Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC

IntroductionProgrammed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC.MethodsPD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed.ResultsPD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (<1%, 1%–49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival.ConclusionsPD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.     

NSCLC Immunotherapy Efficacy and Antibiotic Use: A Systematic Review and Meta-Analysis

Immune checkpoint inhibitors (ICIs) have dramatically improved patient outcomes in a variety of tumor types, but with variable efficacy. Recent research has suggested that antibiotic-induced disruption of the microbiota may impact ICI efficacy. We performed a systematic review and meta-analysis of studies that assessed the impact of antibiotic use on the survival of patients diagnosed with NSCLC and treated with ICI. We systematically searched Medline, the Cochrane Library, and major oncology conferences proceedings. Eligible studies mentioned hazard ratio or Kaplan–Meier curves for progression-free survival (PFS) or overall survival (OS) based on antibiotic exposure before or during ICI treatment. We identified 23 eligible studies. The impact of antibiotics was then evaluated in 2208 patients for PFS and 5560 for OS. For both PFS and OS meta-analyses, the between-study heterogeneity was high (Higgins and Thompson I² of 69% and 80%, respectively). The pooled hazard ratio was 1.47 (95% confidence interval [CI]: 1.13–1.90) for PFS and 1.69 (95% CI: 1.25–2.29) for OS revealing a significantly reduced survival in patients with NSCLC exposed to antibiotics. The median OS was reduced on average by 6.7 months (95% CI: 5.1–8.4) in the patients exposed to antibiotics. The effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics [−60 days; +60 days] around ICI initiation. In patients with NSCLC, the findings of the meta-analysis indicate that antibiotic use before or during treatment with ICI leads to a median OS decreased by more than 6 months. Specifically, exposure shortly before or after ICI initiation seems to be particularly detrimental, whereas antibiotic use later during disease course does not seem to alter survival. Because PFS and OS were difficult to compare between studies owing to heterogeneity and the multiple confounding factors identified, further studies are needed to strengthen the understanding of this phenomenon.     

Bevacizumab Plus Atezolizumab After Progression on Atezolizumab Monotherapy in Pretreated Patients With NSCLC: An Open-Label,Two-Stage,Phase 2 Trial

IntroductionVascular endothelial growth factor promotes an immunosuppressive tumor microenvironment that can be reverted by an antiangiogenic therapy. This two-stage, phase 2 study aimed to determine the treatment efficacy of adding bevacizumab to atezolizumab in patients with metastatic NSCLC whose disease had progressed after atezolizumab monotherapy.MethodsImmune checkpoint inhibitor–naive patients with NSCLC, without EGFR or ALK alterations, whose disease progressed after at least one line of platinum-based chemotherapy were eligible. The patients received atezolizumab 1200 mg once every 3 weeks until radiographic progression (stage I). Then, bevacizumab 15 mg/kg was combined with atezolizumab 1200 mg once every 3 weeks (stage II). The primary end point was the disease control rate (DCR) confined to stage II.ResultsA total of 42 and 24 patients were enrolled in stages I and II, respectively. Most patients had negative programmed death ligand-1 expression (71.4%) and received one or two lines of therapy (95.2%). In stage I, patients achieved a DCR of 35.7% (95% confidence interval [CI]: 21.6–52.0). In stage II, three (12.5%) and 18 (75.0%) of 24 patients had partial response and stable disease, respectively, leading to a DCR of 87.5% (95% CI: 67.6–97.3). For 24 patients enrolled in stage II, the median progression-free survival was 5.6 (95% CI: 4.1–7.1) months and the overall survival was 14.0 (95% CI: 10.7–17.4) months. Treatment-related adverse events occurred in 25% of the patients in stage II, but all were of grade 1 or 2.ConclusionsCombination of bevacizumab plus atezolizumab for patients with metastatic NSCLC whose disease had progressed after atezolizumab monotherapy was found to have a promising antitumor activity with good tolerability.     

