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11th February 2025
Speaking at Hospital Healthcare Europe’s recent Clinical Excellence in Respiratory Care event, Dr Zaheer Mangera shared insights into the evolution of the neoadjuvant lung cancer pathway, its benefits and challenges, and notable changes to the TNM standards used to classify malignant tumours.
Click here to read part one of Dr Mangera’s overview of lung cancer management and diagnosis, including insights into the latest guidance, diagnostic and treatment targets and a deep dive into lung cancer screening and incidental findings.
The neoadjuvant lung cancer pathway has triggered a paradigm shift in how we’re treating our patients. About 20-25% of patients with non-small cell lung cancer have resectable disease at the time of presentation, yet 30-55% of patients undergoing curative surgery have recurrence.
What can we do to try to improve the cure rates in these groups? Historically, there’s always been some modest success with both adjuvant and neoadjuvant approaches.
A big study, CheckMate 816, looked at patients with Stage 1B lung cancer, with a tumour size of over four centimetres without any nodal metastases, to anything up to Stage 3A.
The researchers looked at patients deemed to have resectable disease at the time of multidisciplinary team (MDT) input, with a very good performance status of zero or one. This would be the first instance of having cancer treated, and they shouldn’t have an anaplastic lymphoma kinase/epidermal growth factor receptor (EGFR) mutation.
They were offered nivolumab immunotherapy, regardless of their programmed death-ligand 1. Alongside, they had a platinum-based chemotherapy versus just chemotherapy alone. They then restaged patients then proceeded to surgery.
The primary endpoint was looking at event-free survival and pathological response to treatment. It found clear difference in the event-free survival curve between those who had nivolumab with chemotherapy versus those who had chemotherapy alone. A statistically meaningful difference was sustained well beyond the three-to-four-year period.
It’s now part of NICE guidance, albeit not part of the lung cancer guidance specifically, as it’s a separate NICE technological appraisal (TA876). It’s really made us think about how we can get these patients through a pathway and the challenges involved.
The first patient on this pathway at my hospital had excellent response to the neoadjuvant treatment, then went on to have an uncomplicated surgery and now is just on standard follow-up.
Trying to give chemotherapy before surgery makes an already complex pathway even more complex. It lengthens the pathway considerably, because those three cycles can take over two months to get through, plus the required follow-up scans.
So, although the first treatment would have been given, the time it takes for you to then close the loop at your MDT and say the whole treatment has been finished is definitely elongated.
For most patients, if you offer them surgery, they want a tumour out. Of course, there are lots of other tumour groups where you give neoadjuvant treatment and so having discussions about the process is not new to the oncologist, but it’s new to our surgeons.
There are risks of toxicities, although the trial data reports that the risk is not excessive, and patient tolerance is usually very high. It does mean we need to get an EGFR status as rapidly as possible. If you’re waiting a full four weeks for the EGFR status, before you can start treatment, it can mean considerable wait time to treatment in patients who have high-risk disease – those who are on the cusp of cure and not being cured.
We’re developing rapid EGFR pathways through our pathology labs where you can get the EGFR done more rapidly or even sometimes using the CtDNA blood tests.
And how do you standardise all these care plans and pathways across all cancer alliances and Trusts to ensure everyone is on board, everyone eligible for this treatment is getting it and to ensure we really accurately record it? It’s a real cornerstone of the National Lung Cancer Audit in how we collect our data now.
NICE guidance tells us that anyone with a PET-added lymph node, or a lymph node greater than 10 millimetres, should have an endobronchial ultrasound (EBUS). This sounds reasonable, but we know from different trials that there can be a discrepancy between PET and actual lymph node sampling itself, with false negatives and false positives.
This isn’t ideal if somebody is on the cusp between having radical surgery or needing combination therapy, for example, with neoadjuvant treatment. We know that even with PET/CT and EBUS, you can still miss some patients with nodal disease, and it only becomes evident at time of surgery when you’re removing the entire node.
