Important results and the announcement of several new trials will be communicated at the 2023 ESMO conference, which starts on 20 October in Madrid, showing once again the extent of EORTC’s contribution to innovative, non-commercial cancer research.
Rare cancers include more than 300 different types of cancer and may affect all organs. They represent about 20% of all adult cancer cases, but their mortality rate is 30%. Because there are very small numbers of each cancer, patients may have limited access to molecular profiling and clinical trials, and this can lead to inaccurate diagnosis and limited treatment options. Detecting targets for therapy is therefore a priority.
Dr Marie Morfouace, an EORTC translational scientist, will present results from the ARCAGEN collaborative study 1 carried out within EORTC-SPECTA, a molecular and biological research platform. The goal of ARCAGEN is to detect genetic variations in rare cancers. Over three and a half years, 918 patients from 14 European countries with rare adult solid tumours at an advanced phase received a molecular profile of their cancer. The three most common histotypes (the type of tissues produced by a tumour) found were cancer of unknown primary, mesothelioma (cancer caused by exposure to asbestos), and cholangiocarcinoma (cancer of the bile duct).
Molecular alterations were identified in the tumours of 606 of the patients involved. This enabled the proposition of therapy for 295 patients; 63 for an already approved treatment, and 232 for a treatment approved for another tumour type with a similar molecular alteration. Enrolment in an appropriate clinical trial was offered to 161 patients.
Follow-up and response rate for these patients is ongoing. However, the study already shows that molecular profiling for rare cancer patients is feasible, with a low failure rate and a fast turnaround time [14 days on average], the researchers report, and this should allow for clinical implementation and platform trials for rare cancers to bring new treatment options for patients.
Dr Laura Mezquita will present ALKALINE 2, an ongoing study in patients with ALK-positive advanced non-small cell lung cancer. The ALK mutation is a genetic alteration that causes lung cells to grow abnormally. The study recruits patients who have received treatment but whose tumours have grown again, possibly due to genetic mutations making the tumours resistant to treatment. Such patients are identified by liquid biopsies (blood tests that can identify specific cancer cells), thus avoiding invasive diagnostic methods. They are stratified into three groups – the first with ALK mutations (group A), the second with non-ALK mutations (group B), and the third where no circulating tumour cells have been found (group C).
The study evaluates the activity of lorlatinib, a third-generation ALK inhibitor, to try to identify which patients may benefit most from it. There is also a sub-study for adults with the same cancer type who are receiving treatment with second-generation ALK inhibitors. This assesses the time between identifying a genetic mutation probably making the tumour resistant to treatment and the tumour growing again. At the point the tumour grows, this group of patients were offered the opportunity to take part in the main study. ALKALINE is currently closed for new patients.
The primary endpoint of the study is progression-free survival at 12 months in group A. Secondary endpoints include treatment activity in groups B and C, toxicity, and outcomes reported by the patients themselves will be evaluated.
Additionally, results from a study 3 that forms part of the IMMUcan collaborative project will be presented by Dr Marie Morfouace. The IMMUcan project seeks to enhance understanding of the tumour microenvironment, i.e. the immune and other cells, that surround the tumour.
Results from the study of real-world data from a cohort of patients with non-small cell lung cancer (NSCLC) will be presented. Although immune checkpoint blockers, which work by blocking proteins that stop the immune system from attacking the cancer cells, have brought about considerable advances in treatment for patients with NSCLC, response to them is often limited.
The first NSCLC group to be studied within IMMUcan was made up of 239 patients. The median age was 67; 100 patients were female and 139 were male. The majority were current or former smokers. Tissue specimens were collected from them at the time of their diagnosis, and prior to any treatment, and genomic and other data were amassed and analysed. T-cell infiltration – a sign of ongoing immune activity against a tumour – was assessed in all the samples and associated with improved overall survival. This, and further integration and analysis of the NSCLC patients in IMMUcan will generate more understanding of the process by which cancer cells escape the immune system.
Another study 4 will investigate in detail the effects of radon, a radioactive gas that can accumulate inside homes, and that is one of the leading causes of lung cancer in non-smokers. Its indoor concentrations are measured and regulated in Europe, but the specific regulatory measures vary between countries. BIORADON, a new EORTC study to be presented by Dr Laura Mezquita, will investigate correlations between radon exposure at home and molecular alterations in patients with all stages of non-small cell lung cancer (NSCLC).
A total of 975 patients with a current or previous history of NSCLC who have been living at the same address for more than two years before diagnosis and molecular profiling of their tumour available will be enrolled from thirty centres in five countries. They will be divided into three cohorts based on their tumour’s molecular characteristics; the first with mutations associated with lung cancer, the second with molecular rearrangements associated with lung cancer, and the third a control group with neither. Participants will then be given two detectors to be placed in their homes for three months to measure radon levels. They will be also asked to give a blood sample and to complete a questionnaire on a number of factors including the characteristics of their home, smoking, and other exposures to potential carcinogens. At the end of the three-month period, and after analysis of the radon detectors, they will receive a report of their in-house radon concentration. The researchers believe that their research will provide a better understanding of the relationship between domestic radon exposure and cancer molecular drivers.
Head and neck cancer
Squamous cell carcinomas of the head and neck (SCCHN) are a complex group of cancers that present in a very heterogeneous fashion. To complicate things further, patients often do not seek help until they present symptoms of advanced disease, as symptoms are common to other benign diseases. That is why diagnosis is often not made until an advanced stage.
The EORTC UPSTREAM umbrella trial 5 was set out to investigate the effect of targeting treatment to specific gene alterations (biomarkers) found in the tumour of an individual patient with recurrent or metastatic SCCHN disease. Umbrella trials evaluate a number of targeted treatments for one disease where patients are stratified into subgroups according to their biomarkers. This trial also included cohorts to evaluate the effect of immunotherapies in patients with no specific biomarkers.
Dr Rachel Galot will present the results from one of two cohorts where patients were randomised in a two-to-one ratio to be treated with either the combination of immunotherapies monalizumab and durvalumab or with the standard treatments on use in clinical practice.
Both immunotherapies have shown encouraging results in mice and in other cancers. Of the 66 patients included in the cohort, 60 were evaluable, with 42 in the immunotherapy group, and 18 controls. The median age was 62; 18% had cancer of the oral cavity, 42% of the oropharynx, 20% of the hypopharynx, and 20% of the larynx.
Only one patient in the immunotherapy group had a partial response over the first 16 weeks of treatment (the primary endpoint). The median progression-free survival was two months in the immunotherapy group and 3.1 months in the control group. Median overall survival was 4.3 months in the immunotherapy group and eight months in the control group. Among patients in the immunotherapy group, 9% of patients reported serious treatment-related adverse events. The lack of activity seen with these immunotherapies led the researchers to conclude that they were of no benefit to these patients.
Preliminary results from a further IMMUcan study 6, to be presented by Christian Esposito, from Owkin*, give another example of how the collection and analysis of multiple types of data in a single place can help refine treatment in many types of cancer. In breast cancer, the ability to predict pathologic complete response (pCR) is known to be associated with better outcomes after neoadjuvant (pre-surgery) treatment. The researchers identified a first cohort of 132 and 149 patients with triple-negative and HER2-positive breast cancer, respectively. Triple-negative means that the cancer cells do not have oestrogen or progesterone receptors, and are not positive for a protein called HER2. This reduces the targets for treatment for these patients and generally leads to worse outcomes for them.
The researchers used different Deep Learning approaches to try to predict pCR in each patient from imaging and RNA sequencing of tumours and found that the best predictor involved whole slide imaging integrated with RNA sequencing. Having access to these models and the ability to predict features that are linked to achieving a pCR may assist in improving treatment strategies for breast cancer in the future, according to the researchers.
Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers. However, a subset of TNBC patients have mutations in the BRCA1 or BRCA2 genes, and such mutations may allow for new treatment options.
NOBLE 7, a new trial to be presented by EORTC researcher Dr Emanuel Buhrer, will investigate whether it is possible to treat patients with early TNBC who have BRCA mutations with newer drugs instead of chemotherapy. The trial will use olaparib, which targets BRCA mutations, and durvalumab, an immunotherapy. Patients will be treated before they undergo surgery (neo-adjuvant treatment). In this phase 2 trial, 152 patients from a number of centres will be randomised to olaparib alone or to olaparib plus durvalumab, for four treatment cycles.
The trial will commence in autumn 2023, and the primary endpoint will be the rate of pathologic complete response – the absence of all cancer cells in the breast – at the time of surgery. Patients will be followed up for two years after their surgery. A secondary endpoint will be a response based on RECIST v1.1, i.e. a set of rules that define how tumours respond to treatment. Other secondary endpoints include event-free survival, overall survival, safety, and quality of life.
The primary endpoint is expected to be known approximately five years after the first patient is screened for trial entry.
Furthermore, EORTC Head of the Quality of Life Department, Madeline Pe, will present an update about the SISAQOL-IMI project8 during the ‘ESMO-MCBS: 2023 revolution’ session.
Finally, EORTC Scientific Director Dr Jan Bogaerts will give a talk 9 on Pragmatic Trials in the invited speaker session ‘More Intelligent Trial Design’.
*Owkin is a company specialised in Artificial intelligence and an IMMUcan partner.