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A. Lee



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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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      P1.11-029 - The addition of anti-angiogenic tyrosine kinase inhibitors to chemotherapy for advanced non-small cell lung cancer: a systematic review and meta-analysis of randomised controlled trials (ID 2140)

      09:30 - 09:30  |  Author(s): A. Lee

      • Abstract

      Background
      Non-small cell lung cancer (NSCLC) remains a major cause of death worldwide. Targeting tumour angiogenesis has held great promise in NSCLC based on the ubiquitous role of angiogenesis in NSCLC biology. The monoclonal antibody bevacizumab has shown greatest efficacy when added to first line chemotherapy in the adenocarcinoma subgroup. Small molecule, anti-angiogenic tyrosine kinase inhibitors (AATKIs) have been evaluated in several settings. This review was undertaken to evaluate the benefits and harms of AATKIs when added to chemotherapy for advanced NSCLC.

      Methods
      We undertook a systematic review of randomised controlled trials (RCTs) of AATKIs added to chemotherapy for advanced or metastatic NSCLC. We searched the electronic databases (MEDLINE/PubMed, EMBASE, The Cochrane Library) in addition to conference proceedings from ASCO, ESMO, IASLC WCLC and Clinical Trials Registries. Data was independently extracted by two reviewers. The primary endpoint was overall survival (OS), with secondary endpoints progression-free survival (PFS), objective response rate (ORR) and ≥ grade 3 common toxicity criteria adverse events (G≥3CTCAE). Meta-analysis of the data was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for ORR and G≥3CTCAE. Statistical analysis was performed using Review Manager v5.2 software (Cochrane). Pre-specified subgroup analyses were performed according to line of chemotherapy, second-line chemotherapy partner and histology.

      Results
      Fifteen RCTs involving 7904 patients with advanced NSCLC were included in this meta-analysis. In the overall population (N = 7904), the addition of AATKI to chemotherapy significantly prolonged OS (HR 0.93; 95% confidence interval [CI] 0.88, 0.99; P=0.02) and PFS (HR 0.83; 95% CI 0.79, 0.88; P<0.00001). There was no significant heterogeneity between the RCTs. (Chi² = 12.31, df = 14, P = 0.58; I² = 0% for OS. Chi² = 10.64, df = 13, P = 0.64; I² = 0% for PFS). The addition of AATKI to chemotherapy significantly increased ORR (OR 1.64, 95% CI 1.34, 2.02; P<0.00001) and G≥3CTCAEs (OR 1.78, 95% CI 1.41, 2.25; P<0.00001). Used first line (N = 3867), AATKI significantly prolonged PFS (HR 0.86; 95% CI 0.79, 0.93; P<0.0001) but not OS (HR 0.96; 95% CI 0.89, 1.05; P=0.38). Used second line (N=4037), AATKIs significantly prolonged both OS (HR 0.91; 95% CI 0.84, 0.98; P=0.02) and PFS (HR 0.80; 95% CI 0.74, 0.87; P<0.00001). Here, the greatest OS benefit was seen in patients with adenocarcinoma (HR 0.85; 95% CI 0.75, 0.96, P=0.01) and patients receiving docetaxel (HR 0.89; 95% CI 0.81, 0.98; P=0.02). The addition of AATKIs to second line pemetrexed did not improve OS (HR 0.95; 95% CI 0.79, 1.13; P=0.54) nor in patients with squamous histology (HR 1.01; 95% CI 0.87, 1.16; P=0.92).

      Conclusion
      The addition of AATKIs to chemotherapy in patients with advanced NSCLC prolongs OS, PFS and increases ORR, at the expense of increased toxicity. Greatest benefit is in second line, in adenocarcinomas and in patients receiving docetaxel. Whilst the search for predictive biomarkers of the angiogenic phenotype continues, an individual patient data meta-analysis may clarify subgroups with the most benefit from AATKIs to guide future studies in enriched populations.

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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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      P3.11-046 - ROS1 overexpression by immunohistochemistry in non-small cell lung cancer: clinical characteristics, natural history and potential new therapeutic target based on two Australian cases (ID 3081)

      09:30 - 09:30  |  Author(s): A. Lee

      • Abstract

      Background
      Recent years have seen worldwide interest in the study of driver mutations in lung cancer, in particular epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase gene rearrangement (ALK). ROS1 gene rearrangement is a recently identified driver mutation and potential therapeutic target for crizotinib and similar agents. However little is known of the natural history of patients with ROS1, and moreover the diagnostic value of immunohistochemistry (IHC) compared to fluorescent in-situ hybridization (FISH).

      Methods
      12 patients from a single Australian tertiary institution with advanced non-small cell lung cancer (NSCLC) were screened for ROS1 overexpression and gene rearrangement. Selection was based on negative testing for EGFR and ALK, and unusually long natural history.

      Results
      We report 2 patients with ROS1 overexpressed advanced NSCLC, their unique characteristics, long natural history and the use of IHC as a complementary method to FISH in identifying these patients. Mr GL was a 62 year-old Caucasian man and lifelong non-smoker who presented with an incidental 19mm subpleural left lower lobe lung nodule found on computed tomography (CT) when he was treated for pneumonia in 2008. He was monitored with CT for his pulmonary nodule and pre-existing interstitial lung disease. In 2011, CT and subsequent positron emission tomography (PET) showed new regional lymphadenopathy and widespread sclerotic bone disease with the pulmonary nodule unchanged in size but moderately glucose avid. Axillary and supraclavicular lymph node biopsies confirmed metastatic adenocarcinoma consistent with a lung primary. EGFR and ALK testing was negative. He received induction and maintenance chemotherapy until disease progression in 2013. His original biopsy tested negative for ROS1 rearrangement by FISH but stained strongly positive for ROS1 overexpression by IHC using the Epitomics rabbit monoclonal antibody (D4D6) with diffuse cytoplasmic positivity. He was commenced on crizotinib, achieving and maintaining stable disease after three months. Mrs MM was a 54 year-old Caucasian woman and lifelong non-smoker who presented with an incidental 26mm right lower lobe lung nodule found on CT when she presented with left sided chest pain in 2009. PET and endobronchial biopsy of mediastinal lymph nodes confirmed stage IIIA lung adenocarcinoma. EGFR and ALK testing was negative. She received neo-adjuvant chemotherapy, followed by right lower lobectomy and post-operative radiotherapy. In 2010 she developed right supraclavicular lymph node recurrence and achieved radiological complete response after radiotherapy. In 2011 she developed another isolated nodal recurrence in the right supraclavicular fossa, which was surgically resected and confirmed adenocarcinoma. It stained strongly positive for ROS1 overexpression by IHC and positive for ROS1 rearrangement by FISH. In 2013, PET found an isolated hepatic metastasis. She was commenced on crizotinib with plans for re-staging and consideration for liver directed therapy. Clinical progress of the patients will be updated and presented.

      Conclusion
      Our cases of ROS1 overexpressed NSCLC illustrate unique patient characteristics of never-smoking status, adenocarcinoma histology, negative testing for EGFR and ALK, and an unusually long natural history. Our cases highlight the need for greater understanding of the predictive value of ROS1 overexpression by IHC as opposed to FISH alone for targeted therapy.