SummaryBackgroundMost head and neck squamous-cell carcinomas (HNSCCs) are driven by p16 INK4A inactivation and cyclin D1 overexpression that results in hyperactivation of cyclin-dependent kinase 4 ...and 6 (CDK4/6), rather than by the human papillomavirus (HPV). Deregulated cyclin D1 expression also causes resistance to EGFR inhibitors. We previously reported that palbociclib (a selective CDK4/6 inhibitor) given with cetuximab (an EGFR inhibitor) was safe. The aim of this study was to establish the proportion of patients achieving an objective response with palbociclib and cetuximab in recurrent or metastatic HNSCC. MethodsWe did a multicentre, multigroup, phase 2 trial to evaluate the activity of palbociclib and cetuximab in platinum-resistant (group 1) and cetuximab-resistant (group 2) HPV-unrelated HNSCC. The study was done across eight university sites in the USA. Eligibility required measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1·1 RECIST 1·1), Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, age of 18 years or older, and disease progression on platinum but cetuximab-naive (group 1) or disease progression on cetuximab (group 2). All patients received palbociclib orally (125 mg/day, on days 1–21) and intravenous cetuximab (400 mg/m 2 on cycle one, day 1, then 250 mg/m 2 once per week) in 28-day cycles. The primary endpoint was objective response (complete responses and partial responses per RECIST 1·1). Analyses were done per protocol. This trial was registered with ClinicalTrials.gov, NCT02101034, and is ongoing, but both groups are closed to accrual. FindingsBetween Oct 19, 2015, and Nov 7, 2018, 62 patients were enrolled onto the trial: 30 patients were enrolled in group 1 and 32 in group 2. Median follow-up was 5·4 months (IQR 4·4–12·1) for group 1 and 5·5 months (4·3–8·3) for group 2. In group 1, of 28 evaluable patients, an objective response was achieved by 11 (39%; 95% CI 22–59). In group 2, of 27 evaluable patients, an objective response was achieved by five (19%; 6–38) in group 2. The most common grade 3–4 palbociclib-related adverse event was neutropenia (in 21 34% of 62 patients). No treatment-related deaths occurred. InterpretationIn patients with platinum-resistant or cetuximab-resistant HPV-unrelated HNSCC, palbociclib and cetuximab results in promising activity outcomes. Further studies of CDK4/6 inhibitors are warranted in HPV-unrelated HNSCC. FundingPfizer.
Background
Using next‐generation sequencing (NGS) to guide cancer therapy has created challenges in analyzing and reporting large volumes of genomic data to patients and caregivers. Specifically, ...providing current, accurate information on newly approved therapies and open clinical trials requires considerable manual curation performed mainly by human “molecular tumor boards” (MTBs). The purpose of this study was to determine the utility of cognitive computing as performed by Watson for Genomics (WfG) compared with a human MTB.
Materials and Methods
One thousand eighteen patient cases that previously underwent targeted exon sequencing at the University of North Carolina (UNC) and subsequent analysis by the UNCseq informatics pipeline and the UNC MTB between November 7, 2011, and May 12, 2015, were analyzed with WfG, a cognitive computing technology for genomic analysis.
Results
Using a WfG‐curated actionable gene list, we identified additional genomic events of potential significance (not discovered by traditional MTB curation) in 323 (32%) patients. The majority of these additional genomic events were considered actionable based upon their ability to qualify patients for biomarker‐selected clinical trials. Indeed, the opening of a relevant clinical trial within 1 month prior to WfG analysis provided the rationale for identification of a new actionable event in nearly a quarter of the 323 patients. This automated analysis took <3 minutes per case.
Conclusion
These results demonstrate that the interpretation and actionability of somatic NGS results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing could potentially improve patient care by providing a rapid, comprehensive approach for data analysis and consideration of up‐to‐date availability of clinical trials.
