Challenges and opportunities in the immunotherapy era: balancing expectations with hope in small-cell lung cancer.

Small-cell lung cancer (SCLC) is a biologically aggressive subtype of lung cancer, a lethal disease characterized by rapid tumor growth, early relapse, a strong tendency for early widespread metastasis, and high genomic instability, making it a formidable foe in modern oncology practice. While the management of non-SCLC has been revolutionized in the era of immunotherapy, progress in SCLC has been more muted. Recent randomized phase III clinical trials have combined programmed death ligand-1 inhibitors to a chemotherapy backbone and demonstrated improved survival; however, the absolute benefit observed is short months.

Phase I Study of mTORC1/2 Inhibitor Sapanisertib (CB-228/TAK-228) in Combination with Metformin in Patients with mTOR/AKT/PI3K Pathway Alterations and Advanced Solid Malignancies.

Background: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of 5'-AMP-activated protein kinase (AMPK) suggesting combination therapy may enhance antitumor activity of sapanisertib. We report preliminary safety, tolerability, and efficacy from the dose-escalation study of sapanisertib in combination with metformin in patients with advanced solid tumors.

Antibody-drug conjugates in lung cancer: dawn of a new era?

Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients.

Mutations Define a Distinct Subgroup in Head and Neck Squamous Cell Carcinoma.

Purpose: In head and neck squamous cell carcinoma (HNSCC), mutation is a new actionable oncogene driver. We aimed to evaluate mutational variants, comutation profile, and survival outcomes of this molecularly defined population.

Methods: We leveraged four deidentified patient data sets with -mutant HNSCC, MD Anderson Cancer Center, Kura Oncology, Inc trial, Foundation Medicine, and American Association for Cancer Research GENIE v.

Worth the paper they are printed on? Findings from an independent evaluation of the understandability of patient information leaflets for antiseizure medications.

Objective: The Patient Information Leaflet (PIL) is an authoritative document that all people with epilepsy in the EU receive when prescribed antiseizure medication (ASM). We undertook the first independent, comprehensive assessment to determine how understandable they are. Regulators state that when patients are asked comprehension questions about them, ≥80% should answer correctly.

Targeting un-MET needs in advanced non-small cell lung cancer.

Lung cancer classification has been radically transformed in recent years as genomic profiling has identified multiple novel therapeutic targets including MET exon 14 (METex14) alterations and MET amplification. Utilizing targeted therapies in patients with molecularly-defined NSCLC leads to remarkable objective response rates and improved progression-free survival. However, acquired resistance is inevitable.

Landscape and Clonal Dominance of Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Harboring Exon 14 Skipping.

Unlabelled: exon 14 skipping alterations (ex14) comprise a diverse set of actionable oncogene drivers in non-small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in ex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described.

Clinical Development of AKT Inhibitors and Associated Predictive Biomarkers to Guide Patient Treatment in Cancer Medicine.

The serine/threonine kinase AKT is a critical effector of the phosphoinositide 3-kinase (PI3K) signaling cascade and has a pivotal role in cell growth, proliferation, survival, and metabolism. AKT is one of the most commonly activated pathways in human cancer and dysregulation of AKT-dependent pathways is associated with the development and maintenance of a range of solid tumors. There are multiple small-molecule inhibitors targeting different components of the PI3K/AKT pathway currently at various stages of clinical development, in addition to new combination strategies aiming to boost the therapeutic efficacy of these drugs.

Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition.

Acquired resistance to molecular targeted therapy is a significant challenge of the precision medicine era. The ability to understand these mechanisms of resistance may improve patient selection and allow for the development of rationally designed next-line or combination treatment strategies and improved patient outcomes. AKT is a critical effector of the phosphoinositide 3-kinase signaling cascade, one of the most commonly activated pathways in human cancer.

Taking Aim at the Undruggable.

The term "undruggable" is used to describe a protein that is not pharmacologically capable of being targeted; recently, however, substantial efforts have been made to turn these proteins into "druggable" targets. Thus, "difficult to drug" or "yet to be drugged" are perhaps more appropriate terms. In cancer, a number of elusive targets fall into this category, including transcription factors such as STAT3, TP53, and MYC.

