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With the advent of precision oncology, there is an urgent need to develop improved methods for rapidly detecting responses to targeted therapies. Here, we have developed an ultrasensitive measure of cell-free tumor load using targeted and whole-genome sequencing approaches to assess responses to tyrosine kinase inhibitors in patients with advanced lung cancer. Analyses of 28 patients treated with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders having nearly complete elimination of ctDNA (>98%). Molecular nonresponders displayed limited changes in ctDNA levels posttreatment and experienced significantly shorter progression-free survival (median 1.6 vs. 13.7 months, P < 0.0001; HR = 66.6; 95% confidence interval, 13.0-341.7), which was detected on average 4 weeks earlier than CT imaging. ctDNA analyses of patients with radiographic stable or nonmeasurable disease improved prediction of clinical outcome compared with CT imaging. These analyses provide a rapid approach for evaluating therapeutic response to targeted therapies and have important implications for the management of patients with cancer and the development of new therapeutics.Significance: Cell-free tumor load provides a novel approach for evaluating longitudinal changes in ctDNA during systemic treatment with tyrosine kinase inhibitors and serves an unmet clinical need for real-time, noninvasive detection of tumor response to targeted therapies before radiographic assessment.See related commentary by Zou and Meyerson, p. 1038.

Simple Summary: The current review summarizes the new potential treatment strategies for patients with early-stage non-small cell lung cancer with immunotherapy and targeted therapies and defines the current challenges for making treatment decisions with these approaches in daily practice. The recent advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockers (ICBs) in early-stage non-small cell lung cancer (NSCLC) has dramatically modified treatment strategies by improving the prognosis in this setting. Osimertinib and alectinib, both TKIs, have shown significant improvements in outcomes for patients with resected EGFR- and ALK-positive NSCLC, respectively, changing the standard of care in these subgroups. More recently, the LAURA trial showed the efficacy of osimertinib after chemoradiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. Numerous trials are still ongoing to investigate neoadjuvant/perioperative TKIs in several oncogene-driven NSCLC. In addition, several ICBs have been tested and approved as adjuvant (atezolizumab and pembrolizumab), neoadjuvant (nivolumab), and perioperative treatments (pembrolizumab) for patients with resectable early-stage NSCLC. Despite these advances, many challenges remain regarding the use of TKIs and ICBs in this setting, including the optimal duration of adjuvant TKI or induction ICB therapy, the role of minimal residual disease to identify patients at high-risk of disease relapse and to guide adjuvant treatment decisions, and the role of adjuvant chemotherapy in resected oncogene-driven NSCLC. Furthermore, potential predictive biomarkers for efficacy are needed to eventually intensify the entire perioperative strategies. This review aims to summarize and discuss the available evidence, the ongoing trials, and the challenges associated with TKI- and ICB-based approaches in early-stage NSCLC. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264-76. ©2017 AACR.See related commentary by Yang, p. 250This article is highlighted in the In This Issue feature, p. 235.

