Professor Benjamin Besse, with the support of Professor Silvia Novello, secretary and Professor Thierry Berghmans, treasurer, is the chair of the EORTC Lung Cancer Group. Besse resides as the Head of the Thoracic Oncology Unit at Gustave Roussy Cancer Campus and he is Professor of Medical Oncology at Paris-Sud University, Orsay. As a leader in clinical research for lung cancer, Besse has seen the field evolve and change tremendously over the last 15 years.
“Since the discovery of the EGFR activating mutations in 2004, there has not been one year without a major therapeutic evolution in lung cancer,” said Besse. “The discovery of more activating mutations in very tiny patients subgroup (<5%) such as BRAF and MET mutations, ALK, ROS1, NTRK, RET rearrangements have shown the emergence of promising molecular targeted therapies for non-small lung cancer (NSCLC). At present, up to 20% of non-small cell lung cancer patients, who are predominantly light or never smokers, are eligible for targeted therapies. It means that lung cancer is now a sum of rare diseases, each requesting a specific strategy!”
Besse emphasises that molecular profiles of EGFR, BRAF, ALK abnormalities should be mandatory in any advanced non-squamous lung cancer, and additional biomarkers such as ROS1, MET, RET must be considered for never/light smokers.
“Immunotherapy is the new game changer. It has been driven predominately by results from clinical studies evaluating antagonist antibodies to programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), which have demonstrated prolonged tumour responses in patients with advanced NSCLC. However, the optimal marker for patient selection is still a matter of passionate debate. PD-L1 immunohistochemistry is the standard, and should be the preferred testing in any new advanced NSCLC.”
“The field is now moving into investigating the combination of immunotherapies with standard chemotherapies or radiotherapy, in order to enhance the benefits to patients, but there are number of challenges such as adverse immune reactions and increased costs of combined treatments. Research is also focussing on optimal biomarkers, and defining the mechanisms of primary/secondary resistance.”
As the chair of the EORTC Lung Cancer group, Besse believes that it is important to be part of an independent, clinical research organisation such as EORTC because the field is becoming incredibly complex, with more stringent regulations and costs. EORTC provides infrastructures and knowledge to run clinical trials efficiently.
The Lung Cancer Group has 687 international members and has been very active in the last 3 years, resulting in more than seven trials that just started or are about to start. Among them, Besse highlights:
- EORTC-1416-LCG – PEARLS: A randomized, phase 3 trial with anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) versus placebo for patients with early stage NSCLC after resection and completion of standard adjuvant therapy, in collaboration with ETOP; this is one of the largest trials that explore immunotherapy in the adjuvant setting, after complete resection of lung cancer.
- EORTC-1613-LCG – APPLE: Feasibility and activity of AZD9291(osimertinib) treatment on Positive PLasma T790M in EGFR mutant NSCLC patients; the only trial in the world that compares three strategies in EGFR mutated NSCLC: 1) 3rd generation TKI first, 2) first followed by 3rd generation TKI at the time of progression, 3) first followed by 3rd generation TKI in case of biologic progression (i.e. when liquid biopsy turns positive for a resistance mutation);
- EORTC-1643-LCG – SOLUTION: Randomized phase II study of durvalumab and tremelimumab combination versus standard of care following first-line platinum based chemotherapy in two cohorts of patients with non-squamous and squamous NCSLC. This latter combo might be quite toxic and the target population is so far unknown. Our hypothesis is that patients that derive a benefit to a platinum-based chemotherapy might have an immune system ‘primed’ by the chemotherapy, and thus more willing to benefit from immunotherapy. This is the first trial to test this hypothesis with an immunotherapy/immunotherapy combination. A similar initiative has just started in small cell lung cancer, a disease where there has been no major changes for decades. The REACTION trial investigate the role of immunotherapy in those patients that derive a strong benefit to induction chemotherapy.
- Trials in rare malignancies such as mesothelioma (a trial with pleural decortication and a trial with nintedanib will start in the next few weeks) and in thymic malignancies (an immunotherapy trial, NIVOTHYM, in collaboration with ETOP will start soon).
“One of the strengths of the Lung Cancer Group is a very active Young Investigator subgroup. They are running a survey and literature review to better understand the standard of care and routine practice, so that we can fine tune our inclusion criteria. They also participate in all the steps in the clinical trial as co-coordinator, since it is mandatory for any EORTC Lung Cancer Group trial to have a senior coordinator and a Young Investigator co-coordinator.”
Besse believes there are a number of challenges that investigators are facing in clinical research. “In recent years, cost of treatment has become a major issue but we have to stop complaining and we must act. There is a trend, in industry-conducted trials, to offer the drug to a large number of patients (i.e. in a poorly selected or unselected population). The role of academia is to understand the best population to treat and investigate alternative schedules that can save time and money in hospitals. The latter is called de-escalating trials. A second issue is that many next generation therapies are shown to be more effective than first generation. Nevertheless, it does not mean we have to prescribe the next generation first! A key role of academia is to define the best sequence, i.e. next generation first or first generation followed by next generation at progression.”
Despite game changing advances in lung cancer, the overall survival of patients is still around 16%. “We have to integrate new tools, in our treatment strategy, such as liquid biopsy as a guide to treat and the addition of stereotactic radiotherapy to systemic treatment in the metastatic setting. For the latter, we are currently developing a consensus on the definition of oligo metastatic disease to enrol more homogeneous patient population in the trials. It will be the first consensus from the Lung Cancer Group, reflecting its vitality.” Besse concludes, “Better diagnosis and management of the patient equates to better survival.”