Accurate staging is important. There are different ways of deciding which lymph nodes are higher risk. Sometimes it’s at ultrasonography when you recognise the risk. At the time of EBUS, you can accurately measure the size, which can be more accurate than CT, PET and PET/CT. And you may well see that the nodes are actually a conglomerate of nodes, for example.
The shape can be helpful: is it oval versus round? Are the margins clear? This is a really good one because very often when you can’t find the lymph node or you can’t really see the margins, it can sometimes be reassuring compared to where you see distinct margins.
Is it homogenous, does it echo-signal consistently throughout or have subtle changes between one area and the next? Is the central hilum structure present or is it absent? Is there any evidence of necrosis?
In future, we’re largely trying to transition to any lymph node over 10 millimetres on CT being biopsied, as well as any lymph node with fluorodeoxyglucose avidity and any lymph node with high-risk features. The only way you can do that is by doing an EBUS.
The TNM 8th edition is what we’re using at the moment and the TNM 9th edition, which is due to go live imminently. The changes are reasonably subtle and there’s no significant ground shift in how we stage lung cancers.
First of all, N2 lymph nodes are going to be split into N2a and N2b. Currently it’s just N1, N2, N3 and we’re now going to have a sub-category for lymph node station N2, with N2a being single station involvement and N2b being multiple station involvement.
It doesn’t really comment too much on size here, so it still does need a little bit of working out in MDT with what you’re going to do with different lymph node groups and how it may or may not change your management and approach to the patient.
Then you’ve got your M stages. M1a and M1b are largely unchanged but M1c is split into M1c1 and M1c2.
M1c1 is multiple extrathoracic metastases in a single organ system, so multiple liver or brain metastases, rather than single metastases, and M1c2 is extrathoracic metastases in multiple organ systems.
This will subtly change the staging and may make a difference to what your approach might be. Having metastases doesn’t mean you don’t have radically treatable disease, and our oncology teams have specific MDTs for patients with metastatic disease and stereotactic ablative radiotherapy MDTs.
More and more of these metastatic diseases can be treated and that’s why it’s important to differentiate between M1b, M1c1 and M1c2 because some of these patients, particularly with M1b may well still have radically treatable disease if it’s just a single metastasis in a single organ.
Dr Zaheer Mangera is a respiratory consultant and the lung cancer lead at North Middlesex University Hospital, now part of the Royal Free London NHS Foundation Trust in London, UK.
View the agenda and register for our next Clinical Excellence in Respiratory Care event now.
7th February 2025
New research highlights the potential of a novel diagnostic tool to determine the innate immune profiles of patients with stage 2 melanoma and help predict who is most likely to respond to immunotherapy treatment.
Using immune time-resolved Förster resonance energy transfer (iFRET), researchers measured functional biomarkers and provided real-time information to profile immune responses in melanoma patients. For patients with stage 2 melanoma, iFRET was able to predict the value and effectiveness of neoadjuvant oncolytic virus therapy.
The UK and US researchers used tissue from a pilot phase II study of neoadjuvant talimogene laherparepvec (TVEC) – this is a modified oncolytic virus injected directly into melanoma to stimulate an immune response and destroy cancer cells before standard surgery.
They used iFRET to determine how the therapy affected immune checkpoint activity, specifically examining the interactions of the proteins programmed death-ligand 1 (PD-L1) on tumour cells or immune cells and programmed cell death protein 1 (PD-1) on immune cells in the tumour immune microenvironment before and after therapy.
The tumours responsive to immunotherapy showed a significant increase in iFRET efficiency, reflecting a more active immune response and the likelihood of a better response. Unresponsive tumours either showed decreased checkpoint engagement with fewer PD-L1:PD-1 interactions or failed to demonstrate an immune response to therapy.
The researchers also found that traditional biomarkers did not reliably predict a tumour’s response to immunotherapy, as the level of checkpoint engagement did not link to changes in PD-L1 expression.
