pf-06463922 and Adenocarcinoma

To date, several studies have described the mechanism of resistance to first- or second-generation anaplastic lymphoma kinase (ALK) inhibitors. Secondary ALK mutations, ALK gene amplification, and other bypass signal activations (i.e., KRAS mutation, EGFR mutation, amplification of KIT, and increased autophosphorylation of EGFR) are known as resistance mechanisms. However, little has been previously reported on acquired resistance mechanisms to lorlatinib. Here, we report a case of a patient with ALK-positive lung adenocarcinoma that acquired resistance to lorlatinib during treatment for brain metastasis and showed histological transformation to squamous cell carcinoma with MET amplification. We also review the previous literature on the resistance mechanism to ALK inhibitors.

Topics: Adenocarcinoma; Aminopyridines; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lactams; Middle Aged; Pyrazoles

Crizotinib is recommended as first-line therapy in ROS1-driven lung adenocarcinoma. However, the optimal first-line therapy for this subgroup of lung cancer is controversial according to the available clinical data.. Here, we describe a 57-year-old man who was diagnosed with stage IIIB lung adenocarcinoma and EGFR/KRAS/ALK-negative tumors. The patient received six cycles of pemetrexed plus cisplatin as first-line therapy and then pemetrexed as maintenance treatment, with a progression-free survival (PFS) of 42 months. The patient relapsed and underwent re-biopsy. EZR-ROS1 fusion mutation was detected by next-generation sequencing (NGS). The patient was prescribed crizotinib as second-line therapy and achieved a PFS of 6 months. After disease progression, lorlatinib was administered as third-line therapy, with a favorable response.. Prolonged PFS in patients receiving pemetrexed chemotherapy might be related to the EZR-ROS1 fusion mutation. Lorlatinib is an optimal choice in patients showing crizotinib resistance.

Topics: Adenocarcinoma; Aminopyridines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Crizotinib; Cytoskeletal Proteins; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Oncogene Fusion; Pemetrexed; Progression-Free Survival; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Time Factors

Patients with lung cancer who show EML4-ALK translocation are routinely treated with ALK tyrosine kinase inhibitors, although in the majority of cases, these patients develop resistance over time. The central nervous system is a common of site of recurrence in this population, which calls for next-generation drugs that can penetrate into the brain and achieve clinically meaningful central nervous system activity. Here, I report the case of a female patient diagnosed with adenocarcinoma of the lung in 2005, at the age of 46 years, who underwent lobectomy and then experienced a series of progression episodes 6 years later. Local recurrence was managed by chemotherapy and crizotinib after the patient was included in a named patient use programme in 2012. Over the following years, the patient repeatedly developed lesions at different sites in the brain and spinal cord. Partial remission was obtained twice with local irradiation. When the next-generation ALK tyrosine kinase inhibitors became available, her treatment was switched to brigatinib, which again induced partial remission. Another episode of intrathecal progression prompted the prescription of the third-generation ALK tyrosine kinase inhibitor lorlatinib. This treatment has resulted in complete remission in the patient.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aminopyridines; Anaplastic Lymphoma Kinase; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases; Spinal Cord Neoplasms