Clinical Cancer Research最新文献

Patient reported outcome (PRO) plays a crucial role as clinical endpoint in oncology trials. Traditional statistical methods, such as hypothesis testing, have been commonly used by pharmaceutical industry and regulators to evaluate treatment efficacy on PRO endpoints. However, the analysis of PRO data remains challenging due to high variability and missing data issues. Here, we will present examples where inappropriate statistical analyses of PRO data can confound treatment efficacy analyses. To overcome these challenges, we propose the application of individual participant data and population models. Population models have been extensively used in pharmacokinetics and pharmacodynamics analyses and are well accepted by regulators. However, their potential in PRO data analyses, particularly in the field of oncology, remains largely untapped. This perspective paper aims to highlight the value of population modeling approaches in PRO data analyses for oncology clinicians and researchers. Population models integrate individual participant data and can effectively handle the substantial variability in PRO measurements by incorporating covariates, between-subject variability, and accounting for measurement noise. By leveraging information from the population, this approach also provides accurate estimations for participants with missing data or sparse sampling. Moreover, these models could be applied to predict long-term PRO dynamics. If used appropriately, population modeling approaches could revolutionize the analysis of PRO data in oncology drug development, enabling a more comprehensive understanding of the impact of treatment on patients' lives. Our aim is to encourage stakeholders to consider population modeling as a standard and effective tool to enhance decision-making and ultimately improve patient care.

Purpose: To assess the efficacy and safety of an induction regimen composed of idarubicin, cytarabine, and cladribine (IAC) in patients with de novo acute myeloid leukemia (AML).

Patients and methods: Adult patients with newly diagnosed AML were randomized to the IAC group (cladribine 5 mg/m2/day for 5 days, idarubicin 8 mg/m2/day for 3 days, and cytarabine 100 mg/m2/day for 7 days) and the IA group (idarubicin 12 mg/m2/day for 3 days and cytarabine 100 mg/m2/day for 7 days) at a 1:2 ratio. The primary endpoint was complete remission (CR) after induction. Secondary endpoints included 2-year overall survival (OS), disease-free survival, and cumulative incidence of relapse.

Results: A total of 618 adult patients with newly diagnosed AML were enrolled. The overall CR rate was 80.5% in the IAC group compared with 72.4% in the IA group (P = 0.029). The 2-year OS was 81.3% in the IAC group compared with 70.0% in the IA group (P = 0.011). Patients on the IAC regimen achieved a higher CR rate compared to those on the IA regimen, particularly in those with adverse risk (69.8% vs. 49.1%, P = 0.008), 2-year OS (80.1% vs. IA 58.1%, P = 0.014), and disease-free survival (78.8% vs. 51.3%, P = 0.009). In the subgroup of patients older than 45 years of age, the IAC regimen exerted better CR (77.1% vs. 62.6%, P = 0.033) and 2-year OS (74.7% vs. IA 55.0%, P = 0.019). There were no differences in chemotherapy-related toxicities between the groups.

Conclusions: Cladribine added to the IA regimen was safe and effective in de novo AML. Patients with adverse risk or those between 45 and 60 years of age might benefit significantly on both response and survival with the IAC regimen.

Plasma human papilloma virus (HPV) DNA is a biomarker closely associated with HPV-mediated oropharynx cancer recurrence. This CCR Translations discusses the potential utility of plasma HPV DNA in predicting HPV oropharynx cancer recurrence, and the challenges of application to clinical practice.

Background: Selinexor is a first-in-class, central nervous system (CNS)-penetrant, oral inhibitor of exportin 1 (XPO1), the main nuclear exporter of many key tumor suppressors. We report a phase 1 trial of selinexor in children and adolescents with recurrent CNS and solid tumors (NCT02323880).

Methods: A rolling-six design was used to evaluate the maximum tolerated dose (MTD) and first dose pharmacokinetics (PK) of selinexor administered once (QW, 35-45 mg/m2) or twice (BIW, 20-35 mg/m2) weekly during a 28-day cycle (Part A). Ten additional patients with high-grade glioma (HGG) were treated at the QW MTD (Part B).

Results: In Part A, 49 patients were enrolled. Continuous BIW dosing was limited by extended hematologic toxicity. The MTD on a BIW schedule for three weeks on/one-week off (BIW 3/1) was 20 mg/m2/dose. Dose-limiting toxicities (DLTs) on this schedule included fatigue, acute reversible neurologic changes, neutropenia, thrombocytopenia, and AST/ALT increase. On a continuous QW schedule, the MTD was 35 mg/m2/dose, DLTs included seizure and thrombocytopenia. In Part B (HGG expansion), there were no additional DLTs observed. Non-dose-limiting toxicity included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. There were no objective responses. The median number of cycles received was 1 (range 1-9); Eight of 59 patients (13.5%) received 5-9 cycles, five of whom had HGG.

