Overview of the Impact of Targeted Therapies on Selective Pathways
Welcome to the Oncology Network for Excellence. Below is a transcript of our recent conversation with Dr. John Eckardt who provides us an overview on the impact of targeted therapies on selective pathways.
Dr. Eckardt is a board certified medical oncologist who has 20 years of experience in patient care, oncology drug development, and oncology education. Dr. Eckardt is now the Chief Medical Officer at DAVA Oncology.
Dr. Eckardt, can you tell us your thoughts on the upcoming ASCO Meeting, including what you feel will be important to watch for?
This ASCO is going to bring us another step forward in the use of targeted therapies in the treatment of patients with advanced cancer as we strive to improve the quality of life of our cancer patients. Targeted therapies have become a significant component of our cancer therapeutic armamentarium. I want to highlight a few upcoming studies focusing on these targeted therapies that will help us further advance the field.
BRIM 3 TRIAL
The first trial I would like to highlight is the BRIM 3 Phase III trial, which enrolled 675 pts with advanced melanoma, who had the V600 mutation of the B-RAF gene. V600 mutations create an addiction to RAS/RAF pathway. In earlier trials, inhibition of this pathway with vemurafenib has demonstrated significant results in patients with advanced melanoma. In the BRIM3 trial, vemurafenib was compared to dacarbazine and demonstrated a significant improvement in overall survival (OS). As improvement of OS in melanoma has been very hard to come by, these results have been highly anticipated and fulfill a significant unmet need.
EURTAC TRIAL
I would also like to highlight a 2nd trial entitled the EURTAC trial which studies the EGFR inhibitor erlotinib. The EURTAC trial is a European trial which selected patients only with the EGFR mutation. In this study for first line therapy, they compared erlotinib to standard chemotherapy and demonstrated a significant improvement in progression free survival.
These 2 trials demonstrate the dramatic effects in pathway inhibition in cancers that have mutations which cause pathway addiction. As we see these dramatic benefits of these trials, we need to reflect on the fact that all targeted agents have not shown us the same results. We need to consider whether this is a reflection on the agent or the target itself. So as we view these presentations and look to the future, it begs the question—Will we be able to identify other pathways for which these dramatic results can be seen?
TARGETED THERAPIES AND SELECTIVE PATHWAYS
It is important to note that significant work in pathways, such as the PI3K/AKT/mTOR pathway, have led to improvements in outcome; which we have seen with temsirolimus in renal cell carcinoma, everolimus in renal cell carcinoma and neuroendocrine tumors, and ridaforolimus in sarcoma.
However, these benefits have not had the dramatic effect as seen in the setting of some of the addictive pathways, as mentioned previously with EGFR and B-RAF and also seen with EML4/ALK in NSCLC, BCR-ABL in CML, and cKIT in GIST. In a similar vein, we have had significant success with inhibition of the VEGF pathway, but similar to the PI3K/AKT/mTOR pathway, the benefit is more modest.
What conclusions can we make from this information?
The function of the PI3K/AKT/mTOR pathway is energy metabolism in the cell. This pathway is active in normal and cancerous cells. Mutations and changes in the pathway can lead to enhanced cell survival and growth as seen in many cancers. However, because it is a vital pathway, inhibition of a single protein rarely leads to dramatic changes in the function of this pathway. This is due to the multiple feedback loops and redundancies to protect normal cells from a single mutation being lethal. In the same respect, a single drug inhibiting one of the proteins is unlikely to completely block this pathway.
Compared to an EGFR mutation, which stimulates growth and survival in a cancer cell, but is absent and not required for normal cells. Inhibition of this pathway will have dramatic effects on the cancer cells with minimal effects on normal cells
Is the development of target agents in pathways that are more ubiquitous but vital for the survival for both normal and cancer cells, such as PI3k/AKT/mTOR and VEGF, going to lead to significant, but more modest outcomes? However, can more rare addictive pathways make tremendous impact on the survival of patients?
It will be important as we view these new targeted agents, to understand their role in the inhibition of pathways which are ubiquitous and vital in both cancer and normal cells versus those pathways which cancer cells depend on for their growth and survival.,
Understanding this difference can help lead us to rational trial design; to maximize the benefits of targeted therapies; and to understand which patients are appropriate for these new and innovative therapies.
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