance of G12C clone of Nucleotide Excision Repair and Fanconi Anemia repair mechanisms, which have been associated to the removal of adducts from DNA, was excluded by our experiments.

      Conclusion
      Altogether these data reveal the possibility that the presence of G12C KRAS mutation stimulates a DNA repair mechanism, not yet identified, able to faster remove platinum from DNA before the formation of double strand cross-links. Studies are ongoing to specifically address this point. Understanding why the different KRAS mutations influence the response to cisplatin could be useful in the clinical setting to tailor therapies for patients.

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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): M.C. Garassino

      • 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): M.C. Garassino

      • 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.