Analysis of the resistance profile of real-world alectinib first-line therapy in patients with ALK rearrangement-positive advanced non-small cell lung cancer using organoid technology in one case of lung cancer.

Background: Alectinib has achieved excellent therapeutic efficacy in anaplastic lymphoma kinase (ALK) fusion gene-positive non-small cell lung cancer (NSCLC) patients, however, patients eventually develop resistance to it. Exploring the gene variant mapping after alectinib resistance provides a basis for the whole management of ALK-positive advanced NSCLC. This study aimed to characterize the mutation profiles of real-world ALK rearrangement-positive advanced NSCLC patients after first-line alectinib treatment resistance. The research also investigated the treatment options and coping strategies after resistance. Methods: Clinical data of patients with advanced NSCLC who received first-line alectinib treatment in the First Affiliated Hospital of Guangzhou Medical University between November 2018 and April 2022 were collected. Moreover, next-generation sequencing (NGS) data of the patient's baseline and post-resistance tissues were gathered. One patient underwent lung cancer organoid culture and drug sensitivity testing. Results: Out of 35 first-line alectinib-treated patients with advanced NSCLC, 31 are presently in progression-free survival (PFS; 4.3-35.0 months). Four patients experienced progressive disease, and all of them were sequentially treated with ceritinib. Tissue NGS results before sequential treatment in three patients indicated an echinoderm microtubule-associated protein-like 4-ALK fusion that remained at the original baseline, and the PFS for ceritinib treatment was 0.5-1.3 months. One patient developed acquired resistance mutations in the structural domain of ALK protein kinase (V1180L and E1161D), and the PFS for ceritinib treatment was 6.7 months. For one patient who maintained original baseline ALK rearrangement positive without acquired mutation after progression of ceritinib resistance, lung cancer-like organ culture with sequential brigatinib and lorlatinib led to a PFS of 3.2 and 1.9 months, respectively, which aligned with the corresponding drug susceptibility testing results for this patient. Conclusions: For ALK rearrangement-positive patients, blind sequencing of other second-generation tyrosine kinase inhibitors (TKIs) or third-generation lorlatinib may not guarantee satisfactory tumor suppression following first-line second-generation ALK-TKI alectinib administration for treatment progression. NGS testing of patients' blood or tissue samples after disease progression may provide insight into the etiology of alectinib resistance. Patient-sourced drug sensitivity testing of lung cancer-like organs selects drug-sensitive medications based on NGS results and provides a reference for subsequent drug therapy for patients after drug resistance, particularly those who remain ALK rearrangement-positive at baseline.

A pilot study of nintedanib in molecularly selected patients with advanced non-small cell lung cancer.

Background: Nintedanib is a small molecule tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). The purpose of the study was to evaluate the response rate for patients with advanced non-small cell lung cancer (NSCLC) with mutations in TP53, VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3 treated with nintedanib as part of an open-label, single-arm pilot study. Methods: Patients with advanced NSCLC previously treated with platinum-doublet chemotherapy with the above mutations were enrolled. Exclusion criteria included necrotic tumors with invasion of blood vessels, history of recent thromboembolic events, increased risk of bleeding or thrombosis, myocardial infarction, and weight loss >10% within past 6 months. Nintedanib was administered at a dose of 200 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints included progression-free survival (PFS) and correlating outcomes with specific mutations. This study was registered with ClinicalTrials.gov, number NCT02299141. Results: Between 2015 and 2019, 20 patients were enrolled with a median age was 66 years, 15 (75%) were females, 15 (75%) had adenocarcinoma, and 17 patients had a TP53 mutation (85%). Seventeen (85%) had received prior immunotherapy and 11 (55%) had received at least three prior lines of systemic therapy. The ORR was 15% with three partial responses (PR), while 12 patients had stable disease (SD), with disease control rate (DCR) consisting of a PR and SD greater than or equal to 16 weeks of 65% (n=13). Median PFS was 4.3 months [95% confidence interval (CI): 1.8-7.9] and median overall survival (OS) was 11.3 months (95% CI: 3.5-44.2). Three patients experienced prolonged clinical benefit from nintedanib, remaining on treatment for over 1 year and all three had a TP53 mutation and received prior immunotherapy. The most common adverse events of any grade included nausea (80%), fatigue (70%), diarrhea (60%), and anorexia (60%). Conclusions: In this pilot study in heavily pretreated and molecularly selected patients with metastatic NSCLC, nintedanib showed modest activity.

