Immunotherapy has become the standard of care for advanced and resectable lung cancer, and specific mutations may predict immunotherapy response. For example, mutations, which are more common in African American patients, are associated with immunotherapy resistance. A 68-year-old African American man with stage IIIB lung adenocarcinoma with mediastinal lymph node involvement progressed on first-line concurrent carboplatin-based chemoradiotherapy. Molecular testing of the patient's subcarinal lymph node tissue revealed S216F, R273L, and splice site mutations; high tumor mutation burden (19.0 mutations/Mb); and high PD-L1 22c3 expression (TPS 70%, 2+ intensity). Treatment with carboplatin-based chemotherapy with radiation therapy failed to control the disease, but the patient has tolerated and responded well to intravenous pembrolizumab. Although mutations are associated with immunotherapy resistance, our patient demonstrated an exceptional and sustained response to immunotherapy for over two years. The patient's co-mutation, along with high TMB and PD-L1 22c3 TPS scores, may help explain his continued responsiveness to immunotherapy and longer survival. Importantly, incorporating genetic ancestry differences in mutation prevalence and the impact of specific mutations and co-mutations, may help ensure the equitable and optimal treatment of all patients with lung cancers.