Implications for Practice
The results of this study demonstrate that the interpretation and actionability of somatic next‐generation sequencing results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing can significantly improve patient care by providing a fast, cost‐effective, and comprehensive approach for data analysis in the delivery of precision medicine. Patients and physicians who are considering enrollment in clinical trials may benefit from the support of such tools applied to genomic data.
Next‐generation sequencing (NGS) has emerged as an affordable and reproducible means to query tumors for somatic genetic anomalies. To help interpret somatic NGS data, many institutions have created a molecular tumor board to analyze the results of NGS and make recommendations. This article evaluates the utility of cognitive computing systems to analyze data for clinical decision‐making.
Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study ...was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors.
Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR).
As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval CI: 16-49) for all patients. The 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3-4 in 3 patients. No new safety signals were identified.
In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.
NC-6300 is a novel nanoparticle formulation of epirubicin that has a pH-sensitive linker conjugated to epirubicin. It exhibits selective tumor accumulation owing to enhanced permeability and ...retention effect. We conducted a phase 1b trial to determine MTD and recommended phase II dose (RP2D) of NC-6300 monotherapy in advanced, metastatic, or unresectable solid tumors, including soft-tissue sarcomas.
This phase 1b dose-escalation trial of NC-6300 monotherapy employed a Bayesian continuous reassessment method design. NC-6300 was administered on day 1 of every 21-day cycle, with epirubicin-equivalent dose increments from 125 to 215 mg/m
. Safety, efficacy, quality of life, and pharmacokinetic profile of NC-6300 monotherapy were evaluated.
Twenty-nine subjects (16 male) were enrolled: 17 with soft-tissue sarcoma, one with osteosarcoma, and 11 with other solid tumors. Observed dose-limiting toxicities included thrombocytopenia, stomatitis, lung infection, and febrile neutropenia. The most common grade 3/4 adverse events were neutropenia (59%), anemia (24%), thrombocytopenia (24%), and febrile neutropenia (21%). MTD and RP2D were determined to be 185 mg/m
and 150 mg/m
, respectively. The objective response rate in the evaluable population was 11%. Partial response was observed in angiosarcoma and endometrial stromal sarcoma. A dose-dependent increase was observed in both total and released epirubicin concentrations.
NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses. A signal of preliminary activity was observed in angiosarcoma. NC-6300 warrants further investigation in patients with advanced solid tumors, including sarcoma.
NC-6004, a novel cisplatin nanoparticle developed using micellar technology exhibits sustained release of cisplatin and selective distribution to tumors. Preclinical data demonstrated a favorable ...tolerability profile and preserved or improved antitumor activity compared with cisplatin across animal models. We evaluated the safety and tolerability of NC-6004 and gemcitabine using a Bayesian continual reassessment model (N-CRM) to determine the optimal dose.
Patients with advanced solid tumors received NC-6004 at 60 to 180 mg/m
on day 1 and gemcitabine at 1,250 mg/m
on days 1 and 8 every 3 weeks. Dose escalation of NC-6004 began with a single patient run-in until a dose-limiting toxicity occurred at 180 mg/m
Cohorts of four patients were enrolled at doses predicted by the N-CRM. The maximum tolerated dose (MTD) was defined as having the greatest probability of target toxicity <25%. Quality of life was assessed using EORTC-QLQ-C30.
Among 22 patients, the most common grade III/IV hematologic adverse events were leukopenia (68%) and thrombocytopenia (59%). Of 20 pretreated patients evaluable for response, half were previously exposed to a platinum agent. The MTD was 135 mg/m
Nine patients were treated at the MTD with median treatment duration of 15 weeks (range, 3-50). Tumor shrinkage occurred in 11 (55%), partial responses in 3 (15%), and stable disease in 14 (70%). Most patients reported stable or improved EORTC QLQ-C30 scores.
Greater cisplatin equivalent doses were achieved with no clinically significant neuro-, oto-, or nephrotoxicity. These data demonstrate tolerability and promising activity of NC-6004 in combination with gemcitabine.
.