Simple Summary: Patients with non-small cell lung cancer (NSCLC) have a number of possible systemic treatment options, including targeted therapy, chemotherapy, immunotherapy, or antibody–drug conjugates. Approximately two thirds of lung adenocarcinomas have changes in single genes ('oncogenes' or oncogenic driver alterations), which drive the growth of these cancers. The role of immunotherapy in these cancers is debated, and may be different depending on the mutation present. In this review, we summarize current evidence regarding the use of immunotherapy in specific genomically driven subsets of lung adenocarcinoma. We analyze this in terms of specific mutations, focusing on both efficacy and toxicity, and potential future directions. Over the past 20 years, there has been a paradigm shift in the care of patients with non-small cell lung cancer (NSCLC), who now have a range of systemic treatment options including targeted therapy, chemotherapy, immunotherapy (ICI), and antibody–drug conjugates (ADCs). A proportion of these cancers have single identifiable alterations in oncogenes that drive their proliferation and cancer progression, known as "oncogene-addiction". These "driver alterations" are identified in approximately two thirds of patients with lung adenocarcinomas, via next generation sequencing or other orthogonal tests. It was noted in the early clinical development of ICIs that patients with oncogene-addicted NSCLC may have differential responses to ICI. The toxicity signal for patients with oncogene-addicted NSCLC when treated with ICIs also seemed to differ depending on the alteration present and the specific targeted agent used. Developing a greater understanding of the underlying reasons for these clinical observations has become an important area of research in NSCLC. In this review, we analyze the efficacy and safety of ICI according to specific mutations, and consider possible future directions to mitigate safety concerns and improve the outcomes for patients with oncogene-addicted NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: The landscape of non-small cell lung cancer has changed dramatically over the past decade. This is largely due to the introduction of immunotherapy, and in particular, immune checkpoint blockade inhibitors. Anti-PD-1 immunotherapy is now standard treatment for patients with non-small cell lung cancer. However, not all patients respond to immunotherapy, and few patients achieve long-term survival. Moreover, some patients experience adverse effects from the treatment. In this review, we explain the modes of actions of common immunotherapy strategies, summarise the clinical trials that have led to the widespread use of immunotherapy and present some current challenges in the field of immunotherapy. Immunotherapy has revolutionised anti-cancer treatment in solid organ malignancies. Specifically, the discovery of CTLA-4 followed by PD-1 in the early 2000s led to the practice-changing clinical development of immune checkpoint inhibitors (ICI). Patients with lung cancer, including both small cell (SCLC) and non-small cell lung cancer (NSCLC), benefit from the most commonly used form of immunotherapy in immune checkpoint inhibitors (ICI), resulting in increased survival and quality of life. In NSCLC, the benefit of ICIs has now extended from advanced NSCLC to earlier stages of disease, resulting in durable benefits and the even the emergence of the word 'cure' in long term responders. However, not all patients respond to immunotherapy, and few patients achieve long-term survival. Patients may also develop immune-related toxicity, a small percentage of which is associated with significant mortality and morbidity. This review article highlights the various types of immunotherapeutic strategies, their modes of action, and the practice-changing clinical trials that have led to the widespread use of immunotherapy, with a focus on ICIs in NSCLC and the current challenges associated with advancing the field of immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction Anti-PD-(L)1 immune checkpoint inhibitors (ICI) improve survival in patients with advanced non-small cell lung cancer (aNSCLC). The clinical features, survival, and burden of toxicities of patients with aNSCLC alive >1 year from ICI initiation are poorly understood. Materials and Methods We defined ICI survivors as patients alive >1 year after ICI start and retrospectively reviewed demographics, treatment, and immune-related adverse events (irAEs). Long-term irAEs were defined as ongoing irAEs lasting >1 year; burden of toxicity measures were based on percentage of days a patient experienced toxicity. Using linear and logistic regression, we evaluated association between demographics and disease characteristics with burden of toxicity. Results We identified 114 ICI survivors from 317 patients with aNSCLC. Half (52%) experienced an irAE of any grade, and 23.7% developed long-term irAEs. More ICI survivors with irAES in the first year had never smoked (P =. 018) or received ICIs as frontline therapy (P =. 015). The burden of toxicity in the first year significantly correlated with the burden of toxicity afterward (ρ = 0.72; P <. 001). No patients with progressive disease had a high burden of toxicity, and they experienced 30.6% fewer days with toxicity than those with stable disease. Increased duration of therapy was associated with higher odds of experiencing toxicity. Half of ICI survivors with irAEs were still receiving treatment for unresolved irAEs at time of death or last follow-up. Conclusion Significant proportions of ICI survivors have unresolved long-term toxicities. These data support a growing need to understand long-term toxicity to optimize management of those treated with ICIs. [ABSTRACT FROM AUTHOR]

Introduction: The magnitude of response to immune checkpoint inhibitor (ICI) therapy may be sex-dependent, as females have lower response rates and decreased survival after ICI monotherapy. The mechanisms underlying this sex dimorphism in ICI response are unknown, and may be related to sex-driven differences in the immunogenomic landscape of tumors that shape anti-tumor immune responses in the context of therapy. Methods: To investigate the association of immunogenic mutations with HLA haplotypes, we leveraged whole exome sequence data and HLA genotypes from 482 non-small cell lung cancer (NSCLC) tumors from The Cancer Genome Atlas (TCGA). To explore sex-specific genomic features linked with ICI response, we analyzed whole exome sequence data from patients with NSCLC treated with ICI. Tumor mutational burden (TMB), HLA class I and II restricted immunogenic missense mutation (IMM) load, and mutational smoking signature were defined for each tumor. IMM load was combined with HLA class I and II haplotypes and correlated with therapeutic response and survival following ICI treatment. We examined rates of durable clinical benefit (DCB) for at least six months from ICI treatment initiation. Findings were validated utilizing whole exome sequence data from an independent cohort of ICI treated NSCLC. Results: Analysis of whole exome sequence data from NSCLC tumors of females and males revealed that germline HLA class II diversity (=9 unique HLA alleles) was associated with higher tumor class II IMM load in females (p=0.01) and not in males (p=0.64). Similarly, in tumors of female patients, somatic HLA class II loss of heterozygosity was associated with increased IMM load (p=0.01) while this association was not observed in tumors in males (p=0.20). In females, TMB (p=0.005), class I IMM load (p=0.005), class II IMM load (p=0.004), and mutational smoking signature (p<0.001) were significantly higher in tumors responding to ICI as compared to non-responding tumors. In contrast, among males, there was no significant association between DCB and any of these features. When IMM was considered in the context of HLA zygosity, high MHC-II restricted IMM load and high HLA class II diversity was significantly associated with overall survival in males (p=0.017). Conclusions: Inherent sex-driven differences in immune surveillance affect the immunogenomic determinants of response to ICI and likely mediate the dimorphic outcomes with ICI therapy. Deeper understanding of the selective pressures and mechanisms of immune escape in tumors in males and females can inform patient selection strategies and can be utilized to further hone immunotherapy approaches in cancer. [ABSTRACT FROM AUTHOR]

This commentary outlines the strategy employed by a multidisciplinary immune‐related toxicity team to evaluate patients who may be at high risk for the development of immune‐related toxicity, in particular, those with preexisting lung conditions and subsequent immune‐related pneumonitis. [ABSTRACT FROM AUTHOR]

Background: Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown.Methods: To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n=12) and without CIP (n=6), prior to initiation of first-line therapy for CIP (high dose corticosteroids. We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis and BAL supernatant cytokine measurements.Results: We found increased BAL lymphocytosis, predominantly CD4+ T cells, in CIP. Specifically, we observed increased numbers of BAL central memory T-cells (Tcm), evidence of Type I polarization, and decreased expression of CTLA-4 and PD-1 in BAL Tregs, suggesting both activation of pro-inflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1β and decreased expression of counter-regulatory IL-1RA. We observed increased levels of T cell chemoattractants in the BAL supernatant, consistent with our pro-inflammatory, lymphocytic cellular landscape.Conclusion: We observe several immune cell subpopulations that are dysregulated in CIP, which may represent possible targets that could lead to therapeutics for this morbid immune related adverse event. [ABSTRACT FROM AUTHOR]

Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined.Objectives: To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis.Methods: A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis.Results: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis.Conclusions: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis. [ABSTRACT FROM AUTHOR]

The treatment paradigm for lung cancer has been transformed in recent years by the use of immunotherapy, specifically, immune checkpoint antibodies (mAb), which are agents designed to reinvigorate an immune-mediated anticancer response by releasing the effects of tumor-mediated immunosuppression. Late-phase clinical trials of these agents in patients with advanced lung cancers have translated into improved clinical outcomes compared with standard-of-care chemotherapy for the treatment of metastatic non-small cell lung cancer, and have resulted in FDA approvals for two immune checkpoint mAbs in the second-line setting. In addition, promising results have been seen in early-phase clinical studies in small cell lung cancer (SCLC) and for immune checkpoint combinations in NSCLC thus far. While the efficacy of these agents is exciting, they have also been associated with a unique profile of immune-mediated toxicity that is distinct from classic cytotoxic therapies. As these agents move into the lung cancer clinic, we must seek to maximize the therapeutic potential of this class of agents through optimization of patient selection, improved response assessments, and exploring rational combinations of immune checkpoint mAbs with other potentially synergistic therapies, to improve response rates and extend the "tail on the curve." [ABSTRACT FROM AUTHOR]