However, macrophage behaviour did correlate with patients who responded to the treatment and those who did not, suggesting that tumour-associated macrophage phenotypes play a key role in the effectiveness of TVEC therapy.
Clinicians could potentially reprogramme the tumour’s immune environment by targeting macrophages in non-responding patients, the researchers concluded.
In addition, strong PD-L1:PD-1 interactions in the tumour beds correlated with a better response to the treatment.
The findings highlight the importance of examining the whole immune response environment to predict which patients would be better served by either surgery or immune checkpoint blockade via immunotherapy.
In future work, the team will attempt to characterise all cells contributing to the immune checkpoint interaction, further improving patient stratification and personalised medicine.
Reference
Kirane, A et al. Toward Functional Biomarkers of Response to Neoadjuvant Oncolytic Virus in Stage II Melanoma: Immune-Förster Resonance Energy Transfer and the Dynamic Tumor Immune Microenvironment. JCO Oncology Advances 2025; Jan 02: DOI: 10.1200/OA-24-00049.
20th February 2023
A significant five-year overall survival rate has been observed with the use of neoadjuvant nivolumab in resectable non-small cell lung cancer.
In a 2018 global study, lung cancer was found to be the most commonly diagnosed cancer (11.6% of all cases) as well as the leading cause of cancer deaths. The most common form of lung cancer is non-small cell lung cancer (NSCLC) which accounts for around 80-85% of all cancers. The use of programmed death 1 (PD-1) protein inhibitors as a treatment for patients with advanced NSCLC have been shown to produce a durable response and encouraging survival rates. Until recently, the value of PD-1 blockage in patients with resectable NSCLC has been unclear. However, in a 2018 trial it was found that two preoperative doses of nivolumab in adults who had early, i.e. stage I, II of IIIA, surgically resectable NSCLC, did not cause a delay to surgery and was able to induce a major pathological response in nearly half (45%) of resected tumours. While these were impressive, there was uncertainty over the longer term outcome of such patients.
In the current study, a team from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, US, provided the longest known follow-up study of patients given neoadjuvant nivolumab therapy with any type of cancer. The patient cohort was derived from the team’s earlier 2018 trial described above. Eligible participants received two doses of nivolumab (3mg/kg bodyweight) every two weeks with surgical resection planned for roughly four weeks after the first dose. In this follow-up, the researchers examined exploratory endpoints such as recurrence-free survival (RFS) and overall survival (OS) from the date of the patient’s surgery. They also considered the proportion achieving a major pathological response (MPR).
A total of 20 patients were included and followed for a median of 63 months. The five-year RFS rate was 60% and the OS 80%. In addition, the researchers reported that the use of nivolumab was associated with few side effects and did not delay surgery.
At the time the analysis was undertaken, the hazard ratio (HR) for the presence of a MPR, though not significant, was in the direction of improved RFS (HR = 0.61, 95% CI 0.15 – 2.44). In fact, at the five-year follow-up, eight of nine patients with a MRP were alive and free of disease. In contrast six of the 11 patients without MRP at a tumour relapse, three of whom died.
The authors concluded that five years, the clinical outcomes associated with neoadjuvant therapy were comparatively favourable to the earlier observed response. They added that while there was a trend towards improved RFS, it was difficult to draw any firm conclusions due to the small sample size.
Citation
Rosner S et al. Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer. Clin Cancer Res 2023
29th September 2022
Neoadjuvant therapy (NAT) prior to surgery in patients with DNA mismatch repair deficient (dMMR) colon cancer gave rise to a major pathologic response of 95% according to the findings by Dutch researchers presented at the recent European Society of Medical Oncology Congress.