Conclusions: Selinexor-related toxicities were primarily hematologic and neurologic requiring dose or dose-frequency reduction. The MTD and recommended initial phase 2 dose of selinexor in children and adolescents with recurrent solid and CNS tumors is 35 mg/m2/dose QW.

Purpose: Breast cancers with ESR1 mutations are resistant to antiestrogen therapy. In this study, we aimed to investigate the association of ESR1 mutations with resistance to CDK4/6 inhibitors (CDK4/6i) using real-world data analysis and experimental validation.

Patients and methods: A total of 3,958 patients with estrogen receptor-positive (ER+) metastatic breast cancer with DNA sequencing data were analyzed. Breast tumor DNA and circulating tumor (ct) DNA were sequenced using the Tempus xT tumor assay and Tempus xF liquid biopsy, respectively. Patients were stratified into either treated with CDK4/6i (tumor tissue: 1,070; ctDNA: 1,885) or CDK4/6i naïve (tumor tissue: 750; ctDNA: 253). Engineered MCF7 cells carrying ESR1 Y537S or D538G knock-in mutations were used to study antitumor efficacy of the CDK4/6i palbociclib in vitro and in vivo.

Results: In both xF and xT assays, ESR1 mutations were the only somatic alterations significantly more frequent in patients who received CDK4/6i compared to those who did not. Knock-in of ESR1 Y537S or ESR1 D538G in MCF7 cells resulted in upregulation of cell cycle-related gene signatures upon treatment with CDK4/6i ± antiestrogen compared to cells with non-mutant ESR1. MCF7 xenografts harboring ESR1 Y537S and D538G mutations established in nude mice were resistant to palbociclib.

Conclusions: We report herein real-world and preclinical evidence that ESR1 mutations, particularly Y537S and D538G, can drive resistance to CDK4/6 inhibitors.

Hereditary retinoblastoma is a classic cancer predisposition syndrome with risks beginning in early infancy. About 45% of children with retinoblastoma (RB) have hereditary disease. These children are at risk for both intraocular disease as well as additional neoplasms throughout their lifetime. Germline pathogenic variants (GPVs) in RB1 typically lead to bilateral intraocular disease, elevated risks of trilateral RB, and risks of subsequent malignant neoplasms (non-ocular tumors), especially sarcomas and melanomas. There is further increased risk of subsequent malignant neoplasms if radiation treatment is used. Herein, with a reconvening of the AACR Childhood Cancer Predisposition Workshop, we expand on strategies for identifying individuals with hereditary RB, with a focus on testing strategies for children with RB. We also provide updates from previous recommendations. Given the high penetrance of retinal tumors, we review the importance of close intraocular surveillance and consider recent data regarding surveillance for subsequent malignant neoplasms. Finally, we discuss the importance of counseling for survivors of intraocular disease to address risks of adult-onset tumors as well as to consider reproductive risks.

Backgound: The GeparOLA study evaluated paclitaxel(P) plus olaparib(O) in neoadjuvant chemotherapy (NACT) for patients with HER2-negative early breast cancer (eBC) with homologous recombination deficiency (HRD). HRD was defined by high HRD-score or germline(g)/tumor(t) BRCA1/2 mutations (g/tBRCA1/2mut). Here, we report long-term outcome data.

Patients and methods: GeparOLA (NCT02789332) was a randomized, multicenter, prospective, open-label, phase II trial. Patients with HER2-negative eBC, HRD, indication for chemotherapy (cT2-cT4a-d or cT1c and cN+ or cT1c and pNSLN+ or cT1c and triple-negative[TN]BC or cT1c and Ki-67>20%), were randomly assigned to P+O or P+carboplatin(Cb), both followed by epirubicin+cyclophosphamide(EC). Long-term efficacy endpoints were secondary endpoints and included invasive disease-free survival(iDFS), distant disease-free survival(DDFS) and overall survival(OS).

