Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a ...molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.
Molecular Tumour Boards (MTBs) were created with the purpose of supporting clinical decision-making within precision medicine. Though in use globally, reporting on these meetings often focuses on the ...small percentages of patients that receive treatment via this process and are less likely to report on, and assess, patients who do not receive treatment.
A literature review was performed to understand patient attrition within MTBs and barriers to patients receiving treatment. A total of 51 papers were reviewed spanning a 6-year period from 11 different countries.
In total, 20% of patients received treatment through the MTB process. Of those that did not receive treatment, the main reasons were no mutations identified (27%), no actionable mutations (22%) and clinical deterioration (15%). However, data were often incomplete due to inconsistent reporting of MTBs with only 55% reporting on patients having no mutations, 55% reporting on the presence of actionable mutations with no treatment options and 59% reporting on clinical deterioration.
As patient attrition in MTBs is an issue which is very rarely alluded to in reporting, more transparent reporting is needed to understand barriers to treatment and integration of new technologies is required to process increasing omic and treatment data.
To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma.
This ...retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival OS, progression-free survival PFS and objective response rate ORR) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated.
A total of 697 patients were identified; 472 were treatment-naïve of which 138 (29.2%) had brain metastases, and 225 were previously treated of which 102 (45.3%) had brain metastases. At baseline, 32.3% had stage M1c and 34.4% stage M1d disease. Lactate dehydrogenase was high in 280 patients (40.2%). With a median follow-up of 25.9 months, median OS in the 334 treatment-naïve patients without brain metastases was 53.7 months (95% confidence interval CI 40.8-NR) and 38.7 months (95% CI 18.6-NR) for the 138 treatment-naïve patients with brain metastases. For the entire cohort the ORR was 48%, for treatment-naïve patients without brain metastases ORR was 56.6% with a median PFS of was 13.7 months (95% CI 9.6–26.5). Median PFS was 7.9 months (95% CI 5.8–10.4) and OS 38 months (95% CI 31-NR) for the entire cohort. Grade 3–4 trAE were reported in 44% of patients, and 4 (0.7%) treatment-related deaths (1 pneumonitis, 2 myocarditis and 1 colitis) were recorded.
The outcome and toxicity of combination immunotherapy with ipilimumab and nivolumab in a real-world patient population are similar to those reported in pivotal trials.
•Largest real-world cohort treated with combination immunotherapy for advanced melanoma.•Outcomes for real-world population are similar to registration trial.•Subgroup analyses offer helpful data to guide treatment decisions.
Concerns have been recognized about the operating characteristics of the standard 3 + 3 dose-escalation design. Various innovative phase 1 trial designs have been proposed to address the issues and ...new challenges posed by molecularly targeted agents. However, in spite of these proposals, the conventional design is still the most widely utilized.
A review of the literature of phase 1 trials and relevant statistical studies was performed.
Beyond statistical simulations, sparse clinical data exist to support or refute many of the shortcomings ascribed to the 3 + 3 rule method. Data from phase 1 trials demonstrate that traditional designs identified the correct dose and relevant toxicities with an acceptable level of precision in some instances; however, no single escalation method was proven superior in all circumstances.
Design selection should be guided by the principle of slow escalation in the face of toxicity and rapid dose increases in the setting of minimal or no adverse events. When the toxicity of a drug is uncertain or a narrow therapeutic window is suggested from preclinical testing, then a conservative 3 + 3 method is generally appropriate. However, if the therapeutic window is wide and the expected toxicity is low, then rapid escalation with a novel rule- or model-based design should be employed.
Lung cancer remains the most lethal malignancy in the world. Despite improvements in surgical treatment, systemic therapy and radiotherapy, the 5-year survival rate for all patients diagnosed with ...lung cancer remains between 15-20%. Newer therapeutic strategies rely on specific molecular alterations, or biomarkers, that provide opportunities for a personalized approach to specific patient populations. Classification of lung cancer is becoming increasingly focused on these biomarkers, which renders the term non-small cell lung cancer less clinically useful. Non-small cell lung cancer is now recognized as a complex malignancy and its molecular and genomic diversity allows for patient-centered treatment options. Here we review advances in targeted treatment of lung adenocarcinoma with respect to five clinically relevant biomarkers - EGFR, ALK, MET, ROS-1 and KRAS.
Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 ...monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.
This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling.
Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia both grade 3) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples.
LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing.
Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).
Patients with cancer have been shown to have increased risk of COVID-19 severity. We previously built and validated the COVID-19 Risk in Oncology Evaluation Tool (CORONET) to predict the likely ...severity of COVID-19 in patients with active cancer who present to hospital. We assessed the differences in presentation and outcomes of patients with cancer and COVID-19, depending on the wave of the pandemic. We examined differences in features at presentation and outcomes in patients worldwide, depending on the waves of the pandemic: wave 1 D614G (n = 1430), wave 2 Alpha (n = 475), and wave 4 Omicron variant (n = 63, UK and Spain only). The performance of CORONET was evaluated on 258, 48, and 54 patients for each wave, respectively. We found that mortality rates were reduced in subsequent waves. The majority of patients were vaccinated in wave 4, and 94% were treated with steroids if they required oxygen. The stages of cancer and the median ages of patients significantly differed, but features associated with worse COVID-19 outcomes remained predictive and did not differ between waves. The CORONET tool performed well in all waves, with scores in an area under the curve (AUC) of >0.72. We concluded that patients with cancer who present to hospital with COVID-19 have similar features of severity, which remain discriminatory despite differences in variants and vaccination status. Survival improved following the first wave of the pandemic, which may be associated with vaccination and the increased steroid use in those patients requiring oxygen. The CORONET model demonstrated good performance, independent of the SARS-CoV-2 variants.
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