Targeted Oncology最新文献

Background: In recent years, theranostics has become a promising approach for treating metastatic castration-resistant prostate cancer (mCRPC), with trials investigating targeted radioligand therapy, particularly using prostate-specific membrane antigen labeled with lutetium-177 ([¹⁷⁷Lu]Lu-PSMA). The proper position of [¹⁷⁷Lu]Lu-PSMA in the therapeutic algorithm of mCRPC is yet to be identified.

Design, setting, and participants: We conducted a systematic review and meta-analysis of phase II/III randomized controlled trials to assess the efficacy of [¹⁷⁷Lu]Lu-PSMA in treating mCRPC. Study endpoints included radiographic progression-free survival (rPFS), prostate-specific antigen-PFS, objective response rate, and overall survival.

Outcome measurements and statistical analysis: Data were extracted according to the PRISMA statement. Summary hazard ratios (HRs) were calculated using random- or fixed-effects models. Statistical analyses were performed with RevMan software (v.5.2.3).

Results: [¹⁷⁷Lu]Lu-PSMA reduced the risk of rPFS (HR 0.55; 95% confidence interval [CI] 0.43-0.71; p < 0.00001) and prostate-specific antigen-PFS (HR 0.53; 95% CI 0.41-0.67; p < 0.00001), and improved the objective response rate compared with control therapies (response rate 3.55; 95% CI 1.91-6.60; p < 0.0001), whereas no significant cumulative effect on overall survival was documented (HR 0.92; 95% CI 0.65-1.31; p = 0.63). Notably, in a dedicated subanalysis, comparable effects on rPFS were observed when [¹⁷⁷Lu]Lu-PSMA was compared with active therapy.

Conclusion: [¹⁷⁷Lu]Lu-PSMA has a favorable impact on the radiographic and biochemical control of mCRPC and represents a potential treatment in a scenario where other valuable options are available. Further efforts are required to identify clinical and molecular markers necessary for proper patient stratification.

Background: The efficacy and safety of cyclin-dependent kinase (CDK)4/6 inhibitors in patients with breast cancer have been investigated by large-scale trials sponsored by drug companies. A lack of real-world evidence may lead to biases.

Objective: We systematically reviewed the large-scale clinical trials and real-world data to investigate the efficacy and safety of CDK4/6 inhibitors in patients with breast cancer.

Patients and methods: We searched PubMed, Embase, and Cochrane Library from the inception of each database to January 2024. We included both prospective and retrospective studies reporting the survival outcomes or adverse effects of CDK4/6 inhibitors in patients with breast cancer.

Results: We included 41 prospective trials and 80 retrospective studies involving a total of 69,535 patients. Our meta-analysis of double-arm studies revealed that all types of CDK4/6 inhibitors significantly improved overall survival and progression-free survival. The pooled estimates of the 1-year overall survival (OS) rates and 1-year progression-free survival (PFS) rates in single-arm real-world studies were 74.8% and 49.4% for abemaciclib, 84.1% and 55.7% for palbociclib, and 93.4% and 62.2% for ribobiclib, respectively. In terms of adverse effects, Asian patients were significantly more likely to experience neutropenia and increased alanine aminotransferase, whereas Western patients were significantly more likely to have grade 3 or 4 adverse effects and constipation.

Conclusions: CDK4/6 inhibitors can improve OS and PFS in patients with advanced breast cancer. The incidence of adverse effects may differ with drugs and with ethnicity. On the basis of our findings, clinicians can select suitable CDK4/6 inhibitors for patients by conducting thorough clinical evaluations.

Chondrosarcomas, a rare form of bone sarcomas with multiple subtypes, pose a pressing clinical challenge for patients with advanced or metastatic disease. The lack of US Food and Drug Administration (FDA)-approved medications underscores the urgent need for further research and development in this area. Patients and their families face challenges as there are no systemic therapeutic options available with substantial effectiveness. A significant number (50-80%) of chondrosarcomas have a mutation in the isocitrate dehydrogenase (IDH) genes. This review focuses on IDH-mediated pathogenesis and recent pharmacological advances with novel IDH inhibitors, explores their potential therapeutic value, and proposes potential future avenues for clinical trials combining IDH inhibitors with other systemic agents for chondrosarcomas.

Background: Oncology research is increasingly adopting new clinical trial models that implement the concept of precision medicine. One of these is the basket clinical trial design. Basket clinical trials allow new treatments to be evaluated across multiple tumor types. Patients recruited to basket clinical trials share certain molecular characteristics of their cancer that are predictive of clinical benefit from the experimental treatment.

Objective: Our aim was to describe the risks and benefits of basket clinical trials in oncology.

Methods: Our study was prospectively registered in PROSPERO (CRD42023406401). We systematically searched PubMed, Embase, and ClinicalTrials.gov for reports of basket clinical trials in oncology published between 1 January, 2001, and 14 June, 2023. We measured the risk by treatment-related adverse events (grades 3, 4, and 5), and the benefit by objective response rate. We also extracted and analyzed data on progression-free survival and overall survival. When possible, data were meta-analyzed.

Results: We included 126 arms of 75 basket clinical trials accounting for 7659 patients. The pooled objective response rate was 18.0% (95% confidence interval [CI] 14.8-21.1). The rate of treatment-related death was 0.7% (95% CI 0.4-1.0), while 30.4% (95% CI 24.2-36.7) of patients experienced grade 3/4 drug-related toxicity. The median progression-free survival was 3.1 months (95% CI 2.6-3.9), and the median overall survival was 8.9 months (95% CI 6.7-10.2).

Conclusions: Our results provide an empirical basis for communicating about the risks and benefits of basket clinical trials and for refining new models of clinical trials applied in precision medicine.

