Since the discovery 15 years ago, we have seen a quantum leap in the treatment and survival for individuals diagnosed with ALK+ lung cancers. Unfortunately however, for most, the diagnosis is made in ...an incurable circumstance given the late presentation of symptoms. Through a revolutionary wave of therapeutics, individuals may remarkably live over a decade, however many fall short of this milestone, as the molecular profile of this disease is very heterogeneous, reflected in variable survival outcomes. Despite a significant improval in survival and quality of life with ALK-inhibitor monotherapies, now available across multiple-generations, drug resistance and disease relapse remains inevitable, and treatment is offered in an empiric, stepwise, non personalised biomarker informed fashion. A proposed future focus to treating ALK to improve the chronicity of this disease and even promote cure, is to deliver a personalised dynamic approach to care, with rational combinations of drugs in conjunction with local ablative therapies to prevent and constantly proactively alter clonal selection. Such an approach would be informed by precision imaging with MRI-brain and FDG-PETs sequentially, and by regular plasma sampling including for circulating tumour DNA sequencing with personalised therapeutic switches occurring prior to the emergence of radiological and clinical relapse. Such an approach to care will require a complete paradigm shift in the way we approach the treatment of advanced cancer, however evidence to date in ALK+ lung cancers, support this new frontier of investigation.
The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or ...rearrangements form a unique sub-class, with anaplastic lymphoma kinase (
) and c-ros oncogene 1 (
) targeted agents approved as the standard of care in the first-line setting for advanced disease. There are a number of emerging fusion drivers, however, including neurotrophin kinase (
), rearrangement during transfection (
), and neuregulin 1 (
) for which there are evolving high-impact systemic treatment options. Brain metastases are highly prevalent in NSCLC patients, with molecularly selected populations such as epidermal growth factor receptor (
) mutant and
-rearranged tumors particularly brain tropic. Accordingly, there exists a substantial body of research pertaining to the understanding of brain metastases in such populations. Little is known, however, on the molecular mechanisms of brain metastases in those with other targetable fusion drivers in NSCLC. This review encompasses key areas including the biological underpinnings of brain metastases in fusion-driven lung cancers, the intracranial efficacy of novel systemic therapies, and future directions required to optimize the control and prevention of brain metastases.
Fast Facts: Managing Immune-Related Adverse Events in Oncology, 2nd edition, provides an overview of immuno-oncology and an update on immune checkpoint inhibitors and their associated toxicities, ...alongside the principles of diagnosing and managing immune-related adverse events, important nursing care considerations and a set of convenient management summaries for quick reference. As such, it is essential reading for all members of the cancer care team.
The SARS-CoV-2 pandemic has resulted in considerable consequences for many cancer patients, exacerbating pre-existing systemic health system limitations as well as creating new challenges. From ...socially distanced clinics and the widespread introduction of telehealth, to the halting of clinical trials and the reassessment of what constitutes “essential” treatment, care in oncology has abruptly changed. There is currently limited analysis of cancer patients’ experiences of the pandemic and its impacts on illness, wellness, and everyday life. Through semi-structured interviews with 54 people living with cancer during the 2020 phase of the SARS-CoV-2 pandemic in Australia, we explore how patients experience illness and care in reflecting upon a range of pandemic challenges, including delay, distance, and vulnerability. We find that in some cases, these pandemic conditions redefined the meaning of essential cancer care, reconfigured expectations around clinical trials, constructed new affective distances, and amplified dread and fear for people living with cancer.
Osimertinib is an oral small-molecule tyrosine kinase receptor inhibitor used to treat non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor mutation. Patients may ...experience drug toxicity and require dose deescalation. The study aimed to quantitate osimertinib and its 2 active metabolites, AZ5104 and AZ7550, in microsampled dried blood spots (DBS) collected from patients with NSCLC using a hemaPEN device and compare them with plasma drug levels.
A 6-min ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed and validated using plasma and DBS. The accuracy, selectivity, matrix effect, recovery, and stability were assessed using bioanalytical validation criteria. The hematocrit effect was investigated in DBS. Drug levels were measured in 15 patients with NSCLC, and the Bland-Altman method was used to compare measurements between plasma and DBS.
