73IN - Combining immunotherapies

Date 27 September 2014
Event ESMO 2014
Session The science behind combinations with immunotherapy in melanoma
Topics Cancer Immunology and Immunotherapy
Melanoma and other Skin Tumours
Presenter Christian Blank
Citation Annals of Oncology (2014) 25 (suppl_4): iv26-iv26. 10.1093/annonc/mdu306
Authors C. Blank
  • Medical Oncology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL

Abstract

Body

Abstract:

Recent advances in the treatment of metastatic melanoma are based on applying scientific knowledge about oncogenic signaling and the immunobiology of this cancer from the laboratory to the clinic. The in BRAFV600 mutation drives the growth of approximately 50% of melanomas, and targeted agents inhibiting oncogenic BRAF and/or MEK result in very high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory checkpoints, such as CTLA4 or PD-1, can induce durable responses in a subset of patients with melanoma. These advances have driven the interest to combine both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells, and potentially sensitize the immune system to target tumors. The anticipation of benefits from such a combination are based on the clinically validated individual activity of both modes of therapy, the potentials for combining without limiting overlapping toxicities, the scientific rationale of potential benefits and the supportive evidence from preclinical models. Potential mechanisms of combinatorial activity are based on increased antigen expression and presentation to the immune system upon BRAF inhibition, the inhibition of immune suppressive factors by blocking oncogenic BRAF improving the infiltration of cytotoxic immune cells into the tumor microenviroment, and paradoxical activation of immune cells. It is becoming evident that the effects of paradoxical mitogen-activated protein kinase (MAPK) pathway activation by BRAF inhibitors in non-BRAF mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Therefore, the potential adverse effects of such combinations in terms of increased autoimmune toxicities and interference with the individual antitumor activities need to be considered when translating to the clinic.

Disclosure:

A. Ribas: I have been a consultant for Amgen, GSK, Genentech-Roche, Merck-MSD, Novartis, Pierre-Fabre with the honoraria paid to my institution. I have stock in Kite Pharma, Flexus and Compugen.