Sotorasib for the treatment of locally advanced/metastatic non-small cell lung cancer.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is prognostic of poor survival for patients with non-small cell lung cancer (NSCLC). KRAS G12C mutations occur in 13% of NSCLC cases and despite the frequency of this mutation, advances in drug development against KRAS have historically been impeded due to the extremely high affinity of KRAS for guanosine triphosphate (GTP) and the lack of a binding pocket on the surface of KRAS that is suitable for drug binding. Sotorasib, a first-in-class, highly selective KRAS G12C inhibitor overcomes this issue by irreversibly binding in the switch-II pocket.

Safety and Tolerability of Letetresgene Autoleucel (Lete-cel; GSK3377794): Pilot Studies in Patients With Advanced Non-Small Cell Lung Cancer.

Purpose: To evaluate safety, tolerability, and anti-tumor response of lete-cel, genetically modified autologous T-cells expressing a T-cell receptor specific for NY-ESO-1/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in human leukocyte antigen HLA-A*02-positive (HLA-A*02:01-, HLA-A*02:05-, and/or HLA-A*02:06-) patients with New York esophageal squamous cell carcinoma 1 (NY-ESO-1)- and/or LAGE-1a-positive non-small cell lung cancer (NSCLC).

Experimental Design: Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multi-arm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent NSCLC.

Encorafenib plus binimetinib for BRAF V600E-mutant metastatic NSCLC: clinical implications of the phase 2 PHAROS study.

Drs. Ramalingam and Carlisle discuss the incidence and pathophysiology of BRAF V600E-mutant metastatic non-small cell lung cancer and current treatment options. The podcast provides an overview of the data from the recent Pfizer-sponsored phase 2 PHAROS (NCT03915951) study, which were the basis for the recent US Food and Drug Administration approval of encorafenib plus binimetinib for BRAF V600E-mutant metastatic non-small cell lung cancer.

Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis.

Background: Recent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and non-small cell lung cancer. These data are in line with growing preclinical evidence that the adaptive immune response may be more effectively stimulated earlier in the day. We sought to determine the impact of time-of-day ICI infusions on outcomes among patients with metastatic renal cell carcinoma (mRCC).

BA.5 bivalent booster vaccination enhances neutralization of XBB.1.5, XBB.1.16 and XBB.1.9 variants in patients with lung cancer.

This study reports that most patients with NSCLC had a significant increase in the nAb response to the currently circulating Omicron variants after bivalent booster vaccination and had Ab titers comparable to healthy participants. Interestingly, though the durability of the nAb response persisted in most of the healthy participants, patients with NSCLC had significantly reduced nAb titers after 4-6 months of vaccination. Our data highlight the importance of COVID-19 bivalent booster vaccination as the standard of care for patients with NSCLC given the evolution of new variants of concern.

Characteristics and anatomic location of PD-1TCF1 stem-like CD8 T cells in chronic viral infection and cancer.

CD8 T cells play an essential role in antitumor immunity and chronic viral infections. Recent findings have delineated the differentiation pathway of CD8 T cells in accordance with the progenitor-progeny relationship of TCF1 stem-like and Tim-3TCF1 more differentiated T cells. Here, we investigated the characteristics of stem-like and differentiated CD8 T cells isolated from several murine tumor models and human lung cancer samples in terms of phenotypic and transcriptional features as well as their location compared to virus-specific CD8 T cells in the chronically lymphocytic choriomeningitis virus (LCMV)-infected mice.

Advancing immunotherapy in small cell lung cancer.

Small cell lung cancer (SCLC) is a rapidly progressive neuroendocrine carcinoma that, until recently, had a very small armamentarium of effective treatments. Advances in DNA sequencing and whole transcriptomics have delineated key subtypes; therefore, SCLC is no longer viewed as a homogeneous cancer. Chemoimmunotherapy with PD1 blockade is now the standard of care for advanced disease, and ongoing research efforts are moving this strategy into the limited stage setting.