Neoadjuvant Immunotherapy for NSCLC: Current Concepts and Future Approaches

Lung cancer is the leading cause of cancer-related deaths worldwide. Patients with resectable NSCLC are often treated with surgery and adjuvant chemotherapy. However, these patients continue to have a high risk of recurrence and death. Unfortunately, there has been little progress in the treatment of resectable NSCLC over the past several decades. Neoadjuvant therapy, which has been considered as an approach to improve survival in patients with resectable NSCLC, is a hotly debated topic. A systematic review of 32 randomized trials involving 10,000 patients revealed that there was no difference in survival between preoperative and postoperative chemotherapy. Because of such results and the theoretical concern about resectable tumors progressing on relatively ineffective neoadjuvant chemotherapy, and thus becoming unresectable, neoadjuvant chemotherapy fell out of favor, and many clinicians preferred adjuvant chemotherapy after surgery. However, neoadjuvant therapy has been revived in the past couple of years, with emerging data from various ongoing trials suggesting that neoadjuvant immunotherapy may have significant efficacy and could potentially improve the survival of patients with resectable NSCLC. In this review article, we discuss the evidence supporting the role of neoadjuvant immunotherapy in the multimodal management of resectable NSCLC. We summarize early results of ongoing clinical trials and highlight the challenges in adopting a uniform definition of treatment “success.” We address hurdles to be overcome for seeking regulatory approval for neoadjuvant immunotherapy and establishing it as a standard of care. Finally, we provide some perspectives for the future.     

Double Trouble: A Case Series on Concomitant Genetic Aberrations in NSCLC

Several oncogenic drivers have been identified in non–small cell lung cancer. Targeted therapies for these aberrations have already been successfully developed and implemented in clinical practice. Owing to improved sensitivity in genetic testing, more and more tumors with multiple driver mutations are identified, resulting in dilemmas for treating physicians whether and which targeted therapy to use. In this case series, we provide an overview of patients with intrinsic double mutations in oncogenic drivers and their reported response to targeted therapies, with a focus on epidermal growth factor receptor, anaplastic lymphoma kinase, cMET, and Kirsten rat sarcoma viral oncogene. We also include an unpublished case report on a patient with an epidermal growth factor receptor L858R and cMET exon 14 skipping.     

Assessment of Immune-Related Interstitial Lung Disease in Patients With NSCLC Treated with Immune Checkpoint Inhibitors: A Multicenter Prospective Study

IntroductionProgrammed cell death protein 1 immune checkpoint inhibitors (ICIs) have been reported to improve the survival of patients with NSCLC. On the expansion of clinical administration for a variety of cancers, immune-related adverse events have been typically recognized to be associated with ICIs, therefore, necessitating the monitoring and management of these patients. Among immune-related adverse events, immune-related interstitial lung disease (ir-ILD) is a serious complication that interrupts treatment and can occasionally be fatal. However, no prospective studies have investigated the incidence of ir-ILD and associated risk factors for its development in the clinical setting.MethodsThis is a prospective cohort study consisting of patients with NSCLC treated with ICIs. Baseline characteristics, including laboratory data, pulmonary function tests, daily symptoms of dyspnea defined by the modified Medical Research Council, and antitumor response were assessed.ResultsAmong the 138 patients with NSCLC who received anti–programmed cell death protein 1 monotherapy, 20 patients (14.5%) had ir-ILD within median 51.5 days (interquartile range: 29–147). This was approximately three times higher than those in clinical trials. A total of 11 patients (55.0%), including all eight patients with high-grade ir-ILD (≥grade 3), developed ir-ILD within 60 days. Impaired spirometry, decreased forced vital capacity and forced expiratory volume in 1 second, and daily symptoms of dyspnea measured using the modified Medical Research Council scale were identified as risk factors for ir-ILD development. In addition, combination assessment of forced vital capacity and forced expiratory volume in 1 second successfully classified patients at risk for ir-ILD development.ConclusionsThe incidence of ir-ILD was substantially higher in the clinical setting. Assessment of spirometry and daily dyspneic symptoms before ICI treatment may be useful in monitoring and managing patients with NSCLC.     

