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Introduction: The purpose of this study was to evaluate the association between body composition, overall survival, odds of receiving treatment, and patient-reported outcomes (PROs) in individuals living with metastatic non-small-cell lung cancer (mNSCLC)., Methods: This retrospective analysis was conducted in newly diagnosed patients with mNSCLC who had computed-tomography (CT) scans and completed PRO questionnaires close to metastatic diagnosis date. Cox proportional hazard models and logistic regression evaluated overall survival and odds of receiving treatment, respectively. Hazard ratios (HR) and odds ratios (OR) were evaluated as the interquartile range for body composition compartments. Multiple linear regression evaluated the association between PROs and body composition. Models were adjusted for gender, age at diagnosis, smoking history, and mutation status. The survival model also included adjustment for tumor histology., Results: Our sample (n = 69) included men (52%) and women (48%), with a median age of 67.4-years, history of smoking (67%), wild-type genotype (75.4%), and a tumor histology of adenocarcinoma (68%). Greater skeletal muscle area was associated with higher physical function scores. Larger intermuscular adipose tissue area was associated with higher mortality risk (HR 2.03, 95% CI 1.32, 3.11), lower odds of receiving treatment (OR 0.76, 95% CI 0.61, 0.93), and higher fatigue. Larger subcutaneous adipose tissue area was associated with lower mortality risk (HR 0.42, 95% CI 0.22, 0.82) and higher odds of receiving treatment (OR 1.03, 95% CI 1.01, 1.06). Larger total adipose tissue area was linked with improved survival (HR 0.59, 95% CI 0.36, 0.96)., Conclusion: Findings support an association between different body composition compartments at mNSCLC diagnosis and survival, decisions to treat, and PROs. This work supports the use of data collected in routine CT scans and PROs to inform treatment decisions and supportive care options., (© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction/background: Prognostication by performance status (PS) assessment is a fundamental element of treatment decisions and clinical trial design in oncology, but it is limited by subjectivity and potential miscommunication between patient, physician, and family. Activity tracker offers the potential to collect a broad range of patient-generated data to supplement the assessment of PS., Patients and Methods: Patients with metastatic NSCLC (mNSCLC) participated in a single institute, prospective, observational feasibility study conducted at Huntsman Cancer Institute. Patients were given a Fitbit® activity tracker, which collects their steps taken, distance moved, heart rate, and activity intensity. At baseline, PS was assessed by physicians and patients, and demographics and clinical data were collected. We defined novel indices of health: Heart rate Activity zone Mismatch (HAM) and excessive Sedentary Heart Rate (eSHR). We used multivariable Cox proportional hazards models adjusted for age, sex, and treatment line to estimate and test the prognostic ability of clinical and fitness metrics on overall survival (OS). Each prognostic model was evaluated using Harrell's concordance index (C-index)., Results: Fifty-five patients with mNSCLC were enrolled. The median OS was 10.4 months (95% CI: 7.2, 15.2). PS-physician (HR = 2.0; P < .001) and Fitbit metrics were associated with OS, including daily total steps (1,000-steps) (HR = 0.8; P = .004), HAM (HR = 2; P = .02), eSHR (HR = 0.3; P = .001). The prognostic model that includes PS-physician was associated with the best concordance (C-index = 0.75), followed by daily total distance (C-index = 0.74) and steps (C-index = 0.73) CONCLUSIONS: Tracker-based measures were prognostic of survival in mNSCLC and may be useful as a supplement or alternative to PS in practice and clinical trials., Competing Interests: Disclosure Sonam Puri: Ad board/Consulting for Jazz Pharma, G1 therapeutics, BMS, Pfizer, Novocure, Oncohost, Takeda, all outside the scope of this publication. Kathleen C. Kerrigan: Speaker's bureaus of Sanofi and Genentech, Ad Boards of AstraZeneca, all outside the scope of this publication. Matthew Gumbleton: Reports patents licensed to Alterna Therapeutics and honoraria from MJH Lifesciences and OMNI Health Media, all outside the scope of this publication. Wallace Akerley: Data Safety Monitoring Board- Lilly. None of the other authors have any COI for the content of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See the Appendix for disclaimers and other important information (Appendix 1 and Appendix 2 , online only). Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline .

Introduction: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab., Methods: This is a randomized, phase II, multicenter study evaluating carboplatin, pemetrexed, bevacizumab with and without atezolizumab in 117 patients with stage IV nonsquamous NSCLC. Randomization is 2 to 1 favoring the atezolizumab containing arm. Eligible patients include: 1) those with tumors with sensitizing EGFR alterations in exons 19 or 21 or 2) patients who have never smoked and have wild-type tumors (ie, no EGFR, ALK or ROS1 alterations). Patients are defined as having never smoked if they have smoked less than 100 cigarettes in a lifetime. Patients with EGFR-mutated tumors must have disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate, duration of response, and time to response., Conclusion: This phase II trial is accruing patients at U.S. sites through the National Comprehensive Cancer Network (NCCN). The trial opened in August 2019 and accrual is expected to be completed in the Fall of 2024., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer., Methods: This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC)., Results: Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS., Conclusion: Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall-cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC-affected cousin pairs belonging to high-risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC-affected cousin pairs from eight high-risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the FGF5 gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO 4 that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in FGF5 that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. FGF5 is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support FGF5 as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants., (© 2023 UICC.)

The treatment for locally advanced non-small-cell lung cancer has changed dramatically over the past several years, with consolidative immunotherapy after concurrent chemoradiation becoming the new standard of care. Five-year survival outcomes have substantially improved with this approach. Despite these advances, further improvements are needed as the majority of patients ultimately develop progression of disease. The next-generation immunotherapy trials are currently being conducted that include approaches such as concurrent immunotherapy and addition of other therapeutic agents in the concurrent and consolidative settings. Specific unmet needs continue to exist for patients who develop disease progression after concurrent chemoradiation and immunotherapy, as well as defining the best treatment for patients with driver mutations. Future directions also include refinement of radiation techniques to reduce toxicities as much as possible, as well as the use of circulating tumor DNA in the surveillance setting. The current scientific landscape shows promising approaches that may further improve outcomes for patients with locally advanced non-small-cell lung cancer., Competing Interests: Kristin A. HigginsHonoraria: PrecisCAConsulting or Advisory Role: AstraZeneca, Genentech, Varian Medical SystemsResearch Funding: Reflexion MedicalTravel, Accommodations, Expenses: AstraZeneca Sonam PuriConsulting or Advisory Role: AstraZeneca, G1 Therapeutics Jhanelle E. GrayHonoraria: Merck Sharp & Dohme, Axiom Healthcare Strategies, InivataConsulting or Advisory Role: Novartis, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, EMD Serono, Lilly, Sanofi, Merck Sharp & Dohme, Janssen Scientific AffairsResearch Funding: Array BioPharma, Merck, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Genentech/Roche, G1 Therapeutics, Novartis, Pfizer, Ludwig Institute for Cancer ResearchTravel, Accommodations, Expenses: Merck Sharp & Dohme, Inivata, Merck, EMD Serono, NovartisNo other potential conflicts of interest were reported.