The World Health Organisation estimated that in 20202, there were 1.93 million cases of colorectal cancers and which gave rise to 916 000 deaths. Moreover, defective DNA mismatch repair (dMMR) occurs in approximately 15% of sporadic colorectal cancers and evidence indicates that patients with dMMR colon cancers do not benefit from treatment with adjuvant 5-fluorouracil chemotherapy. In the Nivolumab, Ipilimumab and COX2-inhibition in Early Stage Colon Cancer: an Unbiased Approach for Signals of Sensitivity (NICHE) trial, patients with stage 1-3 adenocarcinoma of the colon and with no signs of distant metastases, were treated with short-term immunotherapy (nivolumab and ipilimumab) and COX2-inhibitors prior to surgical resection of the tumour. The results showed that a pathological response was observed in 20/20 dMMR tumours, with 19 major pathological responses (i.e., ≤10% residual viable tumour, RVT) and 12 pathological complete responses.
Based on these findings, researchers instigated NICHE-2 in which patients with non-metastatic dMMR colon cancer received NAT with 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab in the first cycle, then only nivolumab in the second cycle 2 weeks later, followed by surgery within 6 weeks of enrolling on the trial. They set the primary end points as 3-year disease-free survival (DFS) and safety with secondary end points including major pathological response (MPR) and complete response. For the purposes of the study, a pathologic response (PR) was defined as ≤ 50% residual viable tumour (RVT) and MPR as ≤ 10% RVT.
Neoadjuvant therapy treatment outcomes
A total of 112 patients with a median age of 60 years (58% female) were enrolled. For 107 patients included in the efficacy analysis, baseline radiologic assessment revealed 89% to be at stage III, 77% high-risk stage III and 64% T4 tumours. The median time between the first dose of neoadjuvant therapy and surgery was 5 weeks.
A pathologic response was observed in 106/107 (99%) patients with 95% achieving a MPR and a complete response was observed in 67% of patients with 4% achieving a partial response. After a median follow-up of 13 months none of the patients had disease recurrence.
Grade 3-4 immune-related adverse events were observed in 3% of patients and only 3 experienced delay in surgery, meeting the safety primary endpoint.
The authors concluded by stating that ‘the first survival data suggest a strong potential for neoadjuvant immunotherapy to become standard of care and allow further exploration of organ-sparing approaches.’
Citation
Chalabi M et al. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study LBA7
18th February 2022
Adjuvant pembrolizumab added to chemotherapy post surgery significantly improves event-free survival compared to chemotherapy alone. This was the conclusion of a study by researchers from the Centre of Experimental Cancer Medicine, Barts Cancer Institute, London, UK.
Triple negative breast cancer constitutes 10-15% of female breast cancers and is a more aggressive cancer with more frequent recurrence and worse survival compared with the non-triple negative form.
Clinical trial data has revealed improved disease-free survival with postoperative chemotherapy in patients with either triple-negative or HER2-positive breast cancer who had residual disease after neoadjuvant chemotherapy.
Whether the addition of pembrolizumab to neoadjuvant chemotherapy would increase the proportion of patients with early triple-negative breast cancer who had a pathological complete response after surgery was unclear until publication in 2020, of the KEYNOTE-522 trial.
The trial concluded that the percentage of patients with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.
For the present study, the authors have reported on an updated analysis of the KEYNOTE-522 trial and in particular, event-free survival as well as additional efficacy and updated safety information. Participants were adults with confirmed triple negative breast cancer or those with newly diagnosed and previously untreated non-metastatic disease with primary tumour and regional lymph node involvement.
During the adjuvant phase, patients with previously untreated stage II or III triple negative breast cancer, were randomised 2:1 to receive either pembrolizumab (the pembrolizumab–chemotherapy group) or placebo (the placebo–chemotherapy group), administered once every 3 weeks.
After surgery, patients received either pembrolizumab or placebo and chemotherapy every 3 weeks for up to nine cycles. The primary endpoint was pathological complete response and event-free survival.
Adjuvant pembrolizumab and event-free survival
A total of 1174 patients were randomly assigned to either arm and during follow-up, 123 (15.7%) patients assigned to the pembrolizumab arm had an event or died compared to 93 (23.8%) in the placebo-chemotherapy arm.