Predictive risk score for isolated brain metastasis in non-small cell lung cancer.

Background: Brain metastasis is common with non-small cell lung cancer (NSCLC). Patients with some early-stage cancers don't benefit from routine brain imaging. Currently clinical stage alone is used to justify additional brain imaging. Other clinical and demographic characteristics may be associated with isolated brain metastasis (IBM). We aimed to define the most salient clinical features associated with synchronous IBM, hypothesizing that clinical and demographic factors could be used to determine the risk of brain metastasis. Methods: The National Cancer Database was used to identify patients with NSCLC from 2016-2020. Primary outcome was the presence of IBM relative to patients without evidence of any metastasis. Cohorts were divided into test and validation. The test cohort was used to identify risk factors for IBM using multivariable logistic regression. Using the regression, a scoring system was created to estimate the rate of synchronous IBM. The accuracy of the scoring system was evaluated with receiver operating characteristic (ROC) analysis using the validation cohort. Results: Study population consisted of 396,113 patients: 25,907 IBM and 370,206 without metastatic disease. IBM was associated with age, clinical T stage, clinical N stage, Charlson/Deyo comorbidity score, histology, and grade. A scoring system using these factors showed excellent accuracy in the test and validation cohort in ROC analysis (0.806 and 0.805, respectively). Conclusions: Clinical and demographic characteristics can be used to stratify the risk of IBM among patients with NSCLC and provide an evidence-based method to identify patients who require dedicated brain imaging in the absence of other metastatic disease.

Prognostic significance of immunotherapy in postoperative recurrent non-small cell lung cancer without EGFR mutations or ALK rearrangements.

Background: Limited reports exist regarding postoperative recurrent non-small cell lung cancer (NSCLC) without major driver mutations [epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements] treated with immune checkpoint inhibitors (ICIs) when programmed cell death ligand 1 (PD-L1) is expressed in a real-world setting. The aim of this study was to evaluate the effect of ICIs for those NSCLC. Methods: We enrolled 255 patients with postoperative recurrent NSCLC lacking EGFR mutations or ALK rearrangements who underwent lobectomy or more extensive resection between 2012 and 2021. Factors associated with post-recurrence survival (PRS) were determined using the Cox proportional hazards model. PRS was analyzed using Kaplan-Meier curves and compared using the log-rank test. Results: Multivariable analysis demonstrated that squamous cell carcinoma, pathological stage III, and an Eastern Cooperative Oncology Group (ECOG) performance status ≥2 were significantly associated with worse PRS. Conversely, ICI use at first line was associated with improved PRS. Patients who used ICIs during the first line and subsequent therapies had better PRS than those who received chemotherapy alone. Among patients who used ICIs, there was no significant difference in response rate at the first line, nor in PRS among those with PD-L1 expression ≥50%, 1-49%, and <1% in surgically resected specimens. Conclusions: ICI use at any treatment line improved the PRS of NSCLC patients without major driver mutations, irrespective of PD-L1 expression, in a real-world setting.

Risk factor analysis and nomogram prediction model construction of postoperative complications of thoracoscopic non-small cell lung cancer.

