Since the discovery of anaplastic lymphocyte kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) and subsequent development of increasingly effective and central nervous system (CNS)-penetrant first-generation, second-generation and third-generation ALK tyrosine kinase inhibitors (TKIs), the landscape of resistance mechanisms and treatment decisions has become increasingly complex. Tissue and/or plasma-based molecular tests can identify not only the rearrangement proper but also common resistance mechanisms to guide decision-making for further lines of treatment. However, frequently encountered questions exist regarding how to diagnosis ALK rearrangement, how to select a first-line ALK TKI, how to diagnose and manage ALK TKI resistance, how to control CNS disease and how to handle failure of ALK inhibition. Herein, we attempt to answer these questions through the evidence-based interpretation of studies on ALK-rearranged NSCLC combined with experience gained from our institution. The authors also propose a therapeutic algorithm for the management of this complex and highly treatable disease to assist clinicians globally in the treatment of patients with ALK-positive NSCLC.
Pharmaceuticals, Inivata, MD Serono, and Novartis; fees for speakers bureau from AstraZeneca, Merck Sharp & Dohme, and Roche; and nonfinancial support from Guardant Health through a research collaboration. Dr. Russo reports receiving personal fees for attending advisory board meetings from AstraZeneca, Merck Sharp & Dohme, and Novartis. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serologic assays and NDV-based SARS-CoV-2 vaccines which list Dr. Krammer as coinventor. Mount Sinai has spun out a company, Kantaro, to market serologic tests for SARS-CoV-2. Dr. Krammer has consulted for Merck and Pfizer (before 2020
Background: Ampli cation of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors (TKIs) or antibodies has shown limited e cacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR ampli cation and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer (NSCLC).Methods: We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene ampli cation could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial NGS panel in liquid biopsy.Results: There were ten males (66.7%), and the median patient's age was 56 years (range 38-70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6-12). The median follow-up after recurrence was 17.1 months (95% CI 12.3-22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8-7.3) and overall survival (OS) of 9.0 months (95% CI 3.9-14.0). The PFS6 was 46.7%, and the overall response rate (ORR) was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET ampli cation, STAT3, IGF1R, PTEN, and PDGFR.Conclusions: While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR ampli cation plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful bene t. The ndings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, ndings that contribute to the understanding and targeting in a stepwise rational this pathway.
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