1st june 2015
Immunotherapy: study and management of side effects and combined immunotherapy
Two written communications (poster-discussion and poster) on the 1st June at the 51st ASCO Conference reported advances in immunotherapy in melanoma and non-small cell lung cancer.
The communication on melanoma was a description of the side effects of nivolumab, a monoclonal antibody directed against the PD-1 receptor, and of the management of those side effects. The communication on non-small cell lung cancer described the novel design of a phase III trial aiming to evaluate the efficacy and safety profile of 2 immunotherapeutic agents, administered separately or in combination, compared with conventional treatment.
Monoclonal antibodies alert the immune system so that it can attack the tumour. The proof of concept has been effected, in particular for the case of advanced melanoma, for which marketing authorisation has been granted in the United States (and may soon be in Europe) for pembrolizumab and nivolumab (two anti-PD1 antibodies). Immunotherapy might change the short-term management of various cancers.
Better management of adverse effects in immunotherapy: retrospective analysis of the safety profile of nivolumab (monoclonal anti-pd1 antibody) in patients with metastatic malignant melanoma.
Dr Caroline Robert, dermatologist and oncologist, is head of the Gustave Roussy Department of Dermatology (Villejuif). She presented the results of an analysis of the toxicity profile of nivolumab (a monoclonal anti-PD1 antibody) from 4 phase I to III clinical trials in patients with metastatic melanoma and methods of managing the side effects of this drug. The results confirm that the great majority of side effects are immunological in type and show that severe adverse events (grades 3 and 4) of nivolumab used as monotherapy can be quite easily countered by treating with an immunomodulator (principally corticosteroids) while still maintaining the anti-tumour response. It is also confirmed in this broader patient population that most side effects of this agent are low grade. Patients who received ipilimumab before nivolumab were not more likely to suffer high grade adverse events than those who had not.
The clinical trials studied were conducted in a total of 576 patients receiving nivolumab at a dose of 3 mg/kg twice weekly up to the time of disease progression or development of unacceptable toxicity. The median duration of administration was 3.7 months. 54% of the patients had received prior ipilimumab. The commonest side effects were fatigue (25%), pruritus (17%), diarrhoea (13%) and rash (13%). Grade 3-4 events occurred in 10% of the patient population and in 8% of those who had previously received ipilimumab. Skin symptoms appeared at the end of 5 weeks of treatment and renal adverse effects appeared as late as 15 weeks into treatment. Immunomodulators were prescribed in 35% of patients on phase III trials and 24% of patients received corticosteroids to manage side effects. The median time to resolution of these adverse events was 3 weeks when the liver was involved and 29 weeks for skin effects.
The objective response rate was 44% in patients who received an immunomodulator and 36% in those who did not.
Novel design of a phase III clinical trial: immunotherapeutic agents alone or in combination compared with conventional treatment in non-small cell lung cancer
Le Dr David Planchard, pneumo-oncologue à Gustave Roussy (1er auteur) et le Pr Jean-Charles Soria (dernier auteur), ont présenté le design d’une étude multicentrique de phase III cherchant à inclure 900 patients au total qu’ils coordonneront respectivement au niveau national et international. Cette étude cherchera d’une part à évaluer l’efficacité et la sécurité d’emploi du MEDI4736 un anticorps monoclonal anti PD-L1 versus le traitement standard (gemcitabine, vinorelbine ou erlotinib) chez des patients souffrant d’un cancer bronchique non à petites cellules dont la tumeur surexprime les récepteurs PD-L1 (sous-étude A). D’autre part, les chercheurs évalueront l’efficacité de l’association du MEDI4736 en association avec le tremelimumab, un anticorps anti CTLA4 versus l’une ou l’autre de ces molécules en monothérapie mais également versus le traitement standard chez les patients dont les cellules tumorales ne surexpriment pas le récepteur PD-L1. (sous-étude B)
Des données pré-cliniques ont montré qu’en bloquant à la fois les récepteurs CTLA4 et PD-L1 on obtenait une réaction additive ou synergique anti-tumorale. Par ailleurs, l’essai de phase Ib (NCT02000947) testant le MEDI4736 en association au tremelimumab chez des patients atteints de cancer bronchique non à petites cellules à un stade avancé a montré une sécurité d’emploi et des signes d’activité clinique de cette association.
Les patients éligibles souffrent d’un cancer bronchique non à petites cellules localement avancé ou métastatique qui ont déjà reçu au moins deux traitements dont une chimiothérapie à base de platinum. Les patients porteurs d’une mutation EGFR et d’un réarrangement du gène ALK ne sont pas éligibles.
300 patients seront affectés à la sous-étude A randomisée et 600 patients à la sous-étude B randomisée.