Background: A series of complications will inevitably occur after thoracoscopic pulmonary resection. How to avoid or reduce postoperative complications is an important research area in the perioperative treatment of thoracic surgery. This study analyzed the risk factors for thoracoscopic postoperative complications of non-small cell lung cancer (NSCLC) and established a nomogram prediction model in order to provide help for clinical decision-making. Methods: Patients with NSCLC who underwent thoracoscopic surgery from January 2017 to December 2021 were selected as study subjects. The relationship between patient characteristics, surgical factors, and postoperative complications was collected and analyzed. Based on the results of the statistical regression analysis, a nomogram model was constructed, and the predictive performance of the nomogram model was evaluated. Results: A total of 872 patients who met the study criteria were included in the study. A total of 171 patients had complications after thoracoscopic surgery, accounting for 19.6% of the study population. Logistic regression analysis showed that thoracic adhesion, history of respiratory disease, and lymphocyte-monocyte ratio (LMR) were independent risk factors for complications after thoracoscopic surgery (P<0.05). Variables with P<0.1 in logistic regression analysis were included in the nomogram model. The verification results showed that the area under curve (AUC) of the model was 0.734 [95% confidence interval (CI): 0.693-0.775], and the calibration curve showed that the model had good differentiation. The decision curve analysis (DCA) curve showed that this model has good clinical application value. In subgroup analysis of complications, gender, history of respiratory disease, body mass index (BMI), type of surgical procedure, thoracic adhesion, and Time of operation were identified as significant risk factors for prolonged air leak (PAL) after surgery. Tumor location and forced expiratory volume in the first second (FEV1) were identified as important risk factors for postoperative pulmonary infection. N stage and thoracic adhesion were identified as significant risk factors for postoperative pleural effusion. The AUC for PAL was 0.823 (95% CI: 0.768-0.879). The AUC of postoperative pulmonary infection was 0.714 (95% CI: 0.627-0.801). The AUC of postoperative pleural effusion was 0.757 (95% CI: 0.650-0.864). The calibration curve and DCA curve indicated that the model had good predictive performance and clinical application value. Conclusions: This study analyzed the risk factors affecting the postoperative complications of NSCLC through thoracoscopic surgery, and the nomogram model built based on the influencing factors has certain significance for the identification and reduction of postoperative complications.

Preoperative respiratory assessment predicts post-operative survival in stage IA non-small cell lung cancer.

Background: Respiratory impairment can lead to pulmonary complications after surgery; therefore, it should be considered when determining the choice of surgical procedure. Several studies have examined the relationship between preoperative respiratory function and postoperative mortality and morbidity after lung resection; however, there are no indicators for limited surgical procedure selection. The aim of this study was to examine the association between preoperative respiratory function and postoperative early and late complications, recurrence-free survival (RFS), and overall survival (OS) in patients undergoing pulmonary resection for stage I lung cancer. Methods: We performed a retrospective analysis of data from 192 patients undergoing pulmonary resection for primary pathological stage IA non-small cell lung cancer (NSCLC) at the Iwakuni Clinical Center in Japan between 2012 and 2015. We reviewed clinicopathological characteristics including preoperative pulmonary function and elucidated the relationship between them and postoperative survival. Results: Obstructive ventilatory impairment was present in 55 patients (28.6%), and restrictive ventilatory impairment was present in 31 patients (16.1%). Seven patients (3.6%) had both ventilatory impairment. Obstructive ventilatory impairment did not affect the 5-year RFS (P=0.08) or OS (P=0.21). However, restrictive ventilatory impairment reduced the 5-year RFS (P=0.002) and OS (P=0.009). The rates of early and late complications were not significantly different based on the preoperative respiratory function. Conclusions: In patients with preoperative restrictive ventilatory impairment in whom lobectomy or segmentectomy cannot be performed, careful consideration is needed for surgical indications.

UBQLN4 promotes the proliferation and invasion of non-small cell lung cancer cell by regulating PI3K/AKT pathway.

