Targeted Oncology最新文献

The mitogen-activated protein kinase (MAPK) pathway is a key driver in many histiocytic disorders, including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD). This has led to successful and promising treatment with targeted therapies, including BRAF inhibitors and MEK inhibitors. Additional novel inhibitors have also demonstrated encouraging results. Nevertheless, there are several problems concerning targeted therapy that need to be addressed. These include, among others, incomplete responsiveness and the emergence of resistance to BRAF inhibition as observed in other BRAF-mutant malignancies. Drug resistance and relapse after treatment interruption remain problems with current targeted therapies. Targeted therapy does not seem to eradicate the mutated clone, leading to inevitable relapes, which is a huge challenge for the future. More fundamental research and clinical trials are needed to address these issues and to develop improved targeted therapies that can overcome resistance and achieve long-lasting remissions.

Background: Malignant peripheral sheath tumor (MPNST) is a rare, aggressive form of soft-tissue sarcoma that presents a unique set of diagnostic and treatment challenges and is associated with major unmet treatment medical needs.

Objective: The chief aim of this review is to consider the epidemiology, histology, anatomic distribution, pathologic signaling pathways, diagnosis, and management of MPNST, with a focus on potential targeted therapies. A subordinate objective was to establish benchmarks for the antitumor activity of such treatments.

Results: MPNST has an incidence of 1:100,000 in the general population and 1:3500 among patients with the inherited condition of neurofibromatosis-1. Spindle-cell sarcomas of neural-crest origin, MPNSTs are frequently situated in the extremities and pelvis/trunk, often at the confluence of large nerve roots and bundles. Highly copy-number aberrant and enriched in chromosome 8, MPNSTs have a complex molecular pathogenesis that likely involves the interplay of multiple signaling pathways, including Ras/AKT/mTOR/MAPK, EGFR, p53, PTEN, and PRC2, as well as factors in the tumor microenvironment. A combination of magnetic resonance imaging (MRI) and positron emission tomography with ¹⁸F-fluorodeoxyglucose (FDG-PET) enables comprehensive assessment of both morphology and metabolism, while MRI- and ultrasound-guided core needle biopsy can confirm histopathology. Although surgery with wide excisional margins is now the chief curative approach to localized disease, MPNST-specific survival has not improved in decades. For advanced and metastatic MPNST, radiation and chemotherapy (chiefly with anthracyclines plus ifosfamide) have somewhat promising but still largely uncertain treatment roles, chiefly in local control, downstaging, and palliation. No single druggable target has emerged, no objective responses have been observed with a number of targeted therapies (cumulative disease control rate in our review = 22.9-34.8%), and combinatorial approaches directed toward multiple signal transduction mechanisms are hallmarks of ongoing clinical trials.

Conclusions: Despite advances in our understanding of the genetics and molecular biology of MPNST, further research is warranted to: (1) unravel the complex pathogenesis of this condition; (2) improve diagnostic yield; (3) delineate the appropriate roles of chemotherapy and radiation; and (4) develop a targeted therapy (or combination of such treatments) that is well tolerated and prolongs survival.

Background: The approved dose of Selinexor, 60 mg twice-weekly, is associated with several clinically relevant toxicities. Preclinical studies show that a sustained-release formulation of selinexor results in a lower toxicity profile.

Objective: The phase 1b METSSAR trial assessed the safety and tolerability of an alternative dosing schedule of selinexor (to mimic the sustained-release formulation) in advanced soft tissue sarcoma (STS) patients.

Patients and methods: Selinexor was administered in a split-dose schedule (40 mg, 20 mg, 20 mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15, and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAEs). Secondary objectives were EORTC QLQ-C30 quality of life (QoL) assessment, and preliminary efficacy.

Results: Twenty patients with 12 STS subtypes were enrolled and received a median of four cycles of treatment. There were no grade ≥ 3 TRAEs. Dysgeusia, nausea, fatigue, and thrombocytopenia were the most common grade ≤ 2 TRAEs. No treatments were discontinued due to TRAE, but four patients (20%) required dose reduction. Median change in global health status (GHS) score from baseline to cycle 2 (by QLQ-C30 v3.0) was - 8.33, and only 39% of patients reported a clinically meaningful decline in GHS score (≥ 10 points). Median symptom scale scores on treatment were increased for fatigue (+12.35), nausea/vomiting (+18.52), and anorexia (+16.67), but reduced for pain (- 3.70). The median progression-free survival (PFS) was 4.0 months (95% confidence interval 1.9-7.5).

Conclusions: Split-dose once-weekly selinexor was reasonably well tolerated in this heterogeneous group of advanced STS patients with a better, or at least similar, clinician- and patient-reported toxicity profile compared to the standard dosing regimen. Further clinical evaluation is warranted, as better dose delivery can lead to improved antitumor efficacy.

Background: The benefit of immune checkpoint inhibitors (ICIs) for poor performance status patients with advanced urothelial carcinoma (UC) remains unknown.

