Advanced Lung Cancer Patients Research Articles

The Treatment of a New Entity in Advanced Non-Small Cell Lung Cancer: MET exon 14 Skipping Mutation.

MET (MET Proto-Oncogene, Receptor Tyrosine Kinase) exon 14 skipping mutation represents one of the most common MET alterations, accounting for approximately 1-3% of all mutations in advanced lung adenocarcinomas. While until 2020 no specific treatment was available for this subset of patients, as of today, three MET Tyrosine Kinase Inhibitors (TKIs) are currently approved in this setting, namely capmatinib, tepotinib and savolitinib. This article aims to provide an extensive overview of the current therapeutic standard of care for exon 14 skipped advanced Non-Small Cell Lung Cancer (NSCLC) patients, alongside with mentions of the main future challenges and opportunities. FDA-approved MET-TKIs currently represent the best option for treating exon 14 skipped advanced NSCLC patients, thanks to their excellent efficacy profile, alongside their manageable safety and tolerability. However, we currently lack specific agents to treat patients progressing on capmatinib or tepotinib, due to a limited understanding of the mechanisms underlying both on- and off-target resistance. In this respect, on-target mutations presently constitute the most explored ones from a mechanistic point of view, and type II MET-TKIs are currently under investigation as the most promising agents capable of overcoming the acquired resistance.

Pyrotinib as a salvage treatment for patients with HER-2 positive advanced lung adenocarcinoma after the progression of afatinib treatment.

The efficacy of afatinib or pyrotinib has been demonstrated in HER2-positive advanced non-small cell lung cancer (NSCLC) patients; however, the efficacy of pyrotinib after afatinib progression has yet to be determined. Patients with HER2 mutated advanced lung adenocarcinoma administeredafatinib or pyrotinib monotherapy were enrolled. Those who received pyrotinib after afatinib were further analyzed to determine the efficacy and safety of pyrotinib after progression on afatinib. Survival curves were plotted with the Kaplan-Meier method. A swimming plot was used to describe the specific treatments. Additionally, patient-derived tumor organoids (PDTOs) were established from HER2-amplified NSCLC patient samples to investigate the antitumor activity of pyrotinib in HER2-amplified tumor cells in vitro. A total of 99 patients were enrolled, 13 of whom were administered pyrotinib after progression on afatinib. No statistical difference in PFS of pyrotinib was observed between patients whether be treated after afatinib progression or not (6.7months vs. 4.4months, P = 0.817), thus indicating that progression on afatinib did not affect the efficacy of pyrotinib. Further analysis was conducted on the former patients, which comprising eight patients administered interval chemotherapy after progression on afatinib. Two patients achieved PR after pyrotinib treatment. No independent factors were found to influence the PFS of pyrotinib. PDTOs confirmed the anti-tumor activity of pyrotinib in NSCLC tumor cells with HER2 amplification. Progression after prior afatinib treatment does not influence the efficacy of pyrotinib treatment. Pyrotinib may be a salvage option for patients with HER2 mutation who have experienced progression on afatinib.

Prognostic value of skeletal muscle measured by CT at the T4 level in advanced EGFR-positive non-small cell lung cancer patients treated with ecotinib

Objective: To investigate the prognostic value of skeletal muscle measured by CT at the level of the fourth thoracic vertebra (T4) in advanced epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients treated with ecotinib. Methods: The study retrospectively reviewed clinical and pathological characteristics of 176 patients with advanced EGFR-positive NSCLC who received ecotinib and underwent chest CT scans at Wuhan Union Hospital between January 2017 and October 2020. Among them, 70 were male and 106 were female, with ages ranging from 27 to 80 (58.6±10.6) years. As of August 21, 2021, the median follow-up duration was 19.2 months (95%CI: 15.3 to 23.7 months). The optimal cut-off value of skeletal muscle density (T4-SMD) on CT images at the T4 level were determined using X-tile software. Kaplan-Meier analysis and log-rank test were used to plot progression-free survival curves. Cox proportional hazards regression models were employed to analyze factors influencing 1-year progression-free survival (PFS), and a nomogram prognostic model was constructed accordingly. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were utilized to evaluate the predictive value of the nomogram. Results: The T4-SMD [M (Q1,Q3)] of 176 patients was 42.56 (37.05, 45.93) HU. Patients were divided into low T4-SMD group (n=122) and high T4-SMD group (n=54) based on the cut-off value (The values for males and females were 49.44 and 41.41 HU, respectively) of T4-SMD. The median PFS time and 1-year PFS rate in the low T4-SMD group were significantly lower than those in the high T4-SMD group [10.4 (95%CI: 9.3-11.8) vs 13.7 (95%CI: 11.1-18.5) months, 36.1% vs 59.3%, respectively, P=0.034]. Eastern Cooperative Oncology Group performance status (HR=3.308, 95%CI: 1.183-9.247, P=0.023), lactate dehydrogenase level (HR=1.852, 95%CI: 1.037-3.307, P=0.037), systemic immune-inflammation index (HR=1.772, 95%CI: 1.019-3.080, P=0.043), and T4-SMD (HR=0.563, 95%CI: 0.325-0.974, P=0.040) were prognostic factors for 1-year PFS in advanced EGFR-positive NSCLC patients treated with ecotinib. A nomogram for predicting 1-year PFS of advanced EGFR-positive NSCLC patients treated with ecotinib was constructed based on the four indicators selected by multivariate Cox regression analysis. The area under the ROC curve of the nomogram was 0.775 (95%CI: 0.676-0.874). The calibration curve showed good consistency between the predicted and actual 1-year PFS. DCA demonstrated good clinical prediction effectiveness of the nomogram. Conclusion: Low T4-SMD is a prognostic risk factor for patients with advanced EGFR-positive NSCLC receiving icotinib therapy.

