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Introduction: Limited survival data are available for patients with metastatic non-small cell lung cancer (mNSCLC) who stop immune checkpoint inhibitor therapy (ICI) early for reasons other than progression of disease (POD), such as immune-related adverse events (irAEs). Methods: We conducted a retrospective observational study of all patients with mNSCLC treated with ICIs, with or without combination chemotherapy, at 3 Mayo Clinic sites between 2011 and 2022. Separate analyses were conducted at 6- and 12-month intervals. Patients who discontinued ICI due to POD prior to these time points were excluded from the analysis. Results: A total of 246 patients with stage IV NSCLC used ICIs. Patients were then excluded if they had experienced POD prior to 6 or 12 months, resulting in 81 and 63 patients, respectively, for each timepoint. Sixty-four patients continued treatment beyond 6 months and were found to have longer progression-free survival (PFS) compared to the 17 patients who discontinued treatment (22.8 months vs 11.8 months, P =1.1E-04), as well as a significant increase in overall survival (OS) (33.9 months vs 14.4 months, P =7.2E-08). Forty patients continued treatment beyond 12 months and had longer PFS compared to the 23 patients that discontinued treatment (27.9 months vs 14.8 months, P =1.1E-04), as well as a significant increase in OS (39.7 months vs 18.0 months, P =2.0E-07). The most common reason for ICI discontinuation was irAEs. Other common reasons for stopping ICI were non-irAEs and stable disease. At both time points, 12 patients continued or restarted ICI after experiencing an irAE, and 2 patients experienced recurrent/new grade 1-2 irAEs. More patients continued/rechallenged with ICI after experiencing an irAE in the groups that continued ICI compared to those that discontinued ICI. Conclusions: Patients with mNSCLC and no POD who continued ICI beyond 6 months and 12 months, experienced significantly increased PFS and OS compared to patients who discontinued ICI, with larger increases in those who continued ICI past 12 months. Oncology providers should discuss the survival benefits of continuing ICI and offer support to overcome obstacles to continuation of treatment, if possible, particularly management of grade 1 and 2 irAEs. [ABSTRACT FROM AUTHOR]

The importance of the immune system in the response against cancer has always been a subject of intense investigation. The advent of immune checkpoint inhibitors has transformed the landscape of oncologic treatments, while expanding the understanding of this disease's pathophysiology. Consequently, many therapies are being investigated, with interventions directed at different steps and pathways of the immune response. Relevantly, immunotherapy sensitizers have arisen as approaches focused on the synergistic effects of immunotherapy combination, or the combination of immunotherapy and other treatment modalities, such as chemotherapy or radiation therapy. Concomitantly, novel immunotherapy modalities are also in development. Approaches focusing from the tumor intrinsic pathways to the tumor microenvironment and ex-vivo interventions, such as CAR-T cell therapies and tumor-infiltrating lymphocytes are important examples. Although many of those interventions were initially envisioned as standalone options, their combination has demonstrated promising results in early-phase in vitro studies and clinical trials. The possibility of coupling different immunotherapy modalities, as well as with other techniques, further strengthen the concept of sensitizers, allowing for deeper and more robust responses in cancer treatment. This review aims to present an overview of the concepts of these sensitizing mechanisms that are the basis for the synergistic effects of immunotherapy combination, or the combination of immunotherapy and a multitude of therapeutic strategies. Novel immunotherapy modalities are also presented, focusing on the potential of combining them with sensitizer interventions. Understanding the complexity underlying these principles may be the key for future breakthroughs and improved patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Atezolizumab is superior to docetaxel for patients with advanced non-small-cell lung cancer (NSCLC) who are pretreated with platinum-based chemotherapy based on the POPLAR and OAK trials. However, patients who received