Tumor Immunophenotypic Correlates in Patients Aged 80 Years or Older With Non-Small Cell Lung Cancer and Outcomes to First-Line Pembrolizumab in PD-L1 High (≥50%) Patients.

Background: Non-small cell lung cancer (NSCLC) patients aged ≥80 years [y] are underrepresented in clinical trials. We evaluated whether age correlates with a distinct immunophenotype or impacts outcomes to first-line pembrolizumab in patients with advanced NSCLC, PD-L1 Tumor Proportion Score (TPS) of ≥50%, and aged ≥80y.

Methods: Three NSCLC cohorts were retrospectively analyzed to assess the impact of age (<80y versus ≥80y) on pembrolizumab efficacy and the tumor microenvironment (TME).

Association of Sarcopenia With Toxicity and Survival in Patients With Lung Cancer, a Multi-Institutional Study With External Dataset Validation.

Introduction: Sarcopenia is associated with worse survival in non-small cell lung cancer (NSCLC), but less studied in association with toxicity. Here, we investigated the association between imaging-assessed sarcopenia with toxicity in patients with NSCLC.

Methods: We analyzed a "chemoradiation" cohort (n = 318) of patients with NSCLC treated with chemoradiation, and an external validation "chemo-surgery" cohort (n = 108) who were treated with chemotherapy and surgery from 2002 to 2013 at a different institution.

Determinants of 5-year survival in patients with advanced NSCLC with PD-L1≥50% treated with first-line pembrolizumab outside of clinical trials: results from the Pembro-real 5Y global registry.

Background: Pembrolizumab monotherapy is an established front-line treatment for advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS)≥50%. However, real-world data on its long-term efficacy remains sparse.

Methods: This study assessed 5-year outcomes of first-line pembrolizumab monotherapy in a large, multicenter, real-world cohort of patients with advanced NSCLC and PD-L1 TPS≥50%, referred to as Pembro-real 5Y.

Gene Copy Deletion of STK11, KEAP1, and SMARCA4: Clinicopathologic Features and Association With the Outcomes of Immunotherapy With or Without Chemotherapy in Nonsquamous NSCLC.

Introduction: Mutations in STK11, KEAP1, and SMARCA4 predispose to inferior immune checkpoint inhibitor (ICI) efficacy in NSCLC, particularly among KRAS-mutant cases. Nevertheless, the frequency, clinicopathologic features, and clinical impact of deletions in these genes are poorly characterized.

Methods: Clinicopathologic correlates of STK11, KEAP1, and SMARCA4 deletion were analyzed in cases of nonsquamous NSCLC at Dana-Farber Cancer Institute (DFCI).

MAPK pathway activating alteration and immunotherapy efficacy in squamous cell lung carcinoma: results from the randomized, prospective SQUINT trial.

Background: The role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in lung squamous cell carcinoma (LSCC) patients is largely unknown. The aims of the randomized, phase II SQUINT trial were to assess the efficacy of nivolumab plus ipilimumab (NI) versus platinum-based chemotherapy plus nivolumab (N-CT) and to identify clinically available biomarkers of response to immunotherapy in patients with advanced or metastatic LSCC.

Methods: SQUINT was an open-label, randomized, parallel, non-comparative, phase II trial of NI versus N-CT in chemo-naïve, metastatic or recurrent LSCC adult patients.

Brief Report: Clinical Characteristics and Outcomes of Patients With Thoracic SMARCA4-Deficient Undifferentiated Tumors.

Introduction: Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs) are a recently defined group of aggressive cancers in which the effectiveness of standard treatments for lung cancer is unknown.

Methods: We collected clinical, pathologic, and demographic variables from five institutions for patients whose tumors met criteria for SMARCA4-UTs (undifferentiated phenotype and loss of SMARCA4 (BRG1) by immunohistochemistry).

Results: We identified 92 patients with SMARCA4-UTs; 58 (63%) had stage IV disease at diagnosis and 16 (17%) developed recurrent or metastatic disease after initial diagnosis.

Neoadjuvant Nivolumab Plus Ipilimumab Versus Chemotherapy in Resectable Lung Cancer.

Purpose: Neoadjuvant immune checkpoint blockade with nivolumab plus ipilimumab improves overall survival (OS) in non-small cell lung cancer (NSCLC); however, randomized data for resectable lung cancer are limited. We report results from the exploratory concurrently randomized nivolumab plus ipilimumab and chemotherapy arms of the international phase III CheckMate 816 trial.

Methods: Adults with stage IB-IIIA (American Joint Committee on Cancer seventh edition) resectable NSCLC received three cycles of nivolumab once every 2 weeks plus one cycle of ipilimumab or three cycles of chemotherapy (on day 1 or days 1 and 8 of each 3-week cycle) followed by surgery.