CLINICAL FACTORS PREDECTING T790M MUTATION IN NON-SMALL CELL LUNG CANCER PROGRESSED AFTER FIRST- AND SECOND-GENERATION TKI TREATMENT

Objective: We aimed to identify the T790M mutation rate and clinical factors predicting the occurrence of acquired T790M mutations in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after first- and second-generation tyrosine kinase inhibitor (TKI) treatment. Method: The EGFR-mutant NSCLC patients who experienced progression after first- and second-generation TKI treatment and underwent testing for EGFR using plasma samples between January 2021 and April 2023 were enrolled. The T90M mutation rate and related clinical factors were evaluated. We utilized the Chi-square test or Fisher’s exact test for univariate analysis and multivariable logistic binary regression for multivariate analysis. Results: A total of 247 patients were eligible for the study. Patients harbored the exon 19 deletion mutation (Del19), exon 21 L858R point mutation, and uncommon mutations in 63.2%, 34.4%, and 2.4% of cases, respectively. The overall T790M mutation rate was 33.6%. In multivariate analyses, the Del19 mutation versus L858R mutation, duration of first-line TKI exceeding 12 months versus below 12 months, and solitary lesion progression versus multiple lesion progression were identified as favorable prognostic factors for the occurrence of T790M mutation. Conclusion: Patients with EGFR exon 19 deletion, a prolonged treatment duration of first-line EGFR-TKI, and solitary lesion progression pattern are more likely to acquire the T790M mutation, as detected by the PCR method in plasma samples.

Choline metabolism reprogramming mediates an immunosuppressive microenvironment in non-small cell lung cancer (NSCLC) by promoting tumor-associated macrophage functional polarization and endothelial cell proliferation

IntroductionLung cancer is a prevalent malignancy globally, and immunotherapy has revolutionized its treatment. However, resistance to immunotherapy remains a challenge. Abnormal cholinesterase (ChE) activity and choline metabolism are associated with tumor oncogenesis, progression, and poor prognosis in multiple cancers. Yet, the precise mechanism underlying the relationship between ChE, choline metabolism and tumor immune microenvironment in lung cancer, and the response and resistance of immunotherapy still unclear.MethodsFirstly, 277 advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy in Sun Yat-sen University Cancer Center were enrolled in the study. Pretreatment and the alteration of ChE after 2 courses of immunotherapy and survival outcomes were collected. Kaplan–Meier survival and cox regression analysis were performed, and nomogram was conducted to identify the prognostic and predicted values. Secondly, choline metabolism-related genes were screened using Cox regression, and a prognostic model was constructed. Functional enrichment analysis and immune microenvironment analysis were also conducted. Lastly, to gain further insights into potential mechanisms, single-cell analysis was performed.ResultsFirstly, baseline high level ChE and the elevation of ChE after immunotherapy were significantly associated with better survival outcomes for advanced NSCLC. Constructed nomogram based on the significant variables from the multivariate Cox analysis performed well in discrimination and calibration. Secondly, 4 choline metabolism-related genes (MTHFD1, PDGFB, PIK3R3, CHKB) were screened and developed a risk signature that was found to be related to a poorer prognosis. Further analysis revealed that the choline metabolism-related genes signature was associated with immunosuppressive tumor microenvironment, immune escape and metabolic reprogramming. scRNA-seq showed that MTHFD1 was specifically distributed in tumor-associated macrophages (TAMs), mediating the differentiation and immunosuppressive functions of macrophages, which may potentially impact endothelial cell proliferation and tumor angiogenesis.ConclusionOur study highlights the discovery of ChE as a prognostic marker in advanced NSCLC, suggesting its potential for identifying patients who may benefit from immunotherapy. Additionally, we developed a prognostic signature based on choline metabolism-related genes, revealing the correlation with the immunosuppressive microenvironment and uncovering the role of MTHFD1 in macrophage differentiation and endothelial cell proliferation, providing insights into the intricate workings of choline metabolism in NSCLC pathogenesis.

