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Simple Summary: Non-small cell lung cancer treatment has undergone a revolution in the past decade owing to the discovery of mutations that drive carcinogenesis and the development of molecular testing and treatments that act on them. Here, we detail the way in which lung cancer is currently diagnosed and treated in light of these developments. We focus on some of the key mutations for which targeted therapies have been developed and the trials that led to their approval. We hope to provide a comprehensive review of the current diagnosis and management of non-small cell lung cancer. Treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift. Once a disease with limited potential therapies, treatment options for patients have exploded with the availability of molecular testing to direct management and targeted therapies to treat tumors with specific driver mutations. New in vitro diagnostics allow for the early and non-invasive detection of disease, and emerging in vivo imaging techniques allow for better detection and monitoring. The development of checkpoint inhibitor immunotherapy has arguably been the biggest advance in lung cancer treatment, given that the vast majority of NSCLC tumors can be treated with these therapies. Specific targeted therapies, including those against KRAS, EGFR, RTK, and others have also improved the outcomes for those individuals bearing an actionable mutation. New and emerging therapies, such as bispecific antibodies, CAR T cell therapy, and molecular targeted radiotherapy, offer promise to patients for whom none of the existing therapies have proved effective. In this review, we provide the most up-to-date survey to our knowledge regarding emerging diagnostic and therapeutic strategies for lung cancer to provide clinicians with a comprehensive reference of the options for treatment available now and those which are soon to come. [ABSTRACT FROM AUTHOR]

Pneumonitis has been described as a side effect of immunotherapy as well as traditional chemotherapy. Although immune-related adverse event (IRAE) pneumonitis has been extensively characterized, the relationship between IRAE pneumonitis and pneumonitis secondary to chemotherapy is less clear. Here, we present the first analysis of radiographic features of pneumonitis secondary to immunotherapy compared to chemotherapy. Using our radiology records system, we searched chest computed tomography (CT) reports for the term "pneumonitis". We evaluated medical records to establish chronicity of pneumonitis occurring after medication administration and excluded cases where radiation therapy appeared to be the cause of pneumonitis. We also obtained information regarding demographic, clinical, and treatment characteristics for comparison. Patients treated with immunotherapy demonstrated more specific features of pneumonitis including consolidation, ground glass opacities, septal thickening, traction bronchiectasis, and pulmonary nodules compared to those treated with chemotherapy. Immunotherapy treatment correlated with the development of pulmonary nodules (p = 0.048), and administration of more than one immunotherapy agent correlated with a greater incidence of development of nodules (p = 0.050). Radiographic features in patients treated with immunotherapy all decreased over time. Conversely, in patients treated with chemotherapy the incidence of ground glass opacities, traction bronchiectasis, pulmonary nodules, and mediastinal/hilar adenopathy increased over time. IRAE-pneumonitis has distinct features and a distinct clinical course compared to pneumonitis secondary to chemotherapy. Importantly, IRAE-pneumonitis features decreased over time, suggesting that careful consideration of the benefit-risk ratio may allow for continuation of immunotherapy in some patients who develop pneumonitis. • Here we present the first analysis of radiographic findings of IRAE pneumonitis versus pneumonitis caused by chemotherapy • Immunotherapy was associated pulmonary nodules and the number of immunotherapy agents correlated with incidence of pulmonary nodules • Features of IRAE pneumonitis improved over time while those of chemotherapy pneumonitis worsened [ABSTRACT FROM AUTHOR]

Simple Summary: Although newer cancer medicines that help the immune system recognize and attack cancer cells have improved responses to therapy, most patients ultimately have cancer recurrence. Additional therapies and therapy combinations are needed so that responses can last longer or indefinitely. Molecular targeted radiotherapy is another kind of therapy that targets radioactive particles directly to cancer in the hopes of killing cancer cells to stop tumor growth with limited side effects. Prior studies have shown that targeted radiotherapies activate the immune system and can work together with immunotherapy to improve response. Here, we tested a promising new therapy targeting fibroblast activation protein (FAP) with a therapeutic radionuclide 177Lu alone and with immunotherapy in mouse models of melanoma and lung cancer. The FAP-targeted radiotherapy reduced tumor growth in both models and melanoma, resulting in tumor regression. We saw increased tumor cell death in dual-treated tumors. We also found that myeloid cells were affected by the combined therapy to a greater degree than the additive effect of either therapy. These results demonstrate that this is a promising new therapy regimen and requires further preclinical and clinical study to better understand the molecular mechanisms underpinning response. Immunotherapy has dramatically improved outcomes for some cancer patients; however, novel treatments are needed for more patients to achieve a long-lasting response. FAP-targeted molecular radiotherapy has shown efficacy in both preclinical and clinical models and has immunomodulatory effects. Here, we studied if combined immunotherapy and radiotherapy could increase antitumor efficacy in murine models of lung cancer and melanoma and interrogated the mechanisms by which these treatments attenuate tumor growth. Using LLC1 and B16F10 murine models of lung cancer and melanoma, respectively, we tested the efficacy of 177Lu-FAPI-04 alone and in combination with immunotherapy. Alone, 177Lu-FAPI-04 significantly reduced tumor growth in both models. In animals with melanoma, combined therapy resulted in tumor regression while lung tumor growth was attenuated, but tumors did not regress. Combined therapy significantly increased caspase-3 and decreased Ki67 compared with immunotherapy alone. Flow cytometry demonstrated that tumor-associated macrophages responded in a tumor-dependent manner which was distinct in animals treated with both therapies compared with either therapy alone. These data demonstrate that 177Lu-FAPI-04 is an effective anticancer therapy for melanoma and lung cancer which mediates effects at least partially through induction of apoptosis and modulation of the immune response. Translational studies with immunotherapy and 177Lu-FAPI-04 are needed to demonstrate the clinical efficacy of this combined regimen. [ABSTRACT FROM AUTHOR]

Immunotherapy has become a critical class of anticancer therapy in recent years, functioning by releasing brakes on the immune system that ultimately results in immune cell activation which eliminates cancer cells. Immune related adverse events (IRAEs) are a specific type of adverse event described in patients taking checkpoint inhibitor immunotherapy which results from unrestrained immune activation. Immune related pericardial effusion has been described however has not been comprehensively characterized. Here, we present the most extensive report to date detailing this adverse event. We queried our medical record system to retrospectively identify patients on checkpoint inhibitor therapy for lung cancer who subsequently developed pericardial effusion. We analyzed the clinical and radiographic characteristics, prior therapies, treatment for the effusion, and outcomes in patients with immune related pericardial effusion and compared them to similar patients with pericardial effusion not attributable to checkpoint inhibitor therapy. Our data demonstrate that most of these pericardial effusions were small and not clinically significant. The majority were successfully treated with steroids or resolved spontaneously. Anti-PD-1 inhibitors were the most common checkpoint inhibitor preceding pericardial effusion, and a significant number of patients who went on to develop IRAE pericardial effusion previously had treatment with carboplatin for their cancer. These data suggest that IRAE pericardial effusion is not a clinically significant adverse event however it sometimes leads to permanent discontinuation of checkpoint inhibitor therapy which is not necessary. • Most cases of IRAE pericardial effusion are small and do not cause clinical symptoms • PD-1 inhibitors most frequently directly precede development of IRAE pericardial effusion • Many cases resolve with steroids and the clinical benefit of continuing therapy outweighs the risk of discontinuation [ABSTRACT FROM AUTHOR]