Results: Between 09/2016 and 07/2018, 107 patients were randomized and 106 (PO N=69;PCb N=37) started treatment. The median age was 47.0 years; 35.8% had cT1 tumors; 31.4% were cN+; 86.8% had G3 tumors; 89.6% had Ki-67>20% and 72.6% were TN. After median follow-up of 49.8 months, 18(15 PO; 3 PCb) iDFS events and 7(6 PO; 1 PCb) deaths were reported. The 4-year iDFS (76.0%PO vs 88.5%PCb, HR=2.86 [95%CI 0.83-9.90],log-rank p=0.081), DDFS (81.2%PO vs 93.4%PCb, HR=3.03 [95%CI 0.67-13.67],log-rank p=0.129) and OS (89.2%PO vs 96.9%PCb, HR=3.27 [95%CI 0.39-27.20],log-rank p=0.244) tended to be inferior with O. Patients without g/tBRCA1/2mut benefited from Cb [7/30 patients had iDFS/DDFS events in PO vs 0/16 in PCb].

Conclusion: For HER2-negative eBC with HRD, olaparib showed a tendency for inferior outcomes compared to carboplatin, particularly in patients without g/tBRCA1/2mut. In patients with g/tBRCA1/2mut olaparib may replace carboplatin.

Purpose: Patients with recurrent or metastatic sinonasal squamous cell carcinoma (R/M SNSCC) lack standardized systemic treatment and prospective studies. We evaluated the anti-tumor response and safety of pembrolizumab with nab-paclitaxel and platinum in R/M SNSCC.

Patients and methods: R/M SNSCC patients received pembrolizumab 200mg, nab-paclitaxel 260mg/m2 plus cisplatin 75 mg/m2 or carboplatin at an area under the curve 5 on day 1 every 21 days for up to six cycles, followed by pembrolizumab maintenance until progression or unacceptable toxicity or 35 cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Immunohistochemistry and high-resolution sequencing of the tumor samples were performed.

Results: The ORR in 20 patients was 60.0% (95% CI: 36.1%-80.9%) and two patients (2/20, 10%) achieved CR. The DCR was 100%. Median follow-up was 18.1 months (range:5.2-31.7), the median PFS was 12.2 months (95% CI: 9.0 months-not estimated) and the median OS was not reached. Patients with PD-L1 CPS ≥20 exhibited better ORR (80.0% vs 28.6%, p=0.144), median PFS (not reached vs 7.0 months, p=0.0137), and median OS (not reached vs 17.8 months, p=0.0401) compared to those with PD-L1 CPS < 20. Grade 3/4 treatment-related adverse events (AE) accounted for 30.0% (6/20), and all come from hematologic toxicity. Hypothyroidism was the most common immune-related AE (12/20, 60.0%).

Conclusions: Pembrolizumab plus nab-paclitaxel and platinum shows promising antitumor activity and manageable safety in first-line R/M SNSCC patients.

Introduction: Previous reports have described ETV6-NTRK3 fusion-positive gastrointestinal stromal tumors (GISTs) in cases lacking KIT, PDGFRA, RAS-pathway, or SDHx alterations. However, some investigators have questioned the rigor of these reports and the true existence of NTRK rearrangements in GIST. This study aims to: 1) resolve whether NTRK gene rearrangements exist in GIST; 2) review the relevant literature; and 3) demonstrate a case of NTRK fusion GIST.

Methods: A comprehensive literature review using PubMed identified additional NTRK fusion-reported cases. Under an IRB-approved protocol, we describe a patient with biopsy-proven GIST who underwent genomic and transcriptomic CLIA-certified testing, precision-matched therapy, surgical resection, and pathological analysis.

Results: We identified 17 reported cases of GIST with NTRK fusions. Five studies reported GIST with KIT/DOG-1 expression by IHC, wild-type KIT/PDGFRA, and an ETV6-NTRK3 fusion, consistent with GIST. We demonstrate a case of a 72-year-old female status post resection of a high-risk gastric GIST followed by 45 months of adjuvant imatinib. She developed recurrent disease and biopsy revealed mixed epithelioid and spindleoid GIST with IHC expression of KIT (CD117) and DOG-1. Imatinib was re-initiated, but her disease progressed, prompting molecular testing for the first time. RNA sequencing identified an in-frame fusion of ETV6 with NTRK3. Larotrectinib, a pan-NTRK inhibitor, was initiated for 7 months, resulting in shrinkage in five tumors (range: 4.2-77%). Surgical cytoreduction demonstrated a pathological near complete response (1% viable tumor cells).

Conclusion: Our findings confirm the existence of ETV6-NTRK3 fusion GIST and demonstrate that these imatinib-resistant GISTs may be exquisitely sensitive to TRK.