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Pharmacology Update in Oncology: 2017
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Rowena Schwartz discusses Pharmacology Update in Oncology: 2017 at ONS Congress 2017. For the ability to view on your mobile phone please visit us at MinuteCE.com.

This transcript is software driven, please understand there may be errors.  Should any inaccuracies or omissions be found, please notify transcripts@MedEdOTG.com for correction.

Hello, my name is Rowena Schwartz from the University Of Cincinnati School Of Pharmacy, and today we're going to talk about some of the updates that have occurred in drug therapy and oncology in 2017. We have had a virtual explosion of new drugs in the last few years in cancer, and this last year has been no different. The key thing is that we are learning more about cancer biology. And we're learning about drug-actionable targets within cancer. And from that we've been able to develop drugs that we now see in practice.

This slide presents the list of the new drugs that were approved in oncology by the FDA in the United States, since the last ONS meeting. I think it's important to realize that once these drugs become marketed, the drug development does not stop. And the indications for these drugs continue to evolve over time. Many of the drugs that are approved are approved in one disease state or in one treatment setting, and that will evolve as the data becomes more mature in those different settings. So, let's do a quick overview of the mechanism and some of the strategies behind these new agents.

So the first drug that we will look at is Venetoclax. Venetoclax is the first-in-class drug that targets BCL-2, or B cell lymphoma 2. It was named B cell lymphoma 2 because it was first cloned in a lymphoid cell line. This BCL-2 is part of a family of proteins that are very important in coordinating of proapoptotic signals and antiapoptotic signals within the cell. It sits on the outer surface of the mitochondrial membrane and helps coordinate protein to protein interactions. BCL 2 is a protein that encodes antiapoptotic proteins. And it's thought that in some diseases we see an increased expression of BCL-2, and this causes the cells to become resistant to apoptosis. So, what that means is that you get an accumulation of these long-lived, clonal cells. And one of the key places that we see this is with lymphocytes. So the current indication of this drug is in chronic lymphocyctic leukemia with the deletion of 17p, in patients who have received one prior therapy.

We continue to see advancement in immunopharmacology. So, this year we are looking at PD-L1 inhibitors. So this picture shows a T cell, which is the circle, and you can see what's on the T cell. There are receptors in green that cause activation of T cells. And then you can see in red or orange that those are the receptors that, once stimulated, cause inhibition of T cells. So, the focus is how we can modulate how that T cell functions in the tumor environment. One of the strategies we've seen over the years, is to inhibit some of those receptors that inhibit T cells. So, by inhibiting inhibitors, what we see is an activation of the T cell. So, CTLA4 was the target for Ipilimumab, PD-1 was the target for Nivolumab and Pembrolizumab, and now we go to PD-L1, which sits not only on the T cell and the tumor cells, but on other immune cells.

Programmed death ligand 1, or PD-L1 is expressed in the microenvironment of the tumor. So, this is one of the key issues when we look at the drugs that are approved ... Is how we measure if PD-L1 is overexpressed, and if this would be a good target. A couple key things with PD-L1 inhibitors: that they have been shown to have an activity in a wide variety of solid tumors, and within the last year, not only have we seen the approval of three agents, but those agents have been approved in multiple indications.

So, on this list we can see the three that are outlined in blue. Atezolizumab, that was approved initially in bladder and now has the indication for non-small-cell lung cancer, avelumab, which was initially approved for Merkel-cell lymphoma, a skin cancer that although it is not common, can be very aggressive and chemotherapy doesn't have a lot of activity. So, this has been a really nice addition to the treatment of Merkel-cell cancer. And then, just in May, we have our third PD-L1 inhibitor, durvalumab, which is approved for bladder cancer.

Another drug that was approved this year is olaratumab. This is a drug that is thought to target platelet-derived growth factor. Now, this is the first monoclonal antibody that is specifically targeting this platelet-derived growth factor, though we have many tyrosine kinases that do impact platelet-derived growth factor and its receptor. Platelet-derived growth factor causes tumor progression. So we know that this family of proteins, when it interacts with platelet-derived growth factor receptors causes autophosporylation and then signaling throughout the cell causing cell proliferation, and inhibition of programmed cell death or apoptosis.

