Expert opinion on investigational drugs最新文献

Introduction: KRAS mutations are among the most common oncogenic alterations in colorectal cancer (CRC). These mutations play a central role in tumor initiation and progression through activation of the MAPK signaling pathway. For many years, KRAS was considered an undruggable target. However, recent advances have led to the development of allele-specific inhibitors and combination strategies that directly target KRAS-driven signaling.

Areas covered: This review summarizes KRAS biology and pathway signaling; the prognostic and predictive impact of KRAS variants in CRC; and the emerging therapeutic landscape focused on phase I - II assets. We cover direct KRAS inhibitors (including G12C and non-G12C programs), pan-KRAS/'RAS-ON' and SOS1/SHP2 strategies, vertical MAPK/PI3K co-inhibition, metabolic and ferroptosis approaches, and translational immuno-oncology (checkpoint blockade in MSI-H/dMMR disease, cellular therapies, and vaccines). We also outline ongoing clinical trials, resistance mechanisms, biomarker considerations (tumor sidedness, co-mutations), and practical implications for sequencing and combinations.

Expert opinion: KRAS-targeted therapy in CRC is entering a clinically actionable era. Allele-specific inhibitors are likely to find their place in combinations that suppress adaptive bypass (e.g. SOS1/SHP2, MEK/ERK, EGFR) while leveraging immunotherapy or metabolic vulnerabilities. Prospective biomarker integration and resistance-informed trial designs will be decisive in translating early signals into durable patient benefit.

Background: KL130008, a novel selective JAK1/JAK2 inhibitor demonstrated acceptable safety and tolerability in Phase I studies involving healthy volunteers. This proof-of-concept trial aimed to characterize the pharmacokinetic/pharmacodynamics relationship and preliminary efficacy of KL130008 in rheumatoid arthritis (RA) patients.

Research design and methods: In this randomized, double-blind, single-center trial involving 30 RA patients, 24 received oral KL130008 and 6 received placebo. Pharmacokinetics and pharmacodynamics were evaluated based on drug concentrations and on inhibition of phospho-signal transducer and activator of transcription-3 (pSTAT3). Safety and efficacy outcomes were assessed.

Results: Pharmacokinetics were linear over the dose from 1-4 mg; the drug showed the half-life of 14.34-18.14 h and accumulation factor of 1.27-1.76. The drug inhibited pSTAT3 with a dose-dependent trend, achieving maximal inhibition of 37.61% (1 mg), 61.28% (2 mg), and 71.87% (4 mg). The American College of Rheumatology 20 responses (≥20% improvement from baseline) were 25.0-37.5% across the dose range of 1-4 mg after two weeks of multiple dosing, higher than 16.7% for placebo. Treatment-emergent adverse events, all mild, occurred in two-thirds of patients receiving KL130008.

Conclusion: In RA patients, oral KL130008 shows linear pharmacokinetics, pSTAT3 inhibition, and promising safety. Efficacy are exploratory given the small sample size.

Trial registration: Registered in the Chinese Clinical Trial Register (ChiCTR2000029360).

Introduction: RCC management has evolved toward immunotherapy-based strategies, with adjuvant anti-PD-1 therapy after nephrectomy and immune-VEGF TKI combinations in the metastatic setting now representing standards of care. Outcomes remain variable because of biological heterogeneity, treatment resistance, and the limited performance of currently available biomarkers.

Areas covered: This review synthesizes contemporary standards of care together with advances in tumor biology and biomarker development, and appraises investigational modalities across immune, targeted, and cellular platforms. We analyze how standards of care and translational insights have evolved in recent years, outlining the principal directions of current and investigational treatments.

Expert opinion: The field is moving toward biology-informed treatment selection. Priorities include prospective validation of biomarker strategies, standardization of assay platforms, and integration of dynamic response measures to refine treatment selection, sequencing, and combinations. Molecularly defined subsets and less common histologies warrant dedicated, adequately powered studies. With rigorous methodology and standardized testing methods, emerging approaches have the potential to translate current signals into more consistent and durable clinical benefits in RCC.