BACKGROUND: Ubiquilin-4 (UBQLN4), a member of the ubiquilin family, has received limited attention in cancer research to date. Here, we investigated for the first time the functional role and mechanism of UBQLN4 in non-small cell lung cancer (NSCLC). METHODS: The Cancer Genome Atlas (TCGA) database was employed to validate UBQLN4 as a differentially expressed gene. Expression differences of UBQLN4 in NSCLC cells and tissues were assessed using immunohistochemistry (IHC) experiment and western blotting (WB) experiment. Kaplan-Meier analysis was conducted to examine the association between UBQLN4 expression and NSCLC prognosis. Functional analyses of UBQLN4 were performed through cell counting kit-8 (CCK-8), colony formation, and transwell invasion assays. The impact of UBQLN4 on tumor-associated signaling pathways was assessed using the path scan intracellular signaling array. In vivo tumorigenesis experiments were conducted to further investigate the influence of UBQLN4 on tumor formation. RESULTS: UBQLN4 exhibited up-regulation in both NSCLC tissues and cells. Additionally, over-expression of UBQLN4 was associated with an unfavorable prognosis in NSCLC patients. Functional loss analyses demonstrated that inhibiting UBQLN4 could suppress the proliferation and invasion of NSCLC cells in both in vitro and in vivo settings. Conversely, functional gain experiments yielded opposite results. Path scan intracellular signaling array results suggested that the role of UBQLN4 is associated with the PI3K/AKT pathway, a correlation substantiated by in vitro and in vivo tumorigenesis experiments. CONCLUSION: We validated that UBQLN4 promotes proliferation and invasion of NSCLC cells by activating the PI3K/AKT pathway, thereby facilitating the progression of NSCLC. These findings underscore the potential of targeting UBQLN4 as a therapeutic strategy for NSCLC.

Therapeutic effect of induction therapy including nab-paclitaxel followed by surgical resection for the patients with locally advanced non-small-cell lung cancer.

BACKGROUND: Lung cancer is associated with a high mortality rate worldwide. Non-small-cell lung cancer (NSCLC) is a major subtype of lung cancer. Carboplatin (CBDCA) plus nab-paclitaxel (PTX) has become a standard treatment for advanced unresectable NSCLC. However, treatment with nab-PTX has not been established as a standard therapy for resectable locally advanced (LA)-NSCLC. METHODS: We conducted a comprehensive study involving consecutive patients with locally advanced NSCLC who underwent induction therapy including nab-PTX followed by surgical resection. Fifteen patients with locally advanced NSCLC underwent induction therapy including nab-PTX followed by surgical resection. Concurrent chemoradiotherapy (CRT) consisted of weekly administration of nab-PTX (50 mg/m2) plus CBDCA (area under the plasma concentration time curve (AUC) 2) and thoracic radiotherapy (50 Gy/25 fractions). RESULTS: The clinical stages were as follows: IIB (n =1), IIIA (n =12), and IIIC (n =2). Downstaging was observed in 73% (11/15) of patients on comparison with the clinical stage before concurrent CRT. Adverse drug reactions were observed in seven patients. Complete resection was performed in all patients. The re-evaluated pathological stage after pretreatment was diagnosed as stage 0 in three patients, stage IA1 in six, stage IA2 in one, and stage IIIA in five. The pathological effects of previous therapy were as follows: Ef3 (n =3), Ef2 (n =9), and Ef1a (n =3). CONCLUSION: The therapeutic effect of induction therapy including nab-PTX was promising. Induction CRT, including nab-PTX, followed by resection, may be a viable alternative treatment option for locally advanced NSCLC.

Treatment of unresectable stage III non-small cell lung cancer for patients who are under-represented in clinical trials.

Concurrent chemoradiotherapy (cCRT) followed by one year of consolidation durvalumab is the current standard-of-care for patients with unresectable stage III non-small cell lung cancer (NSCLC), of good functional status. However, cCRT and consolidation durvalumab may be challenging to administer for selected patient populations underrepresented or even excluded in clinical trials: older and/or frail patients; those with cardiovascular or respiratory comorbidities in which treatment-related adverse events may be higher, and patients with pre-existing autoimmune disorders for whom immunotherapy use is controversial. In this narrative review, we discuss the current evidence, challenges, ongoing clinical trials and potential future treatment scenarios in relevant subgroups of patients with locally advanced NSCLC, who are underrepresented in clinical trials.

Immune checkpoint expression as prognostic biomarker candidates in non-small cell lung carcinoma patients.