The validated assay determined accurate and precise quantities, respectively, for osimertinib in both plasma (93.2%-99.3%; 0.2%-2.3%) and DBS (96.7%-99.6%; 0.5%-10.3%) over a concentration of 1-729 ng/mL. The osimertinib metabolites, AZ5104 and AZ7550, were similarly validated in accordance with bioanalytical guidelines. For 30%-60% patient hematocrit, no hematocrit bias was observed with DBS for all analytes. The Bland-Altman method showed high concordance between plasma and DBS analyte levels. Stability experiments revealed that osimertinib and its metabolites were poorly stable in plasma at room temperature, whereas all analytes were stable in DBS for 10 days at room temperature.
The measurement of osimertinib, AZ5104, and AZ7550 from hemaPEN microsampled DBS is a convenient and reliable approach for therapeutic drug monitoring that produces measurements consistent with plasma drug levels.
Introduction:
Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic ...activity in early clinical trials; however, their efficacy in the real-world setting is unknown.
Methods:
A retrospective efficacy and safety analysis was performed on data from RET fusion-positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021.
Results:
Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38–89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1–8). The objective response rate (ORR) was 68% 95% confidence interval (CI), 53–81 in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8–22.4) after a median follow-up of 9 months. In patients with measurable brain metastases (n = 8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade ⩾ 3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death.
Conclusions:
In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated.
Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and ...complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13-24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry ACTRN12622000129785 and approved by the South Western Sydney Local Health District Human Research Ethics Committee 2021/ETH11339. https://clin.larvol.com/trial-detail/ACTRN12622000129785.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•EGFR exon 20 insertions are uncommon in non-small cell lung cancer.•Patient demographics and clinical features are similar to common EGFR mutations.•Platinum-based chemotherapy is the standard of ...care in advanced disease.•There is resistance to standard tyrosine kinase inhibitors, including osimertinib.•Treatment with single-agent immune checkpoint inhibitors is ineffective.
Epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non–small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established; we sought to clarify them using a multinational patient database.
Patients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics.
Among 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51%; P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval CI, 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62).
Although phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective.
EGFR exon 20 insertions are uncommon in non–small cell lung cancer (NSCLC) and resistant to common EGFR tyrosine kinase inhibitors (TKIs). Our data represent one of the largest cohorts yet studied, with a majority of Caucasian ethnic origin. Among the 109 patients, the clinical characteristics resembled common EGFR mutations. Metastatic patients benefited from standard chemotherapy but did not have a significant advantage after exposure to common TKIs and programmed cell death 1/programmed cell death ligand 1 inhibitor monotherapy.
ObjectivesTo explore informal caregivers’ perspectives on precision medicine in cancer care.DesignSemi-structured interviews with the informal caregivers of people living with cancer and receiving ...targeted/immunotherapies. Interview transcripts were analysed thematically using a framework approach.SettingRecruitment was facilitated by two hospitals and five Australian cancer community groups.ParticipantsInformal caregivers (n=28; 16 men, 12 women; aged 18–80) of people living with cancer and receiving targeted/immunotherapies.ResultsThematic analysis identified three findings, centred largely on the pervasive theme of hope in relation to precision therapies including: (1) precision as a key component of caregivers’ hope; (2) hope as a collective practice between patients, caregivers, clinicians and others, which entailed work and obligation for caregivers; and (3) hope as linked to expectations of further scientific progress, even if there may be no personal, immediate benefit.ConclusionsInnovation and change in precision oncology are rapidly reconfiguring the parameters of hope for patients and caregivers, creating new and difficult relational moments and experiences in everyday life and in clinical encounters. In the context of a shifting therapeutic landscape, caregivers’ experiences illustrate the need to understand hope as collectively produced, as emotional and moral labour, and as entangled in broader cultural expectations of medical advances. Such understandings may help clinicians as they guide patients and caregivers through the complexities of diagnosis, treatment, emerging evidence and possible futures in the precision era. Developing a better understanding of informal caregivers’ experiences of caring for patients receiving precision therapies is important for improving support to patients and their caregivers.
EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI ...specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.
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