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• W3137588425 abstract "Seventeen years have now passed since three research groups discovered the association between epidermal growth factor receptor (EGFR) mutations and sensitivity to EGFR-tyrosine kinase inhibitors (TKIs) and 14 years since the discovery of the ALK translocation in non-small cell lung cancer (NSCLC) led to the development of ALK TKIs. Drug development in these genomically defined lung cancer patient subsets has continued, with second and third generation agents that have been developed against the tyrosine kinase domains of the two receptors. The latest agents yield response rates of ≥80% and progression-free survival of 19 months with osimertinib for those NSCLC patients with sensitizing mutations of EGFR, and nearly 3 years for those with ALK rearrangements treated with alectinib. The success of treating these patient subsets which make up 5% or more of the lung cancer population has prompted biomarker testing around the world and deployment of EGFR and ALK tyrosine kinase inhibitors around the world Five more genomic changes have now led to US FDA approvals for agents targeting rarer events in lung cancer including ROS1 rearrangements, BRAF V600E mutations, NTRK rearrangements, RET rearrangements, and MET exon 14 skip mutations: each makes up from fewer than 1% up to 3% of lung cancer patients. These include crizotinib and entrectinib for lung cancer patients with ROS1 rearrangements, dabrafenib plus trametinib for V600E BRAF mutations, and larotrectinib & entrectinib for those with NTRK rearrangements—all approved between 2016 and 2019. The targeted agents approved in 2020 for patients with lung cancer include selpercatinib and pralsetinib for those with RET rearrangements and capmatinib for those with MET exon 14 skip mutations. These agents have all been US FDA approved based on single arms studies. The reported response rates, duration of responses, and progression-free survival in these patient subsets give us information on the outcomes needed for regulatory approval in these rare subsets of lung cancer patients. The 8 targeted agents for these 5 oncogenic drivers which are present in less than 1% to up to 3% of patients with NSCLC have a response rate of 48-77%, a duration of response of approximately 11-35 months, and progression-free survivals of 10-28 months. These 5 oncogenic drivers, plus those lung cancer patients with EGFR sensitizing mutation and ALK rearrangements now make up 30-50% of patients in different parts of the world. Comprehensive biomarker testing in lung cancer patients known to harbor these genomic changes which can be effectively targeted has become increasingly important. Survey data from around the world show that substantial numbers of patients with lung cancer who may harbor these genomic changes are not getting comprehensive biomarker testing. This has prompted multiple professional organizations including the International Association for the Study of Lung Cancer and patient advocacy groups to call for universal comprehensive biomarker testing in our lung cancer patients around the world. Challenges for the commercial development and deployment of these targeted agents is the cost of carrying out the appropriate trials for regulatory approval, the potential revenue from a relatively small patient subsets, and costs of the drugs to third party payors or the patients. Although the number of lung cancer patients needed for regulatory approval in these rare subsets with these specific genomic changes is small (typically around 50->100), the trials need to be carried out in multiple institutions where large numbers of patients are undergoing comprehensive biomarkers testing. The revenue generated by the sale of these targeted agents is limited by the number of lung cancer patients who have the appropriate comprehensive biomarker testing and the rarity of the mutation. For instance, there are approximately 140,000 lung cancer deaths in the US per year, nearly all from advanced disease. Assuming approximately 100,000 of these patients are potentially eligible to be treated with targeted agents at some time during their clinical course, a genomic change present in 1% of the population will give you approximately 1,000 patients eligible for the drug each year in the US. According to prices listed in https://www.drugs.com, a typical yearly course for one of these 8 targeted agents will cost >$200,000 per year. If this is the price charged and if all the charges are collected, this will yield revenues of about $200 million per year which may be a challenge to cover drug development costs. Perhaps an even greater challenge is the impact on our health care systems. If 30% of lung cancer patients are being treated with target agents that cost $200,000 per year, the costs to our health care systems will remain a challenge to sustain by our patients and third-party payors. The ongoing revolution in the evaluation and treatment of patients with lung cancer continue to define rare patient subsets who can be effectively treated with different agents. The task of identifying these patients remain a logistical challenge and the ability of our patients and our health care systems to support the costs of these therapies will continue to tax our system." @default.
• W3137588425 created "2021-03-29" @default.
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• W3137588425 date "2021-03-01" @default.
• W3137588425 modified "2023-09-25" @default.
• W3137588425 title "PL04.03 Evolving Challenges in Drug Development" @default.
• W3137588425 doi "https://doi.org/10.1016/j.jtho.2021.01.012" @default.
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