BACKGROUND: Cancer immunotherapy has had an important role in oncologic therapeutics for patients with non-small cell lung cancer (NSCLC) using checkpoint inhibitors. We will explore the possible prognosis biomarker candidates such as: soluble OX40 (sOX40), OX40L (sOX40L), Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR), and their ligand (GITRL), 4-1BB or tumor necrosis factor receptor superfamily 9 (TNFRS9) and inducible T cell co-stimulator (ICOS) in peripheral blood of NSCLC patients. METHODS: Fifty-eight patients were diagnosed with advanced NSCLC between January 2019 and March 2020. RESULTS: High sOX40 and low s4-1BB levels in smokers compared non-smoker NSCLC patients. Lower sOX40L levels were found in the male than female (p < 0.05). High sOX40 and sGITRL in stage III compared to the stage IV (p < 0.05). With follow-up at 21.4 months, 44.1% and 91.1% were alive in the sGITRhigh and sGITRlow groups, respectively (p = 0.02), and 73.3% and 27.7% were alive in the sGITRLhigh and sGITRLlow groups, respectively (p = 0.02). At 22 months, 38.7% and 92.3% were alive in the sOX40Lhigh and sOX40Llow groups, respectively (p = 0.01). CONCLUSION: sGITR, sGITRL, and sOX40L levels were potential prognostic biomarkers and could have an important role as new targets of immunotherapy in NSCLC patients. sGITR, sGITRL, sOX40L, and sOX40 levels were associated with smoking, sex, stage, and age in NSCLC.

Narrative review of stereotactic body radiation therapy combined with tyrosine kinase inhibitors for oligometastatic EGFR-mutated non-small cell lung cancer: present and future developments.

Background and Objective: A significant number of individuals diagnosed with non-small cell lung cancer (NSCLC) have distant metastases, and the concept of oligometastatic NSCLC has shown promise in achieving a cure. Stereotactic body radiation therapy (SBRT) is currently considered a viable treatment option for a limited number of tumor metastases. It has also been demonstrated that third-generation tyrosine kinase inhibitors (TKIs) are effective in extending the survival of patients with epidermal growth factor receptor (EGFR)-mutated NSCLC. Hence, the combination of SBRT with third-generation TKIs holds the potential to enhance treatment efficacy in patients with oligometastatic EGFR-mutated NSCLC. This review aimed to assess the possibility of combining SBRT with TKIs as an optimum treatment option for patients with oligometastatic EGFR-mutated NSCLC. Methods: We performed a narrative review by searching the PubMed, Web of Science, Elsevier and ClinicalTrials.gov databases for articles published in the English language from January 2009 to February 2024 and by reviewing the bibliographies of key references to identify important literature related to combining SBRT with third-generation TKIs in oligometastatic EGFR-mutated NSCLC. Key Content and Findings: This review aimed to assess the viability of combining SBRT and EGFR-TKIs in oligometastatic EGFR-mutated NSCLC. Current clinical trials suggest that the combined therapies have better progression free survival (PFS) when using SBRT as either concurrent with EGFR-TKIs or consolidated with EGFR-TKIs. Furthermore, research with third-generation EGFR-TKIs and SBRT combinations has demonstrated tolerable toxicity levels without significant additional adverse effects as compared to prior therapies. However, further clinical trials are required to establish its effectiveness. Conclusions: The combined approach of SBRT and TKIs can effectively impede the progression of oligometastatic NSCLC in patients harboring EGFR mutations and, most notably, can prolong progression-free survival rates. However, the feasibility of combining SBRT with third-generation TKIs in clinical trials remains unclear.

Predicting complication risks after sleeve lobectomy for non-small cell lung cancer.

Background: Sleeve lobectomy is a challenging procedure with a high risk of postoperative complications. To facilitate surgical decision-making and optimize perioperative treatment, we developed risk stratification models to quantify the probability of postoperative complications after sleeve lobectomy. Methods: We retrospectively analyzed the clinical features of 691 non-small cell lung cancer (NSCLC) patients who underwent sleeve lobectomy between July 2016 and December 2019. Logistic regression models were trained and validated in the cohort to predict overall complications, major complications, and specific minor complications. The impact of specific complications in prognostic stratification was explored via the Kaplan-Meier method. Results: Of 691 included patients, 232 (33.5%) developed complications, including 35 (5.1%) and 197 (28.5%) patients with major and minor complications, respectively. The models showed robust discrimination, yielding an area under the receiver operating characteristic (ROC) curve (AUC) of 0.853 [95% confidence interval (CI): 0.705-0.885] for predicting overall postoperative complication risk and 0.751 (95% CI: 0.727-0.762) specifically for major complication risks. Models predicting minor complications also achieved good performance, with AUCs ranging from 0.78 to 0.89. Survival analyses revealed a significant association between postoperative complications and poor prognosis. Conclusions: Risk stratification models could accurately predict the probability and severity of complications in NSCLC patients following sleeve lobectomy, which may inform clinical decision-making for future patients.