Shifting Sociodemographic Characteristics of a Phase I Clinical Trial Population at an NCI-Designated Comprehensive Cancer Center in the Southeast.

Racial and ethnic minority populations are consistently under-represented in oncology clinical trials despite comprising a disproportionate share of a cancer burden. Phase I oncology clinical trials pose a unique challenge and opportunity for minority inclusion. Here we compared the sociodemographic characteristics of patients participating in phase 1 clinical trials a National Cancer Institute ( NCI)-designated comprehensive center to all patients at the center, patients with new cancer diagnosis in metropolitan Atlanta and patients with new cancer diagnoses in the state of Georgia.

Safety and efficacy of durvalumab after concurrent chemoradiation in Black patients with locally advanced non-small cell lung cancer.

Background: The PACIFIC trial established consolidative durvalumab after concurrent chemoradiation as standard-of-care in patients with stage III or unresectable non-small cell lung cancer (NSCLC). Black patients, however, comprised just 2% (n = 14) of randomized patients in this trial, warranting real-world evaluation of the PACIFIC regimen in these patients.

Methods: This single-institution, multi-site study included 105 patients with unresectable stage II/III NSCLC treated with concurrent chemoradiation followed by durvalumab between 2017 and 2021.

Impact of radiation dose to the immune cells in unresectable or stage III non-small cell lung cancer in the durvalumab era.

Background/purpose: Higher estimated radiation doses to immune cells (EDIC) have correlated with worse overall survival (OS) in patients with locally-advanced non-small cell lung cancer (NSCLC) prior to the PACIFIC trial, which established consolidative durvalumab as standard-of-care. Here, we examine the prognostic impact of EDIC in the durvalumab era.

Materials/methods: This single-institution, multi-center study included patients with unresectable stage II/III NSCLC treated with chemoradiation followed by durvalumab.

A Phase 2 Study of Docetaxel, Ramucirumab, and Pembrolizumab for Patients With Metastatic or Recurrent Non-Small-Cell Lung Cancer (NSCLC) who Progressed on Platinum-Doublet and PD-1/PD-L1 Blockade.

Background: There is an urgent and unmet need for more effective treatment options for patients with metastatic and recurrent non-small-cell lung cancer (NSCLC) who progressed on platinum-based therapy, immune checkpoint inhibitors (ICI), and targeted therapies. Currently, the combination of docetaxel (D) and ramucirumab (R) is the next best salvage therapy with a modest historical progression free survival (PFS) of 4.5 months and 6-month PFS rate of 37% predating the era of ICI use.

Clinical outcome following checkpoint therapy in renal cell carcinoma is associated with a burst of activated CD8 T cells in blood.

Purpose: Checkpoint therapy is now the cornerstone of treatment for patients with renal cell carcinoma (RCC) with advanced disease, but biomarkers are lacking to predict which patients will benefit. This study proposes potential immunological biomarkers that could developed for predicting therapeutic response in patients with RCC.

Methods: Using flow cytometry, RNA sequencing, and T-cell receptor (TCR) sequencing, we investigated changes in T cells in the peripheral blood of patients with advanced RCC after receiving immunotherapy.

Antibody Response to COVID-19 mRNA Vaccine in Patients With Lung Cancer After Primary Immunization and Booster: Reactivity to the SARS-CoV-2 WT Virus and Omicron Variant.

Purpose: To examine COVID-19 mRNA vaccine-induced binding and neutralizing antibody responses in patients with non-small-cell lung cancer (NSCLC) to SARS-CoV-2 614D (wild type [WT]) strain and variants of concern after the primary 2-dose and booster vaccination.

Methods: Eighty-two patients with NSCLC and 53 healthy volunteers who received SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected longitudinally, and SARS-CoV-2-specific binding and neutralizing antibody responses were evaluated by Meso Scale Discovery assay and live virus Focus Reduction Neutralization Assay, respectively.