Objective: In the present sub-analysis of the ARON-2 study, we investigated the role of pembrolizumab for advanced UC patients with ECOG (Eastern Cooperative Oncology Group) performance status (ECOG-PS) 2.

Patients and methods: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of advanced UC progressing or recurring after platinum-based therapy and treated with pembrolizumab between 1 January 2016 to 1 April 2024 were included. In this sub-analysis we focused on patients with ECOG-PS 2.

Results: We included 1,040 patients from the ARON-2 dataset; of these, 167 patients (16%) presented an ECOG-PS 2. The median overall survival (OS) was 14.8 months (95% confidence interval (CI) 12.5-16.1) in the overall study population, 18.2 months (95% CI 15.8-22.2) in patients with ECOG-PS 0-1, and 3.7 months (95% CI 3.2-5.2) in subjects with ECOG-PS 2 (p < 0.001). The median progression-free survival (PFS) in the overall study population was 5.3 months (95% CI 4.3-97.1), 6.2 months (95% CI 5.5-97.1) in patients with ECOG-PS 0-1, and 2.8 months (95% CI 2.1-3.4) in patients with ECOG-PS 2. Among the latter, liver metastases and progressive disease during first-line therapy were significant predictors of OS at both univariate and multivariate analyses. For PFS, univariate and multivariate analyses showed a prognostic role for lung metastases, liver metastases, and progressive disease during first-line therapy.

Conclusions: This large real-world evidence study suggests the effectiveness of second-line pembrolizumab for mUC patients with poor performance status. The presence of liver metastases and progressive disease during first-line therapy is associated with worse clinical outcomes and, thus, should be taken into account when making treatment decisions in clinical practice.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) targeting HER2-positive malignancies across various tumor types. Through its unique composition, T-DXd achieves selective payload delivery, inducing cell death and halting tumor progression. Clinical trials initially investigated T-DXd's efficacy in HER2-positive advanced or metastatic breast, gastric, lung, and colorectal cancers; however, recent results from the DESTINY-PanTumor02 trial further underscore T-DXd's versatility, prompting T-DXd's US FDA approval for HER2-positive (immunohistochemistry [IHC] 3+) solid tumors. Moreover, in addition to T-DXd's efficacy against brain metastasis, T-DXd is showing promising results in HER2-low and HER2-ultra-low metastatic breast cancer, indicating a broader population of patients who may benefit.

Background: While guidelines recommend immune checkpoint inhibitor (ICI) rechallenge as second-line therapy for unresectable hepatocellular carcinoma (HCC), data supporting this remain limited, particularly regarding a standard regimen for first- and second-line treatments. Tremelimumab/durvalumab was recently approved but data on ICI rechallenge are lacking.

Objectives: The purpose of this study was to evaluate the early efficacy and safety of tremelimumab/durvalumab for HCC as an ICI rechallenge following initial ICI therapy with atezolizumab/bevacizumab.

Patients and methods: This multicenter retrospective study included patients with HCC who underwent treatment with tremelimumab/durvalumab, with relevant available clinical information. We evaluated the safety and efficacy of tremelimumab/durvalumab as ICI rechallenge following initial treatment with atezolizumab/bevacizumab. We analyzed the outcomes in patients who underwent tremelimumab/durvalumab as an ICI rechallenge and those who received tremelimumab/durvalumab as their initial ICI therapy RESULT: A total of 45 patients treated with tremelimumab/durvalumab were included, with 55.6% (25/45) undergoing ICI rechallenge. The objective-response and disease-control rates in patients who underwent ICI rechallenge were 14.3% (3/21) and 47.6% (10/21), respectively, similar to those in patients initially treated with tremelimumab/durvalumab. All patients (n = 3) who experienced the best response to progressive disease (PD) with initial atezolizumab/bevacizumab experienced PD during ICI rechallenge. The incidence rates of adverse events were similar between patient groups treated with tremelimumab/durvalumab as ICI rechallenge and initial ICI. Among patients experiencing immune-related adverse events (irAEs) with atezolizumab/bevacizumab, 75% (3/4) encountered similar irAEs during ICI rechallenge.

Conclusion: Early safety and efficacy profiles of durvalumab/tremelimumab as ICI rechallenge are satisfactory.

Background: Insufficient patient enrollment per month (=accrual) is the leading cause of cancer trial termination.

Objective: To identify and quantify factors associated with patient accrual in trials leading to the US Food and Drug Administration (FDA) approval of new cancer drugs.

Data: All anti-cancer drugs with FDA approval were identified in the Drugs@FDA database (2000-2022). Data on drug indication's background-, treatment-, disease-, and trial-related factors were collected from FDA labels, clinicaltrials.gov, and the Global Burden of Disease study. The association between patient accrual and collected variables was assessed in Poisson regression models reporting adjusted rate ratios (aRR).