The estimated event-free survival after 36 months was 84.5% in the adjuvant pembrolizumab group and 76.8% in the placebo arm, giving a hazard ratio, HR, for an event or death = 0.63, 95% CI 0.48 – 0.82, p < 0.001.
Data on overall survival were described as immature at the time of the analysis and the estimated overall survival at 36 months was 89.7% in the adjuvant pembrolizumab group and 86.9% in the placebo-chemotherapy group. With respect to safety, the authors reported that the reported adverse events were consistent with the established safety profile of both pembrolizumab and chemotherapy.
The authors concluded that among those with early triple negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy and then followed by adjuvant pembrolizumab after surgery, was associated with a significantly longer event-free survival than neoadjuvant chemotherapy alone.
Citation
Schmid P et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer N Engl J Med 2022
15th July 2021
Internationally, data from 2018 reveal how there were just over 1 million cases of gastric cancer, leading to 782,000 deaths. Fortunately, early treatment of gastric cancer either through endoscopic resection or surgery, provides a cure rate of over 90%. In contrast, in patients with locally advanced gastric cancer, prognosis is poor, with a 5-year overall survival rate of 20–30% for surgery-only patients. Among those with advanced gastric cancer, systemic chemotherapy has become the standard treatment, in particular, the combination of S-1, which is an oral fluoropyrimidine derivative and oxaliplatin (SOX) and this regime has been shown to be effective. Another therapeutic approach involves treatments targeting vascular endothelial growth factor (VEGF), which has been shown to have an important role in promoting tumour angiogenesis. Apatinib is a small molecule tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor 2 and which inhibits the action of VEGF. In fact, early data suggest that apatinib can improve overall survival in advanced gastric cancer.
In a review of 14 trials, the use of neoadjuvant chemotherapy, has been shown to improve tumour stage and survival in patients with advanced gastric cancer. However, little is known about the value of Apatinib in combination with neoadjuvant chemotherapy. This led a team from the Department of Gastric Surgery, Fujian Medical University Union Hospital, Fujian Province, China, to examine the effectiveness of this combination in patients with locally advanced gastric cancer. They conducted a multi-centre, open-label phase II, non-randomised controlled trial, in patients with confirmed primary gastric adenocarcinoma, without previous surgery, chemotherapy, radiotherapy or targeted therapy and no evidence of metastases. Patients with MO (i.e., no metastases) and either T2 to T4 (where the tumour has spread through the layers of the muscle into the connective tissue outside the stomach. All enrolled participants received 2 to 5 preoperative and 6 postoperative cycles of apatinib plus SOX every three weeks. Apatinib was given at a dose of 500 mg daily for 21 days and S1 twice daily on days 1 to 14 and intravenous oxaliplatin 130mg/square metre on day 1. Patients achieving a good response underwent surgery whereas those with a poor response received two further courses of adjuvant chemotherapy. The primary endpoint was the RO section rate (i.e., margin-negative resection with no tumour in the primary tumour bed) and which is the goal of surgery. The radiologic response was assessed using contrast-enhanced CT or magnetic resonance imaging.
Findings
A total of 48 patients with a mean age of 63.2 years (77.1% male) were included. All participants received 156 preoperative cycles neoadjuvant chemotherapy. The majority of patients (39.5%) had stage T3 cancer and nearly a third (36.9%) had stage T4 disease. Overall, 40 underwent surgery (38 radical gastrectomy and 2 exploratory laparotomy), with an R0 section rate of 75%. The radiological response rate was 75% and the pathological response rate, 54.2%.
Commenting on these early findings, the authors stated how the data indicated the effectiveness of apatinib and SOX chemotherapy as a neoadjuvant therapy for locally advanced gastric cancer. They concluded that apatinib plus SOX appeared to be an effective and well-tolerated regime and called for more studies to confirm this preliminary conclusion.
Citation
Lin JX et al. Effectiveness and Safety of Apatinib Plus Chemotherapy
as Neoadjuvant Treatment for Locally Advanced Gastric Cancer A Nonrandomised Controlled Trial. JAMA Oncol 2021
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