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15th October 2021
An abnormal chest x-ray can help to triage patients who might have lung cancer although the evidence base to support this role is incomplete. However, many studies in the past have failed to adequately define a positive chest x-ray and because of this, a team from the Department of Clinical Radiology, St James Hospital, Leeds, UK, decided to retrospectively examine a cohort of consecutive “self-request” chest x-rays collected as part of the National Awareness and Early Diagnosis Initiative (NAEDI) in the UK. The aim of their study was to establish the accuracy of the chest x-ray in the investigation of malignancy amongst symptomatic adults over the age of 50 years.
For the purposes of the study, the team defined as positive, an abnormal chest x-ray that resulted in the further investigation with computed tomography (CT). Furthermore, because the term thoracic malignancy encompasses a range of tumours, they focused on evaluating the accuracy of the chest x-rays in the detection of non-small cell carcinomas (NSCLC). As part of the NAEDI, patients completed a questionnaire and were able to obtain a chest x-ray without the need for a referral on a walk-in basis to the radiology department, provided that they met the eligibility criteria (based on the questionnaire results) which were symptoms lasting longer than three weeks (cough, haemoptysis, shortness of breath, chest pain, change in voice or loss of weight). At the time of the study, a history of smoking was not a requirement. The main outcomes reported were the sensitivity and specificity for NSCLC and all primary intrathoracic malignancies within a one and two year period. The team determined the sensitivity as the number of cancer diagnoses identified on the basis of a positive CXR divided by the total number of cancers observed. Specificity was defined as the number of negative CXRs divided by the total number of CXRs in those without cancer.
A total of 8,948 questionnaires were evaluated with 496 (5%) abnormal chest x-rays (i.e., positive) and which resulted in a diagnosis of 133 patients with a primary intrathoracic malignancy in the first year and 168 after 2 years, including 105 and 133 NSCLC in the first and second year respectively.
The sensitivity for NSCLC identified within 1-year was 76.2% (CI 68.0–84.3) and the specificity 95.3% (CI 94.9–95.7). Within 2-years, the corresponding sensitivity was 60.2% (CI 51.8–68.5) and specificity 95.3% (CI 94.8–95.7). Although smoking was excluded from the inclusion criteria, 23% of the cohort were current smokers and 44% ex-smokers. The corresponding 1-year sensitivity for the detection of NSCLC in smokers was 83.3% (95% CI 67.1 – 92.4) and 71.6% (95% CI 57.7 – 82.3) for ex-smokers. The corresponding specificities were 94.2% (current smokers) and 95.4% (ex-smokers).
The authors noted that while a negative chest x-ray does not exclude a diagnosis of malignancy, the baseline risk of lung cancer in the current cohort was 1.9% and that a negative x-ray would reduce this risk to 0.8%. They concluded that a positive chest x-ray is strongly predictive for the presence of malignancy but added that a negative result does not conclusively exclude the diagnosis but allows for an estimation of the risk of malignancy.
Bhartia BSK et al. A prospective cohort evaluation of the sensitivity and specificity of the chest X-ray for the detection of lung cancer in symptomatic adults. Eur J Radiol 2021
5th October 2021
In the UK, lung cancer is the third most common cancer with approximately 47,800 new cases every year or 130 every day. There are two main forms of lung cancer: small cell and non-small cell with non-small cell lung cancer (NSCLC) being the most common form, responsible for between 80 to 85% of cases. Survival depends to some extent, on the stage at diagnosis and in women, for example, five-year net survival drops from 62% when diagnosed at Stage 1, to 3% when diagnosed at Stage 4. Mesenchymal epithelial transition (MET) dysfunction, involving a loss of transcription of exon 14 (i.e., MET exon 14 skipping) and occurs an approximately 5% of NSCLC cases. MET codes for a receptor tyrosine kinase and overactive MET-mediated signalling leads to cell proliferation and tumour growth. Tepotinib is the first oral MET inhibitor to be approved and it received approval from the FDA in February 2021, for the treatment of adult patients with metastatic NSCLC harbouring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. It is also under regulatory review by the European Medicines Agency (EMA).
In the Phase II VISION study tepotinib was given once daily at a dose of 500mg to patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary endpoint was an objective response by independent review among patients who had undergone at least 9 months of follow-up. The study found that a partial response occurred in approximately half the patients given tepotinib. In an updated analysis of 146 patients who had at least 9 months of follow-up and were assessed for efficacy, the overall objective response (OOR), by an independent review was 46.2% (95% CI 37.0 – 53.6), with a median duration of follow-up of 11.1 months.
Tepotinib was approved via the FDA project ORBIS, which reviews and approves any promising cancer treatments concurrently with regulatory authorities in six other countries, including the UK’s MHRA. It aims to deliver faster patient access to innovative cancer treatments with potential benefits over existing therapies across the globe.
Tepotinib was originally approved at a dose 450mg tepotinib (2 tablets) once daily via the MRHA’s Early Access to Medicines Scheme in July 2021.
