Repotrectinib's Clinical Benefit and Its Brain Penetration in a Patient with Meningeal Carcinomatosis from G2032R-Mutated ROS-1 Positive Non-Small Cell Lung Cancer.

In this work, we report on a clinically significant response of meningeal carcinomatosis to repotrectinib in a woman with a heavily pretreated ROS1-rearranged non-small cell lung cancer (NSCLC) that harbored the concomitant solvent front G2032R mutation. Meningeal carcinomatosis has a higher incidence in oncogene addicted NSCLC due to increased life expectancy, yet no report has ever documented the activity of repotrectinib in this context. In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood-brain barrier.

Optimizing the risk stratification of astrocytic tumors by applying the cIMPACT-NOW Update 3 signature: real-word single center experience.

Our work reports implementation of a useful genetic diagnosis for the clinical managment of patients with astrocytic tumors. We investigated 313 prospectively recruited diffuse astrocytic tumours by applying the cIMPACT-NOW Update 3 signature. The cIMPACT-NOW Update 3 (cIMPACT-NOW 3) markers, i.e., alterations of TERT promoter, EGFR, and/or chromosome 7 and 10, characterized 96.4% of IDHwt cases. Interestingly, it was also found in 48,5% of IDHmut cases. According to the genomic profile, four genetic subgroups could be distinguished: (1) IDwt/cIMPACT-NOW 3 (n = 270); (2) IDHwt/cIMPACT-NOW 3 negative (= 10); (3) IDHmut/cIMPACT-NOW 3 (n = 16); and 4) IDHmut/cIMPACT-NOW 3 negative (n = 17). Multivariate analysis confirmed that IDH1/2 mutations confer a favorable prognosis (IDHwt, HR 2.91 95% CI 1.39-6.06), and validated the prognostic value of the cIMPACT-NOW 3 signature (cIMPACT-NOW 3, HR 2.15 95% CI 1.15-4.03). To accurately identify relevant prognostic categories, overcoming the limitations of histopathology and immunohistochemistry, molecular-cytogenetic analyses must be fully integrated into the diagnostic work-up of astrocytic tumors.

BRAFV600 variant allele frequency predicts outcome in metastatic melanoma patients treated with BRAF and MEK inhibitors.

BACKGROUND: The prognostic impact of variant allele frequency (VAF) on clinical outcome in BRAFV600 mutated metastatic melanoma patients (MMPs) receiving BRAF (BRAFi) and MEK inhibitors (MEKi) is unclear. MATERIALS AND METHODS: A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of three Italian Melanoma Intergroup centres. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines. RESULTS: Overall, 107 MMPs were included in the study. The VAF cut-off determined by ROC curve was 41.3%. At multivariate analysis, progression-free survival (PFS) was significantly shorter in patients with M1c/M1d [HR 2.25 (95% CI 1.41-3.6, p < 0.01)], in those with VAF >41.3% [HR 1.62 (95% CI 1.04-2.54, p < 0.05)] and in those with ECOG PS ≥1 [HR 1.82 (95% CI 1.15-2.88, p < 0.05)]. Overall survival (OS) was significantly shorter in patients with M1c/M1d [HR 2.01 (95% CI 1.25-3.25, p < 0.01)]. Furthermore, OS was shorter in patients with VAF >41.3% [HR 1.46 (95% CI 0.93-2.29, p = 0.06)] and in patients with ECOG PS ≥1 [HR 1.52 (95% CI 0.94-2.87, p = 0.14)]. BRAF gene amplification was found in 11% and 7% of samples in the training and validation cohort, respectively. CONCLUSIONS: High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7%-11% of patients.

Lorlatinib beyond progression plus platinum/pemetrexed for ALK-positive non-small cell lung cancer patients: report of two cases.

Lorlatinib is an active treatment for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) pretreated with ALK-tyrosine kinase inhibitors (-TKIs). However, there is paucity of data on the activity of platinum/pemetrexed chemotherapy administered at the time of progression on lorlatinib. In addition, it is uncertain whether continuation of lorlatinib beyond progression (LBP) would provide any additional clinical benefit. Here, we describe two cases experiencing an exceptional response to platinum/pemetrexed chemotherapy plus LBP and make an attempt to identify which patients' characteristics and biologic profiles of the tumor could predict benefit from such an approach. In this report, presence of controlled brain metastases, rapidly progressing extracranial disease, and presence of ALK-dependent mechanisms of resistance were associated with benefit from platinum/pemetrexed chemotherapy plus lorlatinib beyond progression.

Effectiveness of a phone-based nurse monitoring assessment and intervention for chemotherapy-related toxicity: A randomized multicenter trial.

Purpose: Anticancer treatment-related toxicities can impact morbidity and mortality, hamper the administration of treatment, worsen the quality of life and increase the burden on the healthcare system. Therefore, their prompt identification is crucial. NICSO (Italian Network for Supportive Care in Cancer) conducted a nationwide randomized trial to evaluate the role of a planned, weekly phone-based nurse monitoring intervention to prevent and treat chemotherapy, targeted therapy- and immunotherapy-related toxicities. Here, we report the results from the chemotherapy arm. Methods: This was a nationwide, randomized, open-label trial conducted among 29 Italian centers (NCT04726020) involving adult patients with breast, colon, or lung cancer and a life expectancy ≥6 months receiving adjuvant chemotherapy. Patients received either a weekly nurse monitoring phone call and an educational leaflet reporting practical advice about prevention and treatment of toxicities (experimental group) or the educational leaflet only (control group). Results: The addition of a nurse monitoring intervention may help reduce time spent with severe toxicities (grade ≥3), particularly those less frequently reported in clinical practice, such as fatigue. When considering grade 1-2 AEs, times with mild/moderate diarrhea, mucositis, fatigue and pain were shorter in the experimental arm. Time spent without AEs was significantly longer in the experimental arms for all the toxicities. The requirement for special medical attention was comparable between groups. Conclusion: This study suggests the need for implementing a better system of toxicity assessment and management for patients treated with adjuvant chemotherapy to promote effective preventive and/or therapeutic intervention against these events.

Targeting inflamed and non-inflamed melanomas: biological background and clinical challenges.

Immune checkpoint inhibitors (ICIs) have demonstrated impressive antitumor activity in patients with advanced and early stage melanoma, thus improving long-term survival outcomes. However, most patients derive limited benefit from immunotherapy, due to the development of primary, adaptive, or acquired resistance mechanisms. Immunotherapy resistance is a complex phenomenon that depends on genetic and epigenetic mechanisms which, in turn, drive the interplay between cancer cells and the tumor microenvironment (TME). Immunologically "cold" (i.e. non-inflamed) tumors lack or have few tumor infiltrating lymphocytes (TILs) as a result of low tumor mutational burden (TMB), defective antigen presentation, or physical barriers to lymphocyte migration, resulting in a minimal benefit from immunotherapy. In contrast, in most cases immunologically "hot" (i.e. inflamed) tumors display high TMB, implying a higher load of neoantigens and increased programmed cell death ligand 1 (PD-L1) expression, with a consequently higher rate of TILs. However, the presence of TILs does not necessarily denote the tumor as immunologically "hot", since the presence of tumor-specific CD8+ T cells persistently exposed to antigenic stimulation induces a dysfunctional state called "exhaustion", which leads to a reduced response to immunotherapy. In recent years, efforts have been made to characterize mechanisms of resistance to immunotherapy, and to investigate strategies to overcome treatment resistance. Indeed, predictors of response and toxicity to immunotherapy are still lacking and, to date, there are no reliable predictive biomarkers to select patients according to baseline clinical, histological, or genomic characteristics. In this review, we will focus on the morphologic and immunohistochemical characteristics of the TME, and on the molecular determinants of resistance to immunotherapy, differentiating between inflamed and non-inflamed melanomas. Then, we will provide a thorough overview of preclinical data on genetic and epigenetic mechanisms with a potential impact on the immune response and patient outcome. Finally, we will focus our attention on the role of potential biomarkers in determining disease response to immunotherapy, in the adjuvant and metastatic setting, providing an insight into current and future research in this field.

ICH in primary or metastatic brain cancer patients with or without anticoagulant treatment: a systematic review and meta-analysis.

Anticoagulant treatment in patients with primary and metastatic brain cancer is a concern due to risk of intracranial hemorrhage (ICH). We performed a systematic review and meta-analysis to evaluate the risk of ICH in patients with primary or metastatic brain cancer treated with or without anticoagulants. Articles on ICH in patients with primary or metastatic brain cancer treated with or without anticoagulants published up to September 2021 were identified by searching PubMed, EMBASE, and Cochrane Library databases. The primary outcome of this analysis was ICH. Thirty studies were included. Rate of ICH was 13.0% in 1009 patients with metastatic brain cancer and 6.4% in 2353 patients with primary brain cancer (relative risk [RR], 3.26; 95% confidence interval [CI], 2.69-3.94; I2 = 92.8%). In patients with primary brain cancer, ICH occurred in 12.5% and 4.4% of patients treated with or without anticoagulants, respectively (11 studies, 659 treated and 1346 not treated patients; RR, 2.63; 95% CI, 1.48-4.67; I2 = 49.6%). In patients with metastatic brain cancer, ICH occurred in 14.7% and 15.4% (5 studies, 265 treated and 301 not treated patients; RR, 0.92; 95% CI, 0.43-1.93; I2 = 0%). ICH occurred in 8.3% of 172 treated with direct oral anticoagulants (DOACs) and in 11.7% of 278 treated with low-molecular weight heparin (LMWH) (5 studies; RR, 0.44; 95% CI, 0.25-0.79; I2 = 0%). Patients with metastatic brain cancer have a particularly high risk of ICH. Patients with primary brain cancer have an increased risk of ICH during anticoagulation. DOACs are associated with a lower risk of ICH than LMWH.

Inflamed Tumor Phenotype as Predictor of Long-Term Response to Pembrolizumab in an EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC) Patient with Acquired Resistance to Afatinib: a Case Report and Review of the Literature.

Treatment with immune checkpoint inhibitors (ICIs) that target the programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) axis is usually ineffective in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC), either as first-line treatment or in later lines. By contrast, especially for patients with common EGFR mutations (exon 19 deletion/L858R point mutation), an orally bioavailable EGFR tyrosine kinase inhibitor (EGFR-TKI) is the best upfront therapy, being able to provide response rates well above 50% and a median progression-free survival ranging from 11 to 19 months, depending on whether a second-generation (e.g., afatinib) or a third-generation (i.e., osimertinib) EGFR-TKI is used. Unfortunately, treatment options for these patients at the time of acquired resistance are limited. As for afatinib-pretreated patients, those who develop a T790M mutation may benefit from osimertinib, whereas platinum-based chemotherapy is the preferable therapeutic strategy for T790M-negative patients as well as for patients who progress on osimertinib administered as first-line therapy. Here, we describe the case of an exon-19-deleted patient who experienced a complete response to the anti-PD-1 agent pembrolizumab upon the development of T790M-negative acquired resistance to afatinib. Furthermore, we discuss this case in the context of the existing literature, especially focusing on the importance of evaluating multiple markers of immune response post-EGFR-TKI and prior to ICI treatment in order to select the best treatment strategy in this clinical scenario.

Vascular events with immune checkpoint inhibitors in melanoma or non-small cell lung cancer: A systematic review and meta-analysis.