In tumor cells, it's been shown that platelet-derived growth factors, when bound to platelet-growth factor receptors drive malignant cells and also have effect on angiogenesis and the tumor microenvironment. So it's thought to be a very nice target. We see that some tumors overexpress platelet-derived growth factors and some tumors have mutations that activate the platelet-derived growth factor receptor. So this is where this drug was really of great interest. The drug was approved for the treatment of sarcoma and the indication is very specific.

It's very specific in that it is indicated in combination with Doxorubicin for the treatment of adult patients with soft-tissue sarcoma with histologic subtypes for which an Anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. So, one of the very interesting things about this drug and the approval is that the indication of soft-tissue sarcoma is quite large. As we know, there is many subsets of soft-tissue sarcoma, so really there's great interest to see where this drug works, in what specific sarcomas, and we look for that information in the future.


Another focus of drug development that we've seen in the last year is with PARP inhibitors. Now, PARP is an interesting concept because PARP is an enzyme that helps repair DNA when there's damage. So DNA damage from just life exposures that is repaired by PARP. We also know that chemotherapy can cause damage to DNA and PARP could help with the repair. So PARP inhibitors were initially looked at to be used in combination with things like chemotherapy to help exploit the chemotherapy effect. Same thing with radiation. Radiation causes DNA damage. PARP could help repair, so inhibition by PARP inhibitors could help exploit the effect of radiation.

Unfortunately, that has not really shown to be a strategy that's been useful because of toxicity, so I don't think that's something that we won't see in the future. Where we really looked at PARP inhibition is in the use in patients that have genetic abnormalities that makes them at risk. And so, synthetic lethality is the term that's used. That means that when there is a genetic or defective protein that's compatible for cell viability. But when you combine it with another defect, such as PARP inhibition, then it causes cell death. So, that's where we've really seen PARP inhibitors be used.

So you can see that two PARP inhibitors were approved within the last year. We see rucaparib, which is used for monotherapy for treatment of patients with deleterious BRCA mutations, either germline or somatic, associated with ovarian cancer, who have been treated with 2+ chemotherapy. And then we see just recently, in March, niraparib was approved for maintenance treatment in adults with recurrent epithelial ovarian, Fallopian tube, or primary peritoneal cancer who are in CR or PR after platinum based chemotherapy. So, we can see increased evolution of these drugs.

I wanted to talk about two other strategies that have resulted in additional drug approvals. One is cyclin-dependent kinases. Cyclin-dependent kinases, we know, are very important in helping regulate how cells go through the cell cycle, and we know that by inhibiting these cyclin-dependent kinases, we have an impact on how cells develop and divide.

We have approval, this year, of a new drug. It's the second in this group of this class of drugs. So, ribociclib was approved for combination therapy with an aromatase inhibitor, or initial endocrine-based therapy for the treatment of post-menopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

Finally, one of the most recent approvals we saw in the last year was the FLT3 inhibitor. FLT3 has been an area of interest for a while. We know that this is really important in hematologic malignancies and FLT3 receptor is expressed in over 80% of patients with AML. So, with this, when we see either mutations of FLT form, or overexpression of FLT3, we see patients who do not do as well with chemotherapy.

So, now we have a drug that is approved in combination with standard chemotherapy, Cytarabine and Daunorubicin for induction, and with Cytarabine consolidation for treatment of adults with newly diagnosed AML that have FLT3 mutation positive.

I think it's important to at least mention that with these advances and with the science, we are really ... Go hand in hand with the practicalities of placing these new drugs into therapy. So, this is a quote that I think is good to at least mention: "Hand clapping for science is now inextricably linked to hand wringing over affordability." So, although we don't talk a lot in this short period of time about the cost, it's important to realize that these drugs are expensive and we really need to think about how we can assure that the patients who need them are able to get these drugs. So, with that, that concludes my remarks and I want to thank you for your attention.