Hypersensitivity Reactions to Selpercatinib Treatment With or Without Prior Immune Checkpoint Inhibitor Therapy in Patients With NSCLC in LIBRETTO-001

IntroductionImmune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts.MethodsData from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine.ResultsOf 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4).ConclusionsRates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible.     

Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non–Small Cell Lung Cancer

Introduction

Immune checkpoint inhibitors (ICIs) are standard therapies in advanced NSCLC. Although genotype-directed tyrosine kinase inhibitors represent the standard of care for subsets of oncogene-driven NSCLC, patients may receive ICIs during their disease course. The impact of sequential ICI and tyrosine kinase inhibitor therapy on the risk of hepatotoxicity has not been described.

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations

IntroductionApproximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents.MethodsWe conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines.ResultsA total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non–V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line.ConclusionsIn BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.     

Comprehensive Analysis of EGFR-Mutant Abundance and Its Effect on Efficacy of EGFR TKIs in Advanced NSCLC with EGFR Mutations

IntroductionA qualitative detection method for EGFR mutations is not sufficient to guide precise targeted therapy in clinical practice. The aim of this study was to explore the relationship between the abundance of EGFR mutations and efficacy of EGFR tyrosine kinase inhibitors (TKIs).MethodsWe used the amplification refractory mutation system (ARMS) method optimized with competitive blockers and specific mutation quantitation (ARMS+) to quantitatively evaluate the abundance of EGFR mutations in 201 patients with advanced NSCLC. A cutoff value of the abundance of EGFR mutations was determined by receiver operating characteristic analysis in a training group and validated in a validation group.ResultsThe abundance of EGFR activating mutation by ARMS+ was significantly associated with objective response to EGFR TKIs. The abundance of 19DEL was significantly higher than that of L858R, with cutoff values for 19DEL and L858R of 4.9% and 9.5%, respectively. The median progression-free survival in the high group was significantly longer than that in the low group (19DEL, 15.0 versus 2.0 months [p < 0.001] and L858R, 12.3 versus 2.0 months [p < 0.001]) in the training set. Similar results were also observed in the validation set. Nine of 13 patients harboring T790M mutation achieved a partial response to EGFR TKIs. Most (seven of nine) were identified to have a low abundance of T790M mutation. The abundance of EGFR mutations appeared to be more significantly associated with the copy number of EGFR mutations from circulating tumor DNA in 19DEL group.ConclusionThe abundance of EGFR activating mutation by ARMS+ was significantly associated with objective response to EGFR TKIs. The abundance of EGFR^T790M mutation may have an adverse impact on progression-free survival rather than on objective response rate in patients with advanced EGFR-mutant NSCLC treated with EGFR TKIs.     

A Novel Radiogenomics Biomarker for Predicting Treatment Response and Pneumotoxicity From Programmed Cell Death Protein or Ligand-1 Inhibition Immunotherapy in NSCLC

IntroductionPatient selection for checkpoint inhibitor immunotherapy is currently guided by programmed death-ligand 1 (PD-L1) expression obtained from immunohistochemical staining of tumor tissue samples. This approach is susceptible to limitations resulting from the dynamic and heterogeneous nature of cancer cells and the invasiveness of the tissue sampling procedure. To address these challenges, we developed a novel computed tomography (CT) radiomic-based signature for predicting disease response in patients with NSCLC undergoing programmed cell death protein 1 (PD-1) or PD-L1 checkpoint inhibitor immunotherapy.MethodsThis retrospective study comprises a total of 194 patients with suitable CT scans out of 340. Using the radiomic features computed from segmented tumors on a discovery set of 85 contrast-enhanced chest CTs of patients diagnosed with having NSCLC and their CD274 count, RNA expression of the protein-encoding gene for PD-L1, as the response vector, we developed a composite radiomic signature, lung cancer immunotherapy—radiomics prediction vector (LCI-RPV). This was validated in two independent testing cohorts of 66 and 43 patients with NSCLC treated with PD-1 or PD-L1 inhibition immunotherapy, respectively.ResultsLCI-RPV predicted PD-L1 positivity in both NSCLC testing cohorts (area under the curve [AUC] = 0.70, 95% confidence interval [CI]: 0.57–0.84 and AUC = 0.70, 95% CI: 0.46–0.94). In one cohort, it also demonstrated good prediction of cases with high PD-L1 expression exceeding key treatment thresholds (>50%: AUC = 0.72, 95% CI: 0.59–0.85 and >90%: AUC = 0.66, 95% CI: 0.45–0.88), the tumor’s objective response to treatment at 3 months (AUC = 0.68, 95% CI: 0.52–0.85), and pneumonitis occurrence (AUC = 0.64, 95% CI: 0.48–0.80). LCI-RPV achieved statistically significant stratification of the patients into a high- and low-risk survival group (hazard ratio = 2.26, 95% CI: 1.21–4.24, p = 0.011 and hazard ratio = 2.45, 95% CI: 1.07–5.65, p = 0.035).ConclusionsA CT radiomics-based signature developed from response vector CD274 can aid in evaluating patients’ suitability for PD-1 or PD-L1 checkpoint inhibitor immunotherapy in NSCLC.     

