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13th April 2022
The presence of residual ctDNA after treatment of patients with non-small cell lung cancer (NSCLC) is associated with a shorter recurrence-free survival and overall survival. This was the key finding of a study carried out in Cambridge, UK.
In 2020, there were over 2.2 million cases of lung cancer which resulted in nearly 1.8 million deaths. Lung cancer has two main forms; small cell and non-small cell, and in the UK, the latter accounts for around 85% of all cases. Treatment options for NSCLC depend upon disease stage and range from surgical resection or radiotherapy (stage 1) through to surgery and adjuvant chemotherapy or chemo-radiotherapy for those with stage 3. However, an important consideration for any of the different forms of treatment, is the ability to detect the presence of post-therapy residual disease. One emerging potential biomarker is circulating tumour DNA (ctDNA), which is a component of cell-free DNA shed by malignant tumours into the bloodstream and other bodily fluids. It has the potential for prognostication, molecular profiling and monitoring of patients with cancer and has, for example, been shown to be an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. In fact, highly precise ctDNA detection and quantification methods have the potential to transform clinical practice via non-invasive monitoring of solid tumour malignancies, residual disease detection at earlier timepoints than standard clinical and/or imaging surveillance.
For the present study, the researchers set out to assess ctDNA levels in patients with stage 1 to 3 NSCLC to determine whether detection of this DNA tumour fragment post-therapy could predict patient outcomes. Using samples from the Lung cancer circulating tumour DNA study (Lucid), the team first determined the levels of ctDNA prior to lung cancer treatment and then sought to detect the DNA two weeks to four months after therapy.
Predictive value of ctDNA
A total of 363 plasma samples from 88 patients with early-stage NSCLC (stages 1, 2 and 3) treated with curative intent surgery (61), surgery and adjuvant chemotherapy/radiotherapy (8) and chemo-radiotherapy (19) were included in the study.
Prior to therapy, ctDNA was detected in 24%, 77% and 87% of patients with stage I, II and III disease respectively. Post-treatment, ctDNA was found in 64.3% of patients (28) who had a clinical recurrence of their cancer. Detection of ctDNA within the time period of two weeks to 4 months post-treatment occurred in 17% of patients and was associated with shorter recurrence-free survival (hazard ratio, HR = 14.8, 95% CI 5.82 – 37.48, p < 0.00001) and a reduced overall survival (HR = 5.48, 95% CI 2.18 – 13.76, p < 0.0003). Interestingly, ctDNA was also detected 1 – 3 days after surgery in 25% of patients but not associated with disease recurrence.
Among those where ctDNA was found before treatment, there was also a reduced overall survival (HR = 2.97, p = 0.01) and recurrence free survival (HR = 3.14, p = 0.003) compared to samples where ctDNA was not detected prior to treatment.
The authors concluded that their data supported the clinical utility of ctDNA testing to identify residual disease and recurrence and that this was a potentially sensitive tool to determine which patients were at high risk of relapse and who could benefit from additional adjuvant therapy.
Gale D et al. Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer Ann Oncol 2022
4th February 2022
Atezolizumab (Tecentriq) has been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) for patients with non-small cell lung cancer (NSCLC).
Around 85% of lung cancers in the UK are due to NSCLC and according to the World Health Organization, there were 2.21 million cases of lung cancer in 2020 and which resulted in 1.80 million deaths. Moreover, 5-year survival among those with NSCLC is poor, with data from England showing that only around 3 in 20 people survive to five years after their diagnosis.
Immunotherapy, which is a novel method of lung cancer treatment, uses monoclonal antibodies directed against immune-checkpoint molecules including the programmed cell death 1 (PD-1) receptor or its ligand (PD-L1). In the UK, NICE has approved atezolizumab (Tecentriq) as an option for untreated metastatic NSCLC in adults if their tumours have PD-L1 expression on at least 50% of tumour cells or 10% of tumour-infiltrating immune cells and where tumours do not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations. The MHRA has decided that atezolizumab (Tecentriq) can be used in whose have undergone surgery and chemotherapy as such patients are at risk of cancer relapse.
Atezolizumab (Tecentriq) clinical efficacy
Data on the effectiveness of atezolizumab comes from the IMpower010 clinical trial, a Phase III, global, multicentre, open-label, randomised study designed to compare the efficacy of atezolizumab treatment versus best supportive care in participants with Stage IB-Stage IIIA NSCLC following resection and adjuvant chemotherapy. The trial recruited 1005 patients who were randomised to atezolizumab (n=507) or best supportive care (n=498). After a median follow-up of 32·2 months, atezolizumab treatment improved disease-free survival compared to best supportive care (hazard ratio, HR = 0·66, 95% CI 0·50–0·88, p=0·0039), i.e., the risk of recurrence, new primary NSCLC, or death with atezolizumab was reduced by 34% compared to best supportive care. In a further trial, IMpower110, the efficacy of atezolizumab combined with cisplatin or carboplatin chemotherapy and with either pemetrexed (non-squamous disease) or gemcitabine (squamous disease) in PD-L1-selected, chemotherapy-naïve participants with Stage IV non-squamous or squamous NSCLC. The published results showed that the median overall survival was 7.1 months longer in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months).
According to the NHS, more than 850 patients in England are expected to be eligible for the drug in the first year and this is predicted to rise to more than 1000 in the third year. Amanda Pritchard, chief executive of NHS England, said, “The NHS has a strong track record of securing rapid access to cutting-edge, new treatments for our patients, and this is the latest rapid access agreement that places an innovative treatment in the hands of frontline NHS staff, supporting them to continue to deliver world-class patient care.”