27th September 2021
Lung cancer is extremely common and figures from 2018, suggest a global incidence of 17 million cases and 9.6 million associated deaths. Primary lung cancers can be either small cell or non-small cell, with the latter being the most common, accounting for around 80 to 85% of all lung cancer cases. Research has identified the presence of various genetic mutations in lung cancer, one of which is a mutation in the human epidermal growth factor 2 (HER2). This mutation is present in roughly 2 to 4% of non-small cell lung cancer (NSCLC) cases. Given the over-expression of HER2, potential treatments include the anti-HER2 agent, trastuzumab, but when used in combination with chemotherapy, there was a lack of benefit. The antibody-drug conjugate, trastuzumab deruxtecan, has been shown to be effective in both HER2 positive gastric and breast cancers but data on its efficacy in NSCLCL is limited to a single phase 1 trial in 11 patients, which showed an objective response rate in 72.7% (8/11) of patients.
Based on these preliminary findings, an international team, the DESTINY-Lung01 trial investigators, conducted a multi-centre, phase 2 trial of trastuzumab deruxtecan given at a dose of 6.4 mg/kg body weight, to patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment. Eligible patients had unresectable or metastatic non-squamous NSCLC with at least one measurable lesion as defined according to the Response Evaluation Criteria in Solid Tumours (RECIST), which provides a simple and pragmatic methodology to evaluate the activity and efficacy of a new anti-cancer therapy in solid tumours. The primary end point was confirmed objective response, independently assessed on the basis of RECIST. Secondary endpoints included the duration of response, disease control and progression-free survival and overall survival. The study also examined the safety of treatment.
A total of 91 patients with a median age of 60 years (66% female) were enrolled in the study and who had a median of 2 previous cancer therapies. There were 50 (55%) patients who achieved a confirmed objective response, with one patient having a complete response and just over half (54%) having a partial response. In addition, the majority (91%) of patients had disease control and a reduction in tumour size. The median progression-free survival time was 8.2 months and the median overall survival, 17.8 months. In terms of safety, 51% of patients experienced a grade 1 – 2 adverse event and grade 3 or higher drug-related adverse events occurred in 41% of patients. The most common adverse effects were nausea (64%) and fatigue (46%) although these were mainly of grade 1 – 2 severity.
The authors concluded that the use of trastuzumab deruxtecan had shown a response in a high number of patients and durable clinical benefit and that a further randomised trial to further evaluate the drug conjugate is underway.
Li BT et al. Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer. N Eng J Med 2021.
16th July 2021
According to Cancer Research UK, lung cancer is the 3rd most common cancer in the UK with approximately 47,800 new cases every year or 130 every day. There are two different types of primary lung cancer: small cell and non-small cell, with the latter accounting for around 80–85% of all cases. While early detection of non-small cell lung cancer has an excellent prognosis with 5-year survival rates of 70–90%, around three-quarters (75%) of patients have advanced disease (i.e., stages III/IV) at the time of diagnosis. In fact, the one-year survival for patients with stage IV disease is only 19%, dropping to 2.9% at 5 years.
In recent years, it has become apparent that there are molecular abnormalities associated with lung cancer and this has led to the search for treatments specifically directed at these abnormalities. One such abnormality relates to Mesenchymal-epithelial transition (MET) factor gene, which, under normal circumstances, plays a crucial role in various cellular functions. The MET gene encodes for a receptor tyrosine kinase that activates signalling pathways involved in cell proliferation, survival and growth and it is mutations in this gene that drives oncogenic activation. One particular aberration identified in non-small-cell lung cancer is skipping of METex14 whereby substitutions or deletions at intron 13, result in skipping intron 14. MET skipping occurs in approximately 5% of non-small-cell lung cancer cases and the resultant loss of exon 14, increases the concentration of MET protein and which drives activation of downstream signalling that promote tumour development via phosphoinositide 3-kinase pathways.
Tepotinib is an oral MET kinase inhibitor which works by inhibiting MET-dependent downstream signalling pathways. The effectiveness of tepotinib as mono-therapy for patients with metastatic non-small-cell lung cancer with MET exon 14 skipping alterations was examined in the phase II VISION study which was published in May 2020. In this open-label phase 2 study, tepotinib was given as a daily dose of 500mg to patients, 18 years and older, with advanced or metastatic non-small-cell lung cancer, confirmed by either liquid or tissue biopsy, with a MET exon 14 skipping mutation. The primary endpoint was the response rate based on the RECIST 1.1 criteria, which represents a standard way to measure a patient’s response to cancer treatment.
A total of 152 patients received tepotinib, of whom, 99 had 9 months of follow-up. The response rate was 46% (95% CL 36 – 57%). Moreover, this response rate was consistent for both liquid and tissue-biopsy (48% and 50% respectively) and the response was similar regardless of baseline characteristics or the number of prior treatments. Adverse reactions of grade 3 severity or higher occurred in 28% of patients, including, most commonly, peripheral oedema (7%) although adverse effects led to treatment discontinuation in only 11% of patients. The authors of the VISION study concluded that tepotinib was associated with a partial response in at least half of all patients.
Based on these findings, the MHRA has permitted the use of tepotinib, via the Early Access to Medicines Scheme (EAMS), for patients with advanced non-small-cell lung cancer. While this does not mean that tepotinib is actually licensed for use, the EAMS recognises the potential value of a treatment where there is a high unmet clinical need.