Circulating tumor DNA (ctDNA) enables personalized treatment strategies in oncology by providing a noninvasive source of clinical biomarkers. In patients with low ctDNA abundance, tumor-naïve methods ...are needed to facilitate clinical implementation. Here, using locoregionally confined head and neck squamous cell carcinoma (HNSCC) as an example, we demonstrate tumor-naïve detection of ctDNA by simultaneous profiling of mutations and methylation.
We conducted CAncer Personalized Profiling by deep Sequencing (CAPP-seq) and cell-free Methylated DNA ImmunoPrecipitation and high-throughput sequencing (cfMeDIP-seq) for detection of ctDNA-derived somatic mutations and aberrant methylation, respectively. We analyzed 77 plasma samples from 30 patients with stage I-IVA human papillomavirus-negative HNSCC as well as plasma samples from 20 risk-matched healthy controls. In addition, we analyzed leukocytes from patients and controls.
CAPP-seq identified mutations in 20 of 30 patients at frequencies similar to that of The Tumor Genome Atlas (TCGA). Differential methylation analysis of cfMeDIP-seq profiles identified 941 ctDNA-derived hypermethylated regions enriched for CpG islands and HNSCC-specific methylation patterns. Both methods demonstrated an association between ctDNA abundance and shorter fragment lengths. In addition, mutation- and methylation-based ctDNA abundance was highly correlated (
> 0.85). Patients with detectable pretreatment ctDNA by both methods demonstrated significantly worse overall survival (HR = 7.5;
= 0.025) independent of clinical stage, with lack of ctDNA clearance post-treatment strongly correlating with recurrence. We further leveraged cfMeDIP-seq profiles to validate a prognostic signature identified from TCGA samples.
Tumor-naïve detection of ctDNA by multimodal profiling may facilitate biomarker discovery and clinical use in low ctDNA abundance applications.
Human papillomavirus (HPV) DNA offers a convenient circulating tumor DNA (ctDNA) marker for HPV-associated malignancies, but current methods, such as digital PCR (dPCR), provide insufficient accuracy ...for clinical applications in patients with low disease burden. We asked whether a next-generation sequencing approach, HPV sequencing (HPV-seq), could provide quantitative and qualitative assessment of HPV ctDNA in low disease burden settings.
We conducted preclinical technical validation studies on HPV-seq and applied it retrospectively to a prospective multicenter cohort of patients with locally advanced cervix cancer (NCT02388698) and a cohort of patients with oropharynx cancer. HPV-seq results were compared with dPCR. The primary outcome was progression-free survival (PFS) according to end-of-treatment HPV ctDNA detectability.
HPV-seq achieved reproducible detection of HPV DNA at levels less than 0.6 copies in cell line data. HPV-seq and dPCR results for patients were highly correlated (
= 0.95,
= 1.9 × 10
) with HPV-seq detecting ctDNA at levels down to 0.03 copies/mL plasma in dPCR-negative posttreatment samples. Detectable HPV ctDNA at end-of-treatment was associated with inferior PFS with 100% sensitivity and 67% specificity for recurrence. Accurate HPV genotyping was successful from 100% of pretreatment samples. HPV ctDNA fragment sizes were consistently shorter than non-cancer-derived cell-free DNA (cfDNA) fragments, and stereotyped cfDNA fragmentomic patterns were observed across HPV genomes.
HPV-seq is a quantitative method for ctDNA detection that outperforms dPCR and reveals qualitative information about ctDNA. Our findings in this proof-of-principle study could have implications for treatment monitoring of disease burden in HPV-related cancers. Future prospective studies are needed to confirm that patients with undetectable HPV ctDNA following chemoradiotherapy have exceptionally high cure rates.
Abstract Background Concurrent chemoradiotherapy followed by adjuvant chemotherapy (CRT-A) is often the regimen of choice in locoregionally advanced nasopharyngeal carcinoma (NPC). Many alternative ...regimens have been reported in the literature, however, it is unknown how effective these regimens are compared to each other due to the lack of direct comparisons. Our objective was to perform a network meta-analysis (NMA) to determine the relative survival benefits of these treatments for locoregionally advanced NPC. Methods We performed a systematic review following the Cochrane methodology, using MEDLINE, EMBASE and CENTRAL to identify all randomised controlled trials (RCTs) that compared different chemoradiotherapy regimens for locoregionally advanced NPC. Overall survival (OS) was the primary outcome of interest, and hazard ratios (HRs) were extracted using the Parmar method. Bayesian NMAs with random effects were conducted using WinBUGS. Results Twenty-five RCTs (5576 patients) were included in this review. All together, these trials compared seven different regimens: radiotherapy (RT), concurrent chemoradiotherapy (CRT), neoadjuvant followed by CRT (N-CRT), CRT-A, RT-A, N-RT and N-RT-A. All regimens that contained CRT performed significantly better than RT. CRT-A did not improve survival compared to CRT alone (0.98; 95% credible regions: 0.71–1.34). For N-CRT versus CRT, the HR was 1.03 (0.69–1.47). When CRT-A was compared against N-CRT, the resulting HR was 0.96 (0.64–1.48). Conclusions Adjuvant chemotherapy does not appear to improve survival following CRT. The efficacies of CRT, CRT-A and N-CRT all appeared to be similar. Further studies are warranted to determine the value of additional chemotherapy phases in specific patient subgroups.
Eligibility criteria restrict patient enrollment in clinical trials. A Nature paper applied a machine-learning algorithm in a real-world database to show that relaxing some criteria may not ...jeopardize efficacy and safety. This may enable more patients to have earlier access to new therapies and make results more generalizable to clinical practice.