Acute exacerbation predicting poor outcomes in idiopathic interstitial pneumonia and advanced lung cancer patients undergoing cytotoxic chemotherapy

Effective treatment for advanced lung cancer and idiopathic interstitial pneumonia (IIP) remains an unmet medical need. The relationship between chemotherapy’s effectiveness in advanced lung cancer and the risk of acute exacerbation of IIP is poorly investigated. There is limited evidence that patients who experience an acute exacerbation of IIPs during cytotoxic chemotherapy have poorer outcomes than those who do not. Among 1004 patients with advanced lung cancer and IIPs enrolled in our published multi-centre retrospective study from 110 Japanese institutions, 708 patients (male: female, 645:63; mean age, 70.4) received first-line chemotherapy. The occurrence of chemotherapy-triggered acute exacerbations of IIPs and overall survival (OS) were analysed. The OS between groups of patients with and without the occurrence of acute exacerbation was compared at four landmark time points (30, 60, 90, and 120 days), starting from the first-line chemotherapy, using the landmark method. The incidence of acute exacerbation in patients who received first-line chemotherapy with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was more frequent in NSCLC patients than in SCLC (4.2% vs 12.6%; odds ratio [OR]: 3.316; 95% confidence interval [CI] 1.25–8.8). Median survival time was 9.9 months (95% CI 9.2–10.7). Patients who experienced acute exacerbation had significant worse survival outcomes than those who did not at various time points (30 days, hazard ratio [HR]: 5.191, 95% CI 2.889–9.328; 60 days, HR: 2.351, 95% CI 1.104–5.009; 90 days, HR: 2.416, 95% CI 1.232–4.739; and 120 days, HR: 2.521, 95% CI 1.357–4.681). Acute exacerbation during first-line chemotherapy can predict poor survival.Trial Registration number: UMIN000018227.

Tai Chi and Aerobic Exercise on Cancer-Related Dyspnea in Advanced Lung Cancer Patients: A Randomized Clinical Trial

ContextDyspnea, a prevalent and debilitating symptom in patients with advanced lung cancer, negatively affects symptom burden and prognosis. Physical activity has emerged as a promising non-pharmacological intervention for managing dyspnea. ObjectivesThis study compared the effectiveness of two widely-recognized physical activity modalities, namely Tai Chi (TC) and aerobic exercise (AE) for treating dyspnea in patients with advanced lung cancer. MethodsPatients with advanced lung cancer (n=226) were randomized into TC, AE, or control groups. There was no baseline dyspnea requirement for patients. The AE group received two 60-minute supervised sessions and home-based exercises per month, the TC group received 60-minute sessions twice weekly, and the control group received exercise guidelines for 16 weeks. The primary outcome (sleep quality) of the study has been previously reported. In this secondary analysis, we focused on dyspnea outcomes, including overall and lung cancer-specific dyspnea. Assessments were conducted at baseline (T0), 16 weeks (T1), and one year (T2). ResultsCompared to the control group, TC significantly improved overall dyspnea at T1 (between-group difference, −8.69; P=0.03) and T2 (between-group difference, −11.45; P=0.01), but not AE. Both AE (between-group difference, −11.04; P=0.01) and TC (between-group difference, −14.19; P<0.001) significantly alleviated lung cancer-specific dyspnea at T2 compared with the control group. ConclusionBoth TC and AE alleviate dyspnea severity in patients with advanced lung cancer, and continuous exercise can yield substantial improvements. Due to its multi-component nature, Tai Chi has a greater effect on dyspnea.

Development and validation of a nomogram to predict leptomeningeal metastases in lung adenocarcinoma: Cervical lymph node metastasis is an important association factor.

The goal of this study was to create a nomogram using routine parameters to predict leptomeningeal metastases (LMs) in advanced lung adenocarcinoma (LAC) patients to prevent needless exams or lumbar punctures and to assist in accurately diagnosing LMs. Two hundred and seventy-three patients with LMs and brain metastases were retrospectively reviewed and divided into derivation (n = 191) and validation (n = 82) cohorts using a 3:7 random allocation. All LAC patients with LMs had positive cerebrospinal fluid cytology results and brain metastases confirmed by magnetic resonance imaging. Binary logistic regression with backward stepwise selection was used to identify significant characteristics. A predictive nomogram based on the logistic model was assessed through receiver operating characteristic curves. The validation cohort and Hosmer-Lemeshow test were used for internal validation of the nomogram. Five clinicopathological parameters, namely, gene mutations, surgery at the primary lung cancer site, clinical symptoms of the head, N stage, and therapeutic strategy, were used as predictors of LMs. The area under the curve was 0.946 (95% CI 0.912-0.979) for the training cohort and 0.861 (95% CI 0.761-0.961) for the internal validation cohort. There was no significant difference in performance between the two cohorts (p = 0.116). In the internal validation, calibration plots revealed that the nomogram predictions were well suited to the actual outcomes. We created a user-friendly nomogram to predict LMs in advanced lung cancer patients, which could help guide treatment decisions and reduce unnecessary lumbar punctures.

