Advancing precision antibody-drug conjugate therapy: unique proteogenomic profiles of tumor subsets in non-small cell lung cancer.

Antibody-drug conjugates (ADCs) represent a promising therapeutic strategy for non-small cell lung cancer (NSCLC), targeting tumor-specific antigens with precision. However, the molecular heterogeneity of NSCLC necessitates multiplex biomarker approaches to optimize ADC efficacy. This study utilized transcriptomics and proteomics to characterize NSCLC subtypes with distinct ADC target expression profiles.

Molecular Tumor Boards: A Consensus Statement From the International Association for the Study of Lung Cancer.

Context: Molecular tumor boards (MTBs) are multidisciplinary meetings of specialists dedicated to analyzing biomarker test results to provide personalized treatment recommendations. However, global disparities in the successful implementation of MTBs exist, driven by unequal access to molecular diagnostics and supportive multidimensional expertise.

Objective: To establish recommendations for MTB implementation, outline practical frameworks for their operation, and address disparities in expertise and resources between new and established MTBs.

Plinabulin following radiation enhances dendritic cell maturation and checkpoint inhibitor retreatment of relapsed/refractory cancers.

Background: Plinabulin exerts immunomodulatory activity through guanine nucleotide exchange factor (GEF)-H1 release from depolymerizing tubulin in the cytoskeleton, leading to dendritic cell (DC) activation. Preclinical studies demonstrated that irradiation potentiates plinabulin-induced DC maturation and, when combined with immune checkpoint inhibitors (ICIs), triggers an abscopal antitumor response via increased tumor-infiltrating DCs and T cells.

Methods: A phase 1 translational study (NCT04902040) of plinabulin plus ICIs after radiation therapy (RT) initiation was conducted in ICI-relapsed/refractory cancers with primary (safety, tolerability, and objective tumor response rate) and secondary (disease control rate [DCR]) endpoints.

Precision-medicine management recommendations for advanced non-small cell lung cancer: expert consensus.

Lung cancer is the leading cause of cancer-related death and the second most common cancer worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. In the Middle East and North Africa (MENA) region, lung cancer ranks second in incidence and cancer mortality, with a five-year survival rate of about 8%.

Tissue-agnostic cancer therapies: promise, reality, and the path forward.

Tissue-agnostic cancer therapies promise to revolutionize oncology by targeting molecular drivers. Sledge et al.’s study of nearly 300,000 tumors found 21.

From dominance to decline: can we reverse the trend in small molecule and TKI cancer therapies?

Over the past two decades, precision oncology has seen unprecedented advances, particularly with the rise of small molecule drugs. These drugs have significantly benefitted patients with cancer harboring somatic genomic alterations, contributing to precision cancer medicine. Despite their early promise, there is a growing concern that major pharmaceutical companies are recently moving away from developing small molecules and tyrosine kinase inhibitors (TKIs) due to market saturation, primary and secondary resistance, and economic factors.

A phase I, open-label, multicentre, first-in-human study to evaluate safety, pharmacokinetics and efficacy of AMG 404, a PD-1 inhibitor, in patients with advanced solid tumours.

Objective: To evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary antitumour activity of AMG 404, a fully human IgG1 monoclonal antibody targeting programmed cell death-1, in patients with advanced solid tumours.

Design: First-in-human phase I study comprising eight dose expansion cohorts, including cohorts with microsatellite instability-high (MSI-H) tumours and non-small cell lung cancer with high programmed death-ligand 1 expression (NSCLC/PDL1-H, tumour proportion score ≥50%).

Setting: Conducted across 28 global sites.

Larotrectinib Compared With Real-World Non-Tropomyosin Receptor Kinase Inhibitor Therapies in Patients With Tropomyosin Receptor Kinase Fusion Cancer.

Purpose: Neurotrophic tyrosine receptor kinase gene fusions are oncogenic drivers of various solid tumors. Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor approved for patients with TRK fusion cancer on the basis of single-arm trials. This study was a matched comparative effectiveness study of larotrectinib in clinical trials versus standard of care (SOC) in the real-world (RW) setting.

Safety and Activity of Fibroblast Growth Factor Receptor Inhibitors in Advanced Malignancies: A Pooled Analysis of Early-Phase Clinical Trials.

Purpose: Aberrant signaling through the fibroblast growth factor receptor () due to activating somatic alterations has been associated with multiple malignancies. FGFR inhibitors (FGFRi) with distinct profiles recently entered standard of care. This work summarizes the experience of a dedicated clinical trial unit with FGFRi developed in the last decade within the context of clinical trials.

Designing Clinical Trials for Patients With Rare Cancers: Connecting the Zebras.

The field of rare cancer research is rapidly transforming, marked by significant progress in clinical trials and treatment strategies. Rare cancers, as defined by the National Cancer Institute, occur in fewer than 150 cases per million people each year, yet they collectively represent a significant portion of all cancer diagnoses. Because of their infrequency, these cancers pose distinct challenges for clinical trials, including limited patient populations, geographical dispersion, and a general lack of awareness of treatment options.

Pembrolizumab in Patients with Advanced Miscellaneous Rare Cancers: Results from a Phase 2 Basket Trial.