The incidence of venous and arterial thromboembolic events in advanced cancer patients treated with immune checkpoint inhibitors (ICIs) has been sporadically reported. We performed a systematic review and meta-analysis to assess the rate of vascular events in patients with melanoma and non-small cell lung cancer (NSCLC) treated with ICIs. A systematic search of MEDLINE and EMBASE was performed to identify randomized clinical trials and prospective studies. The main outcomes were venous thromboembolism (VTE), stroke or systemic embolism (SE) and myocardial infarction (MI). Secondary outcomes were fatal VTE, fatal stroke or SE and fatal MI. Pooled proportions with 95% confidence intervals (CI) were calculated using random-effects models. A total of 59 trials, 25 in 5,578 patients with melanoma and 34 in 6,543 patients with NSCLC were included. In patients with melanoma, rates of VTE, stroke or SE and MI were 1.5% (95% CI 0.8-2.8), 1.7% (95% CI 0.8-3.7) and 0.4% (95% CI 0.2-0.9), respectively. In patients with NSCLC, corresponding rates were 1.9% (95% CI 1.2-3.2), 1.2% (95% CI 0.6-2.5), and 1.1% (95% CI 0.5-2.1), respectively. Rates of fatal VTE and MI were similar in melanoma and NSCLC patients. Rates of fatal stroke or SE were 1.9% (95% CI 0.4-9.5) and 0.7% (95% CI 0.2-2.3) in melanoma and NSCLC patients, respectively. Rates of VTE (3.1% vs. 1.1%) and myocardial infarction (3.4% Vs. 0.5%) were numerically higher in NSCLC patients treated with combined-ICIs vs mono-ICIs. Our study shows a not negligible rate of vascular events in patients with melanoma or NSCLC treated with ICIs.

Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, their clinical benefit is limited to a minority of patients. To unravel immune-related factors that are predictive of sensitivity or resistance to immunotherapy, we performed a gene expression analysis by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) on a total of 33 advanced NSCLC patients treated with ICI evaluating the expression levels of 365 immune-related genes. We found four genes (CD1C, HLA-DPA1, MMP2, and TLR7) downregulated (p < 0.05) and two genes (IFNB1 and MKI67) upregulated (p < 0.05) in ICI-Responders compared to ICI-Non-Responders. The Bayesian enrichment computational analysis showed a more complex interaction network that involved 10 other genes (IFNA1, TLR4, CD40, TLR2, IL12A, IL12B, TLR9, CD1E, IFNG, and HLA-DPB1) correlated with different functional groups. Five main pathways were identified (FDR < 0.0001). High TLR7 expression levels were significantly associated with a lack of response to immunotherapy (p < 0.0001) and worse outcome in terms of both PFS (p < 0.001) and OS (p = 0.03). The multivariate analysis confirmed TLR7 RNA expression as an independent predictor for both poor PFS (HR = 2.97, 95% CI, 1.16-7.6, p = 0.023) and OS (HR = 2.2, 95% CI, 1-5.08, p = 0.049). In conclusion, a high TLR7 gene expression level was identified as an independent predictor for poor clinical benefits from ICI. These data could have important implications for the development of novel single/combinatorial strategies TLR-mediated for an efficient selection of "individualized" treatments for NSCLC in the era of immunotherapy.

Impact of Circulating and Tissue Biomarkers in Adjuvant and Neoadjuvant Therapy for High-Risk Melanoma: Ready for Prime Time?

The prognosis of patients with metastatic melanoma has substantially improved over the last years with the advent of novel treatment strategies, mainly immune checkpoint inhibitors and BRAF and MEK inhibitors. Given the survival benefit provided in the metastatic setting and the evidence from prospective clinical trials in the early stages, these drugs have been introduced as adjuvant therapies for high-risk resected stage III disease. Several studies have also investigated immune checkpoint inhibitors, as well as BRAF and MEK inhibitors, for neoadjuvant treatment of high-risk stage III melanoma, with preliminary evidence suggesting this could be a very promising approach in this setting. However, even with new strategies, the risk of disease recurrence varies widely among stage III patients, and no available biomarkers for predicting disease recurrence have been established to date. Improved risk stratification is particularly relevant in this setting to avoid unnecessary treatment for patients who have minimum risk of disease recurrence and to reduce toxicities and costs. Research for predictive and prognostic biomarkers in this setting is ongoing to potentially shed light on the complex interplay between the tumor and the host immune system, and to further personalize treatment. This review provides an insight into available data on circulating and tissue biomarkers, including the tumor microenvironment and associated gene signatures, and their predictive and prognostic role during neoadjuvant and adjuvant treatment for cutaneous high-risk melanoma patients.

Sensitivity to Immune Checkpoint Blockade in Advanced Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations.

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16-OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis (p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation.

Immune checkpoint inhibitors for unresectable malignant pleural mesothelioma.