Prognostic importance of prognostic nutritional index and modified Glasgow prognostic score in advanced lung cancer with targetable mutation

BackgroundInflammation and nutrition are important parameters that significantly affect survival in various malignancies. Prognostic nutritional index (PNI) and modified Glasgow prognostic score (mGPS) can reflect both inflammatory and nutritional conditions. Therefore, we aimed to evaluate the prognostic value of PNI and mGPS in patients who had the targetable mutation and also received targeted therapy.Materials and MethodsAdvanced lung cancer patients with EGFR mutation (mut) and ALK rearrangement were enrolled to study, retrospectively. PNI has with the following formula: 10 × serum albumin (g/dl) + 0.005 × peripheral lymphocyte count (per mm3) and threshold value was accepted as 50. Modified GPS was also calculated using albumin and CRP level and patients were scored as range 0 to 2.ResultsA total of 182 patients enrolled in the study. 132 and 50 of 182 patients had EGFR mut and ALK rearrangement, respectively. PFS was significantly longer in high PNI group in both the EGFR and ALK rearrangement-positive subgroups (P = 0.004 for EGFR mut-positive group; P = 0.017 for ALK rearrangement-positive group). Additionally, PFS was significantly shortened from mGPS 0 to 2 (P = < 0.001 for EGFR mut-positive group; P = 0.016 for ALK rearrangement-positive group).ConclusionBoth PNI and mGPS can be used as a reliable, inexpensive, and easily applicable prognostic index in the advanced lung cancer patients who had the targetable mutation and also received targeted therapy.

Efficacy and safety of chemoimmunotherapy in advanced non-small cell lung cancer patients with antibiotics-induced dysbiosis: a propensity-matched real-world analysis

PurposeThe gut microbiota is hypothesized as a prognostic biomarker for cancer immunotherapy. Antibiotic-induced dysbiosis negatively affects the clinical outcomes of immunotherapy. However, the effect of dysbiosis on the efficacy and safety of Chemoimmunotherapy (chemo-IOs), the frontline standard of care, in advanced non-small cell lung cancer (NSCLC) remains unknown. We aimed to compare the efficacy and safety of chemo-IOs in patients exposed to antibiotics before treatment with those of patients who were not exposed.MethodsWe retrospectively reviewed patients with advanced NSCLC treated with first-line chemo-IOs between 2018 and 2020 at the National Cancer Center Hospital. The patients were divided into two groups: those exposed to antibiotics within 30 days before induction therapy (ABx group) and those did not antibiotics (Non-ABx group). Propensity score matching was used to control for potential confounding factors. Clinical outcomes including progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were compared.ResultsOf 201 eligible patients, 21 were in the ABx group, and 42 were in the non-ABx group after propensity score matching. No differences in PFS or OS emerged between the two groups (ABx group vs. Non-ABx group) (PFS:7.0 months vs. 6.4 months, hazard ratio [HR] 0.89; 95% confidence interval [CI], 0.49–1.63, OS:20.4 months vs. 20.1 months, HR 0.87; 95% CI 0.44–1.71). The frequency of irAEs before propensity score matching was similar across any-grade irAEs (39.4% vs. 42.9%) or grade 3 or higher irAEs (9.1% vs. 11.3%).ConclusionAntibiotic-induced dysbiosis may not affect the efficacy of chemo-IOs in patients with advanced NSCLC.

Advances in Pseudoprogression of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer

The advent of immune checkpoint inhibitors (ICIs) has greatly improved the prognosis of advanced lung cancer patients, but can lead to pseudoprogression (PsP), which complicates clinical evaluation and management. PsP is manifested as temporary enlargement of the tumour or the appearance of new lesions, etc., and improvement in imaging occurs with continued treatment, mostly without worsening of clinical symptoms. Currently, there are still difficulties in the early diagnosis of PsP, and its occurrence mechanism is not yet clear, lacking good predictive factors and related biomarkers. This article reviews the current research status of PsP of ICIs in non-small cell lung cancer in order to provide helpful clinical strategies for oncologists using these drugs. .

Acceptability of automatic referrals to supportive and palliative care by patients living with advanced lung cancer: qualitative interviews and a co-design process

PurposeTimely access to supportive and palliative care (PC) remains a challenge. A proposed solution is to trigger an automatic referral process to PC by pre-determined clinical criteria. This study sought to co-design with patients and providers an automatic PC referral process for patients newly diagnosed with stage IV lung cancer.MethodsIn Step 1 of this work, nine one on one phone interviews were conducted with advanced lung cancer patients on their perspectives on the acceptability of phone contact by a specialist PC provider triggered by an automatic referral process. Interviews were thematically analysed. Step 2: Patient advisors, healthcare providers (oncologists, nurses from oncology and PC, clinical social worker, psychologist), and researchers were invited to join a working group to provide input on the development and implementation of the automatic referral process. The group met biweekly (virtually) over the course of six months.ResultsFrom interviews, the concept of an automatic referral process was perceived to be acceptable and beneficial for patients. Participants emphasized the need for timely support, access to peer and community resources. Using these findings, the co-design working group identified eligibility criteria for identifying newly diagnosed stage IV lung cancer patients using the cancer centre electronic health record, co-developed a telephone script for specialist PC providers, handouts on supportive care, and interview and survey guides for evaluating the implemented automatic process.ConclusionA co-design process ensures stakeholders are involved in program development and implementation from the very beginning, to make outputs relevant and acceptable for stage IV lung cancer patients.