Introduction: Rare solid tumors account for one-quarter of cancers among adults in the United States, but few resources have been devoted to their treatment. We evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with rare solid tumors.

Methods: We conducted a phase 2 basket trial that included patients with rare, advanced tumors.

Lefitolimod in Combination with Ipilimumab in Patients with Advanced Solid Tumors: A Phase I Trial.

Introduction: TLR9 agonists are immunomodulators that have been of interest for combined use with cancer immunotherapy. TLR9 agonists, such as lefitolimod (MGN1703), significantly increased Th1 response in preclinical models and have demonstrated efficacy in early clinical trials. This trial assessed the safety and preliminary efficacy of the combination of lefitolimod and ipilimumab in patients with advanced solid tumors.

A Phase IB Trial of Selinexor in Combination With Immune Checkpoint Blockade in Patients With Advanced Renal Cell Carcinoma.

Background: Selinexor (SEL) is a nuclear exportin 1 inhibitor that blocks the transport of nuclear proteins, including tumor suppressors, to the cytoplasm. Preclinical data suggest that the combination of SEL with checkpoint blockade may result in improved response to immunotherapy.

Methods: NCT02419495 was a multiarm phase IB study of SEL in combination with other standard regimens in patients with advanced malignancies.

Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types.

Background: There is uncertainty around clinical applicability of tumor mutational burden (TMB) across cancer types, in part because of inconsistency between TMB measurements from different platforms. The KEYNOTE 158 trial supported United States Food and Drug Administration (FDA) approval of the Foundation Medicine test (FoundationOneCDx) at TMB≥10 mut/Mb as a companion diagnostic (CDx) for single-agent pembrolizumab in second+line. Using a large real-world dataset with validated survival endpoint data, we evaluated clinical validity of TMB measurement by the test in over 8000 patients across 24 cancer types who received single-agent immune checkpoint inhibitor (ICI).

Preclinical study and parallel phase II trial evaluating antisense STAT3 oligonucleotide and checkpoint blockade for advanced pancreatic, non-small cell lung cancer and mismatch repair-deficient colorectal cancer.

Objective: To evaluate signal transducer and activator of transcription 3 (STAT3) inhibition we conducted a co-clinical trial testing danvatirsen, a STAT3 antisense oligonucleotide (ASO) and checkpoint inhibition in conjunction with preclinical experiments.

Methods And Analysis: Orthotopically implanted pancreatic cancer (pancreatic adenocarcinoma (PDAC)) was treated with STAT3 ASO with immune checkpoint inhibition. Tumour infiltrating immune cell populations were characterised via flow cytometry.

Precision Oncology: A Global Perspective on Implementation and Policy Development.

Despite the acknowledged merits of precision oncology (PO) and its increasing global implementation, its full potential for advancing care and prevention remains unrealized. The benefits are currently accessible to only limited patient segments because of multifaceted barriers. Successful implementation hinges on various factors-scientific complexities not limited to technical, clinical, regulatory, economic, administrative, and health care policy-related challenges.

Accelerating the Future of Oncology Drug Development: The Role of Consortia in the Delivery of Precision Oncology Early Phase Clinical Trials.

Purpose: Over the past 15 years, the landscape of early phase clinical trials (EPCTs) has undergone a remarkable expansion in both quantity and intricacy. The proliferation of sites, trials, sponsors, and contract research organizations has surged exponentially, marking a significant shift in research conduct. However, EPCT operations suffer from numerous inefficiencies, such as cumbersome start-up processes, which are particularly critical when drug safety and the recommended phase II dose need to be established in a timely manner.

A first-in-human phase 1/2 dose-escalation study of MAK683 (EED inhibitor) in patients with advanced malignancies.

Purpose: MAK683, a first-in-class and highly selective allosteric inhibitor of the embryonic ectoderm development subunit of polycomb repressive complex 2, has shown sustained antitumor activity in tumor xenograft models. This first-in-human phase 1/2 study evaluated the safety, pharmacokinetics (PK), and clinical activity of single-agent MAK683 in advanced malignancies.

Methods: MAK683 was administered fasted once daily or twice daily continuously in 28-day treatment cycles.

Selpercatinib mitigates cancer cachexia independent of anti-tumor activity in the HT1080 tumor model.

Anorexia is a major cause of cancer cachexia and is induced by growth differentiation factor-15 (GDF15), which activates the rearranged during transfection (RET) protein tyrosine kinase in the hindbrain through GDF family receptor α-like (GFRAL), raising the possibility of targeting RET for cancer cachexia treatment. RET-altered cancer patients treated with RET-selective kinase inhibitors gain weight, however, it is unclear whether this results from tumor regression that improves the overall health of patients. Thus, the potential of using a RET inhibitor to address cancer cachexia remains unknown.

Targeting Oncogenic RET Kinase by Simultaneously Inhibiting Kinase Activity and Degrading the Protein.

The rearranged-during-transfection (RET) kinase is a validated target for the treatment of RET-altered cancers. Currently approved RET-selective kinase inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), increase the oncogenic RET protein level upon treatment, which may affect their efficacy. We seek to reduce the oncogenic RET protein level and RET kinase activity simultaneously.