Unresectable malignant pleural mesothelioma (MPM) is an aggressive disease with a 5-year survival rate of approximately 10%. Recent data suggest that MPM is an immunologically active tumor, in which checkpoint inhibition through the blockade of the anti-cytotoxic T lymphocyte antigen-4 (-CTLA-4) or anti-programmed cell death 1 (PD-1) could play a major therapeutic role. Initially, clinical trials evaluated immune checkpoint inhibitors (ICIs) in the salvage setting after platinum-based chemotherapy with mixed results in terms of efficacy. More recently, the combination of the anti-CTLA-4 agent ipilimumab plus the anti-PD-1 agent nivolumab was tested in the front-line setting, and reported a superior survival as compared to platinum/pemetrexed. While other clinical trials ore ongoing in order to investigate ICIs for MPM, it seems now evident that we have entered a new "era" for the treatment of MPM. In the future, a few issues need to be solved with regard to the use of ICIs for MPM. Among them, there is the identification of biomarkers of sensitivity to immunotherapy that may help enrich the patient population who could benefit the most from treatment, while avoiding for some other patients the potential occurrence of immune-related side effects from therapies that are anticipated to be ineffective.

Supportive Care: Low Cost, High Value.

Supportive care aims to prevent and manage adverse effects of cancer and its treatment across the entire disease continuum. Research and clinical experience in dedicated centers have demonstrated that early appropriate supportive care interventions improve symptoms, quality of life, and overall survival in a cost-effective manner. The challenge is to assess symptoms and needs with validated tools regularly and, ideally, between clinic appointments; electronic patient-reported outcome measures and dedicated easily accessible supportive care units can help. As management of certain problems improves, others come to the fore. Cancer-related fatigue and malnutrition are very frequent and need regular screening, assessment of treatable causes, and early intervention to improve. Pharmacologic agents and phytopharmaceuticals are of little use, but other interventions are valuable: physical exercise, counseling on fatigue, and cognitive behavioral therapy/mind-body interventions (e.g., for fatigue). Nutrition should be oral, rich in proteins, and accompanied by muscle training adapted to the patient's condition. Psychological and societal counseling is often useful; nausea or other problems such as gastrointestinal dysmotility or metabolic derangements must be tackled. Chemotherapy-induced peripheral neuropathy frequently worsens quality of life and has no established prevention strategy (notwithstanding current interest in cryotherapy and compression therapy) and thus requires careful assessment of patient predisposition to develop it with the consideration of feasible dose and treatment alternatives. When painful, duloxetine helps. Nonpharmacologic strategies, including acupuncture, physical exercise, cryotherapy/compression, and scrambler therapy, are promising but require large phase III trials to become the accepted standard. Personalization of chemotherapy, dependent on realistic goals, is key.

High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients.

Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early-stage resectable NSCLC remains unclear. We studied gene expression levels of immune-related genes PD-1, PD-L1, PD-L2, IDO-1, IDO-2 and INFγ in tumor tissue of surgically resected NSCLC and correlated the finding with clinicopathological features and patient outcomes. A total of 191 consecutive early-stage NSCLC patients who underwent curative pulmonary resection were studied. The mRNA expression levels of immune-related genes were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Arrays (Qiagen). PD-1, PD-L2 and IDO-2 gene expression levels were significantly higher in patients with squamous histology (p = 0.001, p = 0.021 and p < 0.001; respectively). PD-1, PD-L1 and IDO-2 gene expression levels were significantly higher in patients with higher stage (p = 0.005, p = 0.048 and p = 0.002, respectively). The univariate analysis for recurrence-free survival (RFS) and overall survival (OS) showed that patients with higher levels of three-genes (PD-L1/PD-L2/INFγ) (hazard ratio (HR)) 1.90 (95% confidence interval (CI), 1.13-3.21), p = 0.015) were associated with a worse RFS, while patients with higher levels of both genes (PD-L1/IDO-2) or (PD-L2/IDO-1) were associated with a worse OS (HR 1.63 95% CI, 1.06-2.51, p = 0.024; HR 1.54 95% CI, 1.02-2.33, p = 0.04; respectively). The multivariate interaction model adjusted for histology and stage confirmed that higher levels of three genes (PD-L1/PD-L2/INFγ) were significantly associated with worse RFS (HR 1.98, p = 0.031) and higher levels of both genes (PD-L1/IDO-2) and (PD-L2/IDO-1) with worse OS (HR 1.98, p = 0.042, HR 1.92, p = 0.022). PD-L1/IDO-2 and PD-L2/IDO-1 co-expression high levels are independent negative prognostic factors for survival in early NSCLC. These features may have important implications for future immune-checkpoint therapeutic approaches.