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients with KRAS mutations: A network meta-analysis.

Previous studies have shown that immune checkpoint inhibitors can improve the survival of patients with advanced non-small cell lung cancer with KRAS mutations; however, there is a lack of comparisons between treatment regimens associated with immune checkpoint inhibitors, and our study aims to compare several treatment parties to find a more effective treatment regimen. A comprehensive literature search was conducted across multiple databases, namely PubMed, Web of Science, Embase, and Cochrane Library, to identify relevant studies. The screened studies were thoroughly examined, and data were collected to establish a Bayesian framework. The study focused on two primary endpoints: overall survival (OS) and progression-free survival (PFS). Data analysis and graphical plotting using R software and Revman (version 5.3). It is worth mentioning that the study protocol was registered with the International Prospective Registry for Systematic Reviews, ensuring transparency and adherence to predetermined protocols (CRD42022379595). In total, our analysis included six RCTs involving 469 patients with KRAS mutations. Among these patients, 224 received chemotherapy, while 245 were treated with immune checkpoint inhibitors. Meta-analysis results showed that the addition of ICIs could significantly improve OS and PFS (0.69, 95% CI 0.55, 0.86; 0.57, 95% CI 0.42, 0.77). The results of the network meta-analysis showed that Pembrolizumab could improve OS (HR 0.42, 95% CI 0.22-0.80) and Pembrolizumab emerged as the most effective treatment option for enhancing OS in patients (SUCRA 65.03%). Additionally, pembrolizumab in combination with chemotherapy showed improvement in PFS (HR 0.47, 95% CI 0.29-0.76). Our analysis found that among advanced NSCLC patients with KRAS gene mutations, first-line treatment with pembrolizumab alone demonstrated greater efficacy. Similarly, second-line treatment with nivolumab alone was found to be more effective in this patient population. However, the sample size of this study was limited, Therefore, additional clinical data is necessary to validate this finding in subsequent research.

Prognostic impact of age in advanced non-small cell lung cancer patients undergoing first-line checkpoint inhibitor immunotherapy and chemotherapy treatment

BackgroundResearch on the association between age and clinical outcome in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy combined with chemotherapy as first-line setting is limited. The aim of study is to determine the influence of age on the progress-free survival (PFS) and overall survival (OS) in those patients after adjusting for potential confounders. MethodsA total of 207 advanced NSCLC patients treated with immunotherapy combined with chemotherapy in the first-line treatment in Guangxi Medical University Cancer Hospital from March 10, 2019, to December 31, 2022, was retrospectively analyzed. χ2 (categorical variables) was used to analyze the differences among the different age groups. Cox regression and Kaplan–Meier analyses were used to assess the association between age and clinical outcomes. P values < 0.05 (two-sided) were considered statistically significant. ResultsThe mean age of the cohort was 58.8 ± 10.3 years. The percentages of patients < 65, 65–69, 70–74, and ≥ 75 years were 66.7 %, 19.3 %, 9.2 % and 4.8 %, respectively. Compared to the aged < 65 years group, the HR for the risk of disease progression for each group are 0.67 (95 %CI = 0.40–1.12, P = 0.125), 0.66 (95 %CI = 0.31, 1.43, P = 0.298), and 2.27 (95 %CI = 0.80, 6.45, P = 0.124), respectively, with no significant differences in the results. And the HR for risk of death for the 65–69 years and 70–74 years groups was 1.16 (95 %CI = 0.64–2.08, P = 0.628) and 0.93 (95 %CI = 0.39–2.23, P = 0.879), respectively. The difference has no statistical significance. Whereas in patients aged ≥ 75, there is an increased risk of death after adjusted confounders with HR = 4.83 (95 %CI = 2.06–11.35). The difference was statistically significant (P < 0.001). Trend test indicates that with advancing age, the patient's risk of death increases (HR = 1.33, 95 % CI = 1.02–1.75, P = 0.034). ConclusionAge may not be the primary factor influencing the efficacy of immunotherapy combined with chemotherapy, but particular attention should be given to the elderly population.

Introduction to the 9th edition of TNM classification for lung cancer

Lung cancer is the second commonly diagnosed cancer and remained the leading cause of cancer-related death, with an estimated 1.8 million deaths in 2020. The identification of driver gene mutation and administration of corresponding tyrosine kinase inhibitor have improved overall survival and quality of life in advanced lung cancer patients. Check point inhibitor has revolutionized treatment strategy of driver gene negative advanced NSCLC patients. TNM staging system is the most widely used classification method, providing an international common language during academic communication and important tool for predicting prognosis and subsequent treatment decision making. Accumulating knowledge about prognostic factors in lung cancer promotes the update of TNM classification. In the World Conference on Lung Cancer (WCLC) held in Singapore, September, 2023, International Association for Study of Lung Cancer (IASLC) released the forthcoming 9th edition of TNM classification for lung cancer, which is supposed to be adopted at January, 2024. The manuscript discussed the history, data resource and limitation of the TNM staging system.