Deep Learning Model for Predicting Immunotherapy Response in Advanced Non-Small Cell Lung Cancer.

Importance: Only a small fraction of patients with advanced non-small cell lung cancer (NSCLC) respond to immune checkpoint inhibitor (ICI) treatment. For optimal personalized NSCLC care, it is imperative to identify patients who are most likely to benefit from immunotherapy.

Objective: To develop a supervised deep learning-based ICI response prediction method; evaluate its performance alongside other known predictive biomarkers; and assess its association with clinical outcomes in patients with advanced NSCLC.

Neoadjuvant atezolizumab + chemotherapy for resectable NSCLC: 3-year clinical update of phase II clinical trial results and translational findings.

Introduction: Neoadjuvant chemoimmunotherapy has achieved overall survival (OS) benefit for patients with resectable non-small cell lung cancer (NSCLC). Here, we present outcomes after 3 years of follow-up from the first reported study of neoadjuvant atezolizumab+chemotherapy.

Methods: This open-label, multicenter single-arm investigator-initiated phase II study conducted at three US hospitals tested up to four cycles of atezolizumab, carboplatin, and nab-paclitaxel prior to surgery.

Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer.

Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ.

Response to Crizotinib After Entrectinib Resistance in -Rearranged, -Amplified Lung Adenocarcinoma.

Crizotinib successfully overcomes MET amplification in ROS1-rearranged NSCLC after entrectinib failure.

Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans.

Immunotherapy leads to cancer eradication despite the tumor's immunosuppressive environment. Here, we used extended long-term in-vivo imaging and high-resolution spatial transcriptomics of endogenous melanoma in zebrafish, and multiplex imaging of human melanoma, to identify domains that facilitate immune response during immunotherapy. We identified crater-shaped pockets at the margins of zebrafish and human melanoma, rich with beta-2 microglobulin (B2M) and antigen recognition molecules.

RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade.

Selective KRAS inhibitors have been developed to covalently lock the oncogene in the inactive GDP-bound state. Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRAS-mutated previously treated advanced non-small cell lung cancer. Drug treatment imposes selective pressures leading to the outgrowth of drug-resistant variants.

Treating deep venous insufficiency with a novel implantable device.

Chronic venous insufficiency (CVI) is increasing in prevalence on a global scale. Current treatment options are limited to improving venous return, ablation of refluxing veins, and reducing outflow obstruction. A new bioprosthetic device, the VenoValve, may bridge the gap of treatment for patients with chronic venous insufficiency who have failed prior treatment.

In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAF lung adenocarcinoma.

The current targeted therapy for BRAF-mutant lung cancer consists of a dual blockade of RAF/MEK kinases often combining dabrafenib/trametinib (D/T). This regimen extends survival when compared to single-agent treatments, but disease progression is unavoidable. By using whole-genome CRISPR screening and RNA sequencing, we characterize the vulnerabilities of both persister and D/T-resistant cellular models.

Transcriptional Phenocopies of Deleterious KEAP1 Mutations Correlate with Survival Outcomes in Lung Cancer Treated with Immunotherapy.

Purpose: Co-occurring mutations in KEAP1 and STK11/KRAS have emerged as determinants of survival outcomes in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. However, these mutational contexts identify a fraction of nonresponders to immune checkpoint inhibitors. We hypothesized that KEAP1 wild-type tumors recapitulate the transcriptional footprint of KEAP1 mutations and that this KEAPness phenotype can determine immune responsiveness with higher precision compared to mutation-based models.

Additional impact of genetic ancestry over race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer.

The KRAS mutation is the most common oncogenic driver in patients with non-small cell lung cancer (NSCLC). However, a detailed understanding of how self-reported race and/or ethnicity (SIRE), genetically inferred ancestry (GIA), and their interaction affect KRAS mutation is largely unknown. Here, we investigated the associations between SIRE, quantitative GIA, and KRAS mutation and its allele-specific subtypes in a multi-ethnic cohort of 3,918 patients from the Boston Lung Cancer Survival cohort and the Chinese OrigiMed cohort with an independent validation cohort of 1,450 patients with NSCLC.

Body Composition in Advanced Non-Small Cell Lung Cancer Treated With Immunotherapy.

Importance: The association between body composition (BC) and cancer outcomes is complex and incompletely understood. Previous research in non-small-cell lung cancer (NSCLC) has been limited to small, single-institution studies and yielded promising, albeit heterogeneous, results.

Objectives: To evaluate the association of BC with oncologic outcomes in patients receiving immunotherapy for advanced or metastatic NSCLC.