To identify a profile of circulating tumor human papilloma virus (HPV) DNA (ctHPVDNA) clearance kinetics that is associated with disease control after chemoradiotherapy (CRT) for HPV-associated ...oropharyngeal squamous cell carcinoma (OPSCC).
A multi-institutional prospective biomarker trial was conducted in 103 patients with (i) p16-positive OPSCC, (ii) M0 disease, and (iii) receipt of definitive CRT. Blood specimens were collected at baseline, weekly during CRT, and at follow-up visits. Optimized multianalyte digital PCR assays were used to quantify ctHPVDNA (types 16/18/31/33/35) in plasma. A control cohort of 55 healthy volunteers and 60 patients with non-HPV-associated malignancy was also analyzed.
Baseline plasma ctHPVDNA had high specificity (97%) and high sensitivity (89%) for detecting newly diagnosed HPV-associated OPSCC. Pretreatment ctHPV16DNA copy number correlated with disease burden, tumor HPV copy number, and HPV integration status. We define a ctHPV16DNA favorable clearance profile as having high baseline copy number (>200 copies/mL) and >95% clearance of ctHPV16DNA by day 28 of CRT. Nineteen of 67 evaluable patients had a ctHPV16DNA favorable clearance profile, and none had persistent or recurrent regional disease after CRT. In contrast, patients with adverse clinical risk factors (T4 or >10 pack years) and an unfavorable ctHPV16DNA clearance profile had a 35% actuarial rate of persistent or recurrent regional disease after CRT (
= 0.0049).
A rapid clearance profile of ctHPVDNA may predict likelihood of disease control in patients with HPV-associated OPSCC patients treated with definitive CRT and may be useful in selecting patients for deintensified therapy.
Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes ...tumor-directed immune stimulation, which may potentiate anti-PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC.
This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling.
Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%-84%) and 75% (51%-88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells.
Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.
Background
Adavosertib (AZD1775) is an inhibitor of the Wee1 kinase. The authors conducted a phase 1b trial to evaluate the safety of adavosertib in combination with definitive chemoradiotherapy for ...patients with newly diagnosed, intermediate‐risk/high‐risk, locally advanced head and neck squamous cell carcinoma (HNSCC).
Methods
Twelve patients with intermediate‐risk/high‐risk HNSCC were enrolled, including those with p16‐negative tumors of the oropharynx, p16‐positive tumors of the oropharynx with ≥10 tobacco pack‐years, and tumors of the larynx/hypopharynx regardless of p16 status. All patients were treated with an 8‐week course of concurrent intensity‐modulated radiotherapy at 70 grays (Gy) (2 Gy daily in weeks 1‐7), cisplatin 30 mg/m2 weekly (in weeks 1‐7), and adavosertib (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8). The primary objective was to determine the maximum tolerated dose and the recommended phase 2 dose of adavosertib given concurrently with radiation and cisplatin. Secondary objectives were to determine the 12‐week objective response rate and progression‐free and overall survival.
Results
Three patients (25%) experienced a dose‐limiting toxicity, including febrile neutropenia (n = 2) and grade 4 thromboembolism (n = 1). Two dose‐limiting toxicities occurred with adavosertib at 150 mg. The median follow‐up was 14.7 months. The 12‐week posttreatment objective response rate determined by positron emission tomography/computed tomography was 100%. The 1‐year progression‐free and overall survival rates were both 90%. The maximum tolerated dose of adavosertib was 100 mg.
Conclusions
Adavosertib 100 mg (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8), in combination with 70 Gy of intensity‐modulated radiotherapy and cisplatin 30 mg/m2, is the recommended phase 2 dose for patients with HNSCC.
In a phase 1b trial, the safety of adavosertib in combination with definitive chemoradiotherapy is evaluated in patients with newly diagnosed, intermediate‐risk/high‐risk, locally advanced head and neck squamous cell carcinoma. The maximum tolerated dose and the recommended phase 2 dose of adavosertib for these patients is 100 mg in combination with 70 grays of intensity‐modulated radiation and cisplatin 30 mg/m2.
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