The role of Schlafen 11 (SLFN11) as a predictive biomarker for targeting the DNA damage response.

The therapeutic landscape of drugs targeting the DNA damage response (DDR) is rapidly expanding; however, an urgent unmet need remains for validated predictive biomarkers of response. SLFN11 has emerged as a promising predictor of sensitivity to DNA-damaging chemotherapies, and recently, been associated with sensitivity to PARP inhibition. We discuss its use as a predictive biomarker of response for targeting the DDR.

Transformation to neuroendocrine carcinoma as a resistance mechanism to lorlatinib.

Objectives: Small cell transformation is a well-recognized mechanism of resistance to EGFR-TKI therapy in EGFR-mutant NSCLC, yet it remains a poorly-described phenomenon in ALK-rearranged NSCLC.

Material And Methods: Chart and literature review.

Results: We report a case of a patient with ALK-rearranged lung cancer progressing on three-lines of ALK-targeted therapies, with development of acquired resistance to lorlatinib, with both transformation to a neuroendocrine carcinoma, and acquisition of ALK 1196 M.

Detection of circulating tumour cell clusters in human glioblastoma.

Human glioblastoma (GBM) is a highly aggressive, invasive and hypervascularised malignant brain cancer. Individual circulating tumour cells (CTCs) are sporadically found in GBM patients, yet it is unclear whether multicellular CTC clusters are generated in this disease and whether they can bypass the physical hurdle of the blood-brain barrier.  Here, we assessed CTC presence and composition at multiple time points in 13 patients with progressing GBM during an open-label phase 1/2a study with the microtubule inhibitor BAL101553.

CNS cancer immunity cycle and strategies to target this for glioblastoma.

Immunotherapeutics have revolutionized the management of solid malignancies over the last few years. Nevertheless, despite relative successes of checkpoint inhibitors in numerous solid tumour types, success in tumours of the central nervous system (CNS) has been lacking. There are several possible reasons for the relative lack of success of immunotherapeutics in this setting, including the immune microenvironment of glioblastoma, lymphocyte tracking through the blood-brain barrier (BBB) into the central nervous system and impairment of drug delivery into the CNS through the BBB.

Where youth matters-clinicopathologic characteristics and emerging trends in treatment and outcomes in young Irish women with breast cancer.

Background: Young women with breast cancer (YWBC) represent 7-12% of breast cancer diagnoses and ostensibly have more biologically aggressive subtypes with higher relapse and mortality rates. We studied the clinical and pathological characteristics in YWBC and examined how outcomes and treatment have evolved.

Methods: YWBC were identified from pathology databases at two tertiary centers.

Safety, efficacy and survival of patients with primary malignant brain tumours (PMBT) in phase I (Ph1) trials: the 12-year Royal Marsden experience.

Background: Primary malignant brain tumours (PMBT) constitute less than 2% of all malignancies and carry a dismal prognosis. Treatment options at relapse are limited. First-in-human solid tumour studies have historically excluded patients with PMBT due to the poor prognosis, concomitant drug interactions and concerns regarding toxicities.

Development of Molecularly Targeted Agents and Immunotherapies in Glioblastoma: A Personalized Approach.

Over the past decade, precision cancer medicine has driven major advances in the management of advanced solid tumours with the identification and targeting of putative driver aberrations transforming the clinical outcomes across multiple cancer types. Despite pivotal advances in the characterization of genomic landscape of glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. Immunotherapy strategies similarly have had limited success.

Comparing Clinical Characteristics and Outcomes of Young-onset and Late-onset Colorectal Cancer: An International Collaborative Study.

Background: Compared with the general population, the incidence of young-onset (YO) colorectal cancer (CRC) is increasing. However, a significant knowledge gap exists in the clinical characteristics, treatment patterns, and outcomes for these patients.

Materials And Methods: Six international tertiary cancer centers conducted a retrospective study.