BACKGROUND Prognostic variables are independently associated with survival and are fundamental to clinical trial design. In the current study, the authors evaluated the impact of stage of disease at the time of the initial diagnosis on overall survival (OS) in 2 independent, oncogene-defined cohorts. METHODS All patients with epidermal growth factor receptor ( EGFR)-mutant and KRAS-mutant metastatic lung adenocarcinomas were identified through routine molecular testing from January 2005 through January 2011. Clinical characteristics were obtained. OS from the date of diagnosis of recurrent or de novo metastatic disease was estimated using the Kaplan-Meier method. RESULTS A total of 635 patients with KRAS-mutant and 496 patients with EGFR-mutant metastatic lung adenocarcinomas were identified. Among patients with KRAS-mutant lung adenocarcinomas, those with de novo metastatic disease were found to have a shorter median OS compared with those with recurrent metastatic disease (13 months vs 18 months; P = .003). In a multivariable analysis of patients with KRAS-mutant lung adenocarcinomas, de novo metastatic disease at the time of diagnosis (TNM stage IV vs stage I-III: hazard ratio, 1.5 [95% confidence interval, 1.2-1.8]; P<.001) was independently associated with shorter OS. In patients with EGFR-mutant lung adenocarcinomas, after controlling for age and Karnofsky performance status, de novo metastatic disease at the time of diagnosis (stage IV vs stage I-III: hazard ratio, 1.3 [95% confidence interval, 1.0-1.7]; P = .03) was found to be independently associated with shorter OS. CONCLUSIONS Among patients with KRAS-mutant lung adenocarcinomas, stage of disease at diagnosis was associated with OS from the time of diagnosis of recurrent/metastatic disease. In multivariable analyses, in both patients with EGFR-mutant and KRAS-mutant lung adenocarcinomas, advanced stage at the time of diagnosis was found to be independently associated with shorter survival. Stage at diagnosis is a prognostic variable that should be accounted for in prospective studies in patients with metastatic lung adenocarcinomas. Cancer 2015;121:2078-2082. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

The pioneers of tumor immunology and cancer immunotherapy, including the late William B. Coley and Lloyd J. Old, have championed the potential for immunotherapy for over a century. Finally, advances in our understanding of the fundamentals of tumor immunology are translating into clinical success, with recent US Food and Drug Administration approval of several immunotherapies that improve clinical outcomes across prostate cancer, metastatic melanoma, non-small cell lung cancer and lymphocytic leukemia. In tandem with these clinical successes, new technologies such as high-throughput DNA/RNA sequencing, genetic engineering, and streamlined ex vivo cell culturing have paved the way for the next generation of immunotherapies and provided new tools for investigating potential biomarkers of response to existing therapies. During the November 2014 Annual Meeting of the Society of the Immunotherapy of Cancer, leaders in tumor immunology and cancer immunotherapy convened at the second annual SITC Primer to review both current knowledge and future directions in the field. Here, we will review the key discussions across a variety of topics, including innate immunity, adaptive immunity, dendritic cells, adoptive T cell therapy, anti-tumor antibodies, cancer vaccines, immune checkpoint blockade, challenges to immunotherapy, monitoring immune responses, and immunotherapy clinical trial design. [ABSTRACT FROM AUTHOR]