Background: Patients with high-risk localized and locally advanced prostate cancer (HR-LPC/LAPC) have increased risk of metastasis, leading to reduced survival rates. Segmenting the disease course [time to recurrence, recurrence to metastasis, and post-metastasis survival (PMS)] may identify disease states for which the greatest impacts can be made to ultimately improve survival.

Objective: Evaluate real-world PMS of patients with HR-LPC/LAPC who received primary radical prostatectomy (RP) or radiotherapy (RT) with or without androgen deprivation therapy (ADT).

Patients and methods: Electronic health records from an oncology database were used to assess PMS. Risk of death was estimated using the Kaplan-Meier method. Hazard ratios (HRs) were used to analyze the impact of treatment and time to metastasis (TTM) on PMS. Standardized mortality ratios (SMRs) were calculated for patients with HR-LPC/LAPC versus the US general male population.

Results: Overall, 5008 patients with HR-LPC/LAPC were identified, and 1231 developed metastases after primary treatment (RP, n = 885; RT only, n = 262; RT+ADT, n = 84). Age-adjusted PMS HR between the RP and RT only cohorts was 1.19 (p = 0.077) and between RP and RT+ADT cohorts was 1.32 (p = 0.078). TTM was unrelated to PMS in unadjusted (HR 1.01, p = 0.2) and age-adjusted models (HR 0.99, p = 0.3). Relative to pre-metastasis SMRs, post-metastasis SMRs increased eightfold and fivefold in patients treated with RP and RT±ADT, respectively.

Conclusions: PMS was unrelated to TTM in patients with HR-LPC/LAPC, suggesting PMS may be independent of the trajectory to development of metastases. Given PMS may be a fixed length of time, delaying the development of metastasis may improve survival in patients with HR-LPC/LAPC.

Background: Although durvalumab has shown promise in improving survival rates in patients with locally advanced non-small cell lung cancer (NSCLC), the ideal duration of treatment has yet to be established.

Objective: The primary objective of this study was to determine the optimal number of durvalumab cycles following definitive chemoradiotherapy for locally advanced NSCLC.

Patients and methods: A total of 178 patients who received chemoradiotherapy for stage III NSCLC at 15 institutions were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were assessed according to the number of consolidation durvalumab cycles by landmark analysis. Landmark analyses were performed at 3-month intervals from the start of durvalumab treatment to 9 months.

Results: The median number of durvalumab cycles was 16 (range 1-27). PFS and OS were significantly better in patients who received ≥20 cycles of durvalumab than in those who did not (p < 0.001 and p < 0.001, respectively). In landmark analysis, significant differences were observed in PFS from 0 to 6 months and OS from 3 to 6 months between patients who continued durvalumab after the time point and those who did not. However, there were no significant differences in PFS or OS between patients who received 13-19 or ≥20 cycles of durvalumab at 9 months.

Conclusions: Durvalumab should be administered for more than 6 months to contribute to the main benefits of consolidation therapy following chemoradiotherapy.

Molecular tumor boards (MTB) are interdisciplinary conferences involving various experts discussing patients with advanced tumors, to derive individualized treatment suggestions based on molecular variants. These discussions involve using heterogeneous internal data, such as patient clinical data, but also external resources such as knowledge databases for annotations and search for relevant clinical studies. This imposes a certain level of complexity that requires huge effort to homogenize the data and use it in a speedy manner to reach the needed treatment. For this purpose, most institutions involving an MTB are heading toward automation and digitalization of the process, hence reducing manual work requiring human intervention and subsequently time in deriving personalized treatment suggestions. The tools are also used to better visualize the patient's data, which allows a refined overview for the board members. In this paper, we present the results of our thorough literature research about MTBs, their process, the most common knowledge bases, and tools used to support this decision-making process.

Background: Adavosertib (AZD1775) is a small-molecule Wee1 inhibitor. Durvalumab is a PD-L1 inhibitor.

Objective: The safety, tolerability, pharmacokinetics, and preliminary antitumor activity of adavosertib plus durvalumab were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).

Patients and methods: This phase 1, non-randomized, open-label study determined MTD/RP2D using dose-escalation cohorts. Eligible patients had histologically confirmed tumors refractory to standard therapy or for which no standard of care existed.

Results: A total of 55 patients received adavosertib with durvalumab. Overall, 3/52 evaluable patients experienced dose-limiting toxicities (DLTs; two grade 3 nausea, one grade 3 diarrhea that did not respond to care within 48 h). The most frequent (in > 5% of patients) treatment-emergent grade ≥ 3 toxicities were fatigue, diarrhea, nausea, anemia, and abdominal pain. MTD for twice-daily (bid) adavosertib dosing was oral adavosertib 150 mg bid (3 days on/4 days off; treatment days 15-17 and 22-24 of a 28-day cycle) with intravenous durvalumab 1500 mg four times a week (Q4W), which was also the RP2D. MTD for once-daily (qd) adavosertib dosing was oral adavosertib 300 mg qd (5 days on/2 days off; treatment days 15-19 and 22-26 of a 28-day cycle) with intravenous durvalumab 1500 mg Q4W.

Conclusions: This study defined the MTD/RP2D of adavosertib plus durvalumab in patients with advanced solid tumors. The safety profile of adavosertib with durvalumab was consistent with the known safety data of each agent. Findings provide preliminary evidence of limited antitumor activity of adavosertib plus durvalumab.

Trial registration: ClinicalTrials.gov, NCT02617277 (registration: 30 November 2015).

Context: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens.

Objective: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials.

Evidence acquisition: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features.

Evidence synthesis: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival.

Conclusions: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.