Eligibility criteria restrict patient enrollment in clinical trials. A Nature paper applied a machine-learning algorithm in a real-world database to show that relaxing some criteria may not jeopardize efficacy and safety. This may enable more patients to have earlier access to new therapies and make results more generalizable to clinical practice.
Clinical trials are key to translating scientific advances into progress in cancer research and care. Confronted by developments in basic science, the landscape of clinical cancer research is rapidly ...evolving. Here, we review recent changes in clinical trials’ design and conduct, and we forecast future directions toward personalized and global impact.
Clinical trials are key to translating scientific advances into progress in cancer research and care. Confronted by developments in basic science, the landscape of clinical cancer research is rapidly evolving. Here, we review recent changes in clinical trials’ design and conduct, and we forecast future directions toward personalized and global impact.
Background
Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti–programmed death 1 (anti–PD‐1) immunotherapy, ...pembrolizumab, in programmed death ligand 1 (PD‐L1)–positive, recurrent glioblastoma.
Methods
Adult patients with PD‐L1–positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE‐028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator‐assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD‐L1 expression levels (prospectively) and T‐cell–inflamed gene expression profile score (retrospectively).
Results
After a median follow‐up of 14 months (range, 2‐55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%‐26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progression‐free survival (median, 2.8 months; 95% CI, 1.9‐8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0‐26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD‐L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment‐related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune‐mediated adverse events and infusion reactions occurred in 7 patients (27%).
Conclusions
Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal‐finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.
In the phase 1 multicohort KEYNOTE‐028 study (ClinicalTrials.gov identifier, NCT02054806), the antitumor activity and safety of pembrolizumab were evaluated among patients with recurrent glioblastoma. Pembrolizumab monotherapy demonstrates antitumor activity in a subset of patients and has acceptable toxicity in this setting, in which current treatment options provide limited benefit and the prognosis is poor.
Flow cytometry is a widely applied approach for exploratory immune profiling and biomarker discovery in cancer and other diseases. However, flow cytometry is limited by the number of parameters that ...can be simultaneously analyzed, severely restricting its utility. Recently, the advent of mass cytometry (CyTOF) has enabled high dimensional and unbiased examination of the immune system, allowing simultaneous interrogation of a large number of parameters. This is important for deep interrogation of immune responses and particularly when sample sizes are limited (such as in tumors). Our goal was to compare the accuracy and reproducibility of CyTOF against flow cytometry as a reliable analytic tool for human PBMC and tumor tissues for cancer clinical trials. We developed a 40+ parameter CyTOF panel and demonstrate that compared to flow cytometry, CyTOF yields analogous quantification of cell lineages in conjunction with markers of cell differentiation, function, activation, and exhaustion for use with fresh and viably frozen PBMC or tumor tissues. Further, we provide a protocol that enables reliable quantification by CyTOF down to low numbers of input human cells, an approach that is particularly important when cell numbers are limiting. Thus, we validate CyTOF as an accurate approach to perform high dimensional analysis in human tumor tissue and to utilize low cell numbers for subsequent immunologic studies and cancer clinical trials.
Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell ...death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC.
Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 TC ≥ 25% using the VENTANA PD-L1 SP263 Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS).
Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval CI, 9.9–24.4); 29.4% (95% CI, 15.1–47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5–21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9–3.7) and 7.1 months (95% CI, 4.9–9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5–22.1) and 33.6% (95% CI, 24.8–42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up.
Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.
•This study assessed durvalumab in patients with R/M HNSCC and PD-L1-high expression.•Patients had failed 1 platinum-based chemotherapeutic regimen in the R/M setting.•The ORR for all patients was 16.2% with a median OS of 7.1 months.•HPV-positive patients had a numerically higher response rate and longer survival.•Durvalumab showed antitumour activity with acceptable safety in the HAWK study.
Abstract
Background
Clinician reporting of symptomatic adverse events (AEs) in phase I trials uses the Common Terminology Criteria for Adverse Events (CTCAE). The utility of the patient-reported ...outcomes (PROs) version of the CTCAE (PRO-CTCAE) in this setting is unknown. This prospective, observational study compared patient- and clinician-reported symptomatic AEs in phase I patients.
Methods
Phase I study–eligible patients at Princess Margaret were surveyed with the PRO-CTCAE full-item library (78 symptomatic AEs) at baseline (BL), mid-cycle 1, and mid-cycle 2 (C2). Patient and trial characteristics, best response, and survival data were collected. Presence or absence of patient- (PRO-CTCAE) or clinician-reported symptomatic AEs were compared (kappa) at defined timepoints and overall (BL+ mid-cycle 1 + C2).
Results
Of 292 patients approached from May 2017 to January 2019, a total of 265 (90.8%) were consented, with 243 (91.7%) evaluable and 552 PRO-CTCAE surveys (completion rate = 98.7%) included in analyses. Evaluation of overall patient-reported symptomatic AEs identified 50 PRO-CTCAE and 11 CTCAE items with 10% or greater reporting frequency. Nineteen CTCAE items were reported as 1% or less despite matched PRO-CTCAE items reporting as 10% or greater. Underreported categories included sexual health, bodily emissions, and cognition. Clinician- relative to patient-reporting frequency (ratio) demonstrated 9 symptomatic AEs with a 50-fold or more lower clinician reporting rate. Overall patient–clinician agreement for individual symptomatic AEs ranged from poor (κ = 0.00-0.19) to moderate (κ = 0.40-0.59), with discordance driven by lack of clinician reporting. Dyspnea (κ = 0.54) and peripheral neuropathy (κ = 0.63) at BL and limb edema (κ = 0.55) at C2 demonstrated the highest patient–clinician agreement.
Conclusions
Poor to moderate patient–clinician agreement for symptomatic AEs suggests clinician underreporting in phase I trials. Analyses of severity and interference PRO categories are ongoing.
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