On September 17, 2024 EORTC reported that important new results and an update on trial in progress were presented at the ESMO (Free ESMO Whitepaper) Congress 2024, held in Barcelona from 13-17 September, further underlining the extent of EORTC’s commitment to innovative, independent cancer research (Press release, EORTC, SEP 17, 2024, View Source [SID1234646700]).

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Prostate cancer
Professor Silke Gillessen presented the primary results from EORTC GUCG-1333 (PEACE III)1, an international, randomised Phase 3 trial designed to test the effect of a combination of enzalutamide, an AR pathway inhibitor (ARPI), with the Radium-223 as first-line treatment for patients with metastatic prostate cancer that no longer responds to androgen deprivation therapy (metastatic castration-resistant prostate cancer, or mCRPC), and who had bone metastases. This trial was a collaboration with several other cancer cooperative groups: Clinical Trial Ireland (CTI), the Canadian Urological Oncology Group (CUOG), the Latin American Cooperative Oncology Group (LACOG), and French UNICANCER cooperative group (GETUG). It took more than eight years to complete from first patient enrolled to the closing of the database.

PEACE-III shows that adding six cycles of Ra223 to enzalutamide as first-line treatment for mCRPC patients significantly improved patient outcome by increasing median progression free survival (the primary endpoint) from 16 to 19 months.

An interim analysis at 80% of events showed also an advantage for enzalutamide+Ra223 in terms of overall survival (OS). Due to non-proportional hazards, this will be tested further in the final OS analysis to confirm and further characterise the result.

PEACE III is the first major Phase 3 trial to suggest that combining an ARPI with another approved medication improves OS considerably. Previous Phase 3 studies that tested combinations of two ARPIs or combining an ARPI with a PARP inhibitor have failed to demonstrate a significant OS in the intent-to-treat population.

Toxicity from the treatment was mild, though the trial did illustrate the importance of giving bone protecting agents to avoid fractures. Given the improved efficacy and acceptable toxicity, the researchers say that the combination of enzalutamide and Ra223 can be a new valid treatment option for patients with mCRPC and bone disease and disease progression on androgen deprivation therapy.

Melanoma
First results from the EORTC 1208 MINITUB2 trial, presented by Professor Alexander C.J. van Akkooi, contribute significantly to the body of evidence indicating that some melanoma patients can be spared from drug treatments or an extensive surgery with little impact on their risk of developing metastatic disease or dying due to melanoma. In the past, patients with a melanoma that had spread to the sentinel node – the first lymph node or groups of nodes to which the cancer usually spreads – at the time of initial diagnosis underwent a complete lymph node dissection in addition to surgery to remove the skin lesion. Lymph node dissection carries significant toxicity and can have a lifelong impact on the patient’s quality of life. Some studies had suggested that the extent to which the sentinel nodes are affected by melanoma might help to predict prognosis, and the objective of the EORTC 1208 MINITUB study was to assess the outcomes of patients with a minimal sentinel node tumour burden who did not undergo a complete lymph node dissection.

The primary study endpoint was the proportion of patients who developed metastatic melanoma after five years from the date of biopsy of the sentinel node. The study was performed in 21 hospitals from nine countries, and 296 patients were enrolled. A small number of patients (17) chose complete lymph node dissection while 279 chose observation. Results showed that patients with minimal sentinel node tumour burden who chose observation had a relatively low risk of developing metastatic disease or dying due to melanoma, thus supporting the current practice of omitting a complete lymph node dissection. The researchers also found overdiagnosis leading to possibly unnecessary treatment in 7% of the patients. They say that their results provide strong evidence that an evaluation of the sentinel node tumour burden is helpful in evaluating prognosis of each patient and that it would be useful to add it to future cancer staging systems. This could help a better evaluation of whether the benefits of melanoma treatments outweigh the risk of toxicities, especially for patients with a relatively low risk of developing metastatic disease. The researchers now intend to follow up the longer-term outcomes for these patients.

Another presentation featured follow up data from the EORTC 1325/KEYNOTE-0543 trial of the immunotherapy treatment pembrolizumab, presented by Professor Alexander Eggermont, show that this treatment administered after a full resection of high-risk stage III melanoma continues to bring clinical benefits to patients in the longer term. The trial enrolled patients in 2015 and 2016, and found that after five years of follow-up, recurrence-free survival, distant metastasis-free survival, and the time from randomisation until a second disease recurrence, progression of the first recurrence, or death, were all significantly improved in the patients who had received the active treatment rather than placebo.

Now, at a median seven-year follow-up, researchers found that these improvements remained present for all these endpoints for those who received the active treatment. Because late recurrences in melanoma are common, these results are important, they say.

Head and neck cancer
The EORTC 1206-HNCG4 trial, conducted in partnership with the International Rare Cancer Initiative (IRCI), was presented by Dr Laura Locati. It is the first-ever randomised study carried out in salivary gland cancers (SGCs) with androgen receptors (ARs), proteins that bind to the male hormone androgen. Salivary gland cancers are rare and make up less than 5% of all head and neck cancers. They are complex, with over 20 different types, each behaving differently and with varied outcomes. One aggressive salivary duct cancer is known to have androgen receptors, and platinum-based chemotherapy is the usual treatment for patients whose cancer has returned or spread. Androgen deprivation therapy (ADT) has shown effectiveness in cancers with AR but to date there has been no evidence that ADT is better than chemotherapy for patients who have not received prior treatment in recurrent and/or metastatic SGSs.

The study included two groups of patients: those who had not received chemotherapy previously, and those who had. Patients in the first group were randomised to either ADT (a combination of triptorelin and bicalutamide) or standard chemotherapy. Patients in the second group received ADT. Results failed to show that ADT was better than chemotherapy for patients with AR-expressing SGCs who had not been treated previously. However, ADT displayed some positive responses regardless of when chemotherapy had been given. But the study had limitations, the researchers say. It used an older form of ADT, and 17% of the patients had HER2 amplification (too many copies of the HER2 gene). The researchers believe that combining ADT with chemotherapy and/or HER2 inhibitors might be the way forward as a future treatment strategy in recurrent and/or metastatic SGSs and will be investigating this further.

Lung cancer
Malignant pleural mesothelioma (MPM) is a rare form of lung cancer with a poor prognosis, for which treatment options are limited. In MPM, tumours form in the lining of the lungs (pleura), and are caused by the inhalation of asbestos fibres.

Previous research has shown that the oral medication nintedanib was effective in improving the quality of life in patients with some other VEGF-dependent malignancies. VEGF is a protein that stimulates the formation of blood vessels (angiogenesis), thus allowing tumours to grow and metastasise. The goal of the EORTC- 08112-NEMO5 trial, results from which were presented by Dr Omar Abdel-Rahman, was to evaluate the role of angiogenesis inhibition using nintedanib as a new maintenance therapy in patients with MPM who were completing four to six cycles of platinum-pemetrexed chemotherapy.

In this trial, patients were enrolled after completing first-line platinum-based chemotherapy (4-6 cycles) for MPM within 60 days from its last administration, and after confirmation of the absence of progressive disease. They were randomised between receiving 200mg of nintedanib twice daily over a 28-day cycle, and placebo twice daily over a 28-day cycle.

However, the active treatment was found to have a negative effect on overall survival in the LUME-Meso randomised phase 3, which led to the early termination of recruitment into the NEMO trial. Consequently, the number of patients involved was too low to be able to draw robust conclusions on progression-free survival, the trial’s primary endpoint. However, the limited progression-free survival and overall survival analyses available seem to indicate that the effect of nintedanib was detrimental to patients, as opposed to placebo, albeit that there was an imbalance in immunotherapy use between the two arms. These results are consistent with those from the LUME-Meso trial, the researchers say.

Rare cancers
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 presented updated results from the ARCAGEN6 collaborative study carried out within EORTC-SPECTA, a molecular and biological research platform. The goal of ARCAGEN is the detection of genetic alterations in rare cancers. Over three and a half years, 990 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 (a cancer caused by exposure to asbestos), and cholangiocarcinoma (cancer of the bile duct).

The presentation focused on specific alterations called rearrangements. These were identified in the tumours of 166 (18%) of the patients in the study. They were clinically significant in 102 (11%), and actionable for 31 (3.1%) of them. Personalised therapy was adopted for 12 out of the 31 patients with rearrangements, with one complete response, seven partial responses and four incomplete/stable responses, and a median progression-free survival of 14 months. Four patients were still on treatment at the time of analysis, including three for longer than 15 months.

The researchers concluded that rearrangements in rare cancers have at least a similar occurrence rate to that seen in common cancers and can be targeted. However, despite the identification of these alterations, treatment access remains limited, they say.

Breast cancer
Details of the EORTC-2129-BCG: TREAT ctDNA7 breast cancer trial, currently recruiting patients, were presented by Dr Michail Ignatiadis. The international trial is investigating the effect of elacestrant, a new type of endocrine therapy, in early breast cancer patients being treated with post-surgery endocrine (hormone) therapy, and who are identified as harbouring a high risk of their cancer coming back (recurrence) by the regular screening for circulating tumour DNA (ctDNA). This biomarker consists of fragments of DNA that have escaped tumours into the bloodstream.

The trial has two phases. In the first phase, patients are screened for ctDNA every six months. The aim is to screen about 2000 patients, of whom about 10% are expected to be positive for ctDNA. Such patients, known to have a higher risk recurrence, will be invited to proceed to the second phase of the study, in which all of them will be offered intensive follow-up including regular CT scans, bone scans, and breast imaging, in order to try to detect recurrence as early as possible. They will be randomised into two groups – one continuing to receive their existing hormone therapy, and the other group who will switch from their current endocrine therapy to elacestrant.

The investigators hope that the trial will help to prevent or delay cancer recurrence in ctDNA-positive patients. Recruitment to the study is now underway in Belgium, Cyprus, France, Germany, Greece, Italy, Ireland, the Netherlands, Portugal, Spain, Sweden, and Switzerland.