High-Dose Osimertinib for CNS Progression in EGFR+ NSCLC: A Multi-Institutional Experience.

Introduction: This multicenter review evaluated the efficacy and safety of osimertinib dose escalation for central nervous system (CNS) progression developing on osimertinib 80 mg in -mutant NSCLC.

Methods: Retrospective review identified 105 patients from eight institutions with advanced -mutant NSCLC treated with osimertinib 160 mg daily between October 2013 and January 2020. Radiographic responses were clinically assessed, and Kaplan-Meier analyses were used.

Tyrosine Kinase Inhibitors, Antibody-Drug Conjugates, and Proteolysis-Targeting Chimeras: The Pharmacology of Cutting-Edge Lung Cancer Therapies.

The number of therapeutic options available for patients with advanced non-small-cell lung cancer has been led by deeper understanding of molecular drivers, immune function, and fundamental biology. In this article, we describe the relevant clinical pharmacologic characteristics of three broad classes of existing and investigational treatments, with a focus on mechanisms of action, adverse event profiles, pharmacokinetic and pharmacodynamic properties, and known and predicted resistance pathways. Specifically, within the kinase inhibitor class, agents directed against the RET, MET, and KRAS pathways are reviewed.

Integration of immunotherapy into adjuvant therapy for resected non-small-cell lung cancer: ALCHEMIST chemo-IO (ACCIO).

Non-small-cell lung cancer (NSCLC) causes significant mortality each year. After successful resection of disease stage IB (>4 cm) to IIIA (per AJCC 7), adjuvant platinum-based chemotherapy improves median overall survival and is the standard of care, but many patients still experience recurrence of disease. An adjuvant regimen with greater efficacy could substantially improve outcomes.

YAP1 Expression in SCLC Defines a Distinct Subtype With T-cell-Inflamed Phenotype.

Introduction: The clinical and biological significance of the newly described SCLC subtypes, SCLC-A, SCLC-N, SCLC-Y, and SCLC-P, defined by the dominant expression of transcription factors ASCL1, NeuroD1, YAP1, and POU2F3, respectively, remain to be established.

Methods: We generated new RNA sequencing expression data from a discovery set of 59 archival tumor samples of neuroendocrine tumors and new protein expression data by immunohistochemistry in 99 SCLC cases. We validated the findings from this discovery set in two independent validation sets consisting of RNA sequencing data generated from 51 SCLC cell lines and 81 primary human SCLC samples.

Efficacy and safety of immune checkpoint blockade in self-identified Black patients with advanced non-small cell lung cancer.

Background: To the authors' knowledge, race-based differences in efficacy for the treatment of patients with advanced non-small cell lung cancer (NSCLC) have not been studied to date due to the underrepresentation of patients of minority backgrounds in pivotal trials. In the current study, the authors examined real-world differences in outcome in a diverse patient population.

Methods: The authors retrospectively analyzed the clinical outcomes of patients with advanced NSCLC who were treated with single-agent immune checkpoint blockade (ICB) between 2013 and July 2018 at Winship Cancer Institute of Emory University in Atlanta, Georgia.

An update on the immune landscape in lung and head and neck cancers.

Immunotherapy has dramatically changed the treatment landscape for patients with cancer. Programmed death-ligand 1/programmed death-1 checkpoint inhibitors have been in the forefront of this clinical revolution. Currently, there are 6 US Food and Drug Administration-approved checkpoint inhibitors for approximately 18 different histologic types of cancer.

Integrating Genetic and Genomic Testing Into Oncology Practice.

Genetic information, both germline and somatic, is an increasingly important consideration in therapeutic decision-making in cancer. Germline mutations in genes associated with increased cancer risk can identify those individuals without cancer who may benefit from enhanced screening and prevention strategies. In individuals with cancer, germline and somatic mutations may help to guide local and systemic management decisions.