Real-world experience with circulating tumor DNA in cerebrospinal fluid from patients with central nervous system tumors.

The characterization of genetic alterations in tumor samples has become standard practice for many human cancers to achieve more precise disease classification and guide the selection of targeted therapies. Cerebrospinal fluid (CSF) can serve as a source of tumor DNA in patients with central nervous system (CNS) cancer. We performed comprehensive profiling of CSF circulating tumor DNA (ctDNA) in 711 patients using an FDA-authorized platform (MSK-IMPACT™) in a hospital laboratory. We identified genetic alterations in 489/922 (53.0%) CSF samples with clinically documented CNS tumors. None of 85 CSF samples from patients without CNS tumors had detectable ctDNA. The distribution of clinically actionable somatic alterations was consistent with tumor-type specific alterations across the AACR GENIE cohort. Repeated CSF ctDNA examinations from the same patients identified clonal evolution and emergence of resistance mechanisms. ctDNA detection was associated with shortened overall survival following CSF collection. Next-generation sequencing of CSF, collected through a minimally invasive lumbar puncture in a routine hospital setting, provides clinically actionable cancer genotype information in a large fraction of patients with CNS tumors.

Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers and MDM2 Amplification.

PURPOSE: MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. MDM2 amplification (MDM2amp) is mutually exclusive with TP53 mutation and is seen in 6% of patients with lung adenocarcinoma (LUAD), with significant enrichment in subsets with receptor tyrosine kinase (RTK) driver alterations. Recent studies have shown synergistic activity of MDM2 and MEK inhibition in patient-derived LUAD models with MDM2amp and RTK driver alterations. However, the combination of MDM2 and RTK inhibitors in LUAD has not been studied. METHODS: We evaluated the combination of MDM2 and RTK inhibition in patient-derived models of LUAD. RESULTS: In a RET-fusion LUAD patient-derived model with MDM2amp, MDM2 inhibition with either milademetan or AMG232 combined with selpercatinib resulted in long-term in vivo tumor control markedly superior to either agent alone. Similarly, in an EGFR-mutated model with MDM2amp, combining either milademetan or AMG232 with osimertinib resulted in long-term in vivo tumor control, which was strikingly superior to either agent alone. CONCLUSION: These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.

Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-mutant, metastatic non-small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum-based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837). METHODS: Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS. RESULTS: Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients. CONCLUSION: Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Intratumoral Escherichia Is Associated With Improved Survival to Single-Agent Immune Checkpoint Inhibition in Patients With Advanced Non-Small-Cell Lung Cancer.

PURPOSEThe impact of the intratumoral microbiome on immune checkpoint inhibitor (ICI) efficacy in patients with non-small-cell lung cancer (NSCLC) is unknown. Preclinically, intratumoral Escherichia is associated with a proinflammatory tumor microenvironment and decreased metastases. We sought to determine whether intratumoral Escherichia is associated with outcome to ICI in patients with NSCLC.PATIENTS AND METHODSWe examined the intratumoral microbiome in 958 patients with advanced NSCLC treated with ICI by querying unmapped next-generation sequencing reads against a bacterial genome database. Putative environmental contaminants were filtered using no-template controls (n = 2,378). The impact of intratumoral Escherichia detection on overall survival (OS) was assessed using univariable and multivariable analyses. The findings were further validated in an external independent cohort of 772 patients. Escherichia fluorescence in situ hybridization (FISH) and transcriptomic profiling were performed.RESULTSIn the discovery cohort, read mapping to intratumoral Escherichia was associated with significantly longer OS (16 v 11 months; hazard ratio, 0.73 [95% CI, 0.59 to 0.92]; P = .0065) in patients treated with single-agent ICI, but not combination chemoimmunotherapy. The association with OS in the single-agent ICI cohort remained statistically significant in multivariable analysis adjusting for prognostic features including PD-L1 expression (P = .023). Analysis of an external validation cohort confirmed the association with improved OS in univariable and multivariable analyses of patients treated with single-agent ICI, and not in patients treated with chemoimmunotherapy. Escherichia localization within tumor cells was supported by coregistration of FISH staining and serial hematoxylin and eosin sections. Transcriptomic analysis correlated Escherichia-positive samples with expression signatures of immune cell infiltration.CONCLUSIONRead mapping to potential intratumoral Escherichia was associated with survival to single-agent ICI in two independent cohorts of patients with NSCLC.

Tumor-Agnostic Genomic and Clinical Analysis of BRAF Fusions Identifies Actionable Targets.