20th January 2022
Smoking cessation at the time of a lung cancer diagnosis is linked to an improved survival from both non-small and small cell lung cancer, according to the findings of a systematic review by a team from the Institute for Cancer Research, Prevention and Clinical Network, Florence, Italy
Data from the World Health Organization shows that in 2020, globally, there were 2.21 million cases of lung cancer and which led to 1.8 million deaths. In addition, lung cancer has a poor prognosis and Cancer Research UK suggests that only around 15% of those with lung cancer will survive for 5 years or more after diagnosis. Cigarette smoking is a major factor in the development of lung cancer, with one analysis of the burden of respiratory tract cancers indicating that smoking contributed to an estimated 64·2% of all deaths from tracheal, bronchus, and lung cancer and 63·4% of all deaths from larynx cancer in 2019.
Although one study with 517 smokers, found that smoking cessation at the time of a lung cancer diagnosis can reduce the risk of future lung cancer, for the present study, the Italian team sought to provide a more robust estimate of the overall prognostic value of smoking cessation at or around the time of a lung cancer diagnosis. They searched for articles which included those who continued to smoke and those who quit in relation to their cancer diagnosis and the associated changes in survival. The team calculated relative risks for the association between smoking cessation and the survival from lung cancer.
A total of 21 studies were included in the systematic review with patients diagnosed with non-small cell lung cancer (10 studies, 5315 patients) and small cell lung cancer (5 studies, 1133 patients), together with a further six studies of both cancer subtypes or where the subtype was not specified. The mean age of lung cancer diagnosis across the studies ranged from 60 to 70 years and the proportion of men ranged from 40.2% to 91.8%. The duration of follow-up also ranged from 12 months to 27.7 years.
Smoking cessation at or around the time of diagnosis was associated with a better overall survival regardless of lung cancer type. For smoking cessation at any time, compared to those who continued smoking (used as the reference group), the relative risk for non-small cell lung cancer was 0.77 (relative risk, RR = 0.77, 95% CI 0.66 – 0.90) and this reduction was broadly similar compared to those stopping strictly at or after their diagnosis or up to 12 months before the diagnosis. For small cell lung cancer, overall survival was also broadly similar (RR = 0.75, 95% CI 0.57 – 0.99). Even in studies where the cancer subtype was not specified, there were survival benefits among quitters (RR = 0.81, 95% CI 0.68 – 0.96).
The authors calculated an overall benefit for those who undertook smoking cessation at or around the time of their lung cancer diagnosis, finding that such individuals had a 29% improvement in their overall survival compared to those who continued to smoke (RR = 0.71, 95% CI 0.64 – 80).
The authors concluded that advice to quit smoking at or around the time of a lung cancer diagnosis, should arguably become a non-optional part of the management of these patients.
Caini S et al. Quitting smoking at or around diagnosis improves the overall survival of lung cancer patients: a systematic review and meta-analysis J Thorac Oncol 2022
19th November 2021
Atezolizumab and nivolumab have been found to prolong overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) cancer say researchers from Hoffmann-La Roche, Basel, Switzerland. NSCLC accounts for 85% of all lung cancers although nearly 40% of patients are diagnosed at stage 4, which has a poor prognosis, warranting systemic therapy. Treatment of NSCLC can be achieved with platinum-based chemotherapy although many patients relapse and in such cases, mono-therapy with the chemotherapeutic agent, docetaxel, has been found to be effective.
In recent years it has been discovered that developing tumours are capable of evading the immune system by avoiding checkpoint signals designed to prevent uncontrolled activation of T lymphocytes. Monoclonal antibodies including nivolumab and atezolizumab, work to either inhibit checkpoint PD-1 surface receptors (nivolumab) or its ligand, PD-L1 (atezolizumab) thereby blocking these receptors and signals, enabling the immune system to combat the tumour. Although both monoclonal antibodies are approved for use in NSCLC, there is a lack of head-to-head studies comparing these two agents even in comparison to docetaxel.
For the present study, researchers examined real-world studies contained within the US nationwide electronic health record, in which patients with advanced NSCLC and prior platinum-based therapy, who had been started on either atezolizumab, nivolumab or docetaxel. They included adults (18 years and over) diagnosed with locally advanced and/or metastatic NSCLC, none of whom had been previously treated with one of the three agents. The team also only included patients with at least 6 months of follow-up data and set the primary endpoint as overall survival.
In total, 3336 patients were included in the analysis with 206 receiving atezolizumab, 500 docetaxel and 2630 nivolumab. Patients in the atezolizumab and nivolumab groups were of a similar mean age, 68.3 and 67.3 years respectively while those in the docetaxel group were slightly younger with a mean age of 65.6 years.
Compared to docetaxel, use of atezolizumab was associated with a significantly longer survival (adjusted hazard ratio, aHR = 0.79, 95% CI 0.64 – 0.97, p = 0.02) even among those with different cancer stages. In contrast, the adjusted hazard ratio for atezolizumab compared with nivolumab was 1.07 (95% CI 0.89 – 1.28, p = 0.47) and this did not differ between patients at different cancer stages. However, the authors recognised that their analysis may not have been sufficiently powered to detect a difference between these two treatments.
The authors concluded that their real-world data suggested that atezolizumab and nivolumab produced a longer overall survival than docetaxel among those who had failed to respond to platinum-based chemotherapy.
Ramagopalan S et al. Comparative Effectiveness of Atezolizumab, Nivolumab, and Docetaxel in Patients With Previously Treated Non–Small Cell Lung Cancer. JAMA Netw Open 2021
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.