Introduction: The combination of MEK and BRAF inhibitors is effective in melanomas and other tumors with BRAF V600E mutations. MEK inhibitors enhance efficacy and delay the development of resistance to BRAF inhibitors. Recently, MEK inhibitors have demonstrated activity in plexiform neurofibromas in patients with type 1 neurofibromatosis and in histiocytic neoplasms. In the preclinical setting, MEK inhibitors are effective in tumors with RAS or receptor tyrosine kinase mutations. However, after the inhibition of MEK, regulatory feedback determines the rebound activation of ERK, thereby limiting the effect of the MEK blockade. In early clinical trials, MEK inhibitor monotherapy has shown limited efficacy in RAS-mutated tumors, whereas trials combining MEK and RAS inhibitors are still ongoing.

Areas covered: Clinical trials have been selected from clinicaltrials.gov searching for 'MEK inhibitors,' and their results have been searched in PubMed and meeting abstracts. Preclinical studies have been searched in PubMed using the names of the MEK inhibitors. This is a descriptive review.

Expert opinion: While MEK inhibitors in combination with BRAF inhibitors obtained one of the first tumor-agnostic FDA approvals for BRAF V600E/K mutated tumors, additional indications for MEK inhibitors alone have been received in very selected diseases for which molecular characterization is crucial.

Introduction: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and significant side effect of cancer treatment, triggered by exposure to widely used chemotherapeutic agents such as vinca alkaloids, taxanes, platinum-based compounds, proteasome inhibitors, thalidomide, epothilones, and antibody-drug conjugates. CIPN can be long-lasting or even permanent, leading to a decline in patients' quality of life and negatively impacting the well-being of cancer survivors. It is typically characterized by polyneuropathy or neuronopathy, primarily affecting the peripheral sensory nervous system.

Areas covered: Emerging evidence suggests that anticancer agents may directly alter neuronal voltage-gated sodium channels (NaV), which could play a crucial role in the development of CIPN. This review explores the mechanisms underlying CIPN, with particular focus on the potential involvement of NaV alterations. Additionally, it examines pharmacological modulators of NaV, offering key insights into the prevention of axonal damage and the management of neuropathic pain associated with CIPN.

Expert opinion: Despite the availability of various strategies to manage CIPN, there are currently few evidence-based options for its prevention or effective treatment once it develops. As a result, CIPN remains an unmet clinical challenge, highlighting the need for further research into its underlying pathophysiological mechanisms to develop innovative therapies.

Introduction: The PI3K/Akt/mTOR pathway plays a crucial role in regulating cell proliferation, survival and metabolism. Its aberrant activation promotes tumor development and progression. The most common oncogenic feature is represented by genetic alterations of PI3KCA that encodes the catalytic subunit p110α. In fact, several studies have highlighted the prevalence of somatic point mutations and/or amplification of PI3KCA in many neoplastic forms, making it a promising therapeutic target. In recent years, some PI3KCA inhibitors have been approved, others are under clinical development.

Areas covered: In this review, we summarize the current knowledge on the PI3K/Akt/mTOR pathway with a focus on PI3KCA genetic alterations in tumor development. Furthermore, we discuss the emerging role of PI3KCA inhibitors (approved and under investigation) as a therapeutic strategy in different tumor types including their current limitations.

Expert opinion: PI3KCA-specific inhibitors represent a new class of promising drugs in the treatment of tumors with the mutated P110α subunit. However, despite the proven improvement in clinical outcomes, the management of patients in terms of efficacy and toxicity remains the main challenge. To maximize efficacy and safety, molecular stratification of patients by genomic profiling and the development of targeted combinations are crucial to optimizing benefits.

Introduction: Lipoprotein(a) [Lp(a)] is an LDL-like particle, which is synthesized and assembled in the liver, and whose plasma levels are strongly associated with, and considered to be causative of, atherosclerotic cardiovascular disease (ASCVD). Several promising pharmacological therapies that directly target Lp(a) are under development.