Predictive value of delta-radiomic features for prognosis of advanced non-small cell lung cancer patients undergoing immune checkpoint inhibitor therapy.

Background: No robust predictive biomarkers exist to identify non-small cell lung cancer (NSCLC) patients likely to benefit from immune checkpoint inhibitor (ICI) therapies. The aim of this study was to explore the role of delta-radiomics features in predicting the clinical outcomes of patients with advanced NSCLC who received ICI therapy. Methods: Data of 179 patients with advanced NSCLC (stages IIIB-IV) from two institutions (Database 1 =133; Database 2 =46) were retrospectively analyzed. Patients in the Database 1 were randomly assigned into training and validation dataset, with a ratio of 8:2. Patients in Database 2 were allocated into testing dataset. Features were selected from computed tomography (CT) images before and 6-8 weeks after ICI therapy. For each lesion, a total of 1,037 radiomic features were extracted. Lowly reliable [intraclass correlation coefficient (ICC) <0.8] and redundant (r>0.8) features were excluded. The delta-radiomics features were defined as the relative net change of radiomics features between two time points. Prognostic models for progression-free survival (PFS) and overall survival (OS) were established using the multivariate Cox regression based on selected delta-radiomics features. A clinical model and a pre-treatment radiomics model were established as well. Results: The median PFS (after therapy) was 7.0 [interquartile range (IQR): 3.4, 9.1] (range, 1.4-13.2) months. To predict PFS, the model established based on the five most contributing delta-radiomics features yielded Harrell's concordance index (C-index) values of 0.708, 0.688, and 0.603 in the training, validation, and testing databases, respectively. The median survival time was 12 (IQR: 8.7, 15.8) (range, 2.9-23.3) months. To predict OS, a promising prognostic performance was confirmed with the corresponding C-index values of 0.810, 0.762, and 0.697 in the three datasets based on the seven most contributing delta-radiomics features, respectively. Furthermore, compared with clinical and pre-treatment radiomics models, the delta-radiomics model had the highest area under the curve (AUC) value and the best patients' stratification ability. Conclusions: The delta-radiomics model showed a good performance in predicting therapeutic outcomes in advanced NSCLC patients undergoing ICI therapy. It provides a higher predictive value than clinical and the pre-treatment radiomics models.

The impact of different modalities of chemoradiation therapy and chemotherapy regimens on lymphopenia in patients with locally advanced non-small cell lung cancer.

Background: Chemotherapy and radiotherapy (RT) would induce lymphopenia, leading to a poor prognosis. This study investigated whether chemotherapy increased lymphopenia during RT and explored the impacts of different chemotherapy regimens on the lymphocyte counts of patients receiving RT. Methods: Clinical parameters and lymphocyte data were collected from 215 patients with locally advanced non-small cell lung cancer (LA-NSCLC). Severe lymphopenia (SRL) was defined as an absolute lymphocyte count (ALC) of ≤0.2×103 cells/µL. Patient overall survival (OS) was analyzed using the Kaplan-Meier method. The predictors of SRL were extracted using univariate and multivariate regression analyses with backward likelihood ratio elimination. Results: Compared with patients without SRL, patients with SRL with LA-NSCLC showed a poorer prognosis in terms of OS (P=0.003). Of the 215 patients, 130 underwent concurrent chemoradiotherapy (CCRT) and 85 underwent sequential chemoradiotherapy (SCRT). The OS was better in patients without SRL (in the CCRT group, P=0.01 and in the SCRT group, P=0.08). The mean ALCs for CCRT and SCRT did not differ significantly (P=0.27). The minimum ALC of CCRT was significantly lower than that of SCRT (P<0.0001). CCRT was a predictor of SRL (P=0.008). However, multivariate analysis showed that the different chemotherapy regimens were not predictors of SRL (all P>0.1). Conclusions: In LA-NSCLC, the outcomes of patients with SRL were poorer than those without SRL. RT and chemotherapy were the main factors affecting SRL development, while different chemotherapy regimens were not significantly associated with lymphocyte counts in LA-NSCLC.

Early discontinuation of immune checkpoint inhibitor therapy prior to disease progression in patients with metastatic non-small cell lung cancer: a survival analysis.

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.

Real-world comprehensive genomic and immune profiling reveals distinct age- and sex-based genomic and immune landscapes in tumors of patients with non-small cell lung cancer.

Introduction: Younger patients with non-small cell lung cancer (NSCLC) (<50 years) represent a significant patient population with distinct clinicopathological features and enriched targetable genomic alterations compared to older patients. However, previous studies of younger NSCLC suffer from inconsistent findings, few studies have incorporated sex into their analyses, and studies targeting age-related differences in the tumor immune microenvironment are lacking. Methods: We performed a retrospective analysis of 8,230 patients with NSCLC, comparing genomic alterations and immunogenic markers of younger and older patients while also considering differences between male and female patients. We defined older patients as those ≥65 years and used a 5-year sliding threshold from <45 to <65 years to define various groups of younger patients. Additionally, in an independent cohort of patients with NSCLC, we use our observations to inform testing of the combinatorial effect of age and sex on survival of patients given immunotherapy with or without chemotherapy. Results: We observed distinct genomic and immune microenvironment profiles for tumors of younger patients compared to tumors of older patients. Younger patient tumors were enriched in clinically relevant genomic alterations and had gene expression patterns indicative of reduced immune system activation, which was most evident when analyzing male patients. Further, we found younger male patients treated with immunotherapy alone had significantly worse survival compared to male patients ≥65 years, while the addition of chemotherapy reduced this disparity. Contrarily, we found younger female patients had significantly better survival compared to female patients ≥65 years when treated with immunotherapy plus chemotherapy, while treatment with immunotherapy alone resulted in similar outcomes. Discussion: These results show the value of comprehensive genomic and immune profiling (CGIP) for informing clinical treatment of younger patients with NSCLC and provides support for broader coverage of CGIP for younger patients with advanced NSCLC.

First-line Osimertinib for Lung Cancer With Uncommon EGFR Exon 19 Mutations and EGFR Compound Mutations.

Introduction: Up to 20% of EGFR-mutated NSCLC cases harbor uncommon EGFR mutations, including atypical exon 19 and compound mutations. Relatively little is known about the efficacy of osimertinib in these cases. Methods: Patients treated with first-line osimertinib for NSCLC with rare EGFR exon 19 (non E746_A750del) or compound mutations were included. Response assessment and time to progression were determined using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Kaplan-Meier analyses were used to estimate progression-free survival (PFS), time to treatment discontinuation (TTD), and overall survival (OS). Results: Thirty-seven patients with NSCLC harboring an atypical EGFR exon 19 mutation or compound mutation were treated with first-line osimertinib at Johns Hopkins from 2016 to 2021. Overall response rate (ORR) was 76% and median PFS, TTD, and OS were 13 months (95% confidence interval [CI]: 10-15), 22 months (95% CI: 17-32) and 36 months (95% CI, 29-48), respectively. Among atypical exon 19 mutations (n = 25), ORR was 80%, median PFS was 12 months (95% CI: 10-15), median TTD was 19 months (95% CI: 17-38), and median OS was 48 months (95% CI: 25-not reached). Compound mutations (n = 12) had an ORR of 67%, median PFS of 14 months (95% CI: 5-22), median TTD of 26 months (95% CI: 5-36), and median OS of 36 months (95% CI: 20-46). Twelve patients (32%) continued first-line osimertinib after local therapy for oligoprogression. Conclusions: Osimertinib exhibited favorable outcomes for rare EGFR exon 19 and compound mutations. The heterogeneity in outcomes among these groups of tumors with similar mutations underscores the need for continued reporting and further study of outcomes among rare variants to optimize management for each patient.