PURPOSE: Even though BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels, few reports have explored their structure and impact on clinical course. EXPERIMENTAL DESIGN: We collected data from patients with BRAF fusion-positive cancers identified through a genotyping protocol of 97,024 samples. Fusions were characterized and reviewed for oncogenic potential (in-frame status, non-BRAF partner gene, and intact BRAF kinase domain). RESULTS: We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5' fusion partners spanning 52 histologies. Thirty-nine fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliogliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. Twenty-four patients spanning multiple histologies were treated with MAPK-directed therapies, of which 20 were evaluable for RECIST. Best response was partial response (N = 2), stable disease (N = 11), and progressive disease (N = 7). The median time on therapy was 1 month with MEK plus BRAF inhibitors [(N = 11), range 0-18 months] and 8 months for MEK inhibitors [(N = 14), range 1-26 months]. Nine patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N = 6), Erdheim-Chester disease (N = 1), extraventricular neurocytoma (N = 1), and melanoma (N = 1)]. Fifteen patients had acquired BRAF fusions. CONCLUSIONS: BRAF fusions are found across histologies and represent an emerging actionable target. BRAF fusions have a diverse set of fusion partners. Durable responses to MAPK therapies were seen, particularly in pilocytic astrocytomas. Acquired BRAF fusions were identified after targeted therapy, underscoring the importance of postprogression biopsies to optimize treatment at relapse in these patients.

Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

NCCN Guidelines® Insights: Mesothelioma: Pleural, Version 1.2024.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

Biomarker Inference and the Timing of Next-Generation Sequencing in a Multi-Institutional, Cross-Cancer Clinicogenomic Data Set.

PURPOSE: Observational clinicogenomic data sets, consisting of tumor next-generation sequencing (NGS) data linked to clinical records, are commonly used for cancer research. However, in real-world practice, oncologists frequently request NGS in search of treatment options for progressive cancer. The extent and impact of this dynamic on analysis of clinicogenomic research data are not well understood. METHODS: We analyzed clinicogenomic data for patients with non-small cell lung, colorectal, breast, prostate, pancreatic, or urothelial cancers in the American Association for Cancer Research Biopharmaceutical Consortium cohort. Associations between baseline and time-varying clinical characteristics and time from diagnosis to NGS were measured. To explore the impact of informative cohort entry on biomarker inference, statistical interactions between selected biomarkers and time to NGS with respect to overall survival were calculated. RESULTS: Among 7,182 patients, time from diagnosis to NGS varied significantly by clinical factors, including cancer type, calendar year of sequencing, institution, and age and stage at diagnosis. NGS rates also varied significantly by dynamic clinical status variables; in an adjusted model, compared with patients with stable disease at any given time after diagnosis, patients with progressive disease by imaging or oncologist assessment had higher NGS rates (hazard ratio for NGS, 1.61 [95% CI, 1.45 to 1.78] and 2.32 [95% CI, 2.01 to 2.67], respectively). Statistical interactions between selected biomarkers and time to NGS with respect to survival, potentially indicating biased biomarker inference results, were explored. CONCLUSION: To evaluate the appropriateness of a data set for a particular research question, it is crucial to measure associations between dynamic cancer status and the timing of NGS, as well as to evaluate interactions involving biomarkers of interest and NGS timing with respect to survival outcomes.

Single-Cell Sequencing Illuminates Thymic Development: An Updated Framework for Understanding Thymic Epithelial Tumors.

Thymic epithelial tumors (TETs) are rare tumors for which treatment options are limited. The ongoing need for improved systemic therapies reflects a limited understanding of tumor biology as well as the normal thymus. The essential role of the thymus in adaptive immunity is largely effected by its epithelial compartment, which directs thymocyte (T-cell) differentiation and immunologic self-tolerance. With aging, the thymus undergoes involution whereby epithelial tissue is replaced by adipose and other connective tissue, decreasing immature T-cell production. Against this natural drive toward involution, a fraction of thymuses will instead undergo oncologic transformation, leading to the formation of TETs, including thymoma and thymic carcinoma. The rarity of these tumors restricts investigation of the mechanisms of tumorigenesis and development of rational treatment options. To this end, the development of technologies which allow deep molecular profiling of individual tumor cells permits a new window through which to view normal thymic development and contrast the malignant changes that result in oncogenic transformation. In this review, we describe the findings of recent illuminating studies on the diversity of cell types within the epithelial compartment through thymic differentiation and aging. We contextualize these findings around important unanswered questions regarding the spectrum of known somatic tumor alterations, cell of origin, and tumor heterogeneity. The perspectives informed by single-cell molecular profiling offer new approaches to clinical and basic investigation of thymic epithelial tumors, with the potential to accelerate development of improved therapeutic strategies to address ongoing unmet needs in these rare tumors.