Immune Checkpoint Inhibitors in Thoracic Malignancies: Review of the Existing Evidence by an IASLC Expert Panel and Recommendations

In the past 10 years, a deeper understanding of the immune landscape of cancers, including immune evasion processes, has allowed the development of a new class of agents. The reactivation of host antitumor immune response offers the potential for long-term survival benefit in a portion of patients with thoracic malignancies.The advent of programmed cell death protein 1/programmed death ligand-1 immune checkpoint inhibitors (ICIs), both as single agents and in combination with chemotherapy, and more recently, the combination of ICI, anti–programmed cell death protein 1, and anticytotoxic T-lymphocyte antigen 4 antibody, have led to breakthrough therapeutic advances for patients with advanced NSCLC, and to a lesser extent, patients with SCLC. Encouraging activity has recently emerged in pretreated patients with thymic carcinoma (TC). Conversely, in malignant pleural mesothelioma, pivotal positive signs of activity have not been fully confirmed in randomized trials. The additive effects of chemoradiation and immunotherapy suggested intriguing potential for therapeutic synergy with combination strategies. This has led to the introduction of ICI consolidation therapy in stage III NSCLC, creating a platform for future therapeutic developments in earlier-stage disease. Despite the definitive clinical benefit observed with ICI, primary and acquired resistance represent well-known biological phenomena, which may affect the therapeutic efficacy of these agents.The development of innovative strategies to overcome ICI resistance, standardization of new patterns of ICI progression, identification of predictive biomarkers of response, optimal treatment duration, and characterization of ICI efficacy in special populations, represent crucial issues to be adequately addressed, with the aim of improving the therapeutic benefit of ICI in patients with thoracic malignancies.In this article, an international panel of experts in the field of thoracic malignancies discussed these topics, evaluating currently available scientific evidence, with the final aim of providing clinical recommendations, which may guide oncologists in their current practice and elucidate future treatment strategies and research priorities.     

Beyond Steroids: Immunosuppressants in Steroid-Refractory or Resistant Immune-Related Adverse Events

IntroductionThe optimal management for immune-related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants on the basis of case reports and expert opinion.MethodsWe evaluated patients with lung cancers at Memorial Sloan Kettering Cancer Center treated with immune checkpoint blockade from 2011 to 2020. Pharmacy records were queried to identify patients who received systemic steroids and an additional immunosuppressant (e.g., tumor necrosis factor-α inhibitor, mycophenolate mofetil). Patient records were manually reviewed to evaluate baseline characteristics, management, and outcomes.ResultsAmong 2750 patients with lung cancers treated with immune checkpoint blockade, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (tumor necrosis factor-α inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after the start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (five of six) and colitis (18 of 27) but less common in neuromuscular (one of five) and pneumonitis (3 of 10). Of the patients who died, 8 of 13 were attributable directly to the irAE and 4 of 13 were related to toxicity from immunosuppression (three infection-related deaths, one drug-induced liver injury leading to acute liver failure).ConclusionsSteroid-refractory or resistant irAEs events are rare. Although existing treatments help patients with hepatitis and colitis, many patients with other irAEs remain refractory or experience toxicities from immunosuppression. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically-informed treatments for severe irAEs.     

