Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. We have divided our discussion into different topics based on these agents' mechanisms of action. This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We will also summarize the currently available phase I/II clinical trial for NSCLC patients at the end of each section.

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While first line targeted therapies are the current standard of care treatment for non-small cell lung cancer (NSCLC) with actionable mutations, the cancer cells inevitably acquire resistance to these agents over time. Immune check-point inhibitors (ICIs) have improved the outcomes of metastatic NSCLC, however, its efficacy in those with targetable drivers is largely unknown. In this manuscript, we reviewed the published data on ICI therapies in NSCLC with ALK, ROS1, BRAF, c-MET, RET, NTRK, KRAS, and HER2 (ERBB2) alterations. We found that the objective response rates (ORRs) associated with ICI treatments in lung cancers harboring the BRAF (0–54%), c-MET (12–49%), and KRAS (18.7-66.7%) alterations were comparable to non-mutant NSCLC, whereas the ORRs in RET fusion NSCLC (less than10% in all studies but one) and ALK fusion NSCLC (0%) were relatively low. The ORRs reported in small numbers of patients and studies of ROS1 fusion, NTRK fusion, and HER 2 mutant NSCLC were 0–17%, 50% and 7–23%, respectively, making the efficacy of ICIs in these groups of patients less clear. In most studies, no significant correlation between treatment outcome and PD-L1 expression or tumor mutation burden (TMB) was identified, and how to select patients with NSCLC harboring actionable mutations who will likely benefit from ICI treatment remains unknown.

Symptomatic gastrointestinal (GI) involvement of melanoma is rare, however, it is a frequent autopsy finding in patients with primary cutaneous melanoma. We present a case of metastatic cutaneous melanoma with initial asymptomatic jejunal involvement as found on a positron emission tomography (PET) scan, with subsequent duodenal perforation.A 69-year-old man presented to the hospital with a three-week history of worsening headache, dizziness, and vomiting with a history of Clark level III malignant melanoma that was completely excised from the right flank three years ago at the hospital. A magnetic resonance image of his brain revealed a subacute right-sided cerebellar hemorrhage adjacent to a 1-cm nodule. He underwent a right suboccipital craniomy with resection; the biopsy of which revealed metastatic malignant melanoma. A staging positron emission tomography (PET) scan revealed areas of increased uptake of fludeoxyglucose (FDG) in the left lower lung and left upper quadrant of the abdomen abutting the small bowel. Subsequent enteroscopy revealed a 40-mm cratered jejunal ulcer with heaped edges; the biopsy of which also revealed malignant melanoma. Since he had widespread disease, abdominal surgery was deferred, and treatment with ipilimumab and radiotherapy to the brain was initiated. He presented three months later with acute abdominal pain and diarrhea. A computed tomography scan of his abdomen revealed free peritoneal air, and an exploratory laparotomy revealed a mass at the antimesenteric border of the duodenum with a biopsy consistent with melanoma. The perforated area was resected and an end-to-end anastomosis was performed. Unfortunately, our patient had a postoperative intracranial hemorrhage and was referred to palliative care.Our case portrays how malignant melanoma may metastasize insidiously and widely and present as a catastrophe. Melanoma involvement in the GI tract is a poor prognostic marker. Our case offers a unique illustration of both the occult and manifest gastrointestinal involvement of melanoma and underscores the importance of clinical suspicion in patients with a history of melanoma who present with unexplained GI symptoms.