A plain language summary of the PHAROS study: the combination of encorafenib and binimetinib for people with BRAF V600E-mutant metastatic non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the results of a study called PHAROS. This study looked at combination treatment with encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®). This combination of medicines was studied in people with metastatic non-small-cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer. Metastatic means that the cancer has spread to other parts of the body. All people in this study had a type of NSCLC that has a change in a gene called BRAF termed a BRAF V600E mutation. A gene is a part of the DNA that has instructions for making things that your body needs to work, and the BRAF V600E mutation contributes to the growth of the lung cancer. WHAT WERE THE RESULTS?: In this study, 98 people with BRAF V600E-mutant metastatic NSCLC were treated with the combination of encorafenib and binimetinib (called encorafenib plus binimetinib in this summary). Before starting the study, 59 people had not received any treatment for their metastatic NSCLC, and 39 people had received previous anticancer treatment. At the time of this analysis, 44 (75%) out of 59 people who did not receive any treatment before taking encorafenib plus binimetinib had their tumors shrink or disappear. Eighteen (46%) out of 39 people who had received treatment before starting encorafenib plus binimetinib also had their tumors shrink or disappear. The most common side effects of encorafenib plus binimetinib were nausea, diarrhea, fatigue, and vomiting. WHAT DO THE RESULTS MEAN?: These results support the use of encorafenib plus binimetinib combination treatment as a new treatment option in people with BRAF V600E-mutant metastatic NSCLC. The side effects of encorafenib plus binimetinib in this study were similar to the side effects seen with encorafenib plus binimetinib in people with a type of skin cancer called metastatic melanoma.

Genomic Characterization and Clinical Outcomes of Patients with Peritoneal Metastases from the AACR GENIE Biopharma Collaborative Colorectal Cancer Registry.

Peritoneal metastases (PM) are common in metastatic colorectal cancer (mCRC). We aimed to characterize patients with mCRC and PM from a clinical and molecular perspective using the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) registry. Patients' tumor samples underwent targeted next-generation sequencing. Clinical characteristics and treatment outcomes were collected retrospectively. Overall survival (OS) from advanced disease and progression-free survival (PFS) from start of cancer-directed drug regimen were estimated and adjusted for the left truncation bias. A total of 1,281 patients were analyzed, 244 (19%) had PM at time of advanced disease. PM were associated with female sex [OR: 1.67; 95% confidence interval (CI): 1.11-2.54; P = 0.014] and higher histologic grade (OR: 1.72; 95% CI: 1.08-2.71; P = 0.022), while rectal primary tumors were less frequent in patients with PM (OR: 0.51; 95% CI: 0.29-0.88; P < 0.001). APC occurred less frequently in patients with PM (N = 151, 64% vs. N = 788, 79%) while MED12 alterations occurred more frequently in patients with PM (N = 20, 10% vs. N = 32, 4%); differences in MED12 were not significant when restricting to oncogenic and likely oncogenic variants according to OncoKB. Patients with PM had worse OS (HR: 1.45; 95% CI: 1.16-1.81) after adjustment for independently significant clinical and genomic predictors. PFS from initiation of first-line treatment did not differ by presence of PM. In conclusion, PM were more frequent in females and right-sided primary tumors. Differences in frequencies of MED12 and APC alterations were identified between patients with and without PM. PM were associated with shorter OS but not with PFS from first-line treatment. SIGNIFICANCE: Utilizing the GENIE BPC registry, this study found that PM in patients with colorectal cancer occur more frequently in females and right-sided primary tumors and are associated with worse OS. In addition, we found a lower frequency of APC alterations and a higher frequency in MED12 alterations in patients with PM.

MIG6 Mediates Adaptive and Acquired Resistance to ALK/ROS1 Fusion Kinase Inhibition through EGFR Bypass Signaling.