Purpose of Review: The use of single-agent or combination immunotherapy strategies has revolutionized the management of patients with non-small cell lung cancer (NSCLC). Here, we review the current role for CTLA-4 inhibitors in early-stage resectable NSCLC, unresectable stage III NSCLC, and in metastatic NSCLC., Recent Findings: Immunotherapy agents alone, or in combination with chemotherapy, represent the new standard of care for the management of metastatic squamous and non-squamous NSCLC without driver mutations. Combination CTLA-4 and PD-1/L1 inhibitors can be efficacious, particularly in tumor mutation burden (TMB) high tumors, providing a chemotherapy-free strategy for metastatic patients. Early signals from neoadjuvant trials suggest a benefit for combination CTLA-4 and PD-1 inhibitions prior to surgery, with improved rates of major pathologic response (MPR). The role for CTLA4 inhibitors is currently unknown in the adjuvant and unresectable stage III setting, although clinical trials are ongoing to evaluate this approach. There is a growing role for CTLA-4 inhibition in the neoadjuvant and metastatic settings for patients with NSCLC. Biomarker selection in ongoing clinical trials will be crucial to guide patient selection for CTLA4 inhibitor therapy. Combination strategies with PD-1/L1 inhibition have demonstrated the greatest efficacy to date., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Nuclear protein transport is essential in guiding the traffic of important proteins and RNAs between the nucleus and cytoplasm. Export of proteins from the nucleus is mostly regulated by Exportin 1 (XPO1). In cancer, XPO1 is almost universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm. Currently, there are no studies evaluating XPO1 amplifications and mutations in NSCLC and the impact on outcomes., Methods: Tumor samples were analyzed using next-generation sequencing (NGS) (NextSeq, 592 Genes), immunohistochemistry (IHC), and whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate., Results: Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations and 24 had amplifications. XPO1 mutant tumors were more likely to have high TMB (79% vs. 52%, p = 0.007) and less likely to have high PD-L1 (32% vs. 68%, p = 0.03). KRAS co-mutations were seen in 19% (n = 5) and EGFR co-mutations were rare (n = 2). Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant. Comparison of survival between XPO1 mutant and WT showed a negative association with a hazard ratio (HR) of 1.932 (95% CI: 1.144-3.264 p = 0.012). XPO1 amplification was not associated with survival., Conclusions: XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Non-small cell lung cancer (NSCLC) in never-smokers (NS) is vastly different from those with a smoking history in terms of etiology, driver mutations, and immunotherapy responsiveness. This study compares the real-world overall survival (OS) of NSCLC patients by smoking history and mutation status., Methods: The study included 30,310 advanced or metastatic NSCLC patients in the Flatiron Health EHR-derived database who received biomarker testing results (EGFR, ALK, ROS1, and BRAF), and initiated therapy between 2011 and 2017, with follow up through June 2018. OS by smoking and driver mutation groups was summarized via Kaplan-Meier survival estimates, and compared in the context of a multivariate Cox proportional hazard model., Results: OS differed by smoking and driver-mutation categories (adjusted and stratified P< .001). The median OS for wild-type (WT) smoking patients was 9.6 months, for mutated (MT) smokers was 19.4 months (adjusted and stratified hazard ratio [HR] relative to WT smokers 0.65; 95% CI 0.60-0.71), for WT NS was 15.1 months (HR 0.78; 95% CI 0.73-0.83 relative to WT smokers), and for MT NS was 25.5 months (HR 0.52; 95% CI 0.48-0.58 relative to WT smokers)., Conclusion: NS with NSCLC survived longer than those with smoking history, in both groups of WT and mutation-positive patients. Findings highlight that in NSCLC patients, a history of never smoking may have similar effect on hazard of death as the presence of an actionable mutation. Taken together, differences in heredity, mutations, and biologic history suggest that NS lung cancer is a distinct clinical entity and must be managed accordingly., Competing Interests: Disclosure Dr. Kerrigan and Dr. Haaland report travel assistance from Flatiron Health. Dr. Haaland has served as a consultant for Astra Zeneca and Prometric Life Sciences. Dr. Adamson is an employee of Flatiron Health, a subsidiary of Roche, and owns stock in Roche. Drs. Puri and Akerley report no relevant financial COI. Ms. Xuechen Wang reports no COI. Dr. Patel reports institutional funding from Takeda., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Sonam PuriConsulting or Advisory Role: AstraZenecaRodrigo DienstmannConsulting or Advisory Role: Roche, Boehringer Ingelheim Speakers' Bureau: Roche, Ipsen, Sanofi, MSD Oncology, Servier, Amgen Research Funding: Merck No other potential conflicts of interest were reported.

Purpose of Review: Treatment of locally advanced, unresectable non-small cell lung cancer (NSCLC) has recently been revolutionized by the incorporation of immunotherapy to standard platinum-based concurrent chemoradiation. This review examines the current standard practices and ongoing studies on the management of locally advanced, unresectable NSCLC., Recent Findings: Concurrent chemoradiation is the cornerstone of treatment of unresectable, locally advanced NSCLC. However, chemoradiation can be associated with high therapy-related toxicities, and risk of disease relapse remains significantly elevated despite treatment with curative intent. Durvalumab, a PD-L1 inhibitor, was recently approved as consolidation therapy following concurrent chemoradiation; this agent represents a major advancement in treatment of unresectable stage III NSCLC. Several clinical trials are currently underway to evaluate the benefit of different immunotherapy sequencing and other biomarker-driven strategies in this disease setting. Multiple trials are presently ongoing to assess novel immunotherapy and targeted therapy strategies to improve outcomes and decrease treatment-associated toxicities in patients with locally advanced NSCLC.

Pyruvate kinase M2 (PKM2) is an alternatively spliced variant, which mediates the conversion of glucose to lactate in cancer cells under normoxic conditions, known as the Warburg effect. Previously, we demonstrated that PKM2 is one of 97 genes that are overexpressed in non-small-cell lung cancer (NSCLC) cell lines. Herein, we demonstrate a novel role of subcellular PKM2 expression as a biomarker of therapeutic response after targeting this gene by shRNA or small molecule inhibitor (SMI) of PKM2 enzyme activity in vitro and in vivo. We examined two established lung cancer cell lines, nine patients derived NSCLC and three normal lung fibroblast cell lines for PKM2 mRNA, protein and enzyme activity by RT-qPCR, immunocytochemistry (ICC), and Western blot analysis. All eleven NSCLC cell lines showed upregulated PKM2 enzymatic activity and protein expression mainly in their cytoplasm. Targeting PKM2 by shRNA or SMI, NSCLC cells showed significantly reduced mRNA, enzyme activity, cell viability, and colony formation, which also downregulated cytosolic PKM2 and upregulated nuclear enzyme activities. Normal lung fibroblast cell lines did not express PKM2, which served as negative controls. PKM2 targeting by SMI slowed tumor growth while gene-silencing significantly reduced growth of human NSCLC xenografts. Tumor sections from responding mice showed >70% reduction in cytoplasmic PKM2 with low or undetectable nuclear staining by immunohistochemistry (IHC). In sharp contrast, non-responding tumors showed a >38% increase in PKM2 nuclear staining with low or undetectable cytoplasmic staining. In conclusion, these results confirmed PKM2 as a target for cancer therapy and an unique function of subcellular PKM2, which may characterize therapeutic response to anti-PKM2 therapy in NSCLC., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Osimertinib was initially approved for T790M-positive non-small cell lung cancer (NSCLC) and, more recently, for first-line treatment of EGFR -mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described., Experimental Design: Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients., Results: In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months, P = 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months, P = 0.02)., Conclusions: Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients. See related commentary by Devarakonda and Govindan, p. 6112 ., (©2018 American Association for Cancer Research.)

Opinion Statement: Surgical resection ± chemotherapy ± radiation or stereotactic body radiation therapy (SBRT) are established treatment modalities for resectable stage non-small cell lung cancer (NSCLC), and concurrent chemotherapy with radiation is the therapy of choice for unresectable locally advanced disease. Despite treatment with curative intent, most patients subsequently relapse and develop distant disease. Treatment with checkpoint inhibitors represents a major advancement in the treatment of metastatic NSCLC. Therapy against programed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) is associated with a significant improvement in overall survival in stage IV disease, and these results have led to a great interest in evaluating these agents in earlier-stage NSCLC. The preliminary data from ongoing trials suggest that the integration of checkpoint blockage into the treatment of early-stage and locally advanced NSCLC is safe, tolerable, and has the potential to improve outcomes without adding substantial toxicity. In the current review, we provide an overview of the emerging data on the role of PD-1/PD-L1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors in the treatment of early-stage and locally advanced NSCLC, with a focus on ongoing clinical trials and combination strategies.

Background: Tumor-derived autophagosome vaccines (DRibbles) have the potential to broaden immune response to poorly immunogenic tumors., Methods: Autologous vaccine generated from tumor cells harvested from pleural effusions was administered to patients with advanced NSCLC with the objectives of assessing safety and immune response. Four patients were vaccinated and evaluable for immune response; each received two to four doses of vaccine. Study therapy included two cycles of docetaxel 75 mg/m 2 on days 1 and 29 to treat the tumor, release hidden antigens and produce lymphopenia. DRibbles were to be administered intradermally on days 14, 43, 57, 71, and 85, together with GM-CSF (50 μg/d x 6d, administered via SQ mini pump). Peripheral blood was tested for immune parameters at baseline and at each vaccination., Results: Three of four patients had tumor cells available for testing. Autologous tumor-specific immune response was seen in two of the three, manifested by IL-5 (1 patient after 3 doses), and IFN-γ, TNF-α, IL-5, IL-10 (after 4 doses in one patient). All 4 patients had evidence of specific antibody responses against potential tumor antigens. All patients came off study after 4 or fewer vaccine treatments due to progression of disease. No significant immune toxicities were seen during the course of the study., Conclusions: DRibble vaccine given with GM-CSF appeared safe and capable of inducing an immune response against tumor cells in this small, pilot study. There was no evidence of efficacy in this small poor-prognosis patient population, with treatment not feasible. Trial registration NCT00850785, initial registration date February 23, 2009.

Introduction: Lung cancer is the most common cause of cancer-related deaths in the world. Despite recent advances, the estimated 5-year overall survival is only around 17%. There is an urgent need for development of new effective drug strategies for the treatment of advanced-stage lung cancer. Areas covered: This review focuses on ongoing research in immune and non-immune oncology combinations for the treatment of non-small cell lung cancer (NSCLC). Here, we will focus on the combination of PD-L1 inhibitors (immunotherapy) with chemotherapy, vascular endothelial growth factor inhibitors, targeted therapies, and radiation. Expert commentary: Immunotherapy is a major advancement in the treatment of NSCLC due to its durable responses and overall favorable toxicity profile. However, these responses are seen in only a subset of patients. Mechanisms of resistance to this therapy continue to emerge. Studies on combination therapies are underway as the therapeutic mechanisms of these established agents are not only distinctly different but also synergistic with immunotherapy. Overall, some benefits have been noted, although associated toxicities have also been shown, and the long-term benefits including overall survival have yet to be determined.