Results: We identified 170 drugs with approval in 455 cancer indications on the basis of 292 randomized and 163 single-arm trials. Among randomized trials, median enrollment per month was 38 patients (interquartile range [IQR]: 26-54) for non-orphan, 21 (IQR: 15-38, aRR 0.88, p = 0.361) for common orphan, 20 (IQR: 10-35, aRR 0.73, p <0.001) for rare orphan, and 8 (IQR 6-12, aRR 0.30, p < 0.001) for ultra-rare orphan indications. Patient enrollment was positively associated with disease burden [aRR: 1.0003 per disability-adjusted life year (DALY), p < 0.001), trial sites (aRR: 1.001 per site, p < 0.001), participating countries (aRR: 1.02 per country, p < 0.001), and phase 3 vs. 1/2 trials (aRR: 1.64, p = 0.037). Enrollment was negatively associated with advanced-line vs. first-line treatments (aRR: 0.81, p = 0.010) and monotherapy vs. combination treatments (aRR: 0.80, p = 0.007). Patient enrollment per month was similar between indications with and without a biomarker (median: 27 vs. 32, aRR 0.80, p = 0.117). Patient enrollment per month was substantially lower in government-sponsored than industry-sponsored trials (median: 14 vs. 32, aRR 0.80, p = 0.209). Enrollment was not associated with randomization ratios, crossover, and study blinding.

Conclusions: Disease incidence and disease burden alongside the number of study sites and participating countries are the main drivers of patient enrollment in clinical trials. For rare disease trials, greater financial incentives could help expedite patient enrollment. Novel trial design features, including skewed randomization, crossover, or open-label masking, did not entice patient enrollment.

Background: The impact of glucocorticoid administration for adverse events (AEs), including immune-related AEs, on the effectiveness of immune checkpoint inhibitor (ICI) combination therapy for advanced renal cell carcinoma (RCC) remains unknown.

Objectives: To clarify the prognostic impact of glucocorticoid use for AEs during first-line ICI combination therapy for advanced RCC.

Patients and methods: We retrospectively evaluated data from 194 patients who received dual ICI combination therapy [i.e., immunotherapy (IO)-IO] or combinations of ICIs with tyrosine kinase inhibitors (TKIs) as first-line therapy. The patients were divided into two groups according to the history of glucocorticoid administration in each treatment group. Survival based on glucocorticoid administration was assessed.

Results: A total of 101 (52.0%) and 93 (48.0%) patients received IO-IO and IO-TKI combination therapy, respectively. Glucocorticoids were administered to 46 (46%) and 22 (24%) patients in the IO-IO and IO-TKI groups, respectively. In the IO-IO group, progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with glucocorticoid administration than in those without administration (median PFS: 14.4 versus 3.45 months, p = 0.0005; median OS: 77.6 versus 33.9 months, p = 0.0025). Multivariable analysis showed that glucocorticoid administration was an independent predictor of longer PFS (hazard ratio: 0.43, p = 0.0005) and OS (hazard ratio: 0.35, p = 0.0067) after adjustment for covariates. In the IO-TKI group, neither PFS nor OS significantly differed between patients treated with and without glucocorticoid administration (PFS: p = 0.0872, OS: p = 0.216).

Conclusions: Glucocorticoid administration did not negatively impact the effectiveness of ICI combination therapy for RCC, prompting glucocorticoid treatment use when AEs develop.

Patients with follicular lymphoma, an indolent form of non-Hodgkin lymphoma, typically experience multiple relapses over their disease course. Periods of remission become progressively shorter with worse clinical outcomes after each subsequent line of therapy. Currently, no clear standard of care/preferred treatment approach exists for patients with relapsed or refractory follicular lymphoma. As novel agents continue to emerge for treatment in the third-line setting, guidance is needed for selecting the most appropriate therapy for each patient. Several classes of targeted therapeutic agents, including monoclonal antibodies, phosphoinositide 3-kinase inhibitors, enhancer of zeste homolog 2 inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies, have been approved by regulatory authorities based on clinical benefit in patients with relapsed or refractory follicular lymphoma. Additionally, antibody-drug conjugates and other immunocellular therapies are being evaluated in this setting. Effective integration of CAR-T cell therapy into the treatment paradigm after two or more prior therapies requires appropriate patient selection based on transformation status following a rebiopsy; a risk evaluation based on age, fitness, and remission length; and eligibility for CAR-T cell therapy. Consideration of important logistical factors (e.g., proximity to the treatment center and caregiver support during key periods of CAR-T cell therapy) is also critical. Overall, an individualized treatment plan that considers patient-related factors (e.g., age, disease status, tumor burden, comorbidities) and prior treatment types is recommended for patients with relapsed or refractory follicular lymphoma. Future analyses of real-world data and a better understanding of mechanisms of relapse are needed to further refine patient selection and identify optimal sequencing of therapies in this setting.