Impact of Age on Outcomes with Immunotherapy in Patients with Non–Small Cell Lung Cancer

Introduction

Immunotherapy has revolutionized the treatment of NSCLC, but little is known about the activity of programmed cell death 1 and programmed death ligand 1 blockade across age groups.

Adequacy of Intraoperative Nodal Staging during Surgical Resection of NSCLC: Influencing Factors and Its Relationship to Survival

IntroductionAdequate intraoperative lymph node sampling is a fundamental part of lung cancer surgery, but adherence to standards is not well known. This study sought to measure the adequacy of intraoperative lymph node sampling at a regional Thoracic Surgery Centre and a tertiary lung cancer center in the United Kingdom.MethodsThis retrospective study analyzed the pathological reports from NSCLC resections over the 4-year period 2011–2014. Adequacy of sampling was assessed against International Association for the Study of Lung Cancer recommendations of at least three mediastinal lymph node stations: station 7 in all patients, station 5 or 6 in left upper lobe tumors, and station 9 in lower lobe tumors. The influence of clinical variables (age, tumor T stage, type of surgery, and laterality) on adequacy of sampling and the effect of adequacy on overall survival were also assessed.ResultsA total of 1301 NSCLC resections were performed from January 11, 2011, to December 31, 2014. Adequate intraoperative lymph node sampling increased significantly from 14% (22 of 160) in 2011 to 53% (206 of 390) in 2014 (p = 0.001). Secondary analysis of clinical variables also revealed that patients with T1a or T4 tumors, those undergoing sublobar resections, those undergoing video-assisted thoracic surgery resections, and those undergoing left-sided resections have significantly higher rates of inadequate lymph node sampling. Overall, there was no statistically significant difference in survival between patients with adequate versus inadequate intraoperative lymph node sampling or when survival was stratified according to overall stage. There was worse survival in inadequate sampling for patients with pN2 disease than for patients with pN2 disease and adequate sampling.ConclusionThis study provides a much-needed benchmark of current thoracic surgical practice in lung cancer in the United Kingdom and important granularity to facilitate changes to improve adequacy of staging.     

Programmed Death-Ligand 1 Copy Number Alteration as an Adjunct Biomarker of Response to Immunotherapy in Advanced NSCLC

IntroductionThis study aimed to evaluate the value of programmed death-ligand 1 (PD-L1) copy number (CN) alteration as an additional biomarker to standard immunohistochemistry (IHC) in predicting response to immune checkpoint inhibitor (ICI) therapy in advanced NSCLC.MethodsBefore ICI monotherapy, tumor PD-L1 CN alteration (gain, neutral, or loss) was called using whole-exome sequencing data and compared with IHC results (tumor proportion score ≥50, 1–49, or 0). Progression-free survival (PFS) and overall survival were correlated with both biomarkers. In addition, the impact of CN alteration was further evaluated in two independent cohorts using next-generation sequencing panel.ResultsA total of 291 patients with advanced-stage NSCLC met the study inclusion criteria. Although the IHC classification distinguished the best responsive group (tumor proportion score ≥ 50), the CN-based classification distinguished the worst responsive group (CN loss) from the others (PFS, p = 0.020; overall survival, p = 0.004). After adjusting for IHC results, CN loss was an independent risk factor for progression (adjusted hazard ratio = 1.32, 95% confidence interval: 1.00–1.73, p = 0.049) and death (adjusted hazard ratio = 1.39, 95% confidence interval: 1.05–1.85, p = 0.022). A risk classification system was developed on the basis of IHC and CN profiles, which outperformed the conventional IHC system. In the validation cohorts, CN loss determined by next-generation sequencing panel was independently associated with worse PFS after ICI treatment, revealing its practical value.ConclusionsThis is the first study to directly compare CN alterations with IHC results and survival outcomes after anti–PD-(L)1 therapy. Tumor PD-L1 CN loss can serve as an adjunct biomarker to predict the lack of response. Prospective studies are required to further validate this biomarker.