prior immunotherapy were excluded from these trials. The standard of care second-line therapy for these patients remains to be docetaxel with or without ramucirumab. The efficacy and safety of atezolizumab as a subsequent therapy in immunotherapy-pretreated patients are unknown. Methods: We conducted a retrospective study of all patients with locally advanced or metastatic NSCLC who were pretreated with immunotherapy at Mayo Clinic Jacksonville and Rochester from 2016 to 2022. Patients who received subsequent therapy of atezolizumab alone (Atezo), docetaxel (Doce), or docetaxel + ramucirumab (Doce+Ram) were included. Results: In this cohort of 165 patients, 12.7% (n=21), 49.1% (n=81), and 38.2% (n=63) patients received subsequent Atezo, Doce, and Doce+Ram, respectively. 1-year landmark progression-free survival (PFS) were 23.8%, 6.2%, and 3.2% (p=0.006), and 2-year landmark PFS were 14.3%, 0%, and 0% (p<0.0001), in the Atezo, Doce, and Doce+Ram groups, respectively. About 20% patients with positive PD-L1 had durable response to atezolizumab. The Atezo group showed significantly greater overall survival (OS) improvement over Doce group (median OS 17.7 vs. 7.7 months, HR 0.47, 95% CI 0.29 - 0.76, p=0.008), and over Doce +Ram group (median OS 17.7 vs. 8.9 months, HR 0.55, 95% CI 0.32 - 0.95, p=0.047). 4 of 21 (19%) patients in the Atezo group developed immune-related adverse events (irAE). Conclusion: We observed statistically significant and clinically meaningful overall survival benefits of atezolizumab monotherapy compared with docetaxel +/- ramucirumab in patients with advanced NSCLC who were pretreated with immunotherapy. The survival benefit seems to be mainly from PD-L1 positive patients. Subsequent immunotherapy with Atezolizumab did not increase irAE rate. [ABSTRACT FROM AUTHOR]

Introduction: Surveillance with computed tomography (CT) imaging following curative treatment of stage I non-small cell lung cancer (NSCLC) is important to identify recurrence or second primary lung cancers (SPLC). The pattern and risks of recurrence following curative therapy and optimal duration of surveillance scans remain unknown. The objective of our study is to assess the pattern of recurrence and development of SPLC to risk stratify patients with stage I NSCLC following curative therapy. Methods: We identified 261 patients who received curative therapy for stage I NSCLC at Mayo Clinic Florida. Data was collected on clinical and demographic features including gender, smoking history, stage, treatment, histologic subtype, and tumor grade. Kaplan-Meier method was used to evaluate the disease free survival (DFS). Cox proportional hazard model was used to identify risk factors for recurrence. Results: Negative tobacco history and stage IA tumors were associated with significantly prolonged DFS after adjusting for co-variates (p=0.001 and p=0.005). Univariate Cox proportional hazards model identified tobacco history and stage 1B as risk factors for recurrence with unadjusted hazard ratio (HR) of 2.8 and 2.0, respectively. After adjusting for covariates, only stage IB was statistically significant predictor of recurrence with a hazard ratio of 2.1 (Confidence Interval (CI) 95% 1.2-3.6; p=0.007). Conclusions: An individualized approach that considers risk factors of stage and smoking history may be useful in determining whether to continue annual CT surveillance after five years post curative therapy for stage I NSCLC. [ABSTRACT FROM AUTHOR]

Background: Lung adenocarcinoma is a molecularly heterogeneous disease. Several studies, including The Cancer Genome Atlas Research Network (TCGA) and Lung Cancer Mutation Consortium (LCMC), explored the genetic alterations among different ethnic groups. However, minority groups are often under-represented in these relevant studies and the genomic alterations among racial groups are not fully understood. Methods: We analyze genomic characteristics among racial groups to understand the diversities and their impact on clinical outcomes. Results: Native Americans had significantly higher rates of insertions and deletions than other races (P<0.001). Among patients with lung adenocarcinomas, EGFR and KRAS were the highest discrepancy genes in the different racial groups (P<0.001). The EGFR exon 21 L858R point mutation was three times higher in Asians than in all other races (P<0.001). Asians, Whites, and Blacks had 4.7%, 3.1%, and 1.8% ALK rearrangement, respectively (P<0.001). White patients had the highest rates of reported KRAS G12C (15.51%) than other races (P<0.001). Whites (17.2%), Blacks (15.1%), and Other (15.7%) had higher rates of STK11 mutation than Asians (3.94%) (P<0.001). RET rearrangement and ERBB2 amplification were more common in Asian patients than in Other racial groups. Apart from point mutations, structural variations, and fusion genes, we identified a significant amount of copy number alterations in each race. Conclusions: The tumor genomic landscape is significantly distinct in different races. This data would shed light on the understanding of molecular alterations and their impacts on clinical management in different lung cancer patients. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to evaluate the expression of different nicotinic acetylcholine receptors (nAChRs), programmed death ligand-1 (PDL1), and dopamine receptor D2 (DRD2) as prognostic factors in lung cancer and any correlation among them. Since all of the above genes are typically upregulated in response to smoking, we hypothesized that a correlation might exist between DRD2, PD-L1, and nAChR expression in NSCLC patients with a smoking history and a prediction model may be developed to assess the clinical outcome. Methods: We retrospectively analyzed samples from 46 patients with primary lung adenocarcinoma who underwent surgical resection at Mayo Clinic Rochester from June 2000 to October 2008. The expression of PD-L1, DRD2, CHRNA5, CHRNA7, and CHRNA9 were analyzed by quantitative PCR and correlated amongst themselves and with age, stage and grade, smoking status, overall survival (OS), and relapse-free survival (RFS). Results: Only PD-L1 showed a statistically significant increase in expression in patients older than 65. All the above genes showed higher expression in stage IIIB than IIIA, but none reached statistical significance. Interestingly, we did not observe significant differences among never, former, and current smokers, but patients with pack years greater than 30 showed significantly higher expression of CHRNA9. We observed a strong positive correlation between PD-L1/DRD2, PD-L1/CHRNA5, and CHRNA5/CHRNA7 and a weak positive correlation between DRD2/CHRNA5 and DRD2/CHRNA7. Older age was independently associated with poor OS, whereas lower CHRNA7 expression was independently associated with better OS. Conclusions: We observed strong positive correlations among PD-L1, DRD2, and some of the nAChRs. We investigated their prognostic significance in lung cancer patients and found CHRNA7 to be an independent prognostic factor. Overall, the results obtained from this preliminary study warrant a large cohortbased analysis that may ultimately lead to potential patient-specific stratification biomarkers predicting cancer-treatment outcomes. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer patients with anaplastic lymphoma kinase or c-ros oncogene 1 mutations who are treated with the tyrosine kinase inhibitor crizotinib rarely develop crizotinib-associated renal cysts (CARCs). Here, we present a case report and review of the literature supporting the hypothesis that CARCs may correlate positively with progression-free survival. [ABSTRACT FROM AUTHOR]

IL-21, a recently identified member of the common γ-chain (γc) receptor cytokine family, has been shown to be an important regulator of both innate and adaptive immune responses. In this study, we investigated whether IL-21 could synergize with another γc cytokine, IL-7, to induce enhanced proliferation and effector function of tumor antigen-specific CD8+ T cells. Our results showed that IL-21 could significantly augment the IL-7-induced expansion of cytotoxic T cells, possibly by preventing the cytokine-induced down-regulation of the IL-7Rα (CD127) on antigen-stimulated T cells. IL-21 also greatly enhanced the production of Th1 and inflammatory cytokines by activated T cells, including IFN-γ, IL-2, tumor necrosis factor-α, granulocyte macrophage colony-stimulating factor, IL-1β and IL-6. Finally, the addition of IL-21 to IL-7-cultured CTLs resulted in a considerably higher level of cytolytic activity, as measured by specific killing of tumor cells or antigen-pulsed target cells. These results suggest that IL-21 may play a cooperative role with IL-7 in modulating primary CD8+ T-cell responses and may have important implications for immunotherapy of cancer. [ABSTRACT FROM AUTHOR]