As the most common cause of acquired resistance to first-generation TKIs is a second EGFR mutation on codon 790, a third-generation EGFR TKI, osimertinib, has been developed to target this new mutation as well. MET amplification is another known mechanism of acquired resistance.ALK inhibitors such as crizotinib showed to be effective against tumors harboring ALK fusions. Most patients previously treated with crizotinib benefited from second-generation ALK inhibitors including ceritinib, alectinib and brigatinib. Resistance to ALK inhibitors can occur with novel acquired ALK mutations or amplifications.Also ROS1-positive tumors have shown high sensitivity to ALK inhibitors due to the high homology between the kinase domains of ROS1 and ALK. Immunotherapy
Immune response can be prevented via activation of immune checkpoints, which consist in the binding of a ligand protein (e.g. PD-L1) to a receptor (e.g. PD-1) on the immune cell surface. As a consequence, cancer cells expressing PD-L1 can inactivate T cells thus fostering tumor growth. Immune checkpoint inhibitors have been developed to restore T cell-mediated antitumor immunity by blocking either the ligand or the receptor.Immune checkpoint inhibitors have been approved for NSCLC, including anti-PD-1 nivolumab and pembrolizumab. Anti-PD-1 agents are used for patients with advanced NSCLC whose tumors progress after first-line cytotoxic chemotherapy. Pembrolizumab was established as a new standard of care for patients with advanced or metastatic NSCLC with high PD-L1 expression levels, and responses are even more pronounced for tumor with a high mutational burden (i.e.
Importantly, many of these signs are commonly due to other causes that are not cancer. A detailed medical history should be obtained from each patient to determine the relevance of further diagnostic workup and management. Extrapulmonary manifestations
Adenocarcinoma, like other forms of lung cancer, is usually advanced or metastatic at time of diagnosis. Patients may complain of signs or symptoms outside of the respiratory tract that represent a hematologic or metabolic complication of the malignancy without, however, resulting necessarily from obstruction or metastasis. These go under the name of paraneoplastic syndromes, which often indicate advanced disease and worse prognosis. The most common paraneoplastic syndromes associated with adenocarcinoma of the lung are described below:

Hypercalcemia of malignancy is more common in squamous cell carcinoma of the lung, but can occur in adenocarcinoma as well. Parathyroid hormone-related peptide (PTHrP) is produced by tumor cells and functions similarly to parathyroid hormone (PTH). The production of this hormonally active peptide by cancer cells causes increased bone resorption via upregulation of osteoclasts, one of the cells responsible for bone remodeling. When bone is broken down, calcium is released into the bloodstream, resulting in hypercalcemia. The signs and symptoms of elevated calcium in the blood include: thirst, fatigue, constipation, polyuria (increased urination), and nausea. It is important to rule out boney metastases in patients with NSCLC because they also present with hypercalcemia. Hypertrophic pulmonary osteoarthropathy (HPO) is fairly rare in adenocarcinoma.