Areas covered: We discuss the role of Lp(a) in ASCVD, describe the pharmacodynamics, pharmacokinetics, and metabolism of muvalaplin, an oral Lp(a) inhibitor, as well as reporting on the findings of the phase II KRAKEN trial in adults at high cardiovascular risk with elevated Lp(a).

Expert opinion: Muvalaplin is the first oral small molecule inhibitor of Lp(a) formation for the treatment of elevated Lp(a). In KRAKEN, muvalaplin significantly reduced Lp(a) levels in high-risk patients by up to 70% and 85.5% by traditional and novel isoform-insensitive intact assays, respectively. Safety and tolerability studies reported to date are promising, with minimal effect on plasminogen activity that was independent of dose. In terms of patient convenience and adherence, the oral dosing of muvalaplin may confer practical advantages over injectable Lp(a)-lowering therapies. The results of the MOVE-Lp(a) phase III trial, which is evaluating the effect of muvalaplin on cardiovascular outcomes in high-risk patients with elevated Lp(a), are eagerly awaited.

Introduction: Cancer cachexia is a multifactorial syndrome affecting up to 80% of advanced cancer patients, associated with poor quality of life, increased cancer-treatment toxicity, and reduced survival. Despite its clinical burden, no FDA- or EMA-approved pharmacologic therapies currently exist.

Areas covered: This review covers key investigational therapies developed over the past five years, with a focus on agents targeting Growth Differentiation Factor 15 (GDF-15), including ponsegromab, AV-380, and NGM120. Additional agents include ghrelin receptor agonists (e.g. anamorelin), anabolic/catabolic modulators (ACM-001), and cannabinoids (ART27.13). The evolving role of low-dose olanzapine is also discussed in the 2023 ASCO guideline update. Advancements in early detection, including AI-driven biomarker models and the use of circulating miRNAs, are discussed.

Expert opinion: Targeting GDF-15 represents a paradigm shift in cancer cachexia treatment, with ponsegromab leading the pipeline and entering Phase 3 trials. Anamorelin has demonstrated clinical utility in improving appetite and body weight. Despite recent progress, cancer cachexia undoubtedly represents a still clinically unmet need in everyday routine praxis. The lack of standardized endpoints, heterogeneity of the syndrome, and absence of FDA-approved treatments remain major barriers to treatment implementation. Multimodal strategies combining pharmacological treatment with nutritional and rehabilitative support are likely to define future therapeutic success.

Introduction: This review evaluates the potential of glucagon‑like peptide‑1 receptor agonists (GLP‑1RAs) - first developed for type 2 diabetes and later approved for chronic weight management and additional indications - to be repurposed as neuroprotective and remyelinating therapies in multiple sclerosis (MS). We synthesize emerging pre‑clinical and early clinical evidence, highlight practical barriers to translation, and outline directions for future research.

Areas covered: In experimental autoimmune encephalomyelitis and toxin-induced demyelination mouse models, GLP-1RAs have been shown to reduce oxidative stress, preserve axonal integrity, suppress microglial and astrocytic activation, and, in some cases, promote remyelination. Early observational data in people with MS suggest GLP-1RAs are well tolerated, provide expected metabolic benefits, and do not exacerbate disease activity. Moreover, signals of reduced neurological impairment and lower dementia incidence in broader diabetic cohorts further support their translational promise. However, to date, there are no published randomized controlled trials of GLP-1RAs in MS.

Expert opinion: Pre‑clinical and early clinical signals support GLP‑1RAs as promising candidates for neuroprotection in MS, yet definitive evidence of disease‑modifying efficacy is lacking. Practical barriers, such as drug availability and cost, together with unresolved mechanistic questions underscore the need for biomarker‑rich mechanistic trials. Rigorous prospective studies are essential to establish whether GLP‑1RAs can meaningfully alter the trajectory of MS.