The discovery of targetable genomic alterations has revolutionized the field of personalized medicine in nonsmall cell lung cancer (NSCLC). As the number of clinically actionable drivers continues to expand, a thorough understanding of the molecular diagnostic platforms that are available for the detection of these changes is required to select the most appropriate test or group of tests in the clinic. This review summarizes the common oncogenic aberrations that occur in NSCLC and the diagnostic assays that are poised to detect them. Molecular diagnostic algorithms have undergone a significant evolution over time, moving from a "one-gene, one-test" paradigm to the inclusion of multiplex assays for common hotspot point mutations, and insertions and deletions. While current testing in most centers is characterized by a combination of several different single-gene or multiplex diagnostic assays, the advent of next-generation sequencing has provided a means of interrogating mutations, rearrangements, and copy number changes across a variety of therapeutically relevant oncogenes and tumor suppressor genes in a single test. As the cost of next-generation sequencing continues to decrease, this platform is likely to become the diagnostic test of choice for clinicians treating patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

In the last decade, immune-checkpoint inhibitors (ICIs) have become the backbone of therapy in advanced, non-oncogene driven, non-small cell lung cancer (NSCLC). More recently, they have been approved by the FDA in the adjuvant NSCLC setting based on positive disease-free survival results. In the neoadjuvant setting, emerging results signal that a therapeutic paradigm shift may be imminent. Yet, it is difficult to ascertain the benefit of neoadjuvant therapy, as the desired result is an improvement in overall survival, which can take many years to mature. In this review, we explore the role and impact of neoadjuvant therapy, data on neoadjuvant chemotherapy, the rationale and potential predictive biomarkers, as well as current and ongoing trials in the setting of neoadjuvant ICIs. [ABSTRACT FROM AUTHOR]

• Exhaled Breath (EBC) and plasma were analysed for 5 genetic alterations using ultrasensitive PCR in lung cancer patients. • Results were compared to corresponding diagnostic tissue samples analysed using targeted NextGeneration Sequencing (NGS). • Higher failure rates owing to unamplifiable DNA were noted in tissue NGS compared to EBC and Plasma. • Significantly higher numbers of mutations in EGFR, KRAS and PIK3CA were identified in EBC and plasma than tissue NGS. • Overlap and divergence was noted in the mutation profiles between EBC and plasma. Small diagnostic tissue samples can be inadequate in testing an expanding list of validated oncogenic driver alterations and fail to reflect intratumour heterogeneity (ITGH) in lung cancer. Liquid biopsies are non-invasive and may better reflect ITGH. Most liquid biopsies are performed in the context of circulating tumour DNA (ctDNA) in plasma but Exhaled Breath Condensate (EBC) shows promise as a lung-specific liquid biopsy. In this prospective, proof-of-concept study we carried out targeted Next Generation Sequencing (NGS) on diagnostic tissue samples from 125 patients with lung cancer and compared results to plasma and EBC for 5 oncogenic driver mutations (EGFR, KRAS, PIK3CA, ERBB2, BRAF) using an ultrasensitive PCR technique (UltraSEEK™ Lung Panel on the MassARRAY® System, Agena Bioscience, San Diego, CA, USA). There was a significantly higher failure rate due to unamplifiable DNA in tissue NGS (57/125, 45.6%) compared to plasma (27/125, 21.6%, p < 0.001 and EBC (26/125,20.8%, p ≤ 0.001. Consequently, both plasma and EBC identified higher number of mutations compared to tissue NGS. Specifically, there were significantly higher numbers of mutations detected in EGFR, KRAS and PIK3CA in plasma (p = 9.82 × 10−3, p = 3.14 × 10−5, p = 1.95 × 10−3) and EBC (p = 2.18 × 10−3, p = 2.28 × 10−4,p = 0.016) compared to tissue NGS. There was considerable divergence in mutation profiles between plasma and EBC with 34/76 (44%) mutations detected in plasma and 37/74 (41.89%) in EBC unique to their respective liquid biopsy. The results suggest that EBC is effective in identifying clinically relevant alterations in patients with lung cancer using UltraSEEK™ and has a potential role as an adjunct to plasma testing. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the effect of concurrent stereotactic radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain metastases (BMs).Methods and Materials: We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs.Results: A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of ≥3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64).Conclusions: Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events. [ABSTRACT FROM AUTHOR]

Objectives The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy. Materials and Methods We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology. Results The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P < 0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P < 0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P = 0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P = 0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P = 0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P < 0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI. Conclusion The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs. [ABSTRACT FROM AUTHOR]