Molecular Profiling and Novel Therapeutic Strategies for Mucosal Melanoma: A Comprehensive Review.

Mucosal melanoma is a rare and aggressive subtype of melanoma. Unlike its cutaneous counterpart, mucosal melanoma has only gained limited benefit from novel treatment approaches due to the lack of actionable driver mutations and poor response to immunotherapy. Over the last years, whole-genome and exome sequencing techniques have led to increased knowledge on the molecular landscape of mucosal melanoma. Molecular studies have underlined noteworthy findings with potential therapeutic implications, including the presence of KIT mutations, which are potential targets of tyrosine kinase inhibitors currently in use in the clinic (imatinib), but also SF3B1 mutation, CDK4 amplifications, and CDKN2A gene deletions, which are presently under investigation in clinical trials. Recent results from a pooled analysis of patients with mucosal melanoma treated with immunotherapy have suggested that the combination of immune checkpoint inhibitors might improve survival outcomes in this subset of patients, as compared with single-agent immunotherapy. However, these results are not confirmed across different studies, and combo-immunotherapy correlates with a higher rate of adverse events. In this review, we describe the clinical, biological, and genetic features of mucosal melanoma. We also provide an update on the results of approved systemic treatment in this setting and overview the therapeutic strategies currently under investigation in clinical trials.

Steroid Use Independently Predicts for Poor Outcomes in Patients With Advanced NSCLC and High PD-L1 Expression Receiving First-Line Pembrolizumab Monotherapy.

BACKGROUND: Real-world data have suggested a detrimental effect of steroid use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immunotherapy. However, previous studies included heterogeneous cohorts of patients receiving different lines of treatment with several immuno-oncology agents and various combinations of chemotherapy and immuno-oncology agents. PATIENTS AND METHODS: A comprehensive clinicopathologic database of patients with NSCLC and programmed cell death ligand 1 >50% treated with frontline pembrolizumab monotherapy was constructed in 14 centers in Italy, Spain, Greece, and Switzerland. A multivariate analysis adjusting for the established prognostic factors was performed using a Cox regression model. RESULTS: For the 265 eligible patients, the median age at diagnosis was 67 years, 66% were male, 90% were current or former smokers, 18% had had an Eastern Cooperative Oncology Group performance status of 2 or 3. Of the NSCLC subtypes, 64% were adenocarcinoma and 25% were squamous cell. Of the patients, 18% had had brain metastases at diagnosis and 24% had received steroids before or during pembrolizumab treatment. The median time to progression was 4.4 months with and 13.7 months without steroid use (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.69-3.85; log-rank P < .001). The median survival was 22.5 months for the whole cohort, 7.7 months for the steroid group, and not reached for the non-steroid group (HR, 3.64; 95% CI, 2.34-5.68; log-rank P < .001). On multivariate analysis accounting for all established prognostic variables, steroid use was still independently associated with a high risk of progression (HR, 1.864; 95% CI, 1.179-2.949; P = .008) and death (HR, 2.292; 95% CI, 1.441-3.644; P < .001) CONCLUSIONS: In patients with advanced NSCLC and programmed cell death ligand 1 expression > 50% receiving frontline pembrolizumab monotherapy, any use of steroids before or during treatment was associated with an 86% increase in the risk of progression and a 2.3-fold increase in the risk of death, even accounting for palliative indication-related bias, including the presence of central nervous system metastasis. The use of steroids for palliative indications should be restricted to absolutely necessary for patients receiving immuno-oncology monotherapy.