Important new results from EORTC trials will be presented at this year’s ESMO conference starting tomorrow (October 9) in Paris. Once again, immunotherapy – the use of drugs that stimulate the immune system so that it can find and attack cancer cells – plays a leading role, as do studies into patients’ quality of life.
Professor Alexander Eggermont will present results from the randomized phase III double-blind EORTC 1325/KEYNOTE-054 trial 1 of the immunotherapy pembrolizumab vs placebo in 1019 patients who had had their high-risk stage III melanomas surgically removed. Between August 2015 and November 2016, patients were given either 200 mg of immunotherapy or a placebo every three weeks until disease recurrence or unacceptable toxicity was observed. At five years’ media follow-up, the researchers found that recurrence-free survival, distant metastasis-free survival, and the time from randomization 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.
A second analysis of the trial results 2 centered on the effect of pembrolizumab on patients’ quality of life. The researchers found that there were no clinically relevant differences in long-term quality of life between the active treatment and the placebo arm. Differences related to physical functioning, role, emotional, cognitive, and social functioning, and fatigue were insignificant, and neither were immune-related adverse events associated with any clinically relevant changes.
A further study of pembrolizumab, this time in early-stage non-small cell lung cancer, will be presented by Professor Solange Peters 3. The PEARLS/KEYNOTE-091 study investigated the effect of pembrolizumab on patients who had had complete surgical resection of stage IB to IIIA tumors. The further analysis presented at ESMO focused on a sub-group of patients who had increased levels of PD-L1, a protein that allows cancer cells to evade the immune system. Earlier results from the trial had appeared to show that pembrolizumab had little benefit in patients with high levels of PD-LI, but further, more detailed analysis showed that disease-free survival in those patients with the highest levels of the protein was improved. The lack of statistically significant benefit for these patients in the earlier analysis most likely results from placebo overperformance, the need for a longer follow-up, and smaller population size. But in any event, the data support the benefit of the treatment for all stage IB to IIIA resected patients, regardless of PD-LI expression, the researchers say.
The EORTC has an important track record in the development and use of Quality of Life (QoL) measurement instruments in clinical trials. Studies usually focus on radiological and survival endpoints with QoL as a supplementary endpoint, but for older patients, it is known that QoL rather than length of life is increasingly important. Evidence on optimal treatments in the elderly with metastatic soft tissue sarcoma is limited, yet patients understandably want to have relevant information before making the decision to start palliative treatment. Therefore a new clinical trial 4, ‘EORTC 1976 TOLERANCE’, for this specific group of metastatic elderly rare cancer patients has been designed with significant input from patients. The study design will be presented by Professor Winette van der Graaf, EORTC President, and study coordinator. In the randomized three-arm study the primary endpoint will be QoL, particularly self-reported physical and role functioning at 12 weeks. In the trial, standard three-weekly doxorubicine will be compared to metronomic (the frequent administration of low dose) schedules of doxorubicin or cyclophosphamide. Patients older than 70, or between 65 and 69 years of age with a G8 score of 14 or less with progressive metastatic soft tissue sarcoma will be entered into the study. A total of 185 patients will be needed to get an answer as to whether metronomic doxorubicin or cyclophosphamide leads to a lower burden in terms of physical and role functioning than the standard doxorubicin schedule.
Also in soft tissue sarcoma, Dr. Georgios Kantidakis, on behalf of the EORTC Soft Tissue and Bone Sarcoma Group, will present new benchmarks for designing clinical trials in advanced metastatic liposarcoma (LPS) and synovial sarcoma (SS) 5. The researchers carried out a meta-analysis to update reference values for phase II soft tissue sarcoma (STS) trials. The information studied included 1030 LPS patients in 25 trials as well as 348 SS patients in 13 trials. Study endpoints were progression-free survival rates at three and six months. The researchers conclude that minimum values in patients receiving first-line therapy are 79% at three months and 69% at six months in LPS, and 82% and 69% respectively for SS. For patients who have already received treatment, recommended progression-free survival rates at three and six months, suggesting drug activity, are 63% and 44% respectively for LPS, and 60% and 41% for SS. These new benchmarks will help better design future trials, the researchers believe.
Dr. Silke Gillessen will present the results of an EORTC analysis of the International Germ Cell Cancer Collaborative Group (IGCCCG) Update database 6. In stage I testicular cancer, active surveillance after orchiectomy (the surgical removal of a testicle) is the preferred management in many patients. However, it is associated with a 15 to 30% relapse rate. The researchers identified all patients with metastatic gonadal germ cell tumors for whom they had complete information on the initial tumor stage, and compared the outcomes of patients relapsing from clinical stage I (CSI) disease to those with de novo metastatic disease. They found no difference progression-free survival or overall survival in patients relapsing from their original CSI as compared with de novo metastatic disease when adjusted for their prognostic group, though a substantial proportion of CSI patients relapsed with intermediate or poor prognostic features in need of intensified treatment. The study underlines the importance of performing active surveillance well in order to detect recurrence in CSI patients as early as possible, say the researchers.
Professor Christian Simon will present the design of an EORTC randomized controlled trial to assess the effect of either surgery or radiotherapy for early-stage oropharyngeal, supraglottic, and hypopharyngeal cancers on the recovery of these head and neck cancer patients’ ability to swallow 7. Both are generally effective at controlling tumor growth but have different side effects, and choice is generally based on the choice of the individual patient and/or institution. Recently the introduction of new surgical and radiotherapeutic techniques has led to an improvement in side effects resulting from treatment. The Phase III trial will enroll 112 patients from 29 European centers, and recruitment had already reached the halfway mark in January 2022. The researchers hope that it will provide a conclusive answer to the question and therefore provide a robust basis for the choice of treatment.
Dr. Jordi Remon, on behalf of the EORTC Lung Cancer Group, will report the results of a clinical trial (APPLE trial-EORTC 1613) 8. This trial supports the hypothesis that among patients with advanced non-small cell lung cancer and epidermal growth factor (EGFR) mutation treated with first-generation EGFR tyrosine kinase drugs, plasma assessment (liquid biopsy) is feasible to detect the mutation of resistance (T790M) to this treatment before radiological progression. This enables personalized treatment to start earlier. In the trial, patients from six countries were enrolled in three arms, results from two of which were presented at ESMO. Patients in Arm B were given the EGFR inhibitor gefitinib until the emergence of T790M in a liquid biopsy or progression of their disease, whereupon they were treated with the targeted therapy osimertinib. In Arm C, the internal control arm, patients received gefitinib until progression and then osimertinib. Median follow-up was 30 months. The researchers found that monitoring of T790M status in plasma gave a good indication of molecular progression before further symptoms appeared, and led to an earlier switch to osimertinib in 17% of patients with satisfactory outcomes in progression-free and overall survival.