Despite the initial benefit from tyrosine kinase inhibitors (TKI) targeting oncogenic ALK and ROS1 gene fusions in non-small cell lung cancer, complete responses are rare and resistance ultimately emerges from residual tumor cells. Although several acquired resistance mechanisms have been reported at the time of disease progression, adaptative resistance mechanisms that contribute to residual diseases before the outgrowth of tumor cells with acquired resistance are less clear. For the patients who have progressed after TKI treatments, but do not demonstrate ALK/ROS1 kinase mutations, there is a lack of biomarkers to guide effective treatments. Herein, we found that phosphorylation of MIG6, encoded by the ERRFI1 gene, was downregulated by ALK/ROS1 inhibitors as were mRNA levels, thus potentiating EGFR activity to support cell survival as an adaptive resistance mechanism. MIG6 downregulation was sustained following chronic exposure to ALK/ROS1 inhibitors to support the establishment of acquired resistance. A higher ratio of EGFR to MIG6 expression was found in ALK TKI-treated and ALK TKI-resistant tumors and correlated with the poor responsiveness to ALK/ROS1 inhibition in patient-derived cell lines. Furthermore, we identified and validated a MIG6 EGFR-binding domain truncation mutation in mediating resistance to ROS1 inhibitors but sensitivity to EGFR inhibitors. A MIG6 deletion was also found in a patient after progressing to ROS1 inhibition. Collectively, this study identifies MIG6 as a novel regulator for EGFR-mediated adaptive and acquired resistance to ALK/ROS1 inhibitors and suggests EGFR to MIG6 ratios and MIG6-damaging alterations as biomarkers to predict responsiveness to ALK/ROS1 and EGFR inhibitors.

Effects of KRAS Genetic Interactions on Outcomes in Cancers of the Lung, Pancreas, and Colorectum.

BACKGROUND: KRAS is among the most commonly mutated oncogenes in cancer, and previous studies have shown associations with survival in many cancer contexts. Evidence from both clinical observations and mouse experiments further suggests that these associations are allele- and tissue-specific. These findings motivate using clinical data to understand gene interactions and clinical covariates within different alleles and tissues. METHODS: We analyze genomic and clinical data from the AACR Project GENIE Biopharma Collaborative for samples from lung, colorectal, and pancreatic cancers. For each of these cancer types, we report epidemiological associations for different KRAS alleles, apply principal component analysis (PCA) to discover groups of genes co-mutated with KRAS, and identify distinct clusters of patient profiles with implications for survival. RESULTS: KRAS mutations were associated with inferior survival in lung, colon, and pancreas, although the specific mutations implicated varied by disease. Tissue- and allele-specific associations with smoking, sex, age, and race were found. Tissue-specific genetic interactions with KRAS were identified by PCA, which were clustered to produce five, four, and two patient profiles in lung, colon, and pancreas. Membership in these profiles was associated with survival in all three cancer types. CONCLUSIONS: KRAS mutations have tissue- and allele-specific associations with inferior survival, clinical covariates, and genetic interactions. IMPACT: Our results provide greater insight into the tissue- and allele-specific associations with KRAS mutations and identify clusters of patients that are associated with survival and clinical attributes from combinations of genetic interactions with KRAS mutations.

Intracranial Outcomes of De Novo Brain Metastases Treated With Osimertinib Alone in Patients With Newly Diagnosed EGFR-Mutant NSCLC.

Introduction: Patients with EGFR-mutant NSCLC have a high incidence of brain metastases. The EGFR-directed tyrosine kinase inhibitor osimertinib has intracranial activity, making the role of local central nervous system (CNS)-directed therapies, such as radiation and surgery, less clear. Methods: Patients with EGFR-mutant NSCLC and brain metastases who received osimertinib as initial therapy after brain metastasis diagnosis were included. Individual lesion responses were assessed using adapted RANO-BM criteria. CNS progression and local progression of brain metastasis from osimertinib start were analyzed using cumulative incidence treating death as a competing risk. Overall survival was estimated using Kaplan-Meier methodology. Results: There were 36 patients who had a median interval from brain metastasis diagnosis to first-line osimertinib initiation of 25 days. In total, 136 previously untreated brain metastases were tracked from baseline. Overall, 105 lesions (77.2%) had complete response and 31 had partial response reflecting best objective response of 100%. Best response occurred at a median of 96 days (range: 28-1113 d) from baseline magnetic resonance imaging. This reflects a best objective response rate of 100%. Two-year overall survival was 80%. CNS progression rates at 1-, 2-, and 3-years post-osimertinib were 21%, 32%, and 41%, respectively. Lesion-level local failure was estimated to be 0.7% and 4.7% at 1- and 2-years post-osimertinib, respectively. No clinicodemographic factors including brain metastasis number were associated with post-osimertinib progression. Conclusions: Intracranial response to osimertinib is excellent for patients with EGFR-mutant NSCLC with de novo, previously untreated brain metastases. Very low local failure rates support a strategy of upfront osimertinib alone in selected patients.

Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

Outcomes of Combination Platinum-Doublet Chemotherapy and Anti-PD(L)-1 Blockade in KRASG12C-Mutant Non-Small Cell Lung Cancer.

BACKGROUND: Direct KRASG12C inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with KRASG12C mutations. PATIENTS AND METHODS: Through next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with KRASG12C by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in KRASG12C versus non-G12C groups. RESULTS: One hundred and thirty eight patients with KRASG12C treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P = .042), squamous cell histology (P = .008), poor ECOG performance status (PS) (P < .001), and comutations in KEAP1 and STK11 (KEAP1MUT/STK11MUT) (P = .015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P = .004) and KEAP1MUT/STK11MUT (P = .009) were associated with worse OS. Patients with KRASG12C (N = 138) experienced similar outcomes to chemo-immunotherapy compared to patients with non-KRASG12C (N = 185) for both PFS (P = .2) and OS (P = .053). CONCLUSIONS: We define the outcomes to first-line chemo-immunotherapy in patients with KRASG12C, which provides a real-world benchmark for clinical trial design involving patients with KRASG12C mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies.

Lorlatinib Tolerability and Association With Clinical Outcomes in Patients With Advanced ALK- or ROS1-Rearranged NSCLC: A Brief Report.

Introduction: Treatment with lorlatinib for patients with advanced ALK- and ROS1-rearranged NSCLC (ALK+ and ROS1+ NSCLC) is associated with a unique set of adverse events (AEs) often requiring dose reduction. However, the impact of dose reductions on outcomes remains unclear and is mainly limited to analyses from prospective studies of lorlatinib in the first-line setting. Methods: We reviewed the course of 144 patients with advanced ALK- or ROS1-rearranged NSCLC treated with lorlatinib in the second-line or later setting to assess the frequency of dose reductions resulting from treatment-related AEs (TRAEs) and the association between dose reductions and progression-free survival (PFS) and overall survival (OS). Results: A total of 58 patients (40%) had TRAE-related dose reductions, most (59%) owing to neurocognitive AEs or neuropathy. Among all patients, the median PFS was 8.1 months (95% confidence interval [CI]: 6.4-11.8); the median OS was 20.7 months (95% CI: 16.3-30.5). Among patients who were started on lorlatinib 100 mg/d (n = 122), a Cox regression model with the occurrence of a dose reduction as a time-dependent covariate indicated no association between dose reduction and PFS (hazard ratio = 0.86, 95% CI: 0.54-1.39) or OS (hazard ratio = 0.78, 95% CI: 0.47-1.30). Conclusions: Lorlatinib dose reductions were not associated with inferior clinical outcomes in this multicenter analysis. Prompt identification of lorlatinib TRAEs and implementation of dose reductions may help maximize tolerability without compromising outcomes.

Clinical and Molecular Features of Long-term Response to Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

PURPOSE: We sought to identify features of patients with advanced non-small cell lung cancer (NSCLC) who achieve long-term response (LTR) to immune checkpoint inhibitors (ICI), and how these might differ from features predictive of short-term response (STR). EXPERIMENTAL DESIGN: We performed a multicenter retrospective analysis of patients with advanced NSCLC treated with ICIs between 2011 and 2022. LTR and STR were defined as response ≥ 24 months and response < 12 months, respectively. Tumor programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), next-generation sequencing (NGS), and whole-exome sequencing (WES) data were analyzed to identify characteristics enriched in patients achieving LTR compared with STR and non-LTR. RESULTS: Among 3,118 patients, 8% achieved LTR and 7% achieved STR, with 5-year overall survival (OS) of 81% and 18% among LTR and STR patients, respectively. High TMB (≥50th percentile) enriched for LTR compared with STR (P = 0.001) and non-LTR (P < 0.001). Whereas PD-L1 ≥ 50% enriched for LTR compared with non-LTR (P < 0.001), PD-L1 ≥ 50% did not enrich for LTR compared with STR (P = 0.181). Nonsquamous histology (P = 0.040) and increasing depth of response [median best overall response (BOR) -65% vs. -46%, P < 0.001] also associated with LTR compared with STR; no individual genomic alterations were uniquely enriched among LTR patients. CONCLUSIONS: Among patients with advanced NSCLC treated with ICIs, distinct features including high TMB, nonsquamous histology, and depth of radiographic improvement distinguish patients poised to achieve LTR compared with initial response followed by progression, whereas high PD-L1 does not.

Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.2.

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis; as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2). Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline.