May 31, 2015
Targeted therapies as monotherapy or in effective combinations in various conditions
Four oral communications on targeted therapies were given at the 51st ASCO Conference. Three of these were at the session devoted to lung cancer on 31st May and the fourth was in a session on sarcomas on 1st June.
Professor Jean-Charles Soria, head of the DITEP department, presented the results of two studies. One of these was about LUX-Lung 8, the largest randomised study on second-line treatment of squamous cell lung carcinoma. This phase III trial compared the effectiveness of two targeted therapies, afatinib and erlotinib, as second-line therapy. The second study showed the efficacy of a 3rd generation EGFR inhibitor in non-small cell lung cancer with EGFR mutation.
Dr David Planchard, pneumo-oncologist in the Gustave Roussy Department of Medical Oncology, reported the initial results of a phase II study on the effectiveness of combined dabrafenib-trametinib therapy in B-RAF mutated lung carcinoma.
Dr Olivier Mir, oncologist and pharmacologist in the Gustave Roussy Department of Medical Oncology, presented promising results from the REGOSARC study, a phase II randomised clinical trial testing regorafenib in patients with soft tissue sarcomas.
Comparing two second-line targeted therapies
Squamous cell carcinoma is one of the non-small cell cancers of lung. Therapeutic options for patients at an advanced stage after first-line platinum-based chemotherapy are limited. Afatinib and erlotinib are agents which target the signalling pathways involved in oncogenesis, especially in this condition and erlotinib is currently one of the standard drugs for it.
The phase III open, randomised LUX-Lung 8 trial presented by Professor Jean-Charles Soria, head of the DITEP department, compared the effects of afatinib to those of erlotinib on disease progression-free and overall survival in patients with squamous cell carcinoma. These patients were in therapeutic failure after platinum-based chemotherapy.
The results showed that afatinib was superior to erlotinib with a 19% reduction in the risk of progression and also a reduction in the risk of death, combined with better quality of life associated with the better responses.
Proof of efficacy of a 3rd generation EGFR inhibitor in lung cancer
In a phase I/II study, Professor Jean-Charles Soria, head of the DITEP department, reported encouraging results with the use of a 3rd generation EGFR inhibitor (rociletinib) in patients with non-small cell lung cancer carrying the T790M mutation, who had previously been treated with one or more other EGFR inhibitors.
456 patients participated in this study. The results presented showed an objective response rate of 60% and a rate of 90% for tumour control. The progression-free survival period was 10.3 months. This study also showed that the T790M mutation may be detected in plasma. When this was the case, the response rate was 57%. The most frequently observed side effects affected less than 15% of patients. These mainly comprised hyperglycaemia, diarrhoea, nausea, fatigue and reduction in appetite.
Combined targeted therapies
Dr David Planchard, pneumo-oncologist in the Gustave Roussy Department of Medical Oncology presented the initial results of a phase II clinical trial evaluating the efficacy and adverse event profile of combined dabrafenib-trametinib in patients with non-small cell lung cancer bearing the BRAF V600E mutation (around 2% of lung cancer). Both of these targeted drugs act on the same intracellular tumour proliferation pathway but at 2 different points. Dabrafenib is a very specific inhibitor of the mutated BRAF-V600E protein, while trametinib is a specific inhibitor of the MEK protein. Both drugs are taken orally, once daily for trametinib and twice daily for dabrafenib.
Two years ago at ASCO Dr Planchard had already reported very promising results for monotherapy with dabrafenib in bronchogenic carcinoma with the BRAF-V600E mutation, in progression after chemotherapy. The overall response rate was 32% and the median duration of treatment was prolonged by 9.6 months. The current study shows that the combination of dabrafenib with trametinib significantly increases effectiveness with an objective tumour response of 63% without an increase in side effects (or even a reduction in these, notably for cutaneous effects). The majority of side effects are minor (grade 1 or 2), easily controlled and in most cases not requiring cessation of treatment (only 6% cessation of treatment) but only a possible reduction in dose. This represents a real potential therapeutic advance for those patients with the BRAF-V600E mutation and, therefore, a new potential therapeutic weapon. The final results of this study need to be awaited to confirm this, with the great majority of patients still taking the medication. The results reported here are only preliminary.
Targeted therapy in sarcomas
The phase II randomised REGOSARC study has shown promising effects of regorafenib in patients with soft tissue sarcomas and the side effect profile is acceptable.
Dr Olivier Mir, oncologist and pharmacologist in the Gustave Roussy Department of Medical Oncology conducted this study for the French Sarcoma Group. This involved 175 patients divided into 4 arms according to sarcoma type: leiomyosarcoma, synovial sarcoma, liposarcoma and other soft tissue sarcomas. Within each cohort the patients were randomised (1:1) to receive regorafenib or placebo. Patients whose disease progressed on placebo then received regorafenib.
The results showed that in the « other soft tissue sarcomas ». cohort there was an improvement in disease progression-free survival (median: 4.6 months on regorafenib compared with 1 month on placebo). In patients with leiomyosarcoma, regorafenib significantly improved overall survival (HR 0.37, i.e. a reduction of 63% in the risk of death).
More about targeted therapies
The goal of these therapies is to target a specific protein or biological mechanism involved in the development of a tumour, so as to spare healthy cells to the maximum extent. Gustave Roussy has now established itself as a major centre for personalised or molecular medicine based on a detailed analysis of a patient’s tumour, seeking to identify genetic abnormalities which are accessible to targeted therapy. The Institute is now one of the few European centres capable of producing within two weeks a molecular portrait to inform therapeutic decisions.