Osimertinib in Patients With Treatment-Naive EGFR-Mutant Non-small Cell Lung Cancer: Overall Survival, Post-progression Management and Budget Impact Analysis in Real-World.

The observational multicenter prospective FLOWER study (NCT04965701) confirmed effectiveness and safety of osimertinib in the real-world (RW) management of untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) patients. Herein, we report updated survival data, post-progression management, cost/effectiveness and budget impact (BI) of osimertinib compared with a RW population receiving gefitinib or erlotinib. Overall, 189 Caucasian patients receiving first-line osimertinib were included. After a follow-up of 20.7 months, 74(39.2%) patients discontinued osimertinib, median time-to-treatment discontinuation (mTTD) was 27.9 months, overall survival 36.8 months. At progression, tissue biopsy was performed in 29 (56.9%), liquid biopsy in 15 (29.4%) and both in 7 (13.7%) cases. The most frequent resistant mechanism was MET amplification (N = 14, 29.8%). At data cutoff, 13 (6.9%) patients were continuing osimertinib beyond progression; 52 (67.5%) received second-line treatment; no further treatments were administered in 25 (32.5%) cases. Thirty-three (63.4%) patients received chemotherapy, 12(23.1%) TKIs combination. Cost-effectiveness analysis showed a total cost per patient based on RW mTTD of 98,957.34€, 21,726.28€ and 19,637.83€ for osimertinib, erlotinib and gefitinib, respectively. The incremental cost-effectiveness ratio (ICER)/month for osimertinib was 359,806.0€/life-year-gained (LYG) and 197,789.77€/LYG compared to erlotinib and gefitinib. For osimertinib, the BI-gap between RW-TTD and theoretical-TTD was 16,501.0€ per patient. This updated analysis confirms the effectiveness of osimertinib in RW. Although the ICER of osimertinib seems not cost-effective, additional costs for the management of disease progression to old generation TKIs were not considered in this study. The BI-gap suggests RW mTTD as a more reliable measure for expense estimation.

Abstract 5037: Development of multiplexed Absolute Q digital PCR assays to rapidly quantify EGFR and KRAS genotype in advanced non-small cell lung cancer (NSCLC) patients’ plasma

Abstract Introduction: There are needs to identify and serially monitor driver and resistance mutations (muts) in therapy-treated cancer patients (pts). Quantitative liquid biopsy in cell-free (cf)DNA has been widely adopted. We have developed and clinically validated droplet digital PCR (ddPCR) assays to detect common driver/resistance muts such as EGFR del19, L858R, T790M and KRAS G12X in the cfDNA of advanced NSCLC pts. We have established ddPCR assays for 30+ driver/resistance muts in multiple genes (BRAF, MET, ESR1, etc.) relevant to melanoma, breast, and colorectal cancer. Our assays use tumor/cell line DNA as positive controls and serve as benchmarks to develop newer assays such as plasma NGS. In this study, we converted existing/validated EGFR and KRAS G12X ddPCR assays to the QuantStudio Absolute Q digital PCR (dPCR) system. The selected mutations maximize actionable clinical information and are designed to study oncogenic and resistance mutations in NSCLC efficiently. dPCR’s accuracy and efficiency enables target multiplexing, providing comprehensive information from limited materials and contributing to liquid biopsy research progress. Methods: Plasma from pts with tumors harboring EGFR and KRAS muts was collected at progression with advanced disease following consent to protocol DFCI #14-147. We designed a multiplex dPCR assay that identifies the most common and therapy-relevant KRAS muts in NSCLC, G12C/D/V, and detects other G12X using a drop-off probe. We also designed 2 EGFR kits, one identifying driver muts, the other resistance muts. Results: To validate assay performance, we used gDNA derived from cell lines with EGFR or KRAS muts. We serially diluted mut gDNA samples in background wt gDNA (16 ~ 1000 mut copies in 1000 wt copies) and performed KRAS and EGFR dPCR assays. We detected 16 mut copies with sensitivities similar to those of ddPCR assays. We then studied 48 cfDNA samples from plasma of NSCLC pts with tumor confirmed KRAS G12X or EGFR L858R, del19, T790M muts. No samples had both EGFR and KRAS muts detected, suggesting our assays are specific. We detected muts in samples with an allele frequency median of 0.9% for KRAS mut, 11.9% for EGFR driver mut, 2.9% for EGFR T790M. The concordance rate is 91.3% between dPCR and ddPCR results. Our findings suggest these assays are as sensitive and specific as our validated ddPCR assays. Multiplexed Absolute Q dPCR saves cfDNA and cuts turnaround time (TAT) to 90 min for KRAS assay and 3hr for EGFR assays. Conclusions: We developed rapid, sensitive and specific quantitative dPCR assays for KRAS and EGFR muts on the QuantStudio Absolute Q platform to quantify plasma genotyping in NSCLC. We will clinically pilot our validated rapid genotyping approach and quantify TAT advantage of multiplexed genotyping in NSCLC pts undergoing standard-of-care tumor genotyping. Citation Format: Benjamin Hanna, Shidong Xu, Cloud P. Paweletz, Yanan Kuang. Development of multiplexed Absolute Q digital PCR assays to rapidly quantify EGFR and KRAS genotype in advanced non-small cell lung cancer (NSCLC) patients’ plasma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5037.

Abstract 2413: Mutated TP53 prevalence in EGFR-mutated advanced non-small cell lung cancer patients with brain metastases

Abstract Introduction: Approximately 50% of patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) develops brain metastases (BM), which is associated with a poor prognosis. Mutations in TP53 are associated with earlier development of resistance to EGFR tyrosine kinase inhibitors, but it is unclear whether patients who develops BM have a higher prevalence of TP53 mutations. Analyses of circulating tumor DNA (ctDNA) in blood have been established as a good alternative to tissue biopsies to assess the genomic landscape of NSCLC. In this study, we aim to analyze ctDNA from patients with advanced EGFR-mutated NSCLC to investigate the prevalence of TP53 mutations in patients with BM, and to explore whether patients with BM exhibit a distinct ctDNA profile compared to patients without. Materials and Methods: Plasma samples collected before treatment commenced from 97 of the 100 patients with EGFR-mutated advanced NSCLC enrolled in the First-line Treatment With Osimertinib in EGFR-mutated Non-small Cell Lung Cancer study (The FIOL study: NCT03804580) were analyzed. Patients were split into cohorts with (n=44) and without BM (n=53) at baseline. The cell-free DNA was isolated and sequenced with targeted next-generation sequencing with the AVENIO ctDNA Surveillance Panel (Roche) containing 197 lung cancer-related genes. Results: Mutations in ctDNA were found in 83 patients (85.6%), with 6 patients with BM having no ctDNA mutations and 8 patients without BM having no ctDNA mutations. Besides EGFR mutations, TP53 was the most frequently mutated gene, with 42 patients (43.3%) harboring TP53 mutations. There was no significant difference in the prevalence of TP53 mutations between the cohort with BM (n=23) and the cohort without (n=19), (p=0.15). There was no difference in the number of identified mutations in the two cohorts (BM: median: 2 (range: 0-6), without BM: median: 2 (range: 0-11), p=0.71). Patients with BM had a numerically lower ctDNA level (median: 45.5 mutant molecules/mL), than patients without BM (median: 75.9 mutant molecules/mL), though the difference was not statistically significant (p=0.68). Conclusion: Prevalence of TP53 mutations in plasma collected before osimertinib treatment initiation in advanced EGFR-mutated NSCLC was similar between patients with and without BM at baseline. Furthermore, there was no difference in the ctDNA profile between these two cohorts. Future experiments will clarify the impact of TP53 mutations in patients with or without BM. Citation Format: Simone Stensgaard, Inger Johanne Z. Eide, Elin Marie Stensland, Åslaug Helland, Simon Ekman, Karin H. Hansen, Saulius Cicenas, Bjørn Henning Grønberg, Peter Meldgaard, Boe S. Sørensen, Odd Terje Brustugun. Mutated TP53 prevalence in EGFR-mutated advanced non-small cell lung cancer patients with brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2413.

Abstract 3702: Dissecting circulating tumor cells phenotype in a cohort of locally advanced non-small cell lung cancer patients undergoing neoadjuvant chemotherapy

Abstract Background: Platinum-based neoadjuvant chemotherapy (pb-NACT) is the primary treatment approach for locally advanced non-small cell lung cancer (LA-NSCLC), despite offering only a limited overall survival (OS) gain. Cisplatin-induced cell damage has been shown to activate the SDF-1/CXCR4 axis in preclinical models of NSCLC, resulting in the recruitment of a cell subset co-expressing the stemness marker CD133 and CXCR4 (SDF-1 receptor) at distant sites. These cells, known as metastasis-initiating cells (MIC), exhibit prometastatic activity. By longitudinally monitoring circulating tumor cells (CTC) in the blood of LA-NSCLC patients (pts) undergoing pb-NACT, our objective is to assess the potential prognostic significance of CTC number and phenotype. Methods: Between February 2019 and August 2023, a total of 61 pts with LA-NSCLC undergoing pb-NACT, were included in the study. Blood samples were obtained at baseline (T1), post-pb-NACT (T2), and post-surgery (T3) for the characterization of CTC, including total CTC, CXCR4+CTCs, and CXCR4+CD133+ MIC. This characterization utilized a validated marker-independent strategy combining Parsortix and DEPArrayTM technologies. Logistic regression models were employed to examine the association between CTC subsets and the response to pb-NACT (Disease Control Rate [DCR], Overall Response Rate [ORR]), while Cox-regression models were used to assess their association with survival endpoints (event-free survival [EFS], OS, disease-free survival [DFS]). Results: Out of the 61 enrolled patients, 34 had available CTC data for analysis. In this population, DCR was 64.7%, and the ORR 29.4%. Surgery was performed in 14 pts (41.2%). At baseline (T1), elevated levels of CXCR4+CTCs were linked to a lower DCR (10 vs 3/mL, odds ratio [OR]=0.02, 95% confidence interval [CI]: 0-0.40, p=0.008), as well as shorter EFS (10 vs 3/mL, HR=4.20, 95% CI: 1.84-9.58, p=0.002) and OS (10 vs 3/mL, HR=3.14, 95% CI: 1.25-7.88, p=0.004). At the post- CT time point (T2), higher levels of MIC were associated with shorter EFS (3 vs 0/mL, HR=1.41, 95% CI: 1.00-1.99, p=0.047) and OS (3 vs 0/mL, HR=1.55, 95% CI: 1.03-2.34, p=0.035). Although the sample size was limited, a higher number of MIC at the post-surgery time point (T3) showed a trend toward reduced DFS. Discussion: CTC could serve as a novel biomarker for assessing the effectiveness of pb-NACT in LA-NSCLC. Elevated levels of CXCR4+CTC both at baseline and after pb-NACT, along with increased MIC post-pb-NACT and post-surgery, indicate unfavorable prognostic factors for survival. Specifically, a higher baseline of CXCR4+CTCs may be linked to a suboptimal response to treatment, suggesting the potential need for treatment intensification in patients exhibiting elevated CXCR4+CTC baseline levels. Citation Format: Rita Leporati, Teresa Beninato, Sara Iadecola, Chiara Andreon, Fabio Murianni, Melissa Balsamo, Antonia Martinetti, Benedetta Lombardi Stocchetti, Laura Mazzeo, Sara Manglaviti, Mario Occhipinti, Marta Brambilla, Arsela Prelaj, Claudia Proto, Rosalba Miceli, Luca Roz, Gabriella Sozzi, Filippo De Braud, Giuseppe Lo Russo, Giulia Bertolini. Dissecting circulating tumor cells phenotype in a cohort of locally advanced non-small cell lung cancer patients undergoing neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3702.

Abstract 2546: Identifying co-mutational signatures in STK11 mutated advanced non-small cell lung cancer (aNSCLC) patients that help overcome poor response to immune checkpoint inhibitors (ICI’s)

Abstract Background: ICIs, either alone or in combination with chemotherapy, have become the primary treatment options for aNSCLC patients without any targetable mutations. However, not all patients benefit similarly from these therapies even after selection based on the currently approved biomarker PD-L1 expression. Previous studies have shown that mutations in certain genes like STK11 and KEAP1 may predict non-response to these therapies. Mutations in STK11 occur in 25-30% of aNSCLC patients. We have used a real-world clinico-genomics dataset to investigate how this STK11+ aNSCLC patient population responds to ICIs in the context of other underlying co-mutations and whether some beneficial co-mutations may help patients overcome resistance due to their STK11 status. Methods: The ConcertAI Genome360TM NSCLC dataset (N=14193) was used in this retrospective study. aNSCLC patients who tested positive for STK11 mutations and received ICIs were considered (N=377). Based on their response to ICIs, the patients were divided into responder (N= 192) and non-responder (N=185) cohorts. Other genes with pathogenic mutations, fusions, and copy number changes were identified in both cohorts, and enrichment analysis was performed to identify co-mutations significantly enriched in one cohort vs the other. Once significant co-mutations were identified, pathway analysis was performed, taking into account the immune signaling network to help rationalise and validate the results. Results: One potential mechanism by which STK11 mutations influence the response to ICIs is through downregulation of the cGas-Sting pathway, which has been shown to play an important role in ICI response. Our co-mutational analysis also strongly supported this theory. We found that additional mutations that can nullify the effect of STK11 mutations on the cGas-Sting pathway led to a positive response (p=0.002) within the STK11+ cohort. Two such co-mutational signatures in responder patients identified were co-mutations in STK11/SMARCA4/TP53 (no KEAP1) (p-value = 0.003) and SKT11/KRAS/RBM10 (p-value = 0.04). Additionally, co-mutations in the DNA damage pathway genes (ATM, BRCA1, BRIP1, PALB2, STAG2) (p-value = 0.001) were also predictive of response to ICIs in the STK11+ cohort. Conclusion: By leveraging a real-world clinico-genomics dataset linking the tumor genomic profiles with patient response to ICIs, we have been able to perform a comprehensive co-mutational analysis of STK11+ aNSCLC patients to tease out the interplay of various biomarkers and signaling pathways that determine response to ICIs. Even though 25-30% aNSCLC patients are STK11+, we find that ~23% of these patients could still benefit from ICI treatment due to the presence of other co-mutations. Citation Format: Neeraj Singh, Smita Agrawal. Identifying co-mutational signatures in STK11 mutated advanced non-small cell lung cancer (aNSCLC) patients that help overcome poor response to immune checkpoint inhibitors (ICI’s) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2546.