81IN - Personalized therapy and bio-molecular driven treatment in lung cancer
|Date||01 October 2012|
|Event||ESMO Congress 2012|
|Session||Latest innovations in NSCLC management|
|Topics|| Non-Small-Cell Lung Cancer, Metastatic
Discovery of activating mutation of the EGFR gene in 2004 opened the era of personalized therapy in thoracic oncology. These tumors are highly dependent on the EGFR pathway and inhibition of this pathway results in dramatic induction of apoptosis in vitro, even though cancer cells may have various genetic alterations (oncogene addiction). These observations were soon translated into clinical trials. Recent 4 phase III clinical trials for patients with EGFR mutation (NEJ 002, WJTOG3405, OPTIMAL, EURTAC) reproducibly showed significantly longer progression free survival for those treated with EGFR-tyrosine kinase inhibitors (TKI) than those treated with platinum doublet chemotherapy. Although there was no difference in overall survival probably due to high crossover rate, it was noteworthy that 40% of patients in EGFR-TKI arm were able to go without platinum doublet and yet had similar survival outcome in WJTOG3405 In 2007, it was found that ∼5% of adenocarcinoma of the lung harbors EML4-ALK translocation and that these tumors are also addicted to the ALK pathway. Clinical development of the first ALK-TKI, crizotinib, focusing on tumors with ALK translocation was quick in spite of its rarity. Just 4 years after discovery of EML4-ALK, crizotinib was approved by FDA for lung cancer with ALK translocation in 2011 We have learned how effective the targeted therapy is, when “addicted oncogene” was pharmacologically inhibited. List of addicted oncogenes is expanding continuously and now it includes HER2, ROS1 or RET in adenocarcinoma of the lung. Efforts are also being made to identify addicted oncogenes in squamous cell carcinoma. Variant III of the EGFR gene, mutations of the DDR2 gene, amplification of the FGFR1 gene seem to be attractive targets of therapy. However, even in patients with dramatic initial response in these addicted tumors, resistance almost inevitably develops typically after less than 1 year. Mechanisms of the resistance include secondary mutation of the targeted gene and activation of alternative pathways. The future clinical trials should be based on individual mechanism found in re-biopsy specimens. It is also a challenge how efficaciously these oncogene alterations are identified in each clinical specimen.Disclosure
T. Mitsudomi: I received honorarium from AstraZeneca, Chugai, Elo-Lilly, Pfizer, Daiichi-Sankyo and Taiho. I also served as an advisory board for Boehringer-Ingelheim, Pfizer, AstraZeneca